Safety and efficacy of pemetrexed for patients with non-small cell lung cancer in the setting of renal impairment: a retrospective study

Safety and efficacy of pemetrexed for patients with non-small cell lung cancer in the setting of renal impairment: a retrospective study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Safety and efficacy of pemetrexed for patients with non-small cell lung cancer in the setting of renal impairment: a retrospective study Yusuke Shima, Hironori Yoshida, Keiichiro Suminaga, Hiroshi Yoshida, and 8 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4689590/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 04 Mar, 2025 Read the published version in BMC Cancer → Version 1 posted 11 You are reading this latest preprint version Abstract Background Pemetrexed is a key treatment for non-small-cell lung cancer (NSCLC), with its usage on the rise. However, due to treatment-related fatality in a patient with severe renal impairment observed during an initial clinical trial, such patients have been excluded from further studies. Consequently, there is limited data on the safety and efficacy of pemetrexed for these patients. This study aims to assess the use of pemetrexed in this patient group within a clinical setting. Methods We conducted a retrospective analysis of lung cancer patients treated with pemetrexed at Kyoto University Hospital from April 2008 to April 2023. Patients were categorized into groups receiving pemetrexed with platinum (n = 349) and pemetrexed-alone (n = 142) groups. Both groups were subdivided into creatinine clearance (CCr) > 45 and ≤ 45 subgroups, and safety and efficacy were compared between the subgroups. The chi-squared test was used to evaluate the correlation between renal impairment and adverse events. Univariate and logistic regression analyses identified independent risk factors for severe adverse events (SAEs) related to renal impairment. We also analyzed progression-free survival (PFS) and overall survival (OS) using log-rank tests. Results A significant increase in the incidence of grade ≥ 3 anemia was observed in the CCr ≤ 45 subgroups of both the platinum-concomitant and the pemetrexed-alone groups (p = 0.03 and p < 0.01, respectively). No significant differences were noted for other SAEs. Multivariate analysis showed that baseline hemoglobin levels were an independent predictor of grade ≥ 3 anemia across both treatment groups, alongside a baseline CCr ≤ 45 mL/min in the pemetrexed-alone group. No significant differences were observed in overall response rates, PFS, or OS between the CCr > 45 and CCr ≤ 45 subgroups in either treatment group. Conclusions While severe anemia was more common in patients with renal impairment, the efficacy of treatment did not differ, indicating that pemetrexed remains a viable treatment option for this population with proper management. pemetrexed non-small cell lung cancer safety and efficacy renal impairment creatinine clearance Figures Figure 1 Figure 2 Background Pemetrexed is widely used due to its relatively low toxicity profile and remarkable efficacy, particularly in patients with non-squamous non-small cell lung carcinoma (NSCLC) [ 1 – 3 ]. Its use in combination therapies with immune checkpoint inhibitors such as pembrolizumab or atezolizumab has been increasing [ 4 , 5 ]. However, there are safety concerns regarding pemetrexed, especially in patients with renal impairment, leading to cautious use. In a phase 1 study involving patients with solid tumors, one patient with a glomerular filtration rate (GFR) of 19 mL/min died from treatment-related toxicity, prompting the discontinuation of accrual for patients with a GFR < 30 mL/min [ 6 ]. Further studies indicated that patients with a creatinine clearance (CCr) ≤ 45 mL/min experienced increased serum concentrations of pemetrexed and were at a higher risk of hematological toxicities [ 7 ]. Consequently, patients with renal impairment are generally excluded from clinical trials and the treatment with pemetrexed is no longer recommended in clinical practice. Yet, the relatively small number of patients in previous studies and the limited data available suggest that some patients may be missing out on potentially optimal treatments. This study retrospectively evaluates the safety and efficacy of pemetrexed in combination with platinum-based agents and as a standalone treatment in a large cohort of patients with renal impairment. Methods Patients and clinical data We conducted a retrospective analysis of 584 patients with NSCLC who were treated with pemetrexed in combination with platinum-based agents or as monotherapy at Kyoto University Hospital from April 2008 to April 2023. We excluded patients who initiated treatment at other hospitals or transferred shortly after starting pemetrexed (n = 39), those who received pemetrexed as rechallenge therapy (n = 35) or in combination with bevacizumab (n = 11), patients diagnosed with squamous cell carcinoma (n = 1), and those with large-cell neuroendocrine carcinoma or pleomorphic carcinoma (n = 7). This resulted in a cohort of 491 patients for the final analysis. Patients were categorized into two groups: those receiving pemetrexed with platinum-based agents (n = 349) and those receiving pemetrexed alone (n = 142). They were then further divided based on their CCr into > 45 mL/min and ≤ 45 mL/min subgroups for safety and efficacy evaluations (Fig. 1 ). CCr was calculated using the Cockcroft-Gault equation. A CCr cutoff of 45 mL/min was used based on previous research linking this threshold to increased adverse events and blood concentration levels in patients with lower CCr [ 8 ] and because the use of pemetrexed in patients with CCr < 45 mL/min is not recommended in Japan. We compiled data from patient records for our final analysis, including age, sex, smoking status, performance status (PS), clinical staging, oncogenic driver mutation status, therapeutic regimens and lines, dose adjustment, blood test results, and clinical courses. Standard doses were defined as 500 mg/m 2 for pemetrexed, combined with either carboplatin (area under the curve 5 or 6) or cisplatin (75 mg/m 2 ). Dose adjustment was defined as a reduction in the dosage at initiation. Baseline hemoglobin levels were assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 and were considered indicative of baseline anemia grade. Adverse events We collected data on objectively evaluable adverse events from clinical records, including hematologic toxicities, elevated liver enzymes, infections, drug-induced pneumonitis, anorexia, elevated creatinine, skin rash, fatigue, acute exacerbation of interstitial lung disease, and treatment-related deaths. The severity of these events was assessed using the CTCAE version 5.0. Each adverse event was categorized into one of two groups: severe (grade ≥ 3) or non-severe. Statistical analyses Continuous variables were analyzed using Student's t-test or the Mann–Whitney U test. Dichotomous variables were evaluated using the chi-squared test or Fisher's exact test. Multivariate analysis identified independent risk factors for adverse events that varied significantly with renal function. Factors that showed significant differences in the univariate analysis were included in the multivariate analysis. The Kaplan–Meier method estimated progression-free survival (PFS) and overall survival (OS), with subgroup comparisons using the log-rank test. PFS was defined as the time from the initiation of pemetrexed-containing regimens until lung cancer progression, death from any cause, or the end of the follow-up period. OS was calculated from the same starting point until the date of death or the end of the follow-up period. The data cutoff was December 14, 2023. Results are presented as odds ratios (ORs) with 95% confidence intervals (CIs). Statistical significance was set at a two-tailed p-value < 0.05. All statistical analyses were conducted using JMP, version 16 (SAS Institute, Cary, NC, USA). Results Patient characteristics Patient characteristics are summarized in Table 1 . Of the 491 patients studied, 349 were in the platinum-concomitant group and 142 were in the pemetrexed-alone group. Within the platinum-concomitant group, there were 300 patients with CCr > 45 mL/min and 49 with CCr ≤ 45 mL/min. In the pemetrexed-alone group, the numbers were 99 and 43, respectively. In both treatment groups, a significantly higher percentage of patients over 75 years of age was observed in the CCr ≤ 45 mL/min subgroup, approximately 70% in the pemetrexed-alone group. The CCr ≤ 45 mL/min subgroup also had a higher number of female patients. Regarding smoking status, there were no differences in the platinum-concomitant group, while the ratio of never-smokers significantly increased in the CCr ≤ 45 mL/min subgroup of the pemetrexed-alone group. Histopathological type, PS, oncogenic driver status, and clinical stage showed no significant differences between groups. Therapeutic lines did not significantly differ in the platinum-concomitant group. However, there was a variance in the tendency of therapeutic lines between the CCr > 45 mL/min and CCr ≤ 45 mL/min subgroups in both treatment groups. In the platinum-concomitant group, most patients were treated with carboplatin, with only one patient receiving cisplatin in the CCr ≤ 45 mL/min subgroup. There was no statistical difference in the ratio of patients on a bevacizumab-containing regimen between the CCr > 45 and CCr ≤ 45 mL/min subgroups. The need for dose adjustment was significantly higher in both treatment groups' CCr ≤ 45 mL/min subgroups. Baseline hemoglobin levels were significantly lower in the CCr ≤ 45 mL/min subgroups of both groups. Specifically, in the platinum-concomitant group, baseline hemoglobin was 12.9 ± 1.7 g/dL in the CCr > 45 mL/min subgroup versus 11.8 ± 1.3 g/dL in the CCr ≤ 45 mL/min subgroup (p < 0.01), and in the pemetrexed-alone group, it was 12.5 ± 1.7 g/dL versus 11.6 ± 2.0 g/dL in the CCr ≤ 45 mL/min subgroup (p = 0.02). Three patients in the pemetrexed-alone group and one in the platinum-concomitant group had baseline anemia equivalent to grade 3. The baseline CCr was statistically lower in the CCr ≤ 45 mL/min subgroups of both treatment groups. Pemetrexed-included chemotherapies were initiated for patients with a CCr 20 ~ 40 mL/min in our cohort. Additional details on the distribution of patients with baseline CCr ≤ 45 mL/min can be found in Additional Fig. 1 . Table 1 Patient characteristics Platinum-concomitant (n = 349) Pemetrexed-alone (n = 142) CCr > 45 (n = 300) CCr ≤ 45 (n = 49) p CCr > 45 (n = 99) CCr ≤ 45 (n = 43) p Age (years) ≥75 21 (7.0) 17 (34.7) < 0.01 27 (27.3) 30 (69.8) < 0.01 <75 279 (93.0) 32 (65.3) 72 (72.7) 13 (30.2) Sex Male 178 (59.3) 14 (28.6) < 0.01 57 (57.6) 15 (34.9) 0.01 Female 122 (40.7) 35 (71.4) 42 (42.4) 28 (65.1) Smoking status Never 119 (39.7) 25 (51.0) 0.14 35 (35.4) 24 (55.8) 0.02 Current or former 181 (60.3) 24 (49.0) 64 (64.6) 19 (44.2) Histology Adenocarcinoma 291 (97.0) 48 (98.0) 0.70 94 (94.9) 41 (95.3) 0.92 NSCLC, NOS 9 (3.0) 1 (2.0) 5 (5.1) 2 (4.7) ECOG PS 0 or 1 285 (95.0) 45 (91.8) 0.74 81 (81.8) 34 (79.1) 0.19 2 11 (3.7) 3 (6.2) 13 (13.2) 9 (20.9) ≥3 1 (0.3) 0 (0) 3 (3.0) 0 (0) Unknown 3 (1.0) 1 (2.0) 2 (2.0) 0 (0) Stage ≤Ⅲ 28 (9.3) 6 (12.2) 0.54 22 (22.2) 9 (20.9) 0.86 Ⅳ 272 (90.7) 43 (87.8) 77 (77.8) 34 (79.1) Oncogenic driver Wild type 151 (50.3) 22 (44.9) 0.75 46 (46.5) 24 (55.8) 0.19 EGFR 118 (39.3) 22 (44.9) 20 (20.2) 11 (25.6) Others or unknown 31 (10.4) 5 (10.2) 33 (33.3) 8 (18.6) Therapeutic lines First line 214 (71.3) 28 (57.1) 0.05 27 (27.3) 21 (48.8) 0.01 ≥Second line 86 (28.7) 21 (42.9) 72 (72.7) 22 (51.2) Platinum drugs Cisplatin 36 (12.0) 1 (2.0) 0.01 Carboplatin 264 (88.0) 48 (98.0) Bevacizumab With 123 (41.0) 21 (42.9) 0.81 Without 177 (59.0) 28 (57.1) Dose adjustment With 25 (8.3) 30 (61.2) < 0.01 1 (1.0) 11 (25.6) < 0.01 Without 275 (91.7) 19 (38.8) 98 (99.0) 32 (74.4) Baseline Hb (g/dL) 12.9±1.7 11.8±1.3 < 0.01 12.5±1.7 11.6±2.0 0.02 Grade ≥ 2 11 (3.7) 2 (4.1) 0.02 7 (7.1) 10 (23.3) 0.02 Grade 1 13 (4.3) 7 (14.3) 3 (3.0) 1 (2.3) Within normal range 276 (92.0) 40 (81.6) 89 (89.9) 32 (74.4) Baseline CCr (mL/min) 67.7±17.6 39.3±4.2 < 0.01 63.5±15.5 36.6±5.3 < 0.01 Values are presented as mean±standard deviation or n (%). CCr, creatinine clearance; SD, standard deviation; NSCLC, non-small cell carcinoma; NOS, not otherwise specified; ECOG PS, Eastern Cooperative Oncology Group Performance Status; EGFR, epidermal growth factor receptor; Hb, hemoglobin [Table 1 here] Adverse events in each group Table 2 presents the adverse events related to blood toxicities and others that were objectively evaluated. The incidence of grade ≥ 3 neutropenia and thrombocytopenia did not reach statistical significance. However, the incidence of grade ≥ 3 anemia was significantly higher in the CCr ≤ 45 mL/min subgroups in both treatment groups. There were no significant differences in the incidence of grade ≥ 3 for other adverse events, including elevated liver enzymes, skin rash, drug-induced pneumonitis, and treatment-related deaths. No cases of grade ≥ 3 treatment-related creatinine elevation were observed. Two instances of treatment-related deaths were recorded. One patient in the CCr ≤ 45 mL/min subgroup of the pemetrexed-alone group succumbed to drug-induced pneumonitis. Another patient from the CCr > 45 mL/min subgroup in the platinum-concomitant group died from disseminated intravascular coagulation following a severe infection. Table 2 Adverse events in the platinum-concomitant and pemetrexed-alone groups Platinum-concomitant (n = 349) Pemetrexed-alone (n = 142) CCr > 45 (n = 300) CCr ≤ 45 (n = 49) p CCr > 45 (n = 99) CCr ≤ 45 (n = 43) p Neutropenia Grade < 3 211 (70.3) 38 (77.6) 0.29 79 (79.8) 31 (72.1) 0.32 Grade ≥ 3 89 (29.7) 11 (22.4) 20 (20.2) 12 (27.9) Anemia Grade < 3 268 (89.3) 38 (77.6) 0.03 93 (93.9) 30 (69.8) < 0.01 Grade ≥ 3 32 (10.7) 11 (22.4) 6 (6.1) 13 (30.2) Thrombocytopenia Grade < 3 266 (88.7) 40 (81.6) 0.19 95 (96.0) 41 (95.3) 0.87 Grade ≥ 3 34 (11.3) 9 (18.4) 4 (4.0) 2 (4.7) Others a Grade < 3 265 (88.3) 40 (81.6) 0.21 89 (89.9) 35 (81.4) 0.17 Grade ≥ 3 35 (11.7) 9 (18.4) 10 (10.1) 8 (18.6) a “Others” included objectively evaluable adverse events, such as elevated liver enzymes, infections, drug-induced pneumonitis, anorexia, elevated creatinine, skin rash, fatigue, acute exacerbation of interstitial lung disease, or treatment-related death. CCr, creatinine clearance. Evaluation of independent risk factors of severe adverse events Univariate analyses were performed for each treatment group to identify risk factors for severe anemia (Table 1 ). In both groups, baseline anemia of grade ≥ 2 and CCr ≤ 45 mL/min were statistically significant risk factors. Additionally, treatment with cisplatin was associated with a significantly higher risk in the platinum-concomitant group. Subsequently, we conducted multivariate analyses, adjusting for age, sex, baseline anemia grade, baseline CCr, and type of platinum drug (Table 3 ). These analyses revealed that baseline anemia of grade ≥ 2 was a significant risk factor for treatment-related grade ≥ 3 anemia in both treatment groups. Additionally, a baseline CCr ≤ 45 mL/min was identified as a risk factor in the pemetrexed-alone group. Table 3 Logistic regression analysis to determine risk factors of grade ≥ 3 anemia Parameters Platinum-concomitant (n = 349) Pemetrexed-alone (n = 142) Odds ratio (95% CI) p Odds ratio (95% CI) p Age, years ≥ 75 1.33 (0.47–3.78) 0.59 0.97 (0.18–5.07) 0.97 <75 Reference Reference Sex Male 1.13 (0.52–2.44) 0.77 0.88 (0.19–4.14) 0.87 Female Reference Reference Baseline anemia Grade ≥ 2 15.6 (5.38–45.4) < 0.01 46.2 (8.17–261) 45 Reference Reference Platinum drugs Cisplatin 0.27 (0.04–2.04) 0.20 Carboplatin Reference CI, confidence interval; CCr, creatinine clearance Comparison of best response, PFS, and OS according to renal function Responses to each treatment are detailed in Table 4 . The overall response rate (ORR) and disease control rate (DCR) were numerically higher in the CCr > 45 mL/min subgroup compared to the CCr ≤ 45 mL/min subgroups in both treatment groups; however, the differences were not statistically significant. PFS and OS are illustrated in Fig. 2 . In the platinum-concomitant group, the median PFSs were 6.0 months (95% CI, 5.3–6.5) for CCr > 45 mL/min and 4.7 months (95% CI, 3.8–6.0) for CCr ≤ 45 mL/min (hazard ratio [HR], 1.14; 95% CI, 0.84–1.55, p = 0.40). The median OSs were 30.7 months (95% CI, 23.7–34.9) for CCr > 45 mL/min and 16.1 months (95% CI, 13.6–20.6) for CCr ≤ 45 mL/min (HR, 1.27; 95% CI, 0.89–1.81, p = 0.19). Although both PFS and OS were numerically longer in the CCr > 45 mL/min group, the differences were not statistically significant. In the pemetrexed-alone group, the median PFSs were 2.9 months (95% CI, 2.4–3.9) for CCr > 45 mL/min and 2.8 months (95% CI, 1.5–4.1) for CCr ≤ 45 mL/min (HR, 1.30; 95% CI, 0.90–1.88, p = 0.16). The median OSs were 15.1 months (95% CI, 12.3–20.8) for CCr > 45 mL/min and 16.2 months (95% CI, 7.6–20.3) for CCr ≤ 45 mL/min (HR, 1.24; 95% CI, 0.84–1.83, p = 0.27). Table 4 Efficacy of pemetrexed-containing chemotherapies Best response Platinum-concomitant (n = 349) Pemetrexed-alone (n = 142) CCr > 45 (n = 300) CCr ≤ 45 (n = 49) p CCr > 45 (n = 99) CCr ≤ 45 (n = 43) p ORR a 134 (49.4) 16 (35.6) 0.82 21 (21.4) 7 (17.9) 0.65 DCR a 230 (84.9) 36 (80.0) 0.42 67 (68.4) 24 (61.5) 0.45 CR 3 (1.0) 1 (2.0) 1 (1.0) 0 (0) PR 131 (43.6) 15 (30.6) 20 (20.2) 7 (16.3) SD 96 (32.0) 20 (40.8) 46 (46.5) 17 (39.5) PD 41 (13.7) 9 (18.4) 31 (31.3) 15 (34.9) NE 29 (9.7) 4 (8.2) 1 (1.0) 4 (0.3) a Thirty-three patients in the platinum-concomitant group and five patients in the pemetrexed-alone group were excluded from the ORR and DCR analyses because their responses were not evaluable. CCr, creatinine clearance; ORR, overall response rate; DCR, disease control rate; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; NE, not evaluable. Discussion This study was a comprehensive retrospective evaluation of the safety and efficacy of pemetrexed-containing chemotherapy in patients with renal impairment. Regarding safety, grade ≥ 3 anemia was significantly more frequent in the CCr ≤ 45 mL/min subgroups. Higher grades of baseline anemia in both treatment groups and a baseline CCr ≤ 45 mL/min in the pemetrexed-alone group were identified as independent risk factors for treatment-related severe anemia. Regarding efficacy, there were no significant differences between the CCr > 45 mL/min and CCr ≤ 45 mL/min subgroups in both the platinum-concomitant and pemetrexed-alone groups. A plausible explanation for the notable frequency of treatment-related severe anemia in the CCr < 45 subgroups is that chemotherapy-induced myelosuppression may be exacerbated in patients with renal impairment. Myelosuppression is a common complication of chemotherapy, and previous clinical trials have reported rates of grade ≥ 3 anemia between 1.1% and 6.4% [ 3 , 9 – 11 ]. Compared to these studies, the incidence of severe anemia in our study was higher, with approximately 20–30% of patients in the CCr < 45 subgroups of both treatment groups experiencing grade ≥ 3 anemia. One study showed that 22% of patients with CCr < 45 mL/min suffered from grade ≥ 3 anemia, indicating that renal impairment is a risk factor for severe hematologic toxicity [ 7 ]. These findings align with our results, suggesting that increased myelosuppression related to chemotherapy can lead to severe treatment-related anemia in patients with renal impairment. Lower baseline hemoglobin levels and treatment-related severe anemia may be associated with renal function. Our study identified a higher grade of baseline anemia as an independent risk factor for treatment-related grade ≥ 3 anemia in both treatment groups. Multivariate analyses further revealed that a lower baseline CCr was also an independent risk factor for severe anemia, but only in the pemetrexed-alone group. However, its impact was less significant than that of grade ≥ 2 baseline anemia. Meanwhile, lower CCr was not an independent risk factor for severe anemia in the platinum-concomitant group. Yet, univariate analysis indicated that treatment-related severe anemia was significantly more common in the CCr ≤ 45 mL/min subgroup (p = 0.02), even within the platinum-concomitant group. The link between anemia and impaired renal function is likely due to renal anemia commonly observed in patients with chronic kidney disease. Several studies have reported that the prevalence of renal anemia increases in patients with renal impairment, specifically when creatinine levels are ≥ 2 mg/dL or CCr < 20–35 mL/min. This increase is often attributed to reduced production of hematopoietic factors in the kidneys or diminished responsiveness in the bone marrow [ 12 – 14 ]. Renal anemia is particularly prevalent in patients with a CCr < 45 mL/min, especially those with diabetic nephropathy [ 15 ]. Indeed, our study found significantly lower baseline hemoglobin levels in the CCr < 45 mL/min subgroup. Drawing on existing research on the relationship between treatment-related severe anemia and renal impairment, it is evident that both baseline and treatment-related anemia are influenced by renal function [ 7 ]. Dose adjustment during chemotherapy may be crucial in reducing the incidence of severe adverse events (SAEs). A study where pemetrexed was administered with a dose reduction based on renal function reported no SAEs [ 7 ]. In our study, a relatively high proportion of patients underwent dose adjustments at initiation, including dose reductions and treatment postponements, based on the physician’s discretion. These findings suggest that pemetrexed is relatively safe, even for patients with renal impairment. The efficacy of pemetrexed-containing chemotherapy appears to be independent of renal function. In both treatment groups in our study, the ORR and DCR, in addition to PFS and OS, were not significantly different, regardless of renal function. These results were comparable to or better than those reported previously. For example, a prior study noted an ORR of 9.1%, a DCR of 54.9%, a median PFS of 2.9 months, and a median OS of 8.3 months [ 1 ]. Another clinical trial reported median PFS and OS of 4.8 and 10.3 months, respectively [ 3 ]. The Keynote-189 clinical trial documented in the control arm an ORR of 18.9%, a DCR of 70.4%, a median PFS of 4.9 months, and a median OS of 10.6 months [ 4 ]. Our study’s median PFS was similar to these previous findings. However, the ORR, DCR, and median OS in our study were notably higher, even in the CCr ≤ 45 mL/min subgroups, compared to those earlier studies. These outcomes indicate that renal function does not influence the efficacy of pemetrexed-containing treatments. Patient characteristics such as sex and age showed significant differences in this study. Consistent with another study that found a higher proportion of older patients with CCr ≤ 45 mL/min [ 16 ], it is logical that a significant portion of the CCr ≤ 45 subgroups in our study comprised older individuals, reflecting the increased prevalence of lung cancer among the older population. Additionally, female patients were more common in the CCr ≤ 45 subgroups, suggesting that older female patients might have lower body weight and muscle mass, potentially leading to an underestimation of their renal function. These findings align with those reported in previous research [ 17 ]. This study has several limitations. Firstly, it was a retrospective study conducted at a single institution, and there was an imbalance in patient characteristics such as age and sex. Consequently, confounding factors that might affect the safety and efficacy of pemetrexed-based therapies cannot be ruled out. Efforts were made to adjust for the effects of these imbalances using multivariate analyses. Secondly, the number of patients with CCr ≤ 45 mL/min was relatively small, which might not sufficiently assess the purpose of this study. Furthermore, the study did not include patients receiving the current mainstream treatment for lung cancer—platinum-based chemotherapy combined with immune checkpoint inhibitors—due to the limited number of patients with renal impairment. Further large-scale studies are necessary to evaluate the safety and efficacy of these therapies in patients with renal impairment. Conclusion This study demonstrated the safety and efficacy of pemetrexed-containing treatments in patients with renal impairment. Although the incidence of grade ≥ 3 anemia was higher in patients with CCr ≤ 45 mL/min, no difference in treatment efficacy was observed. Therefore, pemetrexed-based treatment could be a viable option for such populations, provided that anemia is carefully managed. Abbreviations CCr, creatinine clearance CTCAE, Common Terminology Criteria for Adverse Events CI, confidence interval DCR, disease control rate GFR, glomerular filtration rate HR, hazard ratio NCSLC, non-squamous non-small cell lung carcinoma ORR, overall response rate OS, overall survival PFS, progression-free survival PS, performance status SAEs, severe adverse events Declarations Ethics approval and consent to participate This study was approved by the Kyoto University Hospital Ethics Committee (approval number 023-00932). The requirement for informed consent for the use of clinical records was waived because of the retrospective study design. However, all patients were guaranteed opportunities to learn about and withdraw from the study through notification. Consent for publication The requirement for informed consent to use the clinical information was waived because this was a retrospective study without intervention or preserved specimens. Availability of data and materials The datasets used and/or analyzed in the current study are available from the corresponding author upon reasonable request. Competing interests The authors declare that they have no competing interests. Funding This study was supported by internal funding from Kyoto University Hospital. Author’s contributions YS contributed to the data curation, investigation, validation, formal analysis, methodology, visualization, and writing of the original draft. HY contributed to conceptualization, data curation, formal analysis, investigation, methodology, project administration, funding acquisition, supervision, validation, and writing (review and editing). TH and HO contributed to the funding acquisition, supervision, validation, writing, review, and editing. KS, HA, and TN contributed to the data curation, resource acquisition, investigation, writing, reviewing, and editing. KH, HY, KH, and TF contributed to formal analysis, data curation, investigation, and writing (review and editing). All authors contributed to the resources, writing (review), and editing, and have read and approved the final version of the manuscript. Acknowledgments We would like to thank Editage (www.editage.com) for the English language editing. References Hanna N, Shepherd FA, Fossella FV, Pereira JR, De Marinis F, von Pawel J, et al. 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Atezolizumab Plus Chemotherapy for first-line treatment of nonsquamous NSCLC: Results from the randomized Phase 3 IMpower132 trial. J Thorac Oncol. 2021;16:653-64. Mita AC, Sweeney CJ, Baker SD, Goetz A, Hammond LA, Patnaik A, et al. Phase I and pharmacokinetic study of pemetrexed administered every 3 weeks to advanced cancer patients with normal and impaired renal function. J Clin Oncol. 2006;24:552-62. Hill J, Vargo C, Smith M, Streeter J, Carbone DP. Safety of dose-reduced pemetrexed in patients with renal insufficiency. J Oncol Pharm Pract. 2019;25:1125-9. de Rouw N, Boosman RJ, Huitema ADR, Hilbrands LB, Svensson EM, Derijks HJ, et al. Rethinking the application of pemetrexed for patients with renal impairment: A pharmacokinetic analysis. Clin Pharmacokinet. 2021;60:649-54. Paz-Ares LG, de Marinis F, Dediu M, Thomas M, Pujol JL, Bidoli P, et al. PARAMOUNT: Final overall survival results of the phase III study of maintenance pemetrexed versus placebo immediately after induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small-cell lung cancer. J Clin Oncol. 2013;31:2895-902. Scagliotti GV, Gridelli C, de Marinis F, Thomas M, Dediu M, Pujol JL, et al. Efficacy and safety of maintenance pemetrexed in patients with advanced nonsquamous non-small cell lung cancer following pemetrexed plus cisplatin induction treatment: A cross-trial comparison of two phase III trials. Lung Cancer. 2014;85:408-14. Barlesi F, Scherpereel A, Rittmeyer A, Pazzola A, Ferrer Tur N, Kim JH, et al. Randomized phase III trial of maintenance bevacizumab with or without pemetrexed after first-line induction with bevacizumab, cisplatin, and pemetrexed in advanced nonsquamous non-small-cell lung cancer: AVAPERL (MO22089). J Clin Oncol. 2013;31:3004-11. Hakim RM, Lazarus JM. Biochemical parameters in chronic renal failure. Am J Kidney Dis. 1988;11:238-47. Chandra M, Clemons GK, McVicar MI. Relation of serum erythropoietin levels to renal excretory function: Evidence for lowered set point for erythropoietin production in chronic renal failure. J Pediatr. 1988;113:1015-21. doi: 10.1016/s0022-3476(88)80573-0. McGonigle RJ, Boineau FG, Beckman B, Ohene-Frempong K, Lewy JE, Shadduck RK, et al. Erythropoietin and inhibitors of in vitro erythropoiesis in the development of anemia in children with renal disease. J Lab Clin Med. 1985 ;105:449-58. Locatelli F, Aljama P, Bárány P, Canaud B, Carrera F, Eckardt KU, et al. Revised European best practice guidelines for the management of anaemia in patients with chronic renal failure. Nephrol Dial Transplant. 2004;19;Suppl 2:ii1-47. Ando Y, Hayashi T, Ujita M, Murai S, Ohta H, Ito K, et al. Effect of renal function on pemetrexed-induced haematotoxicity. Cancer Chemother Pharmacol. 2016;78:183-9. Kutluk Cenik B, Sun H, Gerber DE. Impact of renal function on treatment options and outcomes in advanced non-small cell lung cancer. Lung Cancer. 2013;80:326-32. Additional Declarations No competing interests reported. Supplementary Files AdditonalTable1.docx Additional Table 1 Additional Table 1.docx Univariate analysis of each parameter involved in grade ≥3 anemia Baseline anemia was significantly different in both treatment groups, whereas baseline CCr was significantly different only in the pemetrexed-alone group. The platinum concomitant group showed a significant difference in the type of platinum drugs used. a No patients with NSCLC, NOS (n=7) experienced grade ≥3 anemia. CI, confidence interval; NSCLC, non-small cell carcinoma; NOS, not otherwise specified; ECOG PS, Eastern Cooperative Oncology Group Performance Status; EGFR, epidermal growth factor receptor; CCr, creatinine clearance AdditionalFigure1.pptx Additional Figure 1 Additional Figure 1.pptx The distribution of patients with CCr ≤45 Histogram showed the number of patients with CCr ≤45 in both treatment groups. CCr, creatinine clearance Cite Share Download PDF Status: Published Journal Publication published 04 Mar, 2025 Read the published version in BMC Cancer → Version 1 posted Editorial decision: Revision requested 01 Jan, 2025 Reviews received at journal 24 Dec, 2024 Reviewers agreed at journal 22 Dec, 2024 Reviewers agreed at journal 02 Oct, 2024 Reviews received at journal 30 Sep, 2024 Reviewers agreed at journal 08 Sep, 2024 Reviewers invited by journal 16 Jul, 2024 Editor invited by journal 09 Jul, 2024 Editor assigned by journal 05 Jul, 2024 Submission checks completed at journal 05 Jul, 2024 First submitted to journal 05 Jul, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4689590","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":329809351,"identity":"8be97b94-faec-440a-bbe7-32f0ecad1ed0","order_by":0,"name":"Yusuke Shima","email":"","orcid":"","institution":"Kyoto University","correspondingAuthor":false,"prefix":"","firstName":"Yusuke","middleName":"","lastName":"Shima","suffix":""},{"id":329809352,"identity":"982f7966-564e-4377-9823-c71ae48b3545","order_by":1,"name":"Hironori Yoshida","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABFUlEQVRIie3Rv0vDQBTA8RcCd8tzfxJJ/4ULgVax1H/lQqFZEh1dRAIFXYJzSoN/SyCQLgE3yZjJKUOmjtXzZwSbuAred7rj+PDuEgCd7g8mTGCAOLUJUG2zb0dGNESOFu4XwV8JvJJp7iU/SF8Tzh/rJjD9VRIWNZS5fcYjRnA1A3O9f8zJEi+dtGThms59AVXuImaKFHMw0mwvETkurIMYw3sKxgRt7sV0sSVgGRiJHCA78u2OSDVlN0R4YSEKab2R6oMYN4NT2GGK0lnFzUTI0nexzMxj726OvW952DxRg88j2gTjui1ObX4bGVW7ndlOzxdT/0F8rhhIWL4v1ZXQSXoE8LojANfdwYj6iE6n0/2zXgCRy1fO6Jpf8QAAAABJRU5ErkJggg==","orcid":"","institution":"Kyoto University","correspondingAuthor":true,"prefix":"","firstName":"Hironori","middleName":"","lastName":"Yoshida","suffix":""},{"id":329809353,"identity":"d67857dc-87ac-4551-b069-d9b89931423a","order_by":2,"name":"Keiichiro Suminaga","email":"","orcid":"","institution":"Kyoto University","correspondingAuthor":false,"prefix":"","firstName":"Keiichiro","middleName":"","lastName":"Suminaga","suffix":""},{"id":329809354,"identity":"e2ad98fa-ca1d-44b3-8670-f5d8fef7f4ea","order_by":3,"name":"Hiroshi Yoshida","email":"","orcid":"","institution":"Kyoto University","correspondingAuthor":false,"prefix":"","firstName":"Hiroshi","middleName":"","lastName":"Yoshida","suffix":""},{"id":329809355,"identity":"6090bbfa-4f99-4ebc-8f27-66b2389ecade","order_by":4,"name":"Kentaro Hashimoto","email":"","orcid":"","institution":"Kyoto University","correspondingAuthor":false,"prefix":"","firstName":"Kentaro","middleName":"","lastName":"Hashimoto","suffix":""},{"id":329809356,"identity":"6e8cb1c5-9312-4242-9b97-167a24b6ff42","order_by":5,"name":"Tatsuya Ogimoto","email":"","orcid":"","institution":"Kyoto University","correspondingAuthor":false,"prefix":"","firstName":"Tatsuya","middleName":"","lastName":"Ogimoto","suffix":""},{"id":329809357,"identity":"a2771bbc-d647-441b-bf92-985bfe84848e","order_by":6,"name":"Kazutaka Hosoya","email":"","orcid":"","institution":"Kyoto University","correspondingAuthor":false,"prefix":"","firstName":"Kazutaka","middleName":"","lastName":"Hosoya","suffix":""},{"id":329809358,"identity":"37e74b6a-cff2-43c1-94df-03d9e95a3493","order_by":7,"name":"Hitomi Ajimizu","email":"","orcid":"","institution":"Kyoto University","correspondingAuthor":false,"prefix":"","firstName":"Hitomi","middleName":"","lastName":"Ajimizu","suffix":""},{"id":329809359,"identity":"2a97cf5a-0b4b-4b80-b06d-d9092e2d3079","order_by":8,"name":"Tomoko Funazo","email":"","orcid":"","institution":"Kyoto University","correspondingAuthor":false,"prefix":"","firstName":"Tomoko","middleName":"","lastName":"Funazo","suffix":""},{"id":329809360,"identity":"4c8f5dd1-337e-499c-b5bc-521ecc422dd7","order_by":9,"name":"Takashi Nomizo","email":"","orcid":"","institution":"Kyoto University","correspondingAuthor":false,"prefix":"","firstName":"Takashi","middleName":"","lastName":"Nomizo","suffix":""},{"id":329809361,"identity":"a5c0e30d-b38c-4dec-86b5-993dc9a7e8d3","order_by":10,"name":"Hiroaki Ozasa","email":"","orcid":"","institution":"Kyoto University","correspondingAuthor":false,"prefix":"","firstName":"Hiroaki","middleName":"","lastName":"Ozasa","suffix":""},{"id":329809362,"identity":"d4fc0e0f-3bff-4135-9c72-e466b054179a","order_by":11,"name":"Toyohiro Hirai","email":"","orcid":"","institution":"Kyoto University","correspondingAuthor":false,"prefix":"","firstName":"Toyohiro","middleName":"","lastName":"Hirai","suffix":""}],"badges":[],"createdAt":"2024-07-05 04:36:15","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4689590/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4689590/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12885-025-13785-x","type":"published","date":"2025-03-04T15:57:09+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":62124293,"identity":"6119d8cc-d7dd-457d-8794-48493c818cdf","added_by":"auto","created_at":"2024-08-09 14:28:27","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":42405,"visible":true,"origin":"","legend":"\u003cp\u003eFlowchart of patients. LCNEC, large-cell neuroendocrine carcinoma; CCr, creatinine clearance.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-4689590/v1/386133a3959fad137cf37e5c.png"},{"id":62125359,"identity":"d49df3d8-0763-4a65-bb8d-ffa414190f7c","added_by":"auto","created_at":"2024-08-09 14:36:27","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":704991,"visible":true,"origin":"","legend":"\u003cp\u003eComparison of progression-free and overall survival according to renal function. Progression-free survival in the platinum-concomitant (a) and pemetrexed-alone groups (b). Overall survival in the platinum-concomitant (c) and pemetrexed-alone groups (d). CCr, creatinine clearance. No., number; PFS, progression-free survival; OS, overall survival; CI, confidence interval; HR, hazard ratio\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-4689590/v1/2ba54a471f5514d1ae3812c7.png"},{"id":78181316,"identity":"a62775eb-2d36-477e-a554-450b36b9dc22","added_by":"auto","created_at":"2025-03-10 17:46:00","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1874822,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4689590/v1/fba37f9e-fbdb-440a-a467-0114c689617b.pdf"},{"id":62124294,"identity":"e4f2fbde-6464-47fb-8481-d11339836472","added_by":"auto","created_at":"2024-08-09 14:28:27","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":23905,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eAdditional Table 1\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAdditional Table 1.docx\u003c/p\u003e\n\u003cp\u003eUnivariate analysis of each parameter involved in grade ≥3 anemia\u003c/p\u003e\n\u003cp\u003eBaseline anemia was significantly different in both treatment groups, whereas baseline CCr was significantly different only in the pemetrexed-alone group. The platinum concomitant group showed a significant difference in the type of platinum drugs used.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003ea\u003c/sup\u003eNo patients with NSCLC, NOS (n=7) experienced grade ≥3 anemia.\u003c/p\u003e\n\u003cp\u003eCI, confidence interval; NSCLC, non-small cell carcinoma; NOS, not otherwise specified; ECOG PS, Eastern Cooperative Oncology Group Performance Status; EGFR, epidermal growth factor receptor; CCr, creatinine clearance\u003c/p\u003e","description":"","filename":"AdditonalTable1.docx","url":"https://assets-eu.researchsquare.com/files/rs-4689590/v1/d5a07219c1698efd16933ab8.docx"},{"id":62124297,"identity":"9e55c4b7-3ee0-45b4-8d99-8e67d30e5fdd","added_by":"auto","created_at":"2024-08-09 14:28:27","extension":"pptx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":395979,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eAdditional Figure 1\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAdditional Figure 1.pptx\u003c/p\u003e\n\u003cp\u003eThe distribution of patients with CCr ≤45\u003c/p\u003e\n\u003cp\u003eHistogram showed the number of patients with CCr ≤45 in both treatment groups.\u003c/p\u003e\n\u003cp\u003eCCr, creatinine clearance\u003c/p\u003e","description":"","filename":"AdditionalFigure1.pptx","url":"https://assets-eu.researchsquare.com/files/rs-4689590/v1/cc7f3c5abec4f4ed3b6081ab.pptx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Safety and efficacy of pemetrexed for patients with non-small cell lung cancer in the setting of renal impairment: a retrospective study","fulltext":[{"header":"Background","content":"\u003cp\u003ePemetrexed is widely used due to its relatively low toxicity profile and remarkable efficacy, particularly in patients with non-squamous non-small cell lung carcinoma (NSCLC) [\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Its use in combination therapies with immune checkpoint inhibitors such as pembrolizumab or atezolizumab has been increasing [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. However, there are safety concerns regarding pemetrexed, especially in patients with renal impairment, leading to cautious use. In a phase 1 study involving patients with solid tumors, one patient with a glomerular filtration rate (GFR) of 19 mL/min died from treatment-related toxicity, prompting the discontinuation of accrual for patients with a GFR\u0026thinsp;\u0026lt;\u0026thinsp;30 mL/min [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Further studies indicated that patients with a creatinine clearance (CCr)\u0026thinsp;\u0026le;\u0026thinsp;45 mL/min experienced increased serum concentrations of pemetrexed and were at a higher risk of hematological toxicities [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Consequently, patients with renal impairment are generally excluded from clinical trials and the treatment with pemetrexed is no longer recommended in clinical practice.\u003c/p\u003e \u003cp\u003eYet, the relatively small number of patients in previous studies and the limited data available suggest that some patients may be missing out on potentially optimal treatments. This study retrospectively evaluates the safety and efficacy of pemetrexed in combination with platinum-based agents and as a standalone treatment in a large cohort of patients with renal impairment.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatients and clinical data\u003c/h2\u003e \u003cp\u003eWe conducted a retrospective analysis of 584 patients with NSCLC who were treated with pemetrexed in combination with platinum-based agents or as monotherapy at Kyoto University Hospital from April 2008 to April 2023. We excluded patients who initiated treatment at other hospitals or transferred shortly after starting pemetrexed (n\u0026thinsp;=\u0026thinsp;39), those who received pemetrexed as rechallenge therapy (n\u0026thinsp;=\u0026thinsp;35) or in combination with bevacizumab (n\u0026thinsp;=\u0026thinsp;11), patients diagnosed with squamous cell carcinoma (n\u0026thinsp;=\u0026thinsp;1), and those with large-cell neuroendocrine carcinoma or pleomorphic carcinoma (n\u0026thinsp;=\u0026thinsp;7). This resulted in a cohort of 491 patients for the final analysis. Patients were categorized into two groups: those receiving pemetrexed with platinum-based agents (n\u0026thinsp;=\u0026thinsp;349) and those receiving pemetrexed alone (n\u0026thinsp;=\u0026thinsp;142). They were then further divided based on their CCr into \u0026gt;\u0026thinsp;45 mL/min and \u0026le;\u0026thinsp;45 mL/min subgroups for safety and efficacy evaluations (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). CCr was calculated using the Cockcroft-Gault equation. A CCr cutoff of 45 mL/min was used based on previous research linking this threshold to increased adverse events and blood concentration levels in patients with lower CCr [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e] and because the use of pemetrexed in patients with CCr\u0026thinsp;\u0026lt;\u0026thinsp;45 mL/min is not recommended in Japan. We compiled data from patient records for our final analysis, including age, sex, smoking status, performance status (PS), clinical staging, oncogenic driver mutation status, therapeutic regimens and lines, dose adjustment, blood test results, and clinical courses. Standard doses were defined as 500 mg/m\u003csup\u003e2\u003c/sup\u003e for pemetrexed, combined with either carboplatin (area under the curve 5 or 6) or cisplatin (75 mg/m\u003csup\u003e2\u003c/sup\u003e). Dose adjustment was defined as a reduction in the dosage at initiation. Baseline hemoglobin levels were assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 and were considered indicative of baseline anemia grade.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eAdverse events\u003c/h2\u003e \u003cp\u003eWe collected data on objectively evaluable adverse events from clinical records, including hematologic toxicities, elevated liver enzymes, infections, drug-induced pneumonitis, anorexia, elevated creatinine, skin rash, fatigue, acute exacerbation of interstitial lung disease, and treatment-related deaths. The severity of these events was assessed using the CTCAE version 5.0. Each adverse event was categorized into one of two groups: severe (grade\u0026thinsp;\u0026ge;\u0026thinsp;3) or non-severe.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analyses\u003c/h2\u003e \u003cp\u003eContinuous variables were analyzed using Student's t-test or the Mann\u0026ndash;Whitney U test. Dichotomous variables were evaluated using the chi-squared test or Fisher's exact test. Multivariate analysis identified independent risk factors for adverse events that varied significantly with renal function. Factors that showed significant differences in the univariate analysis were included in the multivariate analysis. The Kaplan\u0026ndash;Meier method estimated progression-free survival (PFS) and overall survival (OS), with subgroup comparisons using the log-rank test. PFS was defined as the time from the initiation of pemetrexed-containing regimens until lung cancer progression, death from any cause, or the end of the follow-up period. OS was calculated from the same starting point until the date of death or the end of the follow-up period. The data cutoff was December 14, 2023. Results are presented as odds ratios (ORs) with 95% confidence intervals (CIs). Statistical significance was set at a two-tailed p-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05. All statistical analyses were conducted using JMP, version 16 (SAS Institute, Cary, NC, USA).\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003ePatient characteristics\u003c/h2\u003e \u003cp\u003ePatient characteristics are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Of the 491 patients studied, 349 were in the platinum-concomitant group and 142 were in the pemetrexed-alone group. Within the platinum-concomitant group, there were 300 patients with CCr\u0026thinsp;\u0026gt;\u0026thinsp;45 mL/min and 49 with CCr\u0026thinsp;\u0026le;\u0026thinsp;45 mL/min. In the pemetrexed-alone group, the numbers were 99 and 43, respectively. In both treatment groups, a significantly higher percentage of patients over 75 years of age was observed in the CCr\u0026thinsp;\u0026le;\u0026thinsp;45 mL/min subgroup, approximately 70% in the pemetrexed-alone group. The CCr\u0026thinsp;\u0026le;\u0026thinsp;45 mL/min subgroup also had a higher number of female patients. Regarding smoking status, there were no differences in the platinum-concomitant group, while the ratio of never-smokers significantly increased in the CCr\u0026thinsp;\u0026le;\u0026thinsp;45 mL/min subgroup of the pemetrexed-alone group. Histopathological type, PS, oncogenic driver status, and clinical stage showed no significant differences between groups. Therapeutic lines did not significantly differ in the platinum-concomitant group. However, there was a variance in the tendency of therapeutic lines between the CCr\u0026thinsp;\u0026gt;\u0026thinsp;45 mL/min and CCr\u0026thinsp;\u0026le;\u0026thinsp;45 mL/min subgroups in both treatment groups. In the platinum-concomitant group, most patients were treated with carboplatin, with only one patient receiving cisplatin in the CCr\u0026thinsp;\u0026le;\u0026thinsp;45 mL/min subgroup. There was no statistical difference in the ratio of patients on a bevacizumab-containing regimen between the CCr\u0026thinsp;\u0026gt;\u0026thinsp;45 and CCr\u0026thinsp;\u0026le;\u0026thinsp;45 mL/min subgroups. The need for dose adjustment was significantly higher in both treatment groups' CCr\u0026thinsp;\u0026le;\u0026thinsp;45 mL/min subgroups. Baseline hemoglobin levels were significantly lower in the CCr\u0026thinsp;\u0026le;\u0026thinsp;45 mL/min subgroups of both groups. Specifically, in the platinum-concomitant group, baseline hemoglobin was 12.9\u0026thinsp;\u0026plusmn;\u0026thinsp;1.7 g/dL in the CCr\u0026thinsp;\u0026gt;\u0026thinsp;45 mL/min subgroup versus 11.8\u0026thinsp;\u0026plusmn;\u0026thinsp;1.3 g/dL in the CCr\u0026thinsp;\u0026le;\u0026thinsp;45 mL/min subgroup (p\u0026thinsp;\u0026lt;\u0026thinsp;0.01), and in the pemetrexed-alone group, it was 12.5\u0026thinsp;\u0026plusmn;\u0026thinsp;1.7 g/dL versus 11.6\u0026thinsp;\u0026plusmn;\u0026thinsp;2.0 g/dL in the CCr\u0026thinsp;\u0026le;\u0026thinsp;45 mL/min subgroup (p\u0026thinsp;=\u0026thinsp;0.02). Three patients in the pemetrexed-alone group and one in the platinum-concomitant group had baseline anemia equivalent to grade 3. The baseline CCr was statistically lower in the CCr\u0026thinsp;\u0026le;\u0026thinsp;45 mL/min subgroups of both treatment groups. Pemetrexed-included chemotherapies were initiated for patients with a CCr 20\u0026thinsp;~\u0026thinsp;40 mL/min in our cohort. Additional details on the distribution of patients with baseline CCr\u0026thinsp;\u0026le;\u0026thinsp;45 mL/min can be found in Additional Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePatient characteristics\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003ePlatinum-concomitant (n\u0026thinsp;=\u0026thinsp;349)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c7\" namest=\"c5\"\u003e \u003cp\u003ePemetrexed-alone (n\u0026thinsp;=\u0026thinsp;142)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCCr\u0026thinsp;\u0026gt;\u0026thinsp;45\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;300)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCCr\u0026thinsp;\u0026le;\u0026thinsp;45\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;49)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eCCr\u0026thinsp;\u0026gt;\u0026thinsp;45\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;99)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCCr\u0026thinsp;\u0026le;\u0026thinsp;45\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;43)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003ep\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e21 (7.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17 (34.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e27 (27.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e30 (69.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.01\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e279 (93.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e32 (65.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e72 (72.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e13 (30.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e178 (59.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14 (28.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e57 (57.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e15 (34.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e0.01\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e122 (40.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e35 (71.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e42 (42.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e28 (65.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSmoking status\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNever\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e119 (39.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25 (51.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e0.14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e35 (35.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e24 (55.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e0.02\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCurrent or former\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e181 (60.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24 (49.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e64 (64.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e19 (44.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHistology\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAdenocarcinoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e291 (97.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e48 (98.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e0.70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e94 (94.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e41 (95.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e0.92\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNSCLC, NOS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e9 (3.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (2.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e5 (5.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2 (4.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eECOG PS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e0 or 1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e285 (95.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e45 (91.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\" morerows=\"3\" rowspan=\"4\"\u003e \u003cp\u003e0.74\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e81 (81.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e34 (79.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\" morerows=\"3\" rowspan=\"4\"\u003e \u003cp\u003e0.19\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e11 (3.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (6.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e13 (13.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e9 (20.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1 (0.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3 (3.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3 (1.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (2.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e2 (2.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStage\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026le;Ⅲ\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e28 (9.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (12.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e0.54\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e22 (22.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e9 (20.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e0.86\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eⅣ\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e272 (90.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e43 (87.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e77 (77.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e34 (79.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOncogenic driver\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWild type\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e151 (50.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22 (44.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003e0.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e46 (46.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e24 (55.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003e0.19\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEGFR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e118 (39.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22 (44.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e20 (20.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e11 (25.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOthers or unknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e31 (10.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (10.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e33 (33.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e8 (18.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTherapeutic lines\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFirst line\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e214 (71.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e28 (57.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e0.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e27 (27.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e21 (48.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e0.01\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;Second line\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e86 (28.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21 (42.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e72 (72.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e22 (51.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePlatinum drugs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCisplatin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e36 (12.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (2.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e0.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCarboplatin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e264 (88.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e48 (98.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBevacizumab\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWith\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e123 (41.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21 (42.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e0.81\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWithout\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e177 (59.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e28 (57.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDose adjustment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWith\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e25 (8.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e30 (61.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1 (1.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e11 (25.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.01\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWithout\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e275 (91.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e19 (38.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e98 (99.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e32 (74.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBaseline Hb (g/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e12.9\u0026plusmn;1.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11.8\u0026plusmn;1.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e12.5\u0026plusmn;1.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e11.6\u0026plusmn;2.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.02\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGrade\u0026thinsp;\u0026ge;\u0026thinsp;2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e11 (3.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (4.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003e0.02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e7 (7.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e10 (23.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003e0.02\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGrade 1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e13 (4.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (14.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3 (3.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1 (2.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWithin normal range\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e276 (92.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e40 (81.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e89 (89.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e32 (74.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBaseline CCr (mL/min)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e67.7\u0026plusmn;17.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e39.3\u0026plusmn;4.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e63.5\u0026plusmn;15.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e36.6\u0026plusmn;5.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.01\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003eValues are presented as mean\u0026plusmn;standard deviation or n (%).\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003eCCr, creatinine clearance; SD, standard deviation; NSCLC, non-small cell carcinoma; NOS, not otherwise specified; ECOG PS, Eastern Cooperative Oncology Group Performance Status; EGFR, epidermal growth factor receptor; Hb, hemoglobin\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e[Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e here]\u003c/h2\u003e \u003cdiv id=\"Sec9\" class=\"Section3\"\u003e \u003ch2\u003eAdverse events in each group\u003c/h2\u003e \u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e presents the adverse events related to blood toxicities and others that were objectively evaluated. The incidence of grade\u0026thinsp;\u0026ge;\u0026thinsp;3 neutropenia and thrombocytopenia did not reach statistical significance. However, the incidence of grade\u0026thinsp;\u0026ge;\u0026thinsp;3 anemia was significantly higher in the CCr\u0026thinsp;\u0026le;\u0026thinsp;45 mL/min subgroups in both treatment groups. There were no significant differences in the incidence of grade\u0026thinsp;\u0026ge;\u0026thinsp;3 for other adverse events, including elevated liver enzymes, skin rash, drug-induced pneumonitis, and treatment-related deaths. No cases of grade\u0026thinsp;\u0026ge;\u0026thinsp;3 treatment-related creatinine elevation were observed. Two instances of treatment-related deaths were recorded. One patient in the CCr\u0026thinsp;\u0026le;\u0026thinsp;45 mL/min subgroup of the pemetrexed-alone group succumbed to drug-induced pneumonitis. Another patient from the CCr\u0026thinsp;\u0026gt;\u0026thinsp;45 mL/min subgroup in the platinum-concomitant group died from disseminated intravascular coagulation following a severe infection.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eAdverse events in the platinum-concomitant and pemetrexed-alone groups\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003ePlatinum-concomitant (n\u0026thinsp;=\u0026thinsp;349)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c7\" namest=\"c5\"\u003e \u003cp\u003ePemetrexed-alone (n\u0026thinsp;=\u0026thinsp;142)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCCr\u0026thinsp;\u0026gt;\u0026thinsp;45\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;300)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCCr\u0026thinsp;\u0026le;\u0026thinsp;45 (n\u0026thinsp;=\u0026thinsp;49)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eCCr\u0026thinsp;\u0026gt;\u0026thinsp;45 (n\u0026thinsp;=\u0026thinsp;99)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCCr\u0026thinsp;\u0026le;\u0026thinsp;45 (n\u0026thinsp;=\u0026thinsp;43)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003ep\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNeutropenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGrade\u0026thinsp;\u0026lt;\u0026thinsp;3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e211 (70.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e38 (77.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e0.29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e79 (79.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e31 (72.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e0.32\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGrade\u0026thinsp;\u0026ge;\u0026thinsp;3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e89 (29.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e11 (22.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e20 (20.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e12 (27.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGrade\u0026thinsp;\u0026lt;\u0026thinsp;3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e268 (89.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e38 (77.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e0.03\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e93 (93.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e30 (69.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.01\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGrade\u0026thinsp;\u0026ge;\u0026thinsp;3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e32 (10.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e11 (22.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e6 (6.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e13 (30.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThrombocytopenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGrade\u0026thinsp;\u0026lt;\u0026thinsp;3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e266 (88.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e40 (81.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e0.19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e95 (96.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e41 (95.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e0.87\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGrade\u0026thinsp;\u0026ge;\u0026thinsp;3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e34 (11.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e9 (18.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e4 (4.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e2 (4.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOthers\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGrade\u0026thinsp;\u0026lt;\u0026thinsp;3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e265 (88.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e40 (81.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e0.21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e89 (89.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e35 (81.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e0.17\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGrade\u0026thinsp;\u0026ge;\u0026thinsp;3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e35 (11.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e9 (18.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e10 (10.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e8 (18.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003csup\u003ea\u003c/sup\u003e\u0026ldquo;Others\u0026rdquo; included objectively evaluable adverse events, such as elevated liver enzymes, infections, drug-induced pneumonitis, anorexia, elevated creatinine, skin rash, fatigue, acute exacerbation of interstitial lung disease, or treatment-related death.\u003c/p\u003e \u003cp\u003eCCr, creatinine clearance.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eEvaluation of independent risk factors of severe adverse events\u003c/h2\u003e \u003cp\u003eUnivariate analyses were performed for each treatment group to identify risk factors for severe anemia (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). In both groups, baseline anemia of grade\u0026thinsp;\u0026ge;\u0026thinsp;2 and CCr\u0026thinsp;\u0026le;\u0026thinsp;45 mL/min were statistically significant risk factors. Additionally, treatment with cisplatin was associated with a significantly higher risk in the platinum-concomitant group. Subsequently, we conducted multivariate analyses, adjusting for age, sex, baseline anemia grade, baseline CCr, and type of platinum drug (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). These analyses revealed that baseline anemia of grade\u0026thinsp;\u0026ge;\u0026thinsp;2 was a significant risk factor for treatment-related grade\u0026thinsp;\u0026ge;\u0026thinsp;3 anemia in both treatment groups. Additionally, a baseline CCr\u0026thinsp;\u0026le;\u0026thinsp;45 mL/min was identified as a risk factor in the pemetrexed-alone group.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eLogistic regression analysis to determine risk factors of grade\u0026thinsp;\u0026ge;\u0026thinsp;3 anemia\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eParameters\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003ePlatinum-concomitant (n\u0026thinsp;=\u0026thinsp;349)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003ePemetrexed-alone (n\u0026thinsp;=\u0026thinsp;142)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOdds ratio (95% CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ep\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eOdds ratio (95% CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ep\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge, years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.33 (0.47\u0026ndash;3.78)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.59\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.97 (0.18\u0026ndash;5.07)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.97\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.13 (0.52\u0026ndash;2.44)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.77\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.88 (0.19\u0026ndash;4.14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.87\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBaseline anemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGrade\u0026thinsp;\u0026ge;\u0026thinsp;2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15.6 (5.38\u0026ndash;45.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e46.2 (8.17\u0026ndash;261)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.01\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGrade 1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.55 (0.70\u0026ndash;3.42)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.50 (0.07\u0026ndash;3.29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.47\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWithin normal range\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBaseline CCr\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026le;45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.91 (0.74\u0026ndash;4.89)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6.82 (1.32\u0026ndash;35.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.03\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026gt;45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePlatinum drugs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCisplatin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.27 (0.04\u0026ndash;2.04)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCarboplatin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eCI, confidence interval; CCr, creatinine clearance\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eComparison of best response, PFS, and OS according to renal function\u003c/h2\u003e \u003cp\u003eResponses to each treatment are detailed in Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e. The overall response rate (ORR) and disease control rate (DCR) were numerically higher in the CCr\u0026thinsp;\u0026gt;\u0026thinsp;45 mL/min subgroup compared to the CCr\u0026thinsp;\u0026le;\u0026thinsp;45 mL/min subgroups in both treatment groups; however, the differences were not statistically significant. PFS and OS are illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. In the platinum-concomitant group, the median PFSs were 6.0 months (95% CI, 5.3\u0026ndash;6.5) for CCr\u0026thinsp;\u0026gt;\u0026thinsp;45 mL/min and 4.7 months (95% CI, 3.8\u0026ndash;6.0) for CCr\u0026thinsp;\u0026le;\u0026thinsp;45 mL/min (hazard ratio [HR], 1.14; 95% CI, 0.84\u0026ndash;1.55, p\u0026thinsp;=\u0026thinsp;0.40). The median OSs were 30.7 months (95% CI, 23.7\u0026ndash;34.9) for CCr\u0026thinsp;\u0026gt;\u0026thinsp;45 mL/min and 16.1 months (95% CI, 13.6\u0026ndash;20.6) for CCr\u0026thinsp;\u0026le;\u0026thinsp;45 mL/min (HR, 1.27; 95% CI, 0.89\u0026ndash;1.81, p\u0026thinsp;=\u0026thinsp;0.19). Although both PFS and OS were numerically longer in the CCr\u0026thinsp;\u0026gt;\u0026thinsp;45 mL/min group, the differences were not statistically significant. In the pemetrexed-alone group, the median PFSs were 2.9 months (95% CI, 2.4\u0026ndash;3.9) for CCr\u0026thinsp;\u0026gt;\u0026thinsp;45 mL/min and 2.8 months (95% CI, 1.5\u0026ndash;4.1) for CCr\u0026thinsp;\u0026le;\u0026thinsp;45 mL/min (HR, 1.30; 95% CI, 0.90\u0026ndash;1.88, p\u0026thinsp;=\u0026thinsp;0.16). The median OSs were 15.1 months (95% CI, 12.3\u0026ndash;20.8) for CCr\u0026thinsp;\u0026gt;\u0026thinsp;45 mL/min and 16.2 months (95% CI, 7.6\u0026ndash;20.3) for CCr\u0026thinsp;\u0026le;\u0026thinsp;45 mL/min (HR, 1.24; 95% CI, 0.84\u0026ndash;1.83, p\u0026thinsp;=\u0026thinsp;0.27).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eEfficacy of pemetrexed-containing chemotherapies\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eBest response\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003ePlatinum-concomitant (n\u0026thinsp;=\u0026thinsp;349)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c7\" namest=\"c5\"\u003e \u003cp\u003ePemetrexed-alone (n\u0026thinsp;=\u0026thinsp;142)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCCr\u0026thinsp;\u0026gt;\u0026thinsp;45 (n\u0026thinsp;=\u0026thinsp;300)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCCr\u0026thinsp;\u0026le;\u0026thinsp;45 (n\u0026thinsp;=\u0026thinsp;49)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eCCr\u0026thinsp;\u0026gt;\u0026thinsp;45 (n\u0026thinsp;=\u0026thinsp;99)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCCr\u0026thinsp;\u0026le;\u0026thinsp;45 (n\u0026thinsp;=\u0026thinsp;43)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003ep\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eORR \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e134 (49.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e16 (35.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.82\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e21 (21.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e7 (17.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.65\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDCR \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e230 (84.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e36 (80.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e67 (68.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e24 (61.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.45\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3 (1.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1 (2.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1 (1.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e131 (43.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e15 (30.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e20 (20.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e7 (16.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e96 (32.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e20 (40.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e46 (46.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e17 (39.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e41 (13.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e9 (18.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e31 (31.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e15 (34.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e29 (9.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4 (8.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1 (1.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e4 (0.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003csup\u003ea\u003c/sup\u003eThirty-three patients in the platinum-concomitant group and five patients in the pemetrexed-alone group were excluded from the ORR and DCR analyses because their responses were not evaluable.\u003c/p\u003e \u003cp\u003eCCr, creatinine clearance; ORR, overall response rate; DCR, disease control rate; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; NE, not evaluable.\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study was a comprehensive retrospective evaluation of the safety and efficacy of pemetrexed-containing chemotherapy in patients with renal impairment. Regarding safety, grade\u0026thinsp;\u0026ge;\u0026thinsp;3 anemia was significantly more frequent in the CCr\u0026thinsp;\u0026le;\u0026thinsp;45 mL/min subgroups. Higher grades of baseline anemia in both treatment groups and a baseline CCr\u0026thinsp;\u0026le;\u0026thinsp;45 mL/min in the pemetrexed-alone group were identified as independent risk factors for treatment-related severe anemia. Regarding efficacy, there were no significant differences between the CCr\u0026thinsp;\u0026gt;\u0026thinsp;45 mL/min and CCr\u0026thinsp;\u0026le;\u0026thinsp;45 mL/min subgroups in both the platinum-concomitant and pemetrexed-alone groups.\u003c/p\u003e \u003cp\u003eA plausible explanation for the notable frequency of treatment-related severe anemia in the CCr\u0026thinsp;\u0026lt;\u0026thinsp;45 subgroups is that chemotherapy-induced myelosuppression may be exacerbated in patients with renal impairment. Myelosuppression is a common complication of chemotherapy, and previous clinical trials have reported rates of grade\u0026thinsp;\u0026ge;\u0026thinsp;3 anemia between 1.1% and 6.4% [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan additionalcitationids=\"CR10\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Compared to these studies, the incidence of severe anemia in our study was higher, with approximately 20\u0026ndash;30% of patients in the CCr\u0026thinsp;\u0026lt;\u0026thinsp;45 subgroups of both treatment groups experiencing grade\u0026thinsp;\u0026ge;\u0026thinsp;3 anemia. One study showed that 22% of patients with CCr\u0026thinsp;\u0026lt;\u0026thinsp;45 mL/min suffered from grade\u0026thinsp;\u0026ge;\u0026thinsp;3 anemia, indicating that renal impairment is a risk factor for severe hematologic toxicity [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. These findings align with our results, suggesting that increased myelosuppression related to chemotherapy can lead to severe treatment-related anemia in patients with renal impairment.\u003c/p\u003e \u003cp\u003eLower baseline hemoglobin levels and treatment-related severe anemia may be associated with renal function. Our study identified a higher grade of baseline anemia as an independent risk factor for treatment-related grade\u0026thinsp;\u0026ge;\u0026thinsp;3 anemia in both treatment groups. Multivariate analyses further revealed that a lower baseline CCr was also an independent risk factor for severe anemia, but only in the pemetrexed-alone group. However, its impact was less significant than that of grade\u0026thinsp;\u0026ge;\u0026thinsp;2 baseline anemia. Meanwhile, lower CCr was not an independent risk factor for severe anemia in the platinum-concomitant group. Yet, univariate analysis indicated that treatment-related severe anemia was significantly more common in the CCr\u0026thinsp;\u0026le;\u0026thinsp;45 mL/min subgroup (p\u0026thinsp;=\u0026thinsp;0.02), even within the platinum-concomitant group. The link between anemia and impaired renal function is likely due to renal anemia commonly observed in patients with chronic kidney disease. Several studies have reported that the prevalence of renal anemia increases in patients with renal impairment, specifically when creatinine levels are \u0026ge;\u0026thinsp;2 mg/dL or CCr\u0026thinsp;\u0026lt;\u0026thinsp;20\u0026ndash;35 mL/min. This increase is often attributed to reduced production of hematopoietic factors in the kidneys or diminished responsiveness in the bone marrow [\u003cspan additionalcitationids=\"CR13\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Renal anemia is particularly prevalent in patients with a CCr\u0026thinsp;\u0026lt;\u0026thinsp;45 mL/min, especially those with diabetic nephropathy [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Indeed, our study found significantly lower baseline hemoglobin levels in the CCr\u0026thinsp;\u0026lt;\u0026thinsp;45 mL/min subgroup. Drawing on existing research on the relationship between treatment-related severe anemia and renal impairment, it is evident that both baseline and treatment-related anemia are influenced by renal function [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eDose adjustment during chemotherapy may be crucial in reducing the incidence of severe adverse events (SAEs). A study where pemetrexed was administered with a dose reduction based on renal function reported no SAEs [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. In our study, a relatively high proportion of patients underwent dose adjustments at initiation, including dose reductions and treatment postponements, based on the physician\u0026rsquo;s discretion. These findings suggest that pemetrexed is relatively safe, even for patients with renal impairment.\u003c/p\u003e \u003cp\u003eThe efficacy of pemetrexed-containing chemotherapy appears to be independent of renal function. In both treatment groups in our study, the ORR and DCR, in addition to PFS and OS, were not significantly different, regardless of renal function. These results were comparable to or better than those reported previously. For example, a prior study noted an ORR of 9.1%, a DCR of 54.9%, a median PFS of 2.9 months, and a median OS of 8.3 months [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Another clinical trial reported median PFS and OS of 4.8 and 10.3 months, respectively [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. The Keynote-189 clinical trial documented in the control arm an ORR of 18.9%, a DCR of 70.4%, a median PFS of 4.9 months, and a median OS of 10.6 months [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Our study\u0026rsquo;s median PFS was similar to these previous findings. However, the ORR, DCR, and median OS in our study were notably higher, even in the CCr\u0026thinsp;\u0026le;\u0026thinsp;45 mL/min subgroups, compared to those earlier studies. These outcomes indicate that renal function does not influence the efficacy of pemetrexed-containing treatments.\u003c/p\u003e \u003cp\u003ePatient characteristics such as sex and age showed significant differences in this study. Consistent with another study that found a higher proportion of older patients with CCr\u0026thinsp;\u0026le;\u0026thinsp;45 mL/min [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e], it is logical that a significant portion of the CCr\u0026thinsp;\u0026le;\u0026thinsp;45 subgroups in our study comprised older individuals, reflecting the increased prevalence of lung cancer among the older population. Additionally, female patients were more common in the CCr\u0026thinsp;\u0026le;\u0026thinsp;45 subgroups, suggesting that older female patients might have lower body weight and muscle mass, potentially leading to an underestimation of their renal function. These findings align with those reported in previous research [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThis study has several limitations. Firstly, it was a retrospective study conducted at a single institution, and there was an imbalance in patient characteristics such as age and sex. Consequently, confounding factors that might affect the safety and efficacy of pemetrexed-based therapies cannot be ruled out. Efforts were made to adjust for the effects of these imbalances using multivariate analyses. Secondly, the number of patients with CCr\u0026thinsp;\u0026le;\u0026thinsp;45 mL/min was relatively small, which might not sufficiently assess the purpose of this study. Furthermore, the study did not include patients receiving the current mainstream treatment for lung cancer\u0026mdash;platinum-based chemotherapy combined with immune checkpoint inhibitors\u0026mdash;due to the limited number of patients with renal impairment. Further large-scale studies are necessary to evaluate the safety and efficacy of these therapies in patients with renal impairment.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis study demonstrated the safety and efficacy of pemetrexed-containing treatments in patients with renal impairment. Although the incidence of grade\u0026thinsp;\u0026ge;\u0026thinsp;3 anemia was higher in patients with CCr\u0026thinsp;\u0026le;\u0026thinsp;45 mL/min, no difference in treatment efficacy was observed. Therefore, pemetrexed-based treatment could be a viable option for such populations, provided that anemia is carefully managed.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eCCr, creatinine clearance\u003c/p\u003e\n\u003cp\u003eCTCAE, Common Terminology Criteria for Adverse Events\u003c/p\u003e\n\u003cp\u003eCI, confidence interval\u003c/p\u003e\n\u003cp\u003eDCR, disease control rate\u003c/p\u003e\n\u003cp\u003eGFR, glomerular filtration rate\u003c/p\u003e\n\u003cp\u003eHR, hazard ratio\u003c/p\u003e\n\u003cp\u003eNCSLC, non-squamous non-small cell lung carcinoma\u003c/p\u003e\n\u003cp\u003eORR, overall response rate\u003c/p\u003e\n\u003cp\u003eOS, overall survival\u003c/p\u003e\n\u003cp\u003ePFS, progression-free survival\u003c/p\u003e\n\u003cp\u003ePS, performance status\u003c/p\u003e\n\u003cp\u003eSAEs, severe adverse events\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by the Kyoto University Hospital Ethics Committee (approval number 023-00932). The requirement for informed consent for the use of clinical records was waived because of the retrospective study design. However, all patients were guaranteed opportunities to learn about and withdraw from the study through notification.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe requirement for informed consent to use the clinical information was waived because this was a retrospective study without intervention or preserved specimens.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analyzed in the current study are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was supported by internal funding from Kyoto University Hospital.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor\u0026rsquo;s contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eYS contributed to the data curation, investigation, validation, formal analysis, methodology, visualization, and writing of the original draft. HY contributed to conceptualization, data curation, formal analysis, investigation, methodology, project administration, funding acquisition, supervision, validation, and writing (review and editing). TH and HO contributed to the funding acquisition, supervision, validation, writing, review, and editing. KS, HA, and TN contributed to the data curation, resource acquisition, investigation, writing, reviewing, and editing. KH, HY, KH, and TF contributed to formal analysis, data curation, investigation, and writing (review and editing). All authors contributed to the resources, writing (review), and editing, and have read and approved the final version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe would like to thank Editage (www.editage.com) for the English language editing.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eHanna N, Shepherd FA, Fossella FV, Pereira JR, De Marinis F, von Pawel J, \u003cem\u003eet al.\u003c/em\u003e Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol. 2004;22:1589-97.\u003c/li\u003e\n\u003cli\u003eScagliotti G, Hanna N, Fossella F, Sugarman K, Blatter J, Peterson P, \u003cem\u003eet al.\u003c/em\u003e The differential efficacy of pemetrexed according to NSCLC histology: A review of two Phase III studies. 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J Pediatr. 1988;113:1015-21. doi: 10.1016/s0022-3476(88)80573-0.\u003c/li\u003e\n\u003cli\u003eMcGonigle RJ, Boineau FG, Beckman B, Ohene-Frempong K, Lewy JE, Shadduck RK, \u003cem\u003eet al.\u003c/em\u003e Erythropoietin and inhibitors of in vitro erythropoiesis in the development of anemia in children with renal disease. J Lab Clin Med. 1985 ;105:449-58.\u003c/li\u003e\n\u003cli\u003eLocatelli F, Aljama P, B\u0026aacute;r\u0026aacute;ny P, Canaud B, Carrera F, Eckardt KU, \u003cem\u003eet al.\u003c/em\u003e Revised European best practice guidelines for the management of anaemia in patients with chronic renal failure. Nephrol Dial Transplant. 2004;19;Suppl 2:ii1-47.\u003c/li\u003e\n\u003cli\u003eAndo Y, Hayashi T, Ujita M, Murai S, Ohta H, Ito K, \u003cem\u003eet al.\u003c/em\u003e Effect of renal function on pemetrexed-induced haematotoxicity. Cancer Chemother Pharmacol. 2016;78:183-9.\u003c/li\u003e\n\u003cli\u003eKutluk Cenik B, Sun H, Gerber DE. Impact of renal function on treatment options and outcomes in advanced non-small cell lung cancer. Lung Cancer. 2013;80:326-32.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcan","sideBox":"Learn more about [BMC Cancer](http://bmccancer.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcan/default.aspx","title":"BMC Cancer","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"pemetrexed, non-small cell lung cancer, safety and efficacy, renal impairment, creatinine clearance","lastPublishedDoi":"10.21203/rs.3.rs-4689590/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4689590/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003ePemetrexed is a key treatment for non-small-cell lung cancer (NSCLC), with its usage on the rise. However, due to treatment-related fatality in a patient with severe renal impairment observed during an initial clinical trial, such patients have been excluded from further studies. Consequently, there is limited data on the safety and efficacy of pemetrexed for these patients. This study aims to assess the use of pemetrexed in this patient group within a clinical setting.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe conducted a retrospective analysis of lung cancer patients treated with pemetrexed at Kyoto University Hospital from April 2008 to April 2023. Patients were categorized into groups receiving pemetrexed with platinum (n\u0026thinsp;=\u0026thinsp;349) and pemetrexed-alone (n\u0026thinsp;=\u0026thinsp;142) groups. Both groups were subdivided into creatinine clearance (CCr)\u0026thinsp;\u0026gt;\u0026thinsp;45 and \u0026le;\u0026thinsp;45 subgroups, and safety and efficacy were compared between the subgroups. The chi-squared test was used to evaluate the correlation between renal impairment and adverse events. Univariate and logistic regression analyses identified independent risk factors for severe adverse events (SAEs) related to renal impairment. We also analyzed progression-free survival (PFS) and overall survival (OS) using log-rank tests.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eA significant increase in the incidence of grade\u0026thinsp;\u0026ge;\u0026thinsp;3 anemia was observed in the CCr\u0026thinsp;\u0026le;\u0026thinsp;45 subgroups of both the platinum-concomitant and the pemetrexed-alone groups (p\u0026thinsp;=\u0026thinsp;0.03 and p\u0026thinsp;\u0026lt;\u0026thinsp;0.01, respectively). No significant differences were noted for other SAEs. Multivariate analysis showed that baseline hemoglobin levels were an independent predictor of grade\u0026thinsp;\u0026ge;\u0026thinsp;3 anemia across both treatment groups, alongside a baseline CCr\u0026thinsp;\u0026le;\u0026thinsp;45 mL/min in the pemetrexed-alone group. No significant differences were observed in overall response rates, PFS, or OS between the CCr\u0026thinsp;\u0026gt;\u0026thinsp;45 and CCr\u0026thinsp;\u0026le;\u0026thinsp;45 subgroups in either treatment group.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eWhile severe anemia was more common in patients with renal impairment, the efficacy of treatment did not differ, indicating that pemetrexed remains a viable treatment option for this population with proper management.\u003c/p\u003e","manuscriptTitle":"Safety and efficacy of pemetrexed for patients with non-small cell lung cancer in the setting of renal impairment: a retrospective study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-08-09 14:28:22","doi":"10.21203/rs.3.rs-4689590/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-01-01T05:16:18+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-12-24T10:43:34+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"205055541239993032846601196277014530594","date":"2024-12-23T02:17:51+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"284065668062660508847756315333467534559","date":"2024-10-02T07:51:51+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-09-30T11:08:18+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"42442274027202053525266291806964131145","date":"2024-09-08T16:53:54+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-07-16T19:05:08+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2024-07-09T09:27:34+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-07-05T08:52:22+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-07-05T08:50:34+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Cancer","date":"2024-07-05T04:34:53+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcan","sideBox":"Learn more about [BMC Cancer](http://bmccancer.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcan/default.aspx","title":"BMC Cancer","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"71a20667-dd9f-4643-a37b-0e505b1de5a7","owner":[],"postedDate":"August 9th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-03-10T17:09:19+00:00","versionOfRecord":{"articleIdentity":"rs-4689590","link":"https://doi.org/10.1186/s12885-025-13785-x","journal":{"identity":"bmc-cancer","isVorOnly":false,"title":"BMC Cancer"},"publishedOn":"2025-03-04 15:57:09","publishedOnDateReadable":"March 4th, 2025"},"versionCreatedAt":"2024-08-09 14:28:22","video":"","vorDoi":"10.1186/s12885-025-13785-x","vorDoiUrl":"https://doi.org/10.1186/s12885-025-13785-x","workflowStages":[]},"version":"v1","identity":"rs-4689590","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4689590","identity":"rs-4689590","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}