Turning the Tide for SCLC: Real World Analysis of Atezolizumab and Platinum-based Chemotherapy in Low-Resource Settings

Turning the Tide for SCLC: Real World Analysis of Atezolizumab and Platinum-based Chemotherapy in Low-Resource Settings | 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 Turning the Tide for SCLC: Real World Analysis of Atezolizumab and Platinum-based Chemotherapy in Low-Resource Settings Ullas Batra, Sabeena K. Choudhary, Mansi Sharma, Shrinidhi Nathany, and 9 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6997166/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 5 You are reading this latest preprint version Abstract Background Small-cell lung cancer (SCLC) represents one of the most aggressive forms of lung malignancies. Due to its aggressive nature, most patients are diagnosed in advanced stage and are candidates for palliative systemic therapy only. While the addition of immunotherapy to standard chemotherapy has shown promise in clinical trials, limited data exists on its real-world effectiveness in Indian populations. We aimed to evaluate outcomes of immunotherapy combined with etoposide-carboplatin chemotherapy in Indian patients with extensive-stage SCLC (ES-SCLC). Methods We conducted a retrospective analysis of 38 patients with ES-SCLC at our center who received atezolizumab plus etoposide-carboplatin, followed by atezolizumab maintenance therapy. Primary endpoints included overall survival (OS) and progression-free survival (PFS). Survival analyses were performed using Kaplan-Meier and Cox proportional hazards models. Results The study population (median age 62.5 years) predominantly comprised male patients (86.8%) with a history of smoking (84.2%). Disease progression occurred in 86.8% of patients. Brain metastases were present in 18.4% of patients at diagnosis, with an additional 39.5% developing intracranial disease during the course of treatment. Median OS (mOS) reached 11.0 months (95% CI: 3.5–18.4), with 12-, 18-, and 24-month survival rates of 42%, 33.6%, and 12.8%, respectively. The median PFS (mPFS) was 4.5 months (95% CI: 3.4–5.6). Multivariate analysis revealed that higher ECOG performance status correlated with inferior survival (HR = 2.22; p < 0.001). Conclusion In this Indian cohort, first-line immunotherapy using Atezolizumab with etoposide-carboplatin demonstrated survival outcomes comparable to international standards. These findings support the integration of immune checkpoint inhibition with standard chemotherapy for ES-SCLC in the Indian healthcare context. SCLC ES-SCLC Immunotherapy Atezolizumab Chemo-immunotherapy Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Introduction Lung cancer remains the predominant cause of cancer-related mortality worldwide [ 1 ]. Among its subtypes, small-cell lung cancer (SCLC) presents challenges due to its aggressive nature, early metastatic spread, and a strong correlation with tobacco use [ 2 , 3 ]. This high-grade neuroendocrine malignancy constitutes roughly 15% of all lung carcinomas [ 4 ], with global annual incidence approaching 250,000 cases and approximately 200,000 deaths [ 5 ]. In a retrospective record-based analysis including 1248 patients diagnosed with lung cancer, at a tertiary cancer care center in India, SCLC prevalence was found to be 14.3% [ 6 ]. The disease typically manifests as a substantial hilar mass accompanied by extensive mediastinal lymphadenopathy, producing symptoms such as cough and dyspnea. Its biological behavior is marked by rapid cellular proliferation, brief doubling time, and swift metastatic dissemination [ 7 ]. Patients commonly present with systemic manifestations, including weight loss, generalized weakness, skeletal pain, and neurological complications. Treatment guidelines established by major organizations, the National Comprehensive Cancer Network [ 8 ], European Society for Medical Oncology [ 9 ], and Indian Council of Medical Research [ 10 ], outline therapeutic approaches incorporating radiotherapy, chemotherapy, and, in select cases, surgical intervention. While platinum-based chemotherapy combined with etoposide represents the historical standard for extensive-stage SCLC (ES-SCLC), the development of chemoresistance frequently limits its long-term efficacy [ 11 , 12 ]. Traditional chemotherapeutic approaches yield modest progression-free survival (PFS) and overall survival (OS) rates, with durable responses being exceedingly rare. Attempts to enhance outcomes through modified or intensified chemotherapy protocols have yielded limited success [ 13 ]. The emergence of immune checkpoint inhibitors (atezolizumab and Durvalumab) marks a significant therapeutic advancement in SCLC management [ 9 ]. Atezolizumab, a humanized monoclonal antibody, targets programmed death ligand 1 (PD-L1), disrupting its interactions with programmed death 1 (PD-1) and B7-1 receptors, thereby reactivating tumor-specific immune responses [ 14 ]. Initial Phase 1 investigations demonstrated atezolizumab monotherapy's favorable safety profile and sustained response patterns in relapsed or refractory SCLC [ 15 ]. The integration of immunotherapy with conventional chemotherapy potentially augments antitumor immunity, surpassing the therapeutic ceiling of existing treatments [ 14 ]. The IMpower133 trial established that combining atezolizumab with etoposide and carboplatin significantly improved survival metrics in ES-SCLC patients [ 14 ]. These findings led to regulatory approvals from the United States Food and Drug Administration in March 2019 and the Drugs Controller General of India in September 2019, sanctioning its use alongside carboplatin and etoposide as first-line therapy for adult ES-SCLC patients [ 16 , 17 ]. The CASPIAN trial demonstrated that Durvalumab plus platinum-etoposide significantly improved overall survival in ES-SCLC patients, establishing it as another standard-of-care option. Like atezolizumab, Durvalumab received FDA approval for ES-SCLC (in 2020), offering an alternative immunotherapy-chemotherapy combination approach. Despite these advances, real-world evidence documenting atezolizumab's effectiveness in combination with chemotherapy among Indian SCLC patients remains limited. This knowledge gap necessitates investigations into the regimen's performance within the Indian healthcare context. Our study addresses this need by examining the clinical outcomes of first line immunotherapy plus etoposide-carboplatin in Indian patients with SCLC. Methods Study Design and Population We conducted a single-center retrospective analysis at Rajiv Gandhi Cancer Institute & Research Centre between October 2019 and November 2024. The study protocol received approval from the Institutional Review Board ( RES/SCM/65/2024/58 ) with a waiver of informed consent granted due to the retrospective design. Patient confidentiality was maintained through data anonymization in accordance with ethical research guidelines. Inclusion and Exclusion criteria Eligible patients were aged 18 years or older with histologically or cytologically confirmed ES-SCLC, classified according to Veterans Administration Lung Study Group staging criteria. Patients with brain metastases were included. Patients previously treated with chemoradiotherapy for limited-stage disease were eligible if they had maintained a minimum six-month treatment-free interval. We excluded patients who had coexistent non-small cell lung cancer (NSCLC), patients with transformed SCLC and patients with dual malignancy. Prior immune checkpoint inhibitor exposure, immune-mediated adverse events, pregnancy, and lactation also preclude participation. Treatment and response evaluation Treatment consisted of combination chemotherapy with etoposide (100 mg/m² intravenously, days 1–3) and carboplatin (AUC 5 mg·mL⁻¹·min⁻¹ intravenously, day 1), plus atezolizumab (1200 mg intravenously, day 1) administered in 21-day cycles for four to six cycles. Patients who had non progressive disease at the end of 6 cycles, subsequently received maintenance atezolizumab (1200 mg intravenously) every three weeks until disease progression, death, or unacceptable toxicity. Disease assessment incorporated clinical (emergence or worsening of symptoms), biochemical, and radiological parameters, with response categorized according to RECIST v1.1 criteria as partial response (PR), stable disease (SD), or progressive disease (PD). We extracted patient characteristics from electronic medical records, including demographic data, smoking history, metastatic burden, radiation therapy details (prophylactic cranial irradiation and whole-brain radiation therapy), and ECOG performance status. The date of diagnosis, initiation of first-line chemotherapy, and subsequent first-line treatment were recorded. Endpoints Primary endpoints comprised PFS, measured from treatment initiation to documented progression or death, and overall survival OS, calculated from treatment initiation to death from any cause. Statistical Analysis We performed intent-to-treat analyses using SPSS (Version 30.0). Continuous variables were summarized using standard descriptive statistics; categorical variables were expressed as frequencies and proportions. Survival analyses employed Kaplan-Meier methodology, with median PFS and OS reported with two-sided 95% confidence intervals. We interpolated OS rates at 12-, 18-, and 24- months from survival tables. Multivariable Cox proportional hazards models assessed potential predictors of survival, including age, sex, smoking status, performance status, brain metastases, and metastatic burden. Statistical significance was set at p < 0.05. Results Patient characteristics and demographics Between October 2019 and November 2024, 38 patients received first-line treatment with etoposide, carboplatin, and atezolizumab for extensive-stage SCLC. Baseline characteristics are presented in Table 1 . The study population had a median age of 62.5 years (range 32–74), with male predominance (86.8%) and substantial percentage with smoking history (84.2%). Most patients (65.9%) presented with ECOG performance status of 1, while 18.5% had performance status ≥ 3. Median time from biopsy till the start of treatment was 8 (range: 0-119) days. The median number of cycles of atezolizumab was 5.5 (range 1–56 cycles). Among the 38 patients, 18 (47.4%) received second line treatment at progression. Extra thoracic metastasis 86.8% had extra thoracic metastasis at the initial presentation. The distribution of extra-thoracic disease varied considerably, 13.2% of patients had no extra-thoracic involvement, 39.5% had single-site involvement, 23.7% had two sites, 10.5% had three sites, and 13.2% had four sites. Skeletal system (50.0%, n = 19) and pleural space (44.7%, n = 17) represented the most frequent sites of metastatic spread. Median follow-up duration was 7.7 months (range 2.2–35.2). Table 1 Patient characteristics Variable Frequency (%) Gender Male 33 (86.8) Female 5 (13.2) Smoking Status Smokers 32 (84.2) Non-smokers 6 (15.8) Brain Metastasis at Presentation Yes 7 (18.4) No 31(81.6) Extra-thoracic Metastatic Sites 0 5 (13.2) 1 15 (39.5) 2 9 (23.7) 3 4 (10.5) 4 5 (13.2) Age group 30–40 1(2.6) 41–50 4(10.5) 51–60 9(23.7) 61–70 17(44.7) 71–80 7(18.4) ECOG Performance Status (PS) 1 25 (65.8) 2 6 (15.8) 3 3 (7.9) 4 4 (10.5) Treatment response and Survival outcomes Kaplan-Meier survival analysis revealed a median overall survival (OS) of 11.0 months (95% CI: 3.9–18.4). The median follow-up period was 7.7 months (range: 2.2–35.2). During the follow up, 25 out of 38 patients (65.8%) succumbed to the disease. Additionally, 15.8% were lost to follow-up (LFU) (Table 2 ). The survival function for the cohort is depicted in Fig. 1 . The OS analysis demonstrated an OS rate of 42%, 33.6% and 12.8% at 12-month, 18-month and 24-months respectively. Progression-free survival (PFS) was similarly evaluated, yielding a median of 4.5 months (95% CI: 3.4–5.6). Disease progression was observed in 33 of 38 patients (86.8%) during the study (Figs. 2 and 3). Regarding treatment response, PR was achieved in 68.4% of patients, SD in 13.2%, and PD in 18.4% (Table 2 ). Table 2 Disease progression, treatment response, and survival status (N = 38) Variables n (%) Progression observed Yes 33 (86.8) No 5 (13.2) Response evaluation Partial response 26 (68.4) Progressive disease 7 (18.4) Stable disease 5 (13.2) Status at last follow-up Dead 25 (65.8) Alive 7 (18.4) LFU 6 (15.8) LFU: lost to follow-up Distribution and survival outcomes of brain metastases among patients Seven out of 38 patients (18.4%) had brain metastasis at presentation. Fifteen patients developed brain metastases during the course of the disease out of which five developed brain metastases as the first site or concurrent with systemic progression. Sixteen patients (42.1%) did not experience brain metastasis at any stage (Fig. 4 ). The timeline of brain metastasis following diagnosis revealed that among the 15 patients who developed brain metastases during the course of the disease, 11 (73.3%) did so within the first 12 months from diagnosis (Fig. 5 ). Overall, the median duration of brain metastasis in the patients was 9.1 months (range: 1.6–19.8 months). Longitudinal Assessment of Patient Outcomes The swimmer plot illustrates individual patient outcomes, showing that 26 (68.4%) patients achieved a partial response with prolonged survival, while those with progressive disease (7; 18.4%) had shorter durations and earlier deaths. Progression events occurred primarily within the first year, while some partial responders experienced late progression, indicating potentially acquired resistance. A few patients maintained a durable response beyond 18 months, suggesting long-term benefit (Fig. 6). No complete responses were recorded. The objective response rate (ORR), defined as the proportion of patients with complete or partial response, was 68.4%. Cox Proportional Hazards Regression Analysis Cox proportional hazards regression analysis was performed to evaluate factors affecting overall survival. The model was statistically significant (p = 0.004). Among the covariates, only ECOG Performance Status at admission was significantly associated with mortality (HR = 2.22, 95% CI: 1.39–3.56, p < 0.001) Other variables, including age, smoking status, and number of extra-thoracic metastases did not have a significant impact on survival (Table 3 ). Table 3 Cox proportional hazards regression analysis of clinical variables associated with survival outcomes Variable Hazard Ratio (HR) Significance (p-value) Age 0.99 0.682 Gender 2.19 0.260 Smoking History 1.52 0.526 ECOG PS at admission 2.22 < 0.001 Number of extra thoracic Mets 1.05 0.802 Discussion This study provides a real-world analysis of immunotherapy combined with etoposide and carboplatin as first-line treatment for ES-SCLC in an Indian cohort. Our findings contribute to the growing body of evidence supporting the efficacy of this combination therapy in diverse populations. The objective response rate of 68.4% (all partial responses) observed in our cohort aligns with recent real-world studies. An additional 13.2% of patients achieving stable disease suggest that the majority of patients derive clinical benefit from this combination therapy [ 18 – 21 ]. Our median overall survival was 11.0 months with a 12-, 18- and 24- month OS rate of 42%, 33.6% and 12.8% respectively. This is particularly noteworthy when compared to historical data with chemotherapy alone, ranging from 5.4 to 9.0 months [ 11 , 22 – 23 ]. Another study by Yilmaz et al observed a median OS of 9.0 months, with 12- and 24-month survival probabilities of 33.6% and 5.3%, respectively with the use of chemotherapy alone [ 24 ], both of which are lower than the 12-month and 24-month OS findings in our study. MAURIS trial, reported a median OS of 10.7 months and a 12-month OS rate of 41.9% suggesting the benefit of using immunotherapy alongside chemotherapy in ES-SCLC [ 19 ]. Recent long-term follow-up data from the IMpower 133 trial has demonstrated sustained survival benefits with atezolizumab combination therapy, establishing this approach as a new standard of care (median OS of 12.3 months and a 12-month OS rate of 51.7%) [ 14 ]. Interestingly, our real-world outcomes closely mirror those observed in pivotal trials. However, a higher median OS (13.5 and 16.5 months) and 12-month OS rate (57.8% and 63.7%) than the present study outcomes were reported in the South Korean [ 25 ] and Japanese patients [ 26 ], respectively, likely due to differences in sample size and population variations. The median progression-free survival of 4.5 months in our cohort is consistent with established benchmarks, though slightly lower than some reported figures [ 24 , 26 , 27 ]. Moreover, most retrospective and prospective studies involving atezolizumab plus etoposide and carboplatin combination, including pivotal clinical trials like IMpower133 and MAURIS, have reported mPFS values between 4.6 to 6.0 months that are comparable to the present study findings [ 14 , 18 – 20 , 22 ]. The improved survival outcomes suggest a potential synergistic effect of combining immunotherapy with standard chemotherapy, highlighting the role of atezolizumab in enhancing disease control and delaying progression beyond what is typically achieved with chemotherapy alone. The multivariable analysis revealed that ECOG PS at the start of chemotherapy significantly impacted survival (HR = 2.22, p < 0.001), consistent with studies where ECOG PS was a critical predictor of OS [ 18 , 25 ]. OS and PFS in our study cohort mirrored those in the pivotal trials despite including patients with poorer performance status (18.5% with PS ≥ 3) who would typically be excluded from clinical trials. Brain Metastases in ES-SCLC: Patterns and Implications Brain metastasis at presentation was observed in ~ 9% of patients in IMPower133 trial, and 10% in Caspian study [ 14 , 28 ]. However, patients with brain metastasis were underrepresented in these pivotal trials. In our cohort, we observed brain metastasis in 18.4% at presentation which is much higher than that in the pivotal trials of immune check point inhibitors in ES-SCLC. This difference could be because of stringent exclusion criteria used in these trials and also reflects the advanced stage of disease at which patients present in real world scenario in low- and middle-income countries. The pattern of brain metastases development in our cohort (with 18.4%) warrants particular attention. The cumulative incidence of brain metastases throughout treatment was substantial, with 15 additional patients developing central nervous system involvement during the course of therapy, including 5 who experienced brain metastasis as their first site of progression. These findings align with the growing recognition of the central nervous system as a critical site of disease progression in ES-SCLC. The development of new brain metastases during treatment (39.5% of patients) highlights a critical challenge in ES-SCLC management. Recent real-world studies have suggested that chemoimmunotherapy might influence the pattern of central nervous system progression [ 29 ]. This aspect deserves further investigation in larger cohorts. The high rate of subsequent brain metastases observed in our cohort (36.8%) underscores the need for regular central nervous system surveillance in ES-SCLC patients, even in those without baseline brain involvement. This observation may have implications for clinical practice, suggesting that brain imaging should be considered at regular intervals during follow-up, regardless of neurological symptoms. Our results also raise important questions about the optimal management of patients who develop brain metastases while on immunotherapy. The fact that five patients developed brain metastases as their first site of progression suggests that despite systemic disease control with chemoimmunotherapy, the central nervous system may represent a sanctuary site requiring specific therapeutic considerations. As the first Indian study reporting outcomes with atezolizumab plus carboplatin-etoposide in ES-SCLC, our findings provide valuable insights into the real-world effectiveness of this regimen in a previously understudied population. The tolerability profile observed, particularly with carboplatin-based therapy, supports its feasibility in routine clinical practice. The identification of long-term survivors in our cohort, albeit a small subset, aligns with emerging data on durable responses with immunotherapy combinations in ES-SCLC. Long term benefit The long-term survivors in ES SCLC represent those patients who have OS > 18months, as per the criteria used in IMPower133 study [ 14 ]. Clinical characteristics of long-term survivors are not well described in literature. In IMBRELLA extension of IMPower133 study 5-year OS rate was 12% [ 30 ]. Higher long-term benefit (LTB) was associated with a better ECOG PS, a lower lactate dehydrogenase (LDH) and less metastatic burden. In CASPIAN study, 46 patients were ongoing treatment with immunotherapy at 39.4 months [ 28 ]. Patients with a higher LTB were found to have some baseline characteristics differences in being of younger age group, more often women, better PS, and fewer brain or liver metastasis. Gobbini et. al. conducted a study to evaluate clinical characteristics of long survivors in ES-SCLC. The factors that are thought to play a role in having LTB include age (< 65years old), female sex, never or former smoking status, ECOG PS of 0–1 at diagnosis, platinum sensitivity after first line therapy [ 21 ]. In our series 12-, 18-, and 24-month survival was 42%, 33.6%, and 12.8%, respectively. Two patients are continuing on atezolizumab maintenance having received 31 and 56 cycles of atezolizumab. Out of these two patients, one had brain metastases at presentation. There were no baseline characteristics that were predictive of long-term survival. These findings reaffirm the potential of immunotherapy in achieving long term survival in few patients of ES-SCLC and the unmet need for the search of a predictive biomarker in SCLC. Several limitations of our study warrant consideration. The retrospective design and modest sample size may limit the generalizability of our findings. The single-center nature of the study, while providing consistency in treatment approach, may not fully represent the broader Indian population. Additionally, the lack of a concurrent control group prevents direct comparative effectiveness assessment. Despite these limitations, our results provide valuable real-world evidence supporting the use of atezolizumab-based therapy in ES-SCLC within the Indian healthcare context. Future research should focus on identifying predictive biomarkers for patient selection and investigating strategies to overcome primary and acquired resistance. Recent advances in molecular classification of SCLC suggest potential approaches for treatment optimization, particularly in specific patient subgroups. Prospective studies with larger cohorts are needed to validate these findings and explore novel combination strategies to further improve outcomes in this challenging disease. Conclusion This study provides valuable real-world insights into the efficacy of atezolizumab in combination with etoposide and carboplatin as a first-line treatment for SCLC in an Indian cohort. The OS and PFS findings indicate that the addition of immune checkpoint inhibitors to chemotherapy regimens enhances overall antitumor activity, leading to prolonged survival outcomes. Notably these benefits were observed in a diverse patient population, including those with poor PS, presence of brain and liver metastases. The findings underscore the necessity for further research to optimize patient selection, refine treatment approaches, and explore novel therapeutic combinations to enhance outcomes in SCLC. Abbreviations SCLC: Small cell lung cancer ES-SCLC: Extensive stage small cell lung cancer OS: Overall survival PFS: Progression free survival mOS: Median overall survival mPFS: Median Progression free survival ECOG PS: Eastern Cooperative Oncology Group performance status HR: Hazard ratio PD-L1: Programmed death ligand 1 PD-1: Programmed death 1 FDA: Food and Drug Administration NSCLC: Non-small cell lung cancer RECIST: Response evaluation criteria in solid tumors PR: Partial response SD: Stable disease PD: Progressive disease LTB: Long-term benefits LDH: Lactate dehydrogenase Declarations Ethics approval and consent to participate The study protocol received approval from the Institutional Review Board of Rajiv Gandhi Cancer Institute and Research Centre, Delhi, India (IRB-RGCI) with IRB no: RGCIRC/IRB-BHR/108/2024 (RES/SCM/65/2024/57) issued on 23 rd December 2024 with a waiver of informed consent granted due to the retrospective design. Patient confidentiality was maintained through data anonymization in accordance with ethical research guidelines. This study was conducted in accordance with the ethical principles outlined in the Declaration of Helsinki. Consent for publication Not applicable Availability of data and materials The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. Competing interests The authors declare that they have no competing interests. Funding No funding was received for the preparation of this study. Authors' contributions 1) U.B and S.K.C : Wrote and drafted the main manuscript, conceptualization, interpretation of data and revision 2) M.S, S.N and A.D : Conceptualization, interpretation of data and revision 3) M.W and K.G : Interpretation of data and analysis of data 4) R.C : Conceptualization, data entry 5) R.S and V.B : Data entry 6) R.S :Prepared all figures 7) S.P, K.C and L.M.D : Acquisition and interpretation of data Acknowledgments Editorial support (in the form of medical writing assistance, including preparation of the draft manuscript under the direction and guidance of the authors, collating and incorporating authors’ comments for each draft, statistical analysis, assembling tables and figures, grammatical editing, and referencing) for this article was provided by professional medical writers of NeoCrest Life Sciences Consulting Private Limited. References Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, Jemal A. 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Carboplatin versus cisplatin in combination with etoposide in the first-line treatment of small cell lung cancer: a pooled analysis. BMC cancer. 2021 Dec;21:1-7. Paz-Ares L, Dvorkin M, Chen Y, Reinmuth N, Hotta K, Trukhin D, Statsenko G, Hochmair MJ, Özgüroğlu M, Ji JH, Voitko O. Durvalumab plus platinum–etoposide versus platinum–etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial. The Lancet. 2019 Nov 23;394(10212):1929-39. Noivo D, Bragança M, Vilariça AS, Ferro F, Lopes Machado A, Hasmucrai D, Alves P. Clinical Outcomes of Chemo-Immunotherapy for Extensive Stage Small Cell Lung Cancer: A Real-World Single Centre Study in Portugal. Acta Med Port. 2025 May 2;38(5). Reck M, Dziadziuszko R, Sugawara S, Kao S, Hochmair M, Huemer F, de Castro Jr G, Havel L, Caro RB, Losonczy G, Lee JS. Five-year survival in patients with extensive-stage small cell lung cancer treated with atezolizumab in the Phase III IMpower133 study and the Phase III IMbrella A extension study. Lung Cancer. 2024 Oct 1;196:107924. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Reviewers invited by journal 28 Jul, 2025 Editor assigned by journal 23 Jul, 2025 Editor invited by journal 01 Jul, 2025 Submission checks completed at journal 01 Jul, 2025 First submitted to journal 01 Jul, 2025 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. We do this by developing innovative software and high quality services for the global research community. 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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-6997166","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":493100668,"identity":"73b7a0be-86c6-40b1-84b4-880adeff7fe8","order_by":0,"name":"Ullas Batra","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA3UlEQVRIiWNgGAWjYDACduYGBsYGEIv5AJCQkCGshZkRrEWCgYEtAaSFhxQtPAYgPmEtBocZGz/+3GFXZ95+5vOrGzUWPAzsh49uIKClWZr3TLKEzJncbdY5x4AO40lLu0FAS4M0YxuzhARD7jbjHDagFgkeM0Jamn/+bKuXkOB/88w45x9xWtokeNsOS0hI5DA/zm0jQoskUIs175njkjMknpkx5/ZJ8LAR8gvf8ebDN3/uqOaX4E9+/DnnW50cP/vhY3i1IAM2CTBJrHIQYP5AiupRMApGwSgYOQAA+LREDDo1s3oAAAAASUVORK5CYII=","orcid":"","institution":"Rajiv Gandhi Cancer Institute and Research Center Location of Affiliation","correspondingAuthor":true,"prefix":"","firstName":"Ullas","middleName":"","lastName":"Batra","suffix":""},{"id":493100669,"identity":"73c10b94-aa1f-42e2-99d5-ef5e2ee6fc3c","order_by":1,"name":"Sabeena K. 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Affiliation","correspondingAuthor":false,"prefix":"","firstName":"Sunil","middleName":"","lastName":"Pasricha","suffix":""},{"id":493100682,"identity":"babaf392-8c3d-435b-ac03-839cba9d8ee1","order_by":11,"name":"Kundan Chufal","email":"","orcid":"","institution":"Rajiv Gandhi Cancer Institute and Research Center Location of Affiliation","correspondingAuthor":false,"prefix":"","firstName":"Kundan","middleName":"","lastName":"Chufal","suffix":""},{"id":493100683,"identity":"be9f6e11-7d0c-45e2-99e3-84b2221c0d33","order_by":12,"name":"L M Darlong","email":"","orcid":"","institution":"Rajiv Gandhi Cancer Institute and Research Center Location of Affiliation","correspondingAuthor":false,"prefix":"","firstName":"L","middleName":"M","lastName":"Darlong","suffix":""}],"badges":[],"createdAt":"2025-06-28 10:23:17","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6997166/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6997166/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":88035828,"identity":"7d5706a3-f1a6-4559-b0f7-374f6412eba0","added_by":"auto","created_at":"2025-07-31 16:19:35","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":135030,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSankey diagram illustrating demographics of SCLC patients by sex → smoking status → age-group → performance status (PS).\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-6997166/v1/a3385a7c0fd504b748680baf.jpeg"},{"id":88035827,"identity":"37017fed-108a-4579-a679-1ac225201636","added_by":"auto","created_at":"2025-07-31 16:19:35","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":15577,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eKaplan Meier Overall survival curve.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-6997166/v1/730565c5019ecfcafc01804d.png"},{"id":88035243,"identity":"0ebec1e5-eac8-4ac6-a410-f3f9c2d2ba6f","added_by":"auto","created_at":"2025-07-31 16:11:35","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":28355,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eKaplan Meier progression free survival curve.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-6997166/v1/c28a87b52e0ba6f4dc7af1aa.png"},{"id":88035247,"identity":"db78a135-b75e-4e3a-867d-57009fc4e06d","added_by":"auto","created_at":"2025-07-31 16:11:35","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":43600,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eDistribution of brain metastases in SCLC patients (n=38).\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-6997166/v1/32753dac029a4b249bb51644.png"},{"id":88035826,"identity":"f3f0a94b-305c-4c0f-a6ee-76acaaafec24","added_by":"auto","created_at":"2025-07-31 16:19:35","extension":"jpeg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":55297,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eLine graph showing cumulative incidence of brain metastases over time, with a dashed line indicating cases present at diagnosis (n=7) and solid line representing those that developed subsequently (n=15).\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage5.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-6997166/v1/6d5a06b533af03274593162a.jpeg"},{"id":88035239,"identity":"d74c11ef-1a22-48be-9954-dc1d33764ccf","added_by":"auto","created_at":"2025-07-31 16:11:35","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":110223,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFigure 5: Swimmers plot of all patients (n=38) showing status, survival time, treatment response, first- and second-line treatment.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage6.png","url":"https://assets-eu.researchsquare.com/files/rs-6997166/v1/3f6fbaa461dc2e750e6f8fe0.png"},{"id":88037215,"identity":"fa5b618a-9e59-4e89-9b55-d215e86193f5","added_by":"auto","created_at":"2025-07-31 16:27:36","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1623673,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6997166/v1/a232f393-de20-47d2-a80f-ae1bd8fa83c4.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Turning the Tide for SCLC: Real World Analysis of Atezolizumab and Platinum-based Chemotherapy in Low-Resource Settings","fulltext":[{"header":"Introduction","content":"\u003cp\u003eLung cancer remains the predominant cause of cancer-related mortality worldwide [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Among its subtypes, small-cell lung cancer (SCLC) presents challenges due to its aggressive nature, early metastatic spread, and a strong correlation with tobacco use [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. This high-grade neuroendocrine malignancy constitutes roughly 15% of all lung carcinomas [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e], with global annual incidence approaching 250,000 cases and approximately 200,000 deaths [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. In a retrospective record-based analysis including 1248 patients diagnosed with lung cancer, at a tertiary cancer care center in India, SCLC prevalence was found to be 14.3% [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. The disease typically manifests as a substantial hilar mass accompanied by extensive mediastinal lymphadenopathy, producing symptoms such as cough and dyspnea. Its biological behavior is marked by rapid cellular proliferation, brief doubling time, and swift metastatic dissemination [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Patients commonly present with systemic manifestations, including weight loss, generalized weakness, skeletal pain, and neurological complications.\u003c/p\u003e\u003cp\u003eTreatment guidelines established by major organizations, the National Comprehensive Cancer Network [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], European Society for Medical Oncology [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], and Indian Council of Medical Research [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e], outline therapeutic approaches incorporating radiotherapy, chemotherapy, and, in select cases, surgical intervention. While platinum-based chemotherapy combined with etoposide represents the historical standard for extensive-stage SCLC (ES-SCLC), the development of chemoresistance frequently limits its long-term efficacy [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Traditional chemotherapeutic approaches yield modest progression-free survival (PFS) and overall survival (OS) rates, with durable responses being exceedingly rare. Attempts to enhance outcomes through modified or intensified chemotherapy protocols have yielded limited success [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. The emergence of immune checkpoint inhibitors (atezolizumab and Durvalumab) marks a significant therapeutic advancement in SCLC management [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eAtezolizumab, a humanized monoclonal antibody, targets programmed death ligand 1 (PD-L1), disrupting its interactions with programmed death 1 (PD-1) and B7-1 receptors, thereby reactivating tumor-specific immune responses [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Initial Phase 1 investigations demonstrated atezolizumab monotherapy's favorable safety profile and sustained response patterns in relapsed or refractory SCLC [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. The integration of immunotherapy with conventional chemotherapy potentially augments antitumor immunity, surpassing the therapeutic ceiling of existing treatments [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. The IMpower133 trial established that combining atezolizumab with etoposide and carboplatin significantly improved survival metrics in ES-SCLC patients [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. These findings led to regulatory approvals from the United States Food and Drug Administration in March 2019 and the Drugs Controller General of India in September 2019, sanctioning its use alongside carboplatin and etoposide as first-line therapy for adult ES-SCLC patients [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. The CASPIAN trial demonstrated that Durvalumab plus platinum-etoposide significantly improved overall survival in ES-SCLC patients, establishing it as another standard-of-care option. Like atezolizumab, Durvalumab received FDA approval for ES-SCLC (in 2020), offering an alternative immunotherapy-chemotherapy combination approach.\u003c/p\u003e\u003cp\u003eDespite these advances, real-world evidence documenting atezolizumab's effectiveness in combination with chemotherapy among Indian SCLC patients remains limited. This knowledge gap necessitates investigations into the regimen's performance within the Indian healthcare context. Our study addresses this need by examining the clinical outcomes of first line immunotherapy plus etoposide-carboplatin in Indian patients with SCLC.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cb\u003eStudy Design and Population\u003c/b\u003e\u003c/p\u003e\u003cp\u003eWe conducted a single-center retrospective analysis at Rajiv Gandhi Cancer Institute \u0026amp; Research Centre between October 2019 and November 2024. The study protocol received approval from the Institutional Review Board (\u003cb\u003eRES/SCM/65/2024/58\u003c/b\u003e) with a waiver of informed consent granted due to the retrospective design. Patient confidentiality was maintained through data anonymization in accordance with ethical research guidelines.\u003c/p\u003e\u003cp\u003e\u003cb\u003eInclusion and Exclusion criteria\u003c/b\u003e\u003c/p\u003e\u003cp\u003eEligible patients were aged 18 years or older with histologically or cytologically confirmed ES-SCLC, classified according to Veterans Administration Lung Study Group staging criteria. Patients with brain metastases were included. Patients previously treated with chemoradiotherapy for limited-stage disease were eligible if they had maintained a minimum six-month treatment-free interval. We excluded patients who had coexistent non-small cell lung cancer (NSCLC), patients with transformed SCLC and patients with dual malignancy. Prior immune checkpoint inhibitor exposure, immune-mediated adverse events, pregnancy, and lactation also preclude participation.\u003c/p\u003e\u003cp\u003e\u003cb\u003eTreatment and response evaluation\u003c/b\u003e\u003c/p\u003e\u003cp\u003eTreatment consisted of combination chemotherapy with etoposide (100 mg/m² intravenously, days 1–3) and carboplatin (AUC 5 mg·mL⁻¹·min⁻¹ intravenously, day 1), plus atezolizumab (1200 mg intravenously, day 1) administered in 21-day cycles for four to six cycles. Patients who had non progressive disease at the end of 6 cycles, subsequently received maintenance atezolizumab (1200 mg intravenously) every three weeks until disease progression, death, or unacceptable toxicity. Disease assessment incorporated clinical (emergence or worsening of symptoms), biochemical, and radiological parameters, with response categorized according to RECIST v1.1 criteria as partial response (PR), stable disease (SD), or progressive disease (PD).\u003c/p\u003e\u003cp\u003eWe extracted patient characteristics from electronic medical records, including demographic data, smoking history, metastatic burden, radiation therapy details (prophylactic cranial irradiation and whole-brain radiation therapy), and ECOG performance status. The date of diagnosis, initiation of first-line chemotherapy, and subsequent first-line treatment were recorded.\u003c/p\u003e\u003cp\u003e\u003cb\u003eEndpoints\u003c/b\u003e\u003c/p\u003e\u003cp\u003ePrimary endpoints comprised PFS, measured from treatment initiation to documented progression or death, and overall survival OS, calculated from treatment initiation to death from any cause.\u003c/p\u003e\u003ch2\u003eStatistical Analysis\u003c/h2\u003e\u003cp\u003eWe performed intent-to-treat analyses using SPSS (Version 30.0). Continuous variables were summarized using standard descriptive statistics; categorical variables were expressed as frequencies and proportions. Survival analyses employed Kaplan-Meier methodology, with median PFS and OS reported with two-sided 95% confidence intervals. We interpolated OS rates at 12-, 18-, and 24- months from survival tables. Multivariable Cox proportional hazards models assessed potential predictors of survival, including age, sex, smoking status, performance status, brain metastases, and metastatic burden. Statistical significance was set at p \u0026lt; 0.05.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cb\u003ePatient characteristics and demographics\u003c/b\u003e\u003c/p\u003e\u003cp\u003eBetween October 2019 and November 2024, 38 patients received first-line treatment with etoposide, carboplatin, and atezolizumab for extensive-stage SCLC. Baseline characteristics are presented in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The study population had a median age of 62.5 years (range 32\u0026ndash;74), with male predominance (86.8%) and substantial percentage with smoking history (84.2%). Most patients (65.9%) presented with ECOG performance status of 1, while 18.5% had performance status\u0026thinsp;\u0026ge;\u0026thinsp;3. Median time from biopsy till the start of treatment was 8 (range: 0-119) days. The median number of cycles of atezolizumab was 5.5 (range 1\u0026ndash;56 cycles). Among the 38 patients, 18 (47.4%) received second line treatment at progression.\u003c/p\u003e\u003cp\u003e\u003cb\u003eExtra thoracic metastasis\u003c/b\u003e\u003c/p\u003e\u003cp\u003e86.8% had extra thoracic metastasis at the initial presentation. The distribution of extra-thoracic disease varied considerably, 13.2% of patients had no extra-thoracic involvement, 39.5% had single-site involvement, 23.7% had two sites, 10.5% had three sites, and 13.2% had four sites. Skeletal system (50.0%, n\u0026thinsp;=\u0026thinsp;19) and pleural space (44.7%, n\u0026thinsp;=\u0026thinsp;17) represented the most frequent sites of metastatic spread. Median follow-up duration was 7.7 months (range 2.2\u0026ndash;35.2).\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=\"2\"\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\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eVariable\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eFrequency (%)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGender\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eMale\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e33 (86.8)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eFemale\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e5 (13.2)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eSmoking Status\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eSmokers\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e32 (84.2)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eNon-smokers\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e6 (15.8)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eBrain Metastasis at Presentation\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eYes\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e7 (18.4)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eNo\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e31(81.6)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eExtra-thoracic Metastatic Sites\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e0\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e5 (13.2)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e1\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e15 (39.5)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e2\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e9 (23.7)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e3\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e4 (10.5)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e4\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e5 (13.2)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eAge group\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e30\u0026ndash;40\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e1(2.6)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e41\u0026ndash;50\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e4(10.5)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e51\u0026ndash;60\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e9(23.7)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e61\u0026ndash;70\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e17(44.7)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e71\u0026ndash;80\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e7(18.4)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eECOG Performance Status (PS)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e1\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e25 (65.8)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e2\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e6 (15.8)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e3\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e3 (7.9)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e4\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e4 (10.5)\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\u003c/p\u003e\u003cp\u003e\u003cb\u003eTreatment response and Survival outcomes\u003c/b\u003e\u003c/p\u003e\u003cp\u003eKaplan-Meier survival analysis revealed a median overall survival (OS) of 11.0 months (95% CI: 3.9\u0026ndash;18.4). The median follow-up period was 7.7 months (range: 2.2\u0026ndash;35.2). During the follow up, 25 out of 38 patients (65.8%) succumbed to the disease. Additionally, 15.8% were lost to follow-up (LFU) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The survival function for the cohort is depicted in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The OS analysis demonstrated an OS rate of 42%, 33.6% and 12.8% at 12-month, 18-month and 24-months respectively.\u003c/p\u003e\u003cp\u003eProgression-free survival (PFS) was similarly evaluated, yielding a median of 4.5 months (95% CI: 3.4\u0026ndash;5.6). Disease progression was observed in 33 of 38 patients (86.8%) during the study (Figs.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e and 3). Regarding treatment response, PR was achieved in 68.4% of patients, SD in 13.2%, and PD in 18.4% (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\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\u003eDisease progression, treatment response, and survival status (N\u0026thinsp;=\u0026thinsp;38)\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"2\"\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\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eVariables\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003en (%)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eProgression observed\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e33 (86.8)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5 (13.2)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eResponse evaluation\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePartial response\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e26 (68.4)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eProgressive disease\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e7 (18.4)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eStable disease\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5 (13.2)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eStatus at last follow-up\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDead\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e25 (65.8)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAlive\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e7 (18.4)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLFU\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e6 (15.8)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eLFU: lost to follow-up\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\u003cb\u003eDistribution and survival outcomes of brain metastases among patients\u003c/b\u003e\u003c/p\u003e\u003cp\u003eSeven out of 38 patients (18.4%) had brain metastasis at presentation. Fifteen patients developed brain metastases during the course of the disease out of which five developed brain metastases as the first site or concurrent with systemic progression. Sixteen patients (42.1%) did not experience brain metastasis at any stage (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e4\u003c/span\u003e). The timeline of brain metastasis following diagnosis revealed that among the 15 patients who developed brain metastases during the course of the disease, 11 (73.3%) did so within the first 12 months from diagnosis (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e5\u003c/span\u003e). Overall, the median duration of brain metastasis in the patients was 9.1 months (range: 1.6\u0026ndash;19.8 months).\u003c/p\u003e\u003cp\u003e\u003cb\u003eLongitudinal Assessment of Patient Outcomes\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThe swimmer plot illustrates individual patient outcomes, showing that 26 (68.4%) patients achieved a partial response with prolonged survival, while those with progressive disease (7; 18.4%) had shorter durations and earlier deaths. Progression events occurred primarily within the first year, while some partial responders experienced late progression, indicating potentially acquired resistance. A few patients maintained a durable response beyond 18 months, suggesting long-term benefit (Fig.\u0026nbsp;6). No complete responses were recorded. The objective response rate (ORR), defined as the proportion of patients with complete or partial response, was 68.4%.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eCox Proportional Hazards Regression Analysis\u003c/b\u003e\u003c/p\u003e\u003cp\u003eCox proportional hazards regression analysis was performed to evaluate factors affecting overall survival. The model was statistically significant (p\u0026thinsp;=\u0026thinsp;0.004). Among the covariates, only ECOG Performance Status at admission was significantly associated with mortality (HR\u0026thinsp;=\u0026thinsp;2.22, 95% CI: 1.39\u0026ndash;3.56, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) Other variables, including age, smoking status, and number of extra-thoracic metastases did not have a significant impact on survival (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\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\u003eCox proportional hazards regression analysis of clinical variables associated with survival outcomes\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"3\"\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=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eVariable\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHazard Ratio (HR)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eSignificance (p-value)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eAge\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.99\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.682\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eGender\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.19\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.260\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eSmoking History\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.52\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.526\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eECOG PS at admission\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.22\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eNumber of extra thoracic Mets\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.05\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.802\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study provides a real-world analysis of immunotherapy combined with etoposide and carboplatin as first-line treatment for ES-SCLC in an Indian cohort. Our findings contribute to the growing body of evidence supporting the efficacy of this combination therapy in diverse populations.\u003c/p\u003e\u003cp\u003eThe objective response rate of 68.4% (all partial responses) observed in our cohort aligns with recent real-world studies. An additional 13.2% of patients achieving stable disease suggest that the majority of patients derive clinical benefit from this combination therapy [\u003cspan additionalcitationids=\"CR19 CR20\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eOur median overall survival was 11.0 months with a 12-, 18- and 24- month OS rate of 42%, 33.6% and 12.8% respectively. This is particularly noteworthy when compared to historical data with chemotherapy alone, ranging from 5.4 to 9.0 months [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Another study by Yilmaz et al observed a median OS of 9.0 months, with 12- and 24-month survival probabilities of 33.6% and 5.3%, respectively with the use of chemotherapy alone [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e], both of which are lower than the 12-month and 24-month OS findings in our study.\u003c/p\u003e\u003cp\u003eMAURIS trial, reported a median OS of 10.7 months and a 12-month OS rate of 41.9% suggesting the benefit of using immunotherapy alongside chemotherapy in ES-SCLC [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Recent long-term follow-up data from the IMpower 133 trial has demonstrated sustained survival benefits with atezolizumab combination therapy, establishing this approach as a new standard of care (median OS of 12.3 months and a 12-month OS rate of 51.7%) [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Interestingly, our real-world outcomes closely mirror those observed in pivotal trials. However, a higher median OS (13.5 and 16.5 months) and 12-month OS rate (57.8% and 63.7%) than the present study outcomes were reported in the South Korean [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e] and Japanese patients [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e], respectively, likely due to differences in sample size and population variations.\u003c/p\u003e\u003cp\u003eThe median progression-free survival of 4.5 months in our cohort is consistent with established benchmarks, though slightly lower than some reported figures [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Moreover, most retrospective and prospective studies involving atezolizumab plus etoposide and carboplatin combination, including pivotal clinical trials like IMpower133 and MAURIS, have reported mPFS values between 4.6 to 6.0 months that are comparable to the present study findings [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan additionalcitationids=\"CR19\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. The improved survival outcomes suggest a potential synergistic effect of combining immunotherapy with standard chemotherapy, highlighting the role of atezolizumab in enhancing disease control and delaying progression beyond what is typically achieved with chemotherapy alone.\u003c/p\u003e\u003cp\u003eThe multivariable analysis revealed that ECOG PS at the start of chemotherapy significantly impacted survival (HR\u0026thinsp;=\u0026thinsp;2.22, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), consistent with studies where ECOG PS was a critical predictor of OS [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. OS and PFS in our study cohort mirrored those in the pivotal trials despite including patients with poorer performance status (18.5% with PS\u0026thinsp;\u0026ge;\u0026thinsp;3) who would typically be excluded from clinical trials.\u003c/p\u003e\u003cp\u003e\u003cb\u003eBrain Metastases in ES-SCLC: Patterns and Implications\u003c/b\u003e\u003c/p\u003e\u003cp\u003eBrain metastasis at presentation was observed in ~\u0026thinsp;9% of patients in IMPower133 trial, and 10% in Caspian study [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. However, patients with brain metastasis were underrepresented in these pivotal trials. In our cohort, we observed brain metastasis in 18.4% at presentation which is much higher than that in the pivotal trials of immune check point inhibitors in ES-SCLC. This difference could be because of stringent exclusion criteria used in these trials and also reflects the advanced stage of disease at which patients present in real world scenario in low- and middle-income countries.\u003c/p\u003e\u003cp\u003eThe pattern of brain metastases development in our cohort (with 18.4%) warrants particular attention. The cumulative incidence of brain metastases throughout treatment was substantial, with 15 additional patients developing central nervous system involvement during the course of therapy, including 5 who experienced brain metastasis as their first site of progression. These findings align with the growing recognition of the central nervous system as a critical site of disease progression in ES-SCLC. The development of new brain metastases during treatment (39.5% of patients) highlights a critical challenge in ES-SCLC management. Recent real-world studies have suggested that chemoimmunotherapy might influence the pattern of central nervous system progression [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. This aspect deserves further investigation in larger cohorts. The high rate of subsequent brain metastases observed in our cohort (36.8%) underscores the need for regular central nervous system surveillance in ES-SCLC patients, even in those without baseline brain involvement. This observation may have implications for clinical practice, suggesting that brain imaging should be considered at regular intervals during follow-up, regardless of neurological symptoms.\u003c/p\u003e\u003cp\u003eOur results also raise important questions about the optimal management of patients who develop brain metastases while on immunotherapy. The fact that five patients developed brain metastases as their first site of progression suggests that despite systemic disease control with chemoimmunotherapy, the central nervous system may represent a sanctuary site requiring specific therapeutic considerations.\u003c/p\u003e\u003cp\u003eAs the first Indian study reporting outcomes with atezolizumab plus carboplatin-etoposide in ES-SCLC, our findings provide valuable insights into the real-world effectiveness of this regimen in a previously understudied population. The tolerability profile observed, particularly with carboplatin-based therapy, supports its feasibility in routine clinical practice. The identification of long-term survivors in our cohort, albeit a small subset, aligns with emerging data on durable responses with immunotherapy combinations in ES-SCLC.\u003c/p\u003e\u003cp\u003e\u003cb\u003eLong term benefit\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThe long-term survivors in ES SCLC represent those patients who have OS\u0026thinsp;\u0026gt;\u0026thinsp;18months, as per the criteria used in IMPower133 study [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Clinical characteristics of long-term survivors are not well described in literature. In IMBRELLA extension of IMPower133 study 5-year OS rate was 12% [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Higher long-term benefit (LTB) was associated with a better ECOG PS, a lower lactate dehydrogenase (LDH) and less metastatic burden. In CASPIAN study, 46 patients were ongoing treatment with immunotherapy at 39.4 months [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Patients with a higher LTB were found to have some baseline characteristics differences in being of younger age group, more often women, better PS, and fewer brain or liver metastasis. Gobbini \u003cem\u003eet. al.\u003c/em\u003e conducted a study to evaluate clinical characteristics of long survivors in ES-SCLC. The factors that are thought to play a role in having LTB include age (\u0026lt;\u0026thinsp;65years old), female sex, never or former smoking status, ECOG PS of 0\u0026ndash;1 at diagnosis, platinum sensitivity after first line therapy [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eIn our series 12-, 18-, and 24-month survival was 42%, 33.6%, and 12.8%, respectively. Two patients are continuing on atezolizumab maintenance having received 31 and 56 cycles of atezolizumab. Out of these two patients, one had brain metastases at presentation. There were no baseline characteristics that were predictive of long-term survival. These findings reaffirm the potential of immunotherapy in achieving long term survival in few patients of ES-SCLC and the unmet need for the search of a predictive biomarker in SCLC.\u003c/p\u003e\u003cp\u003eSeveral limitations of our study warrant consideration. The retrospective design and modest sample size may limit the generalizability of our findings. The single-center nature of the study, while providing consistency in treatment approach, may not fully represent the broader Indian population. Additionally, the lack of a concurrent control group prevents direct comparative effectiveness assessment. Despite these limitations, our results provide valuable real-world evidence supporting the use of atezolizumab-based therapy in ES-SCLC within the Indian healthcare context.\u003c/p\u003e\u003cp\u003eFuture research should focus on identifying predictive biomarkers for patient selection and investigating strategies to overcome primary and acquired resistance. Recent advances in molecular classification of SCLC suggest potential approaches for treatment optimization, particularly in specific patient subgroups. Prospective studies with larger cohorts are needed to validate these findings and explore novel combination strategies to further improve outcomes in this challenging disease.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis study provides valuable real-world insights into the efficacy of atezolizumab in combination with etoposide and carboplatin as a first-line treatment for SCLC in an Indian cohort. The OS and PFS findings indicate that the addition of immune checkpoint inhibitors to chemotherapy regimens enhances overall antitumor activity, leading to prolonged survival outcomes. Notably these benefits were observed in a diverse patient population, including those with poor PS, presence of brain and liver metastases. The findings underscore the necessity for further research to optimize patient selection, refine treatment approaches, and explore novel therapeutic combinations to enhance outcomes in SCLC.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003e\u003cstrong\u003eSCLC:\u0026nbsp;\u003c/strong\u003eSmall cell lung cancer\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eES-SCLC:\u0026nbsp;\u003c/strong\u003eExtensive stage small cell lung cancer\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOS:\u0026nbsp;\u003c/strong\u003eOverall survival\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePFS:\u0026nbsp;\u003c/strong\u003eProgression free survival\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003emOS:\u0026nbsp;\u003c/strong\u003eMedian overall survival\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003emPFS:\u0026nbsp;\u003c/strong\u003eMedian Progression free survival\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eECOG PS:\u0026nbsp;\u003c/strong\u003eEastern Cooperative Oncology Group performance status\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHR:\u0026nbsp;\u003c/strong\u003eHazard ratio\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePD-L1:\u0026nbsp;\u003c/strong\u003eProgrammed death ligand 1\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePD-1:\u0026nbsp;\u003c/strong\u003eProgrammed death 1\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFDA:\u0026nbsp;\u003c/strong\u003eFood and Drug Administration\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eNSCLC:\u0026nbsp;\u003c/strong\u003eNon-small cell lung cancer\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRECIST:\u0026nbsp;\u003c/strong\u003eResponse evaluation criteria in solid tumors\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePR:\u0026nbsp;\u003c/strong\u003ePartial response\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSD:\u0026nbsp;\u003c/strong\u003eStable disease\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePD:\u0026nbsp;\u003c/strong\u003eProgressive disease\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLTB:\u0026nbsp;\u003c/strong\u003eLong-term benefits\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLDH:\u0026nbsp;\u003c/strong\u003eLactate dehydrogenase\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003eEthics approval and consent to participate\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study protocol received approval from the Institutional Review Board of Rajiv Gandhi Cancer Institute and Research Centre, Delhi, India (IRB-RGCI) with IRB no: RGCIRC/IRB-BHR/108/2024 (RES/SCM/65/2024/57) issued on 23\u003csup\u003erd\u003c/sup\u003e December 2024 with a waiver of informed consent granted due to the retrospective design. Patient confidentiality was maintained through data anonymization in accordance with ethical research guidelines. This study was conducted in accordance with the ethical principles outlined in the Declaration of Helsinki.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eConsent for publication\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAvailability of data and materials\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eCompeting interests\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cem\u003e\u003cbr\u003e\u0026nbsp;\u003c/em\u003e\u003c/strong\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eFunding\u003c/em\u003e\u003c/strong\u003e\u003cbr\u003e\u0026nbsp;No funding was received for the preparation of this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAuthors\u0026apos; contributions\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e1) U.B and S.K.C : Wrote and drafted the main manuscript, conceptualization, interpretation of data and revision\u003cbr\u003e\u0026nbsp;2) M.S, S.N and A.D : Conceptualization, interpretation of data and revision\u003cbr\u003e\u0026nbsp;3) M.W and K.G : Interpretation of data and analysis of data\u0026nbsp;\u003cbr\u003e\u0026nbsp;4) R.C : Conceptualization, data entry\u0026nbsp;\u003cbr\u003e\u0026nbsp;5) R.S and V.B : Data entry\u003cbr\u003e\u0026nbsp;6) R.S :Prepared all figures\u0026nbsp;\u003cbr\u003e\u0026nbsp;7) S.P, K.C and L.M.D : Acquisition and interpretation of data\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAcknowledgments\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEditorial support (in the form of medical writing assistance, including preparation of the draft manuscript under the direction and guidance of the authors, collating and incorporating authors\u0026rsquo; comments for each draft, statistical analysis, assembling tables and figures, grammatical editing, and referencing) for this article was provided by professional medical writers of NeoCrest Life Sciences Consulting Private Limited.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eBray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, Jemal A. 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Available from: https://www.nccn.org/patients/guidelines/content/PDF/SCLC-patient-guideline.pdf.\u003c/li\u003e\n\u003cli\u003eDingemans AM, Fr\u0026uuml;h M, Ardizzoni A, Besse B, Faivre-Finn C, Hendriks LE, Lantuejoul S, Peters S, Reguart N, Rudin CM, De Ruysscher D. Small-cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up☆. Annals of Oncology. 2021 Jul 1;32(7):839-53.\u003c/li\u003e\n\u003cli\u003eIndian Council of Medical Research. Standard Treatment Workflow (STW): Lung Cancer, ICD-10-C34.90 [Internet]. New Delhi: Indian Council of Medical Research; 2020 [cited 2025 Mar 13]. Available from: https://www.icmr.gov.in/icmrobject/uploads/STWs/1726568902_lung_cancer.pdf.\u003c/li\u003e\n\u003cli\u003eOwonikoko TK, Behera M, Chen Z, Bhimani C, Curran WJ, Khuri FR, Ramalingam SS. A systematic analysis of efficacy of second-line chemotherapy in sensitive and refractory small-cell lung cancer. 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Clinical activity, safety and predictive biomarkers results from a phase Ia atezolizumab (atezo) trial in extensive-stage small cell lung cancer (ES-SCLC). Annals of Oncology. 2016 Oct 1;27:vi493.\u003c/li\u003e\n\u003cli\u003eU.S. Food and Drug Administration. Highlights of prescribing information: TECENTRIQ\u0026reg; (atezolizumab) injection, for intravenous use. Initial U.S. Approval: 2016 [Internet]. Silver Spring (MD): U.S. Food and Drug Administration; 2016 [cited 2025 Mar 13]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/761034s019lbl.pdf.\u003c/li\u003e\n\u003cli\u003eRoche Products (India) Pvt. Ltd. Roche\u0026rsquo;s Atezolizumab receives DCGI approval for treatment of extensive-stage small cell lung cancer in India [Internet]. Mumbai (IN): Roche Products (India) Pvt. Ltd.; 2019 Nov 21 [cited 2025 Apr 07]. 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Efficacy and safety of carboplatin and etoposide in older extensive‐stage small‐cell lung cancer patients with a poor performance status. Thoracic Cancer. 2023 Mar;14(9):805-14.\u003c/li\u003e\n\u003cli\u003eYilmaz U, Polat G, Anar C, Halilcolar H. Carboplatin plus etoposide for extensive stage small-cell lung cancer: An experience with AUC 6 doses of carboplatin. Indian Journal of Cancer. 2011 Oct 1;48(4):454-9.\u003c/li\u003e\n\u003cli\u003eChoi MG, Kim YJ, Lee JC, Ji W, Oh IJ, Lee SY, Yoon SH, Lee SY, Lee JE, Kim EY, Choi CM. The Real-World Outcome of First Line Atezolizumab in Extensive-Stage Small Cell Lung Cancer: A Multicenter Prospective Cohort Study. Cancer Research and Treatment: Official Journal of Korean Cancer Association. 2023 Oct 23;56(2):422-9.\u003c/li\u003e\n\u003cli\u003eMiyauchi E, Nishio M, Ohashi K, Osoegawa A, Kikuchi E, Kimura H, Goto Y, Shimizu J, Yoshioka H, Yoshino I, Misumi T. J-TAIL-2: A Prospective, Observational Study of Atezolizumab Combined With Carboplatin and Etoposide in Patients With Extensive-Stage SCLC in Japan. JTO Clinical and Research Reports. 2025 Mar 1;6(3):100783.\u003c/li\u003e\n\u003cli\u003eJiang S, Huang L, Zhen H, Jin P, Wang J, Hu Z. Carboplatin versus cisplatin in combination with etoposide in the first-line treatment of small cell lung cancer: a pooled analysis. BMC cancer. 2021 Dec;21:1-7.\u003c/li\u003e\n\u003cli\u003ePaz-Ares L, Dvorkin M, Chen Y, Reinmuth N, Hotta K, Trukhin D, Statsenko G, Hochmair MJ, \u0026Ouml;zg\u0026uuml;roğlu M, Ji JH, Voitko O. Durvalumab plus platinum\u0026ndash;etoposide versus platinum\u0026ndash;etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial. The Lancet. 2019 Nov 23;394(10212):1929-39.\u003c/li\u003e\n\u003cli\u003eNoivo D, Bragan\u0026ccedil;a M, Vilari\u0026ccedil;a AS, Ferro F, Lopes Machado A, Hasmucrai D, Alves P. Clinical Outcomes of Chemo-Immunotherapy for Extensive Stage Small Cell Lung Cancer: A Real-World Single Centre Study in Portugal. Acta Med Port. 2025 May 2;38(5). \u003c/li\u003e\n\u003cli\u003eReck M, Dziadziuszko R, Sugawara S, Kao S, Hochmair M, Huemer F, de Castro Jr G, Havel L, Caro RB, Losonczy G, Lee JS. Five-year survival in patients with extensive-stage small cell lung cancer treated with atezolizumab in the Phase III IMpower133 study and the Phase III IMbrella A extension study. Lung Cancer. 2024 Oct 1;196:107924.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"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":"SCLC, ES-SCLC, Immunotherapy, Atezolizumab, Chemo-immunotherapy","lastPublishedDoi":"10.21203/rs.3.rs-6997166/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6997166/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eSmall-cell lung cancer (SCLC) represents one of the most aggressive forms of lung malignancies. Due to its aggressive nature, most patients are diagnosed in advanced stage and are candidates for palliative systemic therapy only. While the addition of immunotherapy to standard chemotherapy has shown promise in clinical trials, limited data exists on its real-world effectiveness in Indian populations. We aimed to evaluate outcomes of immunotherapy combined with etoposide-carboplatin chemotherapy in Indian patients with extensive-stage SCLC (ES-SCLC).\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eWe conducted a retrospective analysis of 38 patients with ES-SCLC at our center who received atezolizumab plus etoposide-carboplatin, followed by atezolizumab maintenance therapy. Primary endpoints included overall survival (OS) and progression-free survival (PFS). Survival analyses were performed using Kaplan-Meier and Cox proportional hazards models.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eThe study population (median age 62.5 years) predominantly comprised male patients (86.8%) with a history of smoking (84.2%). Disease progression occurred in 86.8% of patients. Brain metastases were present in 18.4% of patients at diagnosis, with an additional 39.5% developing intracranial disease during the course of treatment. Median OS (mOS) reached 11.0 months (95% CI: 3.5\u0026ndash;18.4), with 12-, 18-, and 24-month survival rates of 42%, 33.6%, and 12.8%, respectively. The median PFS (mPFS) was 4.5 months (95% CI: 3.4\u0026ndash;5.6). Multivariate analysis revealed that higher ECOG performance status correlated with inferior survival (HR\u0026thinsp;=\u0026thinsp;2.22; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003eIn this Indian cohort, first-line immunotherapy using Atezolizumab with etoposide-carboplatin demonstrated survival outcomes comparable to international standards. These findings support the integration of immune checkpoint inhibition with standard chemotherapy for ES-SCLC in the Indian healthcare context.\u003c/p\u003e","manuscriptTitle":"Turning the Tide for SCLC: Real World Analysis of Atezolizumab and Platinum-based Chemotherapy in Low-Resource Settings","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-31 16:11:30","doi":"10.21203/rs.3.rs-6997166/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewersInvited","content":"","date":"2025-07-28T09:44:41+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-07-23T11:32:42+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-07-01T11:33:30+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-07-01T10:23:54+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Cancer","date":"2025-07-01T10:21:01+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":"b91747cb-2c3e-43a4-9150-958e0a6018db","owner":[],"postedDate":"July 31st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2025-07-31T16:11:30+00:00","versionOfRecord":[],"versionCreatedAt":"2025-07-31 16:11:30","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6997166","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6997166","identity":"rs-6997166","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}