Efficacy of targeted therapy in lung cancer with rare ALK fusions

Efficacy of targeted therapy in lung cancer with rare ALK fusions | 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 Article Efficacy of targeted therapy in lung cancer with rare ALK fusions Marie-Elisabeth Leßmann, Felix Carl Saalfeld, Lea Ruge, Diego Kauffmann-Guerrero, and 39 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7545687/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 9 You are reading this latest preprint version Abstract Paradigms about anaplastic lymphoma kinase (ALK)-driven non-small cell lung cancer (NSCLC) have been shaped by EML4::ALK. There is little evidence on the remaining patients, presenting with a plethora of other fusion partners ( rare ALK ). We compared real-world data of patients with advanced NSCLC and rare ALK fusions to patients with EML4::ALK fusions. Patients with rare ALK fusions (n = 51) were older and more likely to have a history of smoking. Overall survival (OS) tended to be shorter. Tyrosine kinase inhibitors (TKI) were used less and chemotherapies more frequently as first-line palliative treatment. Patients with rare ALK fusions had a significantly shorter progression-free survival (PFS) when treated with first-line platinum-based chemotherapy as opposed to TKI. There was, however, no PFS difference between rare ALK and EML4::ALK positive patients receiving TKI as first-line treatment. Taken together, patients with advanced NSCLC harboring rare ALK fusions derive comparable benefit from TKI as patients with EML4::ALK. Biological sciences/Cancer Health sciences/Oncology Rare ALK fusion EML4::ALK Non-small cell lung cancer (NSCLC) Targeted therapy Figures Figure 1 Figure 2 Figure 3 Figure 4 INTRODUCTION The frequency of Anaplastic Lymphoma Kinase (ALK) fusions in non-small cell lung cancer (ALK + NSCLC) ranges between 3–5%. Affected patients are predominantly non-smokers and considerably younger than the general NSCLC population. [ 1 ], [ 2 ] It has been clearly shown that treatment with an ALK-specific tyrosine kinase inhibitor (TKI) is superior to platinum-based combination therapy in these patients. [ 3 ] More recently, first-line treatment with the 3rd generation TKI lorlatinib has been associated with an unprecedented 5-year progression-free survival (PFS) rate of 60%. [ 4 ] Echinoderm Microtubule Associated Protein-Like 4 (EML4) is the ALK fusion partner in 80%-90% of ALK + NSCLC. [ 5 ] In the remaining 10%-20%, ALK fusions involve a heterogeneous group of over 90 different partner genes [ 6 ]. Evidence regarding the optimal treatment of patients with these rare ALK fusions ( rare ALK ) is currently limited to case reports and small case series. [ 7 ] Crizotinib was the TKI used in most of these reports and showed significant benefit in some, but not all cases [ 8 ]. Considerable uncertainty therefore remains on how to treat patients with rare ALK in the palliative first-line setting. Here, we report a large international real-world analysis of rare ALK fusion positive NSCLC treated with second and third generation TKI and compare their characteristics and outcome to an EML4::ALK positive control cohort. RESULTS ALK fusion prevalence and patient characteristics In an international, retrospective, multicenter approach, we collected data from 26,152 NSCLC patients (62% adenocarcinoma) that underwent local NGS-testing capable of detecting both EML4::ALK and rare ALK fusions. An EML4::ALK fusion was identified in 509 (1.9%) and a rare ALK fusion in 55 (0.2%) patients. Sufficient clinical data was available for 242 and 28 patients, respectively. An additional 119 and 20 cases, respectively, were contributed from other centers that did not report the total number of NSCLC samples tested at their site. In the rare ALK cohort, seven patients were excluded due to early-stage disease ( N =2), non-validation of the ALK fusion (sequencing artifact, N =1), concurrent other driver alteration ( N =3), and less than three months follow-up ( N =1). In the control cohort, 84 cases were excluded for not meeting eligibility criteria as follows: early-stage disease ( N =8), implausible data (e.g., diagnosis date after initial treatment, N =33), and lack of follow-up ( N =43). In the entire cohort, 277 (EML4::ALK) and 51 ( rare ALK ) patients met the eligibility criteria and were hence used for further analyses (see Supplement 1 for the study flowchart). Compared to the EML4::ALK cohort, patients with rare ALK fusions tended to be older (median age 66 vs 59 years, p=0.04) and were more likely to be current or former smokers (59% vs 35%, p=0.006). Smokers with rare ALK fusions reported more pack years than those with EML4::ALK (14.7 vs. 6.7 pack years, p=0.009). Squamous histology was infrequently reported in the EML4::ALK cohort (1%) but occurred in 10% of the rare ALK patients (see Table 1 for full patient characteristics). We detected a total of 21 different fusion partners of which 15 occurred only once (non-recurrent rare ALK fusions). The most common fusions were KIF5B::ALK (12/51, 24%), HIP1::ALK (6/51, 12%), GCC2::ALK (5/51, 10%) and KLC1::ALK (5/51, 10%). In all rare ALK fusions reported, ALK was the 3’ fusion partner preserving an intact tyrosine kinase domain (exons 20 to 29). A complete list of fusions with breakpoints is provided in Supplement 2 . TKIs, predominately alectinib, were used as first line of palliative treatment in nearly all patients with EML4::ALK (96%) but only in 71 % of patients with rare ALK . In the latter group, 14% of patients received platinum-based chemotherapy and 10% best supportive care as the primary treatment approach. In contrast, none of the patients with EML4::ALK was managed with chemotherapy in the palliative first-line setting and only 4% were deemed unsuitable for any tumor-directed treatment. Of note, 18% of the subjects in the rare ALK group never received a TKI during the course of their disease ( Table 1, Figure 1 ). Table 1. Patient characteristics. In case of missing data, the number of individuals with available data is indicated next to the respective variable. Where data were completely available, no indication was made. CNS: Central nervous system. NA = not available. Other therapy included: pembrolizumab (N=1), capecitabin + temozolomide (N=1), erlotinib + onartuzumab (N=1). *difference statistically significant by t-test or Pearson Chi-square at alpha 0.05. Characteristics EML4::ALK Rare ALK Total number of patients 277 51 Age, y, median (25 th ; 75 th percentile) 59 (49; 69)* 66 (53; 72)* Sex ( N =277, 51), N (%) Female Male 143 (52) 134 (48) 21 (41) 30 (59) Smoking ( N =266, 49), N (%) Active Smoker Former Smoker Never Smoker Pack years in smokers (N = 249, 48), median 32 (12) 63 (23) 161 (58)* 6,7* 11 (22) 19 (37) 19 (37)* 14,7* CNS metastases ( N =276, 51), N (%) CNS metastases at first diagnosis CNS metastasis at any time point NA 104 (38) 11 (22) 19 (37) Histology at first diagnosis ( N =277, 51), N (%) Adenocarcinoma Squamous-cell carcinoma Adenosquamous carcinoma Undifferentiated carcinoma NOS 261 (94) 4 (1) 4 (1) 5 (2) 45 (88) 5 (10) 1 (2) First line treatment in advanced stage ( N =264, 51), N (%) Crizotinib Brigatinib Ceritinib Alectinib Lorlatinib Platinum based chemotherapy Other therapy No therapy 30 (11) 50 (19) 3 (1) 149 (56) 22 (8) 0 0 (0) 10 (4) 5 (10) 2 (4) 0 (0) 24 (47) 5 (10) 7 (14) 3 (6) 5 (10) Treatment outcome Overall survival for the entire cohort irrespective of treatment was shorter in patients with rare ALK as opposed to EML4::ALK fusions (median 27 months vs 57 months, HR 1.6, 95% CI 0.9-2.6, p=0.08; Supplement 3 ). However, when analyzing response to the first TKI ever received, efficacy of ALK inhibitors in patients with rare ALK was considerable with an objective response rate (ORR) of 71% (95% CI 56%-83%) and a disease control rate (DCR) of 88% (95% CI 73%-96%) ( Figure 2A). Responses to TKI were observed in all types of recurrent rare ALK fusions (CLIP::ALK, DCTN1::ALK, GCC2::ALK, HIP1::ALK, KLC1::ALK) and in the majority (7/9) of the non-recurrent fusions. Response rates ranged between 40% and 100% in the former group ( Figure 2B ). In the latter group, the two non-responding patients (ETV6::ALK, SFTB::ALK) achieved prolonged disease stabilization beyond six months upon first exposure to an TKI. There was no evident association between the likelihood of response to a TKI and the specific exonic breakpoint at which the ALK fusion occurred ( Supplement 4 ). Among responders (n=30), all patients tested for ALK expression by immunohistochemistry (IHC) were IHC positive (19/19). Among non-responders (N=12), 9/12 tested patients were IHC positive. For two of them, ALK FISH was available and tested positive ( Supplement 5 ). When focusing on patients receiving an ALK inhibitor as first-line therapy, ORR was similar between EML4::ALK (85%, 95% CI 79-89) and rare ALK (74%, 95% CI 56-87; p=0.9) groups. Median PFS was 25 months in the former and 23 months and the latter group (HR 0.9, 95% CI 0.6-1.5, p=0.7) with 53% (132/247) and 50% (18/36) of PFS events having occurred, respectively ( Figure 3A ). Overall survival (OS) was immature (34% and 31 % of events having occurred in EML4::ALK and rare ALK, respectively). Nevertheless, survival curves were largely overlapping (median OS 57 vs 40 months, HR 0.9, 96% CI 0.5-1.6, p=0.6) for patients with EML4::ALK and rare ALK fusions receiving a TKI as first-line therapy ( Figure 3B ). In contrast, the use of platinum-based chemotherapy in palliative first-line was associated with a significantly reduced PFS compared to treatment with TKI in patients with rare ALK (HR 3.1, 95% CI 1.2-8, p = 0.02, Figure 4A ). In addition, OS tended to be inferior in these patients (median 24 months vs 40 months for platinum vs targeted therapy, HR 2, 95% CI 0.7-5.9) although this trend did not reach statistical significance (p=0.2; Figure 4B ). Beyond treatment with platinum-based chemotherapy, non-adenocarcinoma histology was also associated with shorter PFS in patients with rare ALK fusions (HR 9.6, 95% CI 2.6-36.3, p<0.01). A history of smoking and an ECOG performance status of 2-3 showed a statistically non-significant trend towards impaired PFS ( Supplement 6 ). DISCUSSION The broad application of NGS gene fusion assays has led to an increasing number of rare ALK fusion partners being identified. Little is known on the specific efficacy of TKIs in this subgroup, with most of the evidence being derived from case reports or small case series[ 6 ]. It has been described for other actionable genomic alterations in NSCLC that rare and atypical alterations may be generally insensitive to standard targeted therapy (EGFR Exon 20 insertions[ 9 ]) or in itself very heterogeneous (BRAF non-V600 mutations[ 10 ], [ 11 ]). Here, we describe a cohort of patients with rare ALK fusions and compare characteristics and outcome to a group of EML4::ALK positive NSCLC treated at the same set of institutions within the same period. The observed frequency of ALK fusions (3.5% in adenocarcinoma, 1.9% in unselected NSCLC) is in line with previous reports (2–8%) [ 12 ], [ 13 ], [ 14 ]. In the overall cohort, median OS was about 30 months shorter in rare ALK compared to EML4::ALK fusion positive patients (27 vs. 57 months). This might relate to differences both in tumor biology and in patient characteristics, especially to the higher proportion of current or former smokers and the higher median age within the rare ALK cohort. It is, however, notable that fewer patients with rare ALK fusions received a TKI as first line of palliative treatment (71% vs. 96%). The use of a platinum-doublet regimen in this group and setting was associated with a significantly inferior PFS compared to a TKI (HR 3.1, 95% CI 1.2-8, p = 0.02). The median PFS with chemotherapy (5 months) aligned well with real-world reports on chemotherapy treated unselected ALK fusion positive patients[ 3 ]. Another notable difference between the rare ALK and EML4::ALK cohort was the higher proportion of patients assigned to best supportive care in the former (10% vs. 4%). When focusing on those individuals who received a TKI (mainly alectinib) as their first line of treatment, ORR and PFS did not differ significantly between rare ALK and EML4::ALK patients (ORR 74% vs. 85%, median PFS 23 vs. 25 months). Along the same lines, a similar efficacy has been described for crizotinib in a smaller Chinese single center study comparing 11 rare ALK to 49 EML4::ALK fusion positive patients[ 15 ]. We observed clinical activity of ALK inhibitors across all fusion partners, which suggests that rare ALK fusions as a group should be seen as TKI-sensitive in NSCLC provided the individual rearrangement preserves the tyrosine kinase domain and passes quality controls of the applied assay. ALK IHC did not allow for predicting response in rare ALK as all but three tested patients were positive. Our study has several limitations inherent to its multicenter retrospective design. First, the exact estimation of fusion frequency is limited by differences in the assays used across 29 different institutions. In addition, the differential outcome between TKI and chemotherapy-treated rare ALK patients might be due to selection bias, with patients presenting with an aggressive disease phenotype being more likely to receive chemotherapy upfront. The median PFS observed in our first-line TKI-treated rare ALK and EML4::ALK cohorts compares unfavorably to the alectinib arm of the phase III ALEX trial (23 vs. 25 vs. 35 months). It is, however, similar to recently published real world data [ 16 ]. Finally, we lack comprehensive data on the efficacy of third generation ALK inhibitors since most patients were treated before lorlatinib became widely available and a standard-of-care first-line approach[ 17 ]. Acknowledging these limitations and in the absence of prospective evidence, we conclude that our study supports the use of TKIs as first line of treatment in NSCLC with rare ALK fusions. METHODS Study design We conducted a retrospective, multicenter chart analysis among 29 international lung cancer centers from 6 countries (Germany, Switzerland, Austria, Greece, Slovenia, Israel). Adult patients were eligible for inclusion if they had (1) histologic diagnosis of NSCLC in advanced stage without curative treatment options, (2) an ALK fusion as detected by next generation sequencing (NGS), and (3) follow-up of at least three months after start of palliative therapy. Patients with additional driver alterations were excluded. Data were collected for two cohorts: (a) the rare ALK cohort (defined as any ALK fusion with a partner other than EML4) for which a comprehensive dataset was compiled including patient characteristics, detailed NGS findings as reported by clinical routine testing, and clinical outcomes across all lines of therapy, and (b) and a control cohort of patients with EML4::ALK fusions in which we collected a reduced data set focused on key patient characteristics and first-line targeted therapy. Overall, the dataset was largely complete, though some variables (e.g., ECOG performance status, TP53 status) were occasionally missing at random. In addition to individual patient data, we requested institution-level molecular testing data. Centers reported the total number of NSCLC patients (all histologic subtypes) tested with an NGS assay capable of detecting ALK fusions, and among those patients the frequency of EML4::ALK and rare ALK fusions. Analysis of patient characteristics and clinical endpoints Patient characteristics were analyzed with appropriate descriptive statistics and compared with t-test at alpha 0.05 or Pearson’s chi-squared test. Evaluation of treatment response was performed at the individual centers according to the Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST), assessed by the investigator or local radiologist without central review. 95% confidence intervals for objective response rate (ORR) were calculated using the Wilson method. Progression-free survival (PFS) was analyzed using Kaplan-Meier estimates, calculated from the start of therapy to the date of progression, initiation of a new systemic anti-cancer therapy, or death. Data were censored at the date of last follow-up if none of these events had occurred at the time of analysis. Overall survival (OS) was assessed using Kaplan-Meier estimates, calculated from start of therapy until date of death. For patients who were alive at their latest follow-up, data were censored accordingly. We performed Cox-regression analyses and estimated hazard ratios to compare survival outcomes. Statistical analyses were performed with IBM SPSS Statistics (version 30.0) and R (R version 4.4.1, R Foundation for Statistical Computing). The figures and tables were generated using R and Microsoft Office 2019. Declarations Declaration of potential conflicts of interest MEL : Honoraria: AstraZeneca. FCS : Advisory Board / Consultancy: Johnson/Johnson, BMS, Boehringer Ingelheim, AstraZeneca, Pfizer, MSD, Roche. Honoraria: Johnson/Johnson, Takeda, AstraZeneca, Lilly, Pfizer, Novartis, Accord Healthcare, Thieme, German Society for Thoracic Surgery, CME Verlag, GWT-TUD. Travel Expenses: Johnson&Johnson, AstraZeneca, Lilly, Takeda. Research Funding: Roche. LR : Advisory Board / Consultancy: Amgen, Johnson&Johnson. Travel Expenses: Amgen. DKG: Honoraria: AstraZeneca, Boehringer Ingelheim, BMS, Roche, MSD, Pfizer, GSK, Novartis, Janssen, Takeda. Speakers’ Bureau: Daiichi Sankyo, Boehringer Ingelheim. Travel Expenses: Takeda, Pfizer, AstraZeneca, Johnson&Johnson. Daiichi Sankyo. Research Funding: Gilead. OI: Honoraria: Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Johnson&Johnson, Merck Sharp & Dohme, Pfizer, and Roche . Advisory Board / Consultancy: Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Johnson&Johnson, Merck Sharp & Dohme, Pfizer, and Roche. Speakers’ Bureau: Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Menarini, Merck Sharp & Dohme, Pfizer, and Roche. Research Funding: Amgen and AstraZeneca. Travel Expenses: Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Merck Sharp & Dohme, Pfizer, and Roche. AS: Advisory Board / Consultancy: Amgen, Astellas Pharma, AstraZeneca, Bayer, Bristol-Myers Squibb, Illumina, Incyte, Janssen, Lilly, MSD, Novartis, SERVIER, Takeda, Thermo Fisher Scientific. Speakers' Bureau: Astellas Pharma, AstraZeneca, Bayer, Bristol-Myers Squibb, Illumina, MSD, Novartis, Roche, SERVIER, Thermo Fisher Scientific. Research Funding: Bayer, Bristol-Myers Squibb, Chugai Pharma, Incyte. KMF: Honoraria: AstraZeneca. AR : Advisory Board / Consultancy: AbbVie, AstraZeneca/MedImmune, Boehringer Ingelheim, Bristol-Myers Squibb, Daichi Sankyo, GlaxoSmithKline, Lilly, MSD, Novartis, Pfizer, Roche/Genentech. Speakers' Bureau: Bristol-Myers Squibb, Lilly, MSD, Roche/Genentech. Uncompensated Relationships: Roche/Genentech. IG : Travel Expenses: Novartis, AstraZeneca. BE: Honoraria: AstraZeneca. Advisory Board / Consultancy: Sanofi. CS: Honoraria: AstraZeneca. SIR: Honoraria: Amgen (Inst), AstraZeneca (Inst), Bayer (Inst), Boehringer Ingelheim (Inst), Bristol-Myers Squibb (Inst), Eisai (Inst), Janssen Oncology (Inst), Lilly (Inst), Merck Serono (Inst), MSD Oncology (Inst), Novartis (Inst), Otsuka (Inst), Pfizer (Inst), PharmaMar (Inst), Roche Pharma AG (Inst), Sanofi (Inst), Takeda (Inst). Consulting or Advisory Role: Amgen (Inst), AstraZeneca (Inst), Boehringer Ingelheim (Inst), Bristol-Myers Squibb (Inst), Eisai (Inst), Lilly (Inst), Merck Serono (Inst), MSD Oncology (Inst), Novartis (Inst), Otsuka (Inst), Pfizer (Inst), PharmaMar (Inst), Roche Pharma AG (Inst), Takeda (Inst). Speakers' Bureau: Amgen (Inst), AstraZeneca (Inst), AstraZeneca (Inst), Roche Pharma AG (Inst), Sanofi/Aventis (Inst), Takeda (Inst). Research Funding: Abbvie (Inst), AstraZeneca (Inst), Boehringer Ingelheim (Inst), Bristol-Myers Squibb (Inst), Merck Serono (Inst), Roche Pharma AG (Inst). Travel, Accommodations, Expenses: Amgen (Inst), Amgen (Inst), AstraZeneca (Inst), Boehringer Ingelheim (Inst), Bristol-Myers Squibb (Inst), MSD Oncology (Inst), Roche Pharma AG (Inst), Sanofi; Takeda (Inst). Other Relationship: Federal Drug Commission of the Swiss Federal Office of Public Health, Swiss Group for Clinical Cancer Research (SAKK) (Inst). CG : Honoraria: Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Merck Sharp & Dohme, Pfizer, Roche. Consulting or Advisory Role: Boehringer Ingelheim, Merck Sharp & Dohme, Novartis, Pfizer, Roche. KA : Consulting or Advisory Role: AstraZeneca, BeiGene, Bristol-Myers Squibb, MSD, Roche, Takeda. KM : Honoraria: Amgen, AstraZeneca, Bristol-Myers Squibb, Janssen, MSD, Pfizer, Takeda. Consulting or Advisory Role: Amgen, AstraZeneca, Bristol-Myers Squibb, Janssen, MSD, Pfizer, Takeda. UJ: Honoraria: AstraZeneca, Boehringer Ingelheim, MSD Oncology, Pfizer, Roche, Takeda. CFW : Honoraria: Alvotech, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai Pharma, Lilly, Merck, Merck Sharp & Dohme, Mylan/Viatris, Novartis, Pfizer, Roche, Takeda. Consulting or Advisory Role: Alvotech, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai/Roche, Lilly, Merck, MSD, Mylan/Viatris, Novartis/Ipsen, Pfizer, Roche, Takeda, Vifor Pharma. Travel Expenses: AstraZeneca, Bristol-Myers Squibb, Ipsen, Janssen, Lilly. TRO : Advisory Board / Consultancy: AstraZeneca, BMS GmbH & Co. KG, Boehringer Ingelheim, Daiichi Sankyo Europe GmbH, Johnson & Johnson/Janssen, Merck KGaA, Pfizer, Pierre Fabre, Roche. Travel Expenses: AstraZeneca, Daiichi Sankyo Europe Gmb. LAM : Advisory Board / Consultancy: Amgen, AstraZeneca, BMS, Merck, MSD, Novartis, Pfizer, Roche Pharma, Regeneron, Janssen, Daichii-Sankyo. Research funding: AstraZeneca, Gilead. Honoraria: Merck, AstraZeneca. Expert testimony: BMS. Travel and accommodations: Sanofi, AstraZeneca, and Roche. MW : Honoraria / Advisory Board / Consultancy: Amgen, AstraZeneca, Daiichi Sankyo, GlaxoSmithKline, Janssen, Novartis, Pfizer, Roche, Takeda. Research funding: Bristol-Myers Squibb, Takeda. MF: Research funding: AstraZeneca, BMS, MSD, and Roche. Honoraria / Consultancy: AstraZeneca, MSD, Roche, BMS, AstraZeneca, MSD, Roche, BMS. WK : Honoraria: MSD, Bristol-Myers Squibb, Novartis, and AstraZeneca. MI: Honoraria / Advisory Board: Amgen, AstraZeneca, Astellas Pharma, Bayer, Boehringer Ingelheim, Janssen, Merck Sharp & Dohme, Pfizer, Roche, and Takeda. SMB: Honoraria / Advisory Board: AstraZeneca, Novartis, Roche, BMS, Illumina, DLS, Daiichi-Sankyo, QuIP, Stemline. Research Funding: AstraZeneca, Roche, Zytovision QuIP. CW: Honoraria: AstraZeneca. DEA : Honoraria: Roche, AstraZeneca, MSD, Pfizer. MT : Honoraria: Amgen, AstraZeneca, BeiGene, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Chugai Pharma, Daiichi Sankyo Europe GmbH, GlaxoSmithKline, Janssen Oncology, Lilly, Merck, MSD, Novartis, Pfizer, Roche, Sanofi, Takeda. Consulting or Advisory Role: Amgen, AstraZeneca, BeiGene, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Chugai Pharma, Daiichi Sankyo Europe GmbH, GlaxoSmithKline, Janssen Oncology, Lilly, Merck, MSD, Novartis, Pfizer, Roche, Sanofi, Takeda. Research Funding: AstraZeneca (Inst), Bristol-Myers Squibb (Inst), Merck (Inst), Roche (Inst), Takeda (Inst). Travel, Accommodations, Expenses: Astrazeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo Europe GmbH, Janssen Oncology, Lilly, Merck, MSD, Novartis, Pfizer, Roche, Sanofi, Takeda. MJH : Consulting or Advisory Role: AstraZeneca/Daiichi Sankyo, Lilly, Roche, Takeda. Speakers' Bureau: Lilly, MSD Oncology, Novartis, Roche. PC : Honoraria: AstraZeneca, Boehringer Ingelheim, Chugai Pharma, Daiichi Sankyo/Astra Zeneca, Gilead Sciences, Merck Serono, Novartis, Pfizer, Roche, Takeda. Research Funding: Amgen (Inst), AstraZeneca (Inst), Boehringer Ingelheim (Inst), Merck Serono (Inst), Roche (Inst), Takeda (Inst). MW : Honoraria: Amgen, BMS GmbH & Co. KG, Boehringer Ingelheim, GWT, Janssen, Lilly, Merck Serono, Merck Serono, Novartis, Pfizer, SYNLAB. Consulting or Advisory Role: Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo Europe GmbH, ImCheck therapeutics, immatics, ISA Pharmaceuticals, Lilly, Novartis, PharmaMar, Regeneron, Tacalyx, Zymeworks. Research Funding: Roche (Inst). Travel, Accommodations, Expenses: Amgen, AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo Europe GmbH, GEMoaB, immatics, Iovance Biotherapeutics, Janssen Oncology, Merck Serono, Pfizer, Sanofi/Aventis. The other authors (KS, AR, AT, SH, SB, RS, KS, RL, SS, UW, SSF, HS, RV) have nothing to declare. Informed consent / Ethics committee The study was carried out in accordance with the Code of Ethics of the World Medical Association (Declaration of Helsinki) and was approved by the ethics committee of the Technische Universität Dresden, Germany (BO-EK-253062024). Informed consent was obtained if required by law. DATA AVAILABILITY Informed consent of participating patients does not cover unrestricted publication of complete data. Upon request to the corresponding author, anonymized data can be made available if intended use is in compliance with informed consent. Funding and Acknowledgements This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. The authors thank the Stiftung Deutsche Krebshilfe (DKH) that generously funded the National Network Genomic Medicine Lung Cancer (nNGM), which is the structural framework supporting this multicentric collaboration. The authors would like to thank the nNGM main investigators in their role as non-author contributors for making possible this collaborative effort: Prof. David Horst (Charité Universitätsmedizin, Berlin), Prof. Ulrich Keilholz (Charité Universitätsmedizin, Berlin), Prof. Thomas Mairinger (Lungenklinik Heckeshorn, Helios Klinikum Emil von Behring, Berlin), Prof. Maike de Wit (Vivantes Klinikum Neukölln, Berlin), Prof. Hubert Schorle (University Hospital Bonn), Prof. Martin Wermke (TU Dresden, University Hospital Carl Gustav Carus, Dresden), Univ.-Prof. Irene Esposito (University Hospital Düsseldorf), Prof. Arndt Hartmann (University Hospital Erlangen), Univ.-Prof. Martin Schuler (Universitätsmedizin Essen, University Hospital), Dr. Martin Sebastian (University Hospital Frankfurt), Prof. Martin Werner (University Hospital Freiburg), Prof. Stefan Gattenlöhner (University Hospital Gießen), Prof. Philipp Ströbel (University Hospital Göttingen), Prof. Claudia Wickenhauser (University Medicine Halle), Prof. Carsten Bokemeyer (University Hospital Hamburg Eppendorf), Prof. Ludwig Wilkens (KRH Klinikum Hannover), Prof. Ulrich Lehmann (Medizinische Hochschule Hannover), Prof. Albrecht Stenzinger (University Hospital Heidelberg), Prof. Andrea Tannapfel (Ruhr-Universität Bochum, Lungenklinik Hemer), Univ.-Prof. Jürgen Wolf (University Hospital Cologne), Prof. Jutta Kirfel (Universitätsklinikum Schleswig-Holstein), Univ.-Prof. Wilfried Roth (University Hospital Mainz, Germany), Prof. Frederick Klauschen (Ludwig-Maximilians-Universität Munich, Germany), Dipl.-Biol. Nicole Pfarr (TUM Klinikum rechts der Isar, Munich), Dr. Lukas Heukamp (Pius Hospital Oldenburg), Prof. Matthias Evert (University Hospital Regensburg), Prof. Falko Fend (University Hospital Tübingen), Prof. Stephan Stilgenbauer (University Hospital Ulm), Prof. Ralf Christian Bargou (University Hospital Würzburg). Author contributions (CREDIT) M. E. Leßmann, F. C. Saalfeld: Conceptualization, Data curation, Formal analysis, Methodology, Project administration, Roles/Writing - original draft. P. Christopoulos, M. Wermke: Conceptualization, Methodology, Resources, Supervision, Validation, Roles/Writing - original draft. L. Ruge, D. Kauffmann-Guerrero, O. Illini, A. Stenzinger, K. Minuth-Fuchs, A. Rittmeyer, I. Goetting, K. Schildknecht, B. Eul, C. Schubart, S. I. Rothschild, C. Grohé, K. Armster, K. Mohorčič, U. Janžič, C. F. Waller, T. R. Overbeck, R. Vesce, H. Schulte, L. A. Mauti, S. Stephan-Falkenau, M. Wiesweg, M. Faehling, U. Gerstenmaier, S. Schmid, W. Kian, R. Lozynskyy , M. Ivanović, K. Syrigos, R. Simon, S. Merkelbach-Bruse, C. Wenzel, S. Brückmann, S. Herold, D. E. Aust, M. Thomas, M. J. Hochmair, A. Tufman, A. Rasokat: Data curation, Investigation, Writing - review & editing. National Network Genomic Medicine Lung Cancer (nNGM): Resources. References W. Xia, J. Yang, H. Li, L. Li, und J. Liu, „Comparing Genomic Profiles of ALK Fusion-Positive and ALK Fusion-Negative Nonsmall Cell Lung Cancer Patients“, Glob. Med. Genet. , Bd. 11, Nr. 02, S. 175–186, Juni 2024, doi: 10.1055/s-0044-1787301 . A. T. Shaw u. a. , „Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK“, J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. , Bd. 27, Nr. 26, S. 4247–4253, Sep. 2009, doi: 10.1200/JCO.2009.22.6993 . M. Takeda, I. Okamoto, K. Sakai, H. Kawakami, K. Nishio, und K. Nakagawa, „Clinical outcome for EML4-ALK -positive patients with advanced non-small-cell lung cancer treated with first-line platinum-based chemotherapy“, Ann. Oncol. , Bd. 23, Nr. 11, S. 2931–2936, Nov. 2012, doi: 10.1093/annonc/mds124 . B. J. Solomon u. a. , „Lorlatinib Versus Crizotinib in Patients With Advanced ALK-Positive Non–Small Cell Lung Cancer: 5-Year Outcomes From the Phase III CROWN Study“, J. Clin. Oncol. , S. JCO.24.00581, Mai 2024, doi: 10.1200/JCO.24.00581 . J. S. Ross u. a. , „ALK Fusions in a Wide Variety of Tumor Types Respond to Anti-ALK Targeted Therapy“, The Oncologist , Bd. 22, Nr. 12, S. 1444–1450, Dez. 2017, doi: 10.1634/theoncologist.2016-0488 . S.-H. I. Ou, V. W. Zhu, und M. Nagasaka, „Catalog of 5’ Fusion Partners in ALK -positive NSCLC Circa 2020“, JTO Clin. Res. Rep. , Bd. 1, Nr. 1, S. 100015, März 2020, doi: 10.1016/j.jtocrr.2020.100015 . Y. Xiang u. a. , „Therapeutic Advances of Rare ALK Fusions in Non-Small Cell Lung Cancer“, Curr. Oncol. , Bd. 29, Nr. 10, S. 7816–7831, Okt. 2022, doi: 10.3390/curroncol29100618 . W. Li u. a. , „Potential Unreliability of Uncommon ALK, ROS1, and RET Genomic Breakpoints in Predicting the Efficacy of Targeted Therapy in NSCLC“, J. Thorac. Oncol. , Bd. 16, Nr. 3, S. 404–418, März 2021, doi: 10.1016/j.jtho.2020.10.156 . J. Naidoo u. a. , „Epidermal growth factor receptor exon 20 insertions in advanced lung adenocarcinomas: Clinical outcomes and response to erlotinib“, Cancer , Bd. 121, Nr. 18, S. 3212–3220, Sep. 2015, doi: 10.1002/cncr.29493 . C. Kropf-Sanchen u. a. , „Response to targeted and immune therapy in patients with NSCLC and BRAF non-V600E mutations: A retrospective, multicenter analysis within the national Network Genomic Medicine Lung Cancer (nNGM) in Germany.“, J. Clin. Oncol. , Bd. 42, Nr. 16_suppl, S. 8591–8591, Juni 2024, doi: 10.1200/JCO.2024.42.16_suppl.8591 . A. Zaman, W. Wu, und T. G. Bivona, „Targeting Oncogenic BRAF: Past, Present, and Future“, Cancers , Bd. 11, Nr. 8, S. 1197, Aug. 2019, doi: 10.3390/cancers11081197 . P. Hofman, „ALK in Non-Small Cell Lung Cancer (NSCLC) Pathobiology, Epidemiology, Detection from Tumor Tissue and Algorithm Diagnosis in a Daily Practice“, Cancers , Bd. 9, Nr. 8, Art. Nr. 8, Aug. 2017, doi: 10.3390/cancers9080107 . F. Barlesi u. a. , „Routine molecular profiling of patients with advanced non-small-cell lung cancer: results of a 1-year nationwide programme of the French Cooperative Thoracic Intergroup (IFCT)“, The Lancet , Bd. 387, Nr. 10026, S. 1415–1426, Apr. 2016, doi: 10.1016/S0140-6736(16)00004-0 . N. Frost u. a. , „Lung Cancer in Germany“, J. Thorac. Oncol. , Bd. 17, Nr. 6, S. 742–750, Juni 2022, doi: 10.1016/j.jtho.2022.03.010 . Y. Li u. a. , „Response to crizotinib in advanced ALK -rearranged non-small cell lung cancers with different ALK -fusion variants“, Lung Cancer , Bd. 118, S. 128–133, Apr. 2018, doi: 10.1016/j.lungcan.2018.01.026 . Q. Zhang u. a. , „Real-World Comparative Effectiveness of First-Line Alectinib Versus Crizotinib in Patients With Advanced ALK -Positive NSCLC With or Without Baseline Central Nervous System Metastases“, JTO Clin. Res. Rep. , Bd. 4, Nr. 4, S. 100483, Apr. 2023, doi: 10.1016/j.jtocrr.2023.100483 . A. T. Shaw u. a. , „First-Line Lorlatinib or Crizotinib in Advanced ALK-Positive Lung Cancer“, N. Engl. J. Med. , Bd. 383, Nr. 21, S. 2018–2029, Nov. 2020, doi: 10.1056/NEJMoa2027187 . Additional Declarations Competing interest reported. MEL: Honoraria: AstraZeneca. FCS: Advisory Board / Consultancy: Johnson/Johnson, BMS, Boehringer Ingelheim, AstraZeneca, Pfizer, MSD, Roche. Honoraria: Johnson/Johnson, Takeda, AstraZeneca, Lilly, Pfizer, Novartis, Accord Healthcare, Thieme, German Society for Thoracic Surgery, CME Verlag, GWT-TUD. Travel Expenses: Johnson&Johnson, AstraZeneca, Lilly, Takeda. Research Funding: Roche. LR: Advisory Board / Consultancy: Amgen, Johnson&Johnson. Travel Expenses: Amgen. DKG: Honoraria: AstraZeneca, Boehringer Ingelheim, BMS, Roche, MSD, Pfizer, GSK, Novartis, Janssen, Takeda. Speakers’ Bureau: Daiichi Sankyo, Boehringer Ingelheim. Travel Expenses: Takeda, Pfizer, AstraZeneca, Johnson&Johnson. Daiichi Sankyo. Research Funding: Gilead. OI: Honoraria: Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Johnson&Johnson, Merck Sharp & Dohme, Pfizer, and Roche. Advisory Board / Consultancy: Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Johnson&Johnson, Merck Sharp & Dohme, Pfizer, and Roche. Speakers’ Bureau: Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Menarini, Merck Sharp & Dohme, Pfizer, and Roche. Research Funding: Amgen and AstraZeneca. Travel Expenses: Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Merck Sharp & Dohme, Pfizer, and Roche. AS: Advisory Board / Consultancy: Amgen, Astellas Pharma, AstraZeneca, Bayer, Bristol-Myers Squibb, Illumina, Incyte, Janssen, Lilly, MSD, Novartis, SERVIER, Takeda, Thermo Fisher Scientific. Speakers' Bureau: Astellas Pharma, AstraZeneca, Bayer, Bristol-Myers Squibb, Illumina, MSD, Novartis, Roche, SERVIER, Thermo Fisher Scientific. Research Funding: Bayer, Bristol-Myers Squibb, Chugai Pharma, Incyte. KMF: Honoraria: AstraZeneca. AR: Advisory Board / Consultancy: AbbVie, AstraZeneca/MedImmune, Boehringer Ingelheim, Bristol-Myers Squibb, Daichi Sankyo, GlaxoSmithKline, Lilly, MSD, Novartis, Pfizer, Roche/Genentech. Speakers' Bureau: Bristol-Myers Squibb, Lilly, MSD, Roche/Genentech. Uncompensated Relationships: Roche/Genentech. IG: Travel Expenses: Novartis, AstraZeneca. BE: Honoraria: AstraZeneca. Advisory Board / Consultancy: Sanofi. CS: Honoraria: AstraZeneca. SIR: Honoraria: Amgen (Inst), AstraZeneca (Inst), Bayer (Inst), Boehringer Ingelheim (Inst), Bristol-Myers Squibb (Inst), Eisai (Inst), Janssen Oncology (Inst), Lilly (Inst), Merck Serono (Inst), MSD Oncology (Inst), Novartis (Inst), Otsuka (Inst), Pfizer (Inst), PharmaMar (Inst), Roche Pharma AG (Inst), Sanofi (Inst), Takeda (Inst). Consulting or Advisory Role: Amgen (Inst), AstraZeneca (Inst), Boehringer Ingelheim (Inst), Bristol-Myers Squibb (Inst), Eisai (Inst), Lilly (Inst), Merck Serono (Inst), MSD Oncology (Inst), Novartis (Inst), Otsuka (Inst), Pfizer (Inst), PharmaMar (Inst), Roche Pharma AG (Inst), Takeda (Inst). Speakers' Bureau: Amgen (Inst), AstraZeneca (Inst), AstraZeneca (Inst), Roche Pharma AG (Inst), Sanofi/Aventis (Inst), Takeda (Inst). Research Funding: Abbvie (Inst), AstraZeneca (Inst), Boehringer Ingelheim (Inst), Bristol-Myers Squibb (Inst), Merck Serono (Inst), Roche Pharma AG (Inst). Travel, Accommodations, Expenses: Amgen (Inst), Amgen (Inst), AstraZeneca (Inst), Boehringer Ingelheim (Inst), Bristol-Myers Squibb (Inst), MSD Oncology (Inst), Roche Pharma AG (Inst), Sanofi; Takeda (Inst). Other Relationship: Federal Drug Commission of the Swiss Federal Office of Public Health, Swiss Group for Clinical Cancer Research (SAKK) (Inst). CG: Honoraria: Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Merck Sharp & Dohme, Pfizer, Roche. Consulting or Advisory Role: Boehringer Ingelheim, Merck Sharp & Dohme, Novartis, Pfizer, Roche. KA: Consulting or Advisory Role: AstraZeneca, BeiGene, Bristol-Myers Squibb, MSD, Roche, Takeda. KM: Honoraria: Amgen, AstraZeneca, Bristol-Myers Squibb, Janssen, MSD, Pfizer, Takeda. Consulting or Advisory Role: Amgen, AstraZeneca, Bristol-Myers Squibb, Janssen, MSD, Pfizer, Takeda. UJ: Honoraria: AstraZeneca, Boehringer Ingelheim, MSD Oncology, Pfizer, Roche, Takeda. CFW: Honoraria: Alvotech, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai Pharma, Lilly, Merck, Merck Sharp & Dohme, Mylan/Viatris, Novartis, Pfizer, Roche, Takeda. Consulting or Advisory Role: Alvotech, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai/Roche, Lilly, Merck, MSD, Mylan/Viatris, Novartis/Ipsen, Pfizer, Roche, Takeda, Vifor Pharma. Travel Expenses: AstraZeneca, Bristol-Myers Squibb, Ipsen, Janssen, Lilly. TRO: Advisory Board / Consultancy: AstraZeneca, BMS GmbH & Co. KG, Boehringer Ingelheim, Daiichi Sankyo Europe GmbH, Johnson & Johnson/Janssen, Merck KGaA, Pfizer, Pierre Fabre, Roche. Travel Expenses: AstraZeneca, Daiichi Sankyo Europe Gmb. LAM: Advisory Board / Consultancy: Amgen, AstraZeneca, BMS, Merck, MSD, Novartis, Pfizer, Roche Pharma, Regeneron, Janssen, Daichii-Sankyo. Research funding: AstraZeneca, Gilead. Honoraria: Merck, AstraZeneca. Expert testimony: BMS. Travel and accommodations: Sanofi, AstraZeneca, and Roche. MW: Honoraria / Advisory Board / Consultancy: Amgen, AstraZeneca, Daiichi Sankyo, GlaxoSmithKline, Janssen, Novartis, Pfizer, Roche, Takeda. Research funding: Bristol-Myers Squibb, Takeda. MF: Research funding: AstraZeneca, BMS, MSD, and Roche. Honoraria / Consultancy: AstraZeneca, MSD, Roche, BMS, AstraZeneca, MSD, Roche, BMS. WK: Honoraria: MSD, Bristol-Myers Squibb, Novartis, and AstraZeneca. MI: Honoraria / Advisory Board: Amgen, AstraZeneca, Astellas Pharma, Bayer, Boehringer Ingelheim, Janssen, Merck Sharp & Dohme, Pfizer, Roche, and Takeda. SMB: Honoraria / Advisory Board: AstraZeneca, Novartis, Roche, BMS, Illumina, DLS, Daiichi-Sankyo, QuIP, Stemline. Research Funding: AstraZeneca, Roche, Zytovision QuIP. CW: Honoraria: AstraZeneca. DEA: Honoraria: Roche, AstraZeneca, MSD, Pfizer. MT: Honoraria: Amgen, AstraZeneca, BeiGene, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Chugai Pharma, Daiichi Sankyo Europe GmbH, GlaxoSmithKline, Janssen Oncology, Lilly, Merck, MSD, Novartis, Pfizer, Roche, Sanofi, Takeda. Consulting or Advisory Role: Amgen, AstraZeneca, BeiGene, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Chugai Pharma, Daiichi Sankyo Europe GmbH, GlaxoSmithKline, Janssen Oncology, Lilly, Merck, MSD, Novartis, Pfizer, Roche, Sanofi, Takeda. Research Funding: AstraZeneca (Inst), Bristol-Myers Squibb (Inst), Merck (Inst), Roche (Inst), Takeda (Inst). Travel, Accommodations, Expenses: Astrazeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo Europe GmbH, Janssen Oncology, Lilly, Merck, MSD, Novartis, Pfizer, Roche, Sanofi, Takeda. MJH: Consulting or Advisory Role: AstraZeneca/Daiichi Sankyo, Lilly, Roche, Takeda. Speakers' Bureau: Lilly, MSD Oncology, Novartis, Roche. PC: Honoraria: AstraZeneca, Boehringer Ingelheim, Chugai Pharma, Daiichi Sankyo/Astra Zeneca, Gilead Sciences, Merck Serono, Novartis, Pfizer, Roche, Takeda. Research Funding: Amgen (Inst), AstraZeneca (Inst), Boehringer Ingelheim (Inst), Merck Serono (Inst), Roche (Inst), Takeda (Inst). MW: Honoraria: Amgen, BMS GmbH & Co. KG, Boehringer Ingelheim, GWT, Janssen, Lilly, Merck Serono, Merck Serono, Novartis, Pfizer, SYNLAB. Consulting or Advisory Role: Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo Europe GmbH, ImCheck therapeutics, immatics, ISA Pharmaceuticals, Lilly, Novartis, PharmaMar, Regeneron, Tacalyx, Zymeworks. Research Funding: Roche (Inst). Travel, Accommodations, Expenses: Amgen, AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo Europe GmbH, GEMoaB, immatics, Iovance Biotherapeutics, Janssen Oncology, Merck Serono, Pfizer, Sanofi/Aventis. The other authors (KS, AR, AT, SH, SB, RS, KS, RL, SS, UW, SSF, HS, RV) have nothing to declare. Supplementary Files Supplements.pdf Supplements.docx (6 figures and/or tables). Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 11 Nov, 2025 Reviews received at journal 10 Nov, 2025 Reviewers agreed at journal 27 Oct, 2025 Reviews received at journal 14 Oct, 2025 Reviewers agreed at journal 13 Oct, 2025 Reviewers invited by journal 05 Oct, 2025 Editor assigned by journal 04 Oct, 2025 Submission checks completed at journal 22 Sep, 2025 First submitted to journal 05 Sep, 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. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-7545687","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":530234322,"identity":"686bb8c8-d44c-4f7a-984a-957ddc4be344","order_by":0,"name":"Marie-Elisabeth Leßmann","email":"","orcid":"","institution":"TU Dresden","correspondingAuthor":false,"prefix":"","firstName":"Marie-Elisabeth","middleName":"","lastName":"Leßmann","suffix":""},{"id":530234323,"identity":"81d0a8c5-47a9-45d9-89b1-ba1b19bf3530","order_by":1,"name":"Felix Carl Saalfeld","email":"","orcid":"","institution":"TU Dresden","correspondingAuthor":false,"prefix":"","firstName":"Felix","middleName":"Carl","lastName":"Saalfeld","suffix":""},{"id":530234324,"identity":"4d5f5d3c-5533-4358-9098-2b262c8d9d2f","order_by":2,"name":"Lea Ruge","email":"","orcid":"","institution":"University Hospital Cologne","correspondingAuthor":false,"prefix":"","firstName":"Lea","middleName":"","lastName":"Ruge","suffix":""},{"id":530234325,"identity":"47ebd4f1-38c1-40e0-a65f-542d96d989ee","order_by":3,"name":"Diego Kauffmann-Guerrero","email":"","orcid":"","institution":"LMU Klinikum","correspondingAuthor":false,"prefix":"","firstName":"Diego","middleName":"","lastName":"Kauffmann-Guerrero","suffix":""},{"id":530234326,"identity":"d1154f17-3f91-4c86-a8e6-3e58c36b1d3f","order_by":4,"name":"Oliver Illini","email":"","orcid":"","institution":"Klinik Floridsdorf, Vienna Healthcare Group","correspondingAuthor":false,"prefix":"","firstName":"Oliver","middleName":"","lastName":"Illini","suffix":""},{"id":530234327,"identity":"71ce873c-547e-44c7-a494-2c8874a88ae5","order_by":5,"name":"Albrecht Stenzinger","email":"","orcid":"","institution":"University Hospital Heidelberg","correspondingAuthor":false,"prefix":"","firstName":"Albrecht","middleName":"","lastName":"Stenzinger","suffix":""},{"id":530234328,"identity":"0a5505ec-9fe1-48ba-a723-fc62d07d44e5","order_by":6,"name":"Kaija Minuth-Fuchs","email":"","orcid":"","institution":"University Hospital Regensburg","correspondingAuthor":false,"prefix":"","firstName":"Kaija","middleName":"","lastName":"Minuth-Fuchs","suffix":""},{"id":530234329,"identity":"dfbff79a-9f12-48b9-a4d6-3c4bd92578be","order_by":7,"name":"Achim Rittmeyer","email":"","orcid":"","institution":"LKI Lungenfachklinik Immenhausen","correspondingAuthor":false,"prefix":"","firstName":"Achim","middleName":"","lastName":"Rittmeyer","suffix":""},{"id":530234330,"identity":"89c21f31-8a41-43c5-8711-d79631e91169","order_by":8,"name":"Isabell Goetting","email":"","orcid":"","institution":"Universitätsklinikum Tübingen","correspondingAuthor":false,"prefix":"","firstName":"Isabell","middleName":"","lastName":"Goetting","suffix":""},{"id":530234331,"identity":"b439f660-072f-49d0-9e25-b47e2c627183","order_by":9,"name":"Katharina Schildknecht","email":"","orcid":"","institution":"Robert Bosch Hospital","correspondingAuthor":false,"prefix":"","firstName":"Katharina","middleName":"","lastName":"Schildknecht","suffix":""},{"id":530234332,"identity":"a94ffd3b-6e6c-45cc-b92c-b7ee17488fb9","order_by":10,"name":"Bastian Eul","email":"","orcid":"","institution":"Justus-Liebig-University Giessen","correspondingAuthor":false,"prefix":"","firstName":"Bastian","middleName":"","lastName":"Eul","suffix":""},{"id":530234333,"identity":"6e4151a5-071c-401a-9afc-8eaa3123e282","order_by":11,"name":"Christoph Schubart","email":"","orcid":"","institution":"Friedrich-Alexander-Universität Erlangen-Nürnberg","correspondingAuthor":false,"prefix":"","firstName":"Christoph","middleName":"","lastName":"Schubart","suffix":""},{"id":530234334,"identity":"d701369a-b771-45fa-86af-1d789517efb3","order_by":12,"name":"Sacha I. Rothschild","email":"","orcid":"","institution":"Kantonsspital Baden","correspondingAuthor":false,"prefix":"","firstName":"Sacha","middleName":"I.","lastName":"Rothschild","suffix":""},{"id":530234335,"identity":"a1acccb4-2187-4b5c-af36-0f1e53415017","order_by":13,"name":"Christian Grohé","email":"","orcid":"","institution":"Evangelische Lungenklinik Berlin","correspondingAuthor":false,"prefix":"","firstName":"Christian","middleName":"","lastName":"Grohé","suffix":""},{"id":530234336,"identity":"4a82deb5-ba73-4e32-a02a-2e6029f7c23e","order_by":14,"name":"Karin Armster","email":"","orcid":"","institution":"Karl Landsteiner University of Health Sciences","correspondingAuthor":false,"prefix":"","firstName":"Karin","middleName":"","lastName":"Armster","suffix":""},{"id":530234337,"identity":"b5a6f065-a009-497d-8fba-ed7a8528c06d","order_by":15,"name":"Katja Mohorčič","email":"","orcid":"","institution":"University Clinic Golnik","correspondingAuthor":false,"prefix":"","firstName":"Katja","middleName":"","lastName":"Mohorčič","suffix":""},{"id":530234338,"identity":"999019b6-dead-42d2-8381-d3c105c25ca7","order_by":16,"name":"Urska Janzic","email":"","orcid":"","institution":"University Clinic Golnik","correspondingAuthor":false,"prefix":"","firstName":"Urska","middleName":"","lastName":"Janzic","suffix":""},{"id":530234339,"identity":"7d553ab9-005a-4c7f-be63-0252520a8cd9","order_by":17,"name":"Cornelius F. Waller","email":"","orcid":"","institution":"Medical Center-University of Freiburg, University of Freiburg","correspondingAuthor":false,"prefix":"","firstName":"Cornelius","middleName":"F.","lastName":"Waller","suffix":""},{"id":530234340,"identity":"2b9aa57e-967d-4d56-84e0-ece7811bee29","order_by":18,"name":"Tobias Raphael Overbeck","email":"","orcid":"","institution":"University Medical Center Göttingen, Göttingen University","correspondingAuthor":false,"prefix":"","firstName":"Tobias","middleName":"Raphael","lastName":"Overbeck","suffix":""},{"id":530234341,"identity":"05be4149-8eb3-4a86-95e7-76ee04ce6535","order_by":19,"name":"Rita Vesce","email":"","orcid":"","institution":"Düsseldorf University Hospital, Heinrich Heine University","correspondingAuthor":false,"prefix":"","firstName":"Rita","middleName":"","lastName":"Vesce","suffix":""},{"id":530234342,"identity":"837a7454-3276-4ef4-b18f-10b9e7e11438","order_by":20,"name":"Hanna Schulte","email":"","orcid":"","institution":"University of Frankfurt","correspondingAuthor":false,"prefix":"","firstName":"Hanna","middleName":"","lastName":"Schulte","suffix":""},{"id":530234343,"identity":"d3387db9-2134-4d92-8736-e3b07d80c9b4","order_by":21,"name":"Laetitia Arja Mauti","email":"","orcid":"","institution":"Cantonal Hospital Winterthur","correspondingAuthor":false,"prefix":"","firstName":"Laetitia","middleName":"Arja","lastName":"Mauti","suffix":""},{"id":530234344,"identity":"51d2d85d-aa6e-41c6-a2f6-3f3e32fbf3e0","order_by":22,"name":"Susann Stephan-Falkenau","email":"","orcid":"","institution":"Helios Klinikum Emil von Behring","correspondingAuthor":false,"prefix":"","firstName":"Susann","middleName":"","lastName":"Stephan-Falkenau","suffix":""},{"id":530234345,"identity":"3de63d63-70d6-42f4-8bf3-44301e14aec7","order_by":23,"name":"Marcel Wiesweg","email":"","orcid":"","institution":"West German Cancer Center, University Duisburg-Essen","correspondingAuthor":false,"prefix":"","firstName":"Marcel","middleName":"","lastName":"Wiesweg","suffix":""},{"id":530234346,"identity":"eb6cd9db-58eb-4ccc-a73f-8bfb951da291","order_by":24,"name":"Martin Faehling","email":"","orcid":"","institution":"Klinikum Esslingen","correspondingAuthor":false,"prefix":"","firstName":"Martin","middleName":"","lastName":"Faehling","suffix":""},{"id":530234347,"identity":"d5514db5-eb07-4376-b30a-ea18acfb18ed","order_by":25,"name":"Uwe Gerstenmaier","email":"","orcid":"","institution":"University Ulm","correspondingAuthor":false,"prefix":"","firstName":"Uwe","middleName":"","lastName":"Gerstenmaier","suffix":""},{"id":530234348,"identity":"ad0e8e0c-b2e3-4a1b-a047-f73a4f93f015","order_by":26,"name":"Sabine Schmid","email":"","orcid":"","institution":"Inselspital, University Hospital Bern","correspondingAuthor":false,"prefix":"","firstName":"Sabine","middleName":"","lastName":"Schmid","suffix":""},{"id":530234349,"identity":"2863f51d-8cf1-43aa-adfc-80806e5b4d6f","order_by":27,"name":"Waleed Kian","email":"","orcid":"","institution":"Assuta Ashdod University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Waleed","middleName":"","lastName":"Kian","suffix":""},{"id":530234350,"identity":"75987260-0730-4c2f-8885-ef014ac438e0","order_by":28,"name":"Rostyslav Lozynskyy","email":"","orcid":"","institution":"German Cancer Research Center","correspondingAuthor":false,"prefix":"","firstName":"Rostyslav","middleName":"","lastName":"Lozynskyy","suffix":""},{"id":530234351,"identity":"9de291ed-efcc-447a-bc09-ca9d9059b2fe","order_by":29,"name":"Marija Ivanović","email":"","orcid":"","institution":"University Medical Centre Maribor","correspondingAuthor":false,"prefix":"","firstName":"Marija","middleName":"","lastName":"Ivanović","suffix":""},{"id":530234352,"identity":"e3c4ca16-17e9-490e-9e10-c066cc5d53b3","order_by":30,"name":"Konstantinos Syrigos","email":"","orcid":"","institution":"National and Kapodistrian University of Athens","correspondingAuthor":false,"prefix":"","firstName":"Konstantinos","middleName":"","lastName":"Syrigos","suffix":""},{"id":530234353,"identity":"cb422409-db77-4844-87ef-03a58ae0ba77","order_by":31,"name":"Ronald Simon","email":"","orcid":"","institution":"University Medical Center Hamburg-Eppendorf","correspondingAuthor":false,"prefix":"","firstName":"Ronald","middleName":"","lastName":"Simon","suffix":""},{"id":530234354,"identity":"ec49c3cb-0ab3-4fc3-8609-d741500689fc","order_by":32,"name":"Sabine Merkelbach-Bruse","email":"","orcid":"","institution":"University Hospital Cologne","correspondingAuthor":false,"prefix":"","firstName":"Sabine","middleName":"","lastName":"Merkelbach-Bruse","suffix":""},{"id":530234355,"identity":"8a613624-02ee-4502-b9b9-61e597ff91f7","order_by":33,"name":"Carina Wenzel","email":"","orcid":"","institution":"TU Dresden","correspondingAuthor":false,"prefix":"","firstName":"Carina","middleName":"","lastName":"Wenzel","suffix":""},{"id":530234356,"identity":"1dd9a877-6142-4626-ae6c-7ea265c166c2","order_by":34,"name":"Sascha Brückmann","email":"","orcid":"","institution":"TU Dresden","correspondingAuthor":false,"prefix":"","firstName":"Sascha","middleName":"","lastName":"Brückmann","suffix":""},{"id":530234357,"identity":"84224006-af9f-49fe-8d76-761ad3857b43","order_by":35,"name":"Sylvia Herold","email":"","orcid":"","institution":"TU Dresden","correspondingAuthor":false,"prefix":"","firstName":"Sylvia","middleName":"","lastName":"Herold","suffix":""},{"id":530234358,"identity":"c231db9c-fab8-425c-9018-13d9c528579b","order_by":36,"name":"Daniela E Aust","email":"","orcid":"","institution":"TU Dresden","correspondingAuthor":false,"prefix":"","firstName":"Daniela","middleName":"E","lastName":"Aust","suffix":""},{"id":530234359,"identity":"b577e3c9-ee81-4450-93ea-c5e5a68caecb","order_by":37,"name":"Michael Thomas","email":"","orcid":"","institution":"Thoraxklinik at Heidelberg University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Michael","middleName":"","lastName":"Thomas","suffix":""},{"id":530234360,"identity":"bc3ff5c8-cb93-4a77-9350-7c12b31275fd","order_by":38,"name":"Maximilian Johannes Hochmair","email":"","orcid":"","institution":"Klinik Floridsdorf, Vienna Healthcare Group","correspondingAuthor":false,"prefix":"","firstName":"Maximilian","middleName":"Johannes","lastName":"Hochmair","suffix":""},{"id":530234361,"identity":"6169c906-ac6a-41a7-9d8c-e96141b3fe21","order_by":39,"name":"Amanda Tufman","email":"","orcid":"","institution":"LMU Klinikum","correspondingAuthor":false,"prefix":"","firstName":"Amanda","middleName":"","lastName":"Tufman","suffix":""},{"id":530234362,"identity":"e66db068-ba0a-4cfc-83ca-06172b716924","order_by":40,"name":"Anna Rasokat","email":"","orcid":"","institution":"University Hospital Cologne","correspondingAuthor":false,"prefix":"","firstName":"Anna","middleName":"","lastName":"Rasokat","suffix":""},{"id":530234363,"identity":"4e0e315b-0723-406a-ad1a-0bef5f240829","order_by":41,"name":"Petros Christopoulos","email":"","orcid":"","institution":"Thoraxklinik at Heidelberg University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Petros","middleName":"","lastName":"Christopoulos","suffix":""},{"id":530234364,"identity":"2792bdb9-c0ea-4658-93dd-2dcab608feae","order_by":42,"name":"Martin Wermke","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA40lEQVRIiWNgGAWjYLCCBAjFzMBQwWDAcCCBQYKABsYGhJYzxGphgGlhbCNCi2772ecPHu5gSOyXPp1s8HHeYWO+4wmMNz7g0WJ2Jt2wIfEMQ+LMvtzNiTO3HTaTPPOA2XIGPi0H0hgbEtsYcjec4d18mHfbYRuDGwls0jz4tJx/BtGyH6Tl7xyolj/4tNyA2cLDuzmZseGwGVgLPu+b3XjGOCOxTaJ+BtAWw55j6caSZx42W/bgdVgaw8efbTbG/D28myV+1Fgb9h1PPnjjBz5rIAAlIuARNQpGwSgYBaOAXAAAFyZVQ5cPcpIAAAAASUVORK5CYII=","orcid":"","institution":"TU Dresden","correspondingAuthor":true,"prefix":"","firstName":"Martin","middleName":"","lastName":"Wermke","suffix":""}],"badges":[],"createdAt":"2025-09-05 15:38:28","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7545687/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7545687/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":93730909,"identity":"3211bc04-cdfb-4a37-9896-5b2749e4b613","added_by":"auto","created_at":"2025-10-17 02:22:16","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":2091326,"visible":true,"origin":"","legend":"","description":"","filename":"rareALKManuskriptNPJPO1.1.docx","url":"https://assets-eu.researchsquare.com/files/rs-7545687/v1/d34c97b53a2f8e30a7e27fa5.docx"},{"id":93730908,"identity":"35322ff6-4bcd-4d37-93e9-dad58cefd971","added_by":"auto","created_at":"2025-10-17 02:22:16","extension":"json","order_by":1,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":45493,"visible":true,"origin":"","legend":"","description":"","filename":"88d9de1a91eb4a76a09efac79cfadca4.json","url":"https://assets-eu.researchsquare.com/files/rs-7545687/v1/494f91bb2ddf5de1ada31dd1.json"},{"id":93732349,"identity":"64503509-16fe-496a-a322-b0fed7072a15","added_by":"auto","created_at":"2025-10-17 02:30:16","extension":"pdf","order_by":2,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":251158,"visible":true,"origin":"","legend":"","description":"","filename":"Supplements.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7545687/v1/434b58f730e0746ca7a90796.pdf"},{"id":93730917,"identity":"d9f0b0ff-4a53-4324-8e31-e38603d8cfa4","added_by":"auto","created_at":"2025-10-17 02:22:16","extension":"xml","order_by":3,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":111099,"visible":true,"origin":"","legend":"","description":"","filename":"88d9de1a91eb4a76a09efac79cfadca41enriched.xml","url":"https://assets-eu.researchsquare.com/files/rs-7545687/v1/bfc5ad7f1765362c93dd023c.xml"},{"id":93730914,"identity":"11d70f63-e961-49ca-ac60-9993642035a3","added_by":"auto","created_at":"2025-10-17 02:22:16","extension":"png","order_by":8,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":33454,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-7545687/v1/282bc3382694db117563d97f.png"},{"id":93730916,"identity":"87f38f0d-c718-4e6d-8045-9cbc9fad0e81","added_by":"auto","created_at":"2025-10-17 02:22:16","extension":"png","order_by":9,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":70846,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-7545687/v1/bb8982b986e4d2cbadaa3b5f.png"},{"id":93730918,"identity":"28c72c24-fa8f-4381-8460-f53bce806783","added_by":"auto","created_at":"2025-10-17 02:22:16","extension":"png","order_by":10,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":78888,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-7545687/v1/a7ef053cfd5072343a48a27f.png"},{"id":93730919,"identity":"9cccaccc-8958-4f9e-9178-d42268009847","added_by":"auto","created_at":"2025-10-17 02:22:16","extension":"png","order_by":11,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":65489,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-7545687/v1/3bb45dee829204a58a586344.png"},{"id":93730911,"identity":"d6bf3fd9-8e0a-4cd7-86ca-719d7116a5f6","added_by":"auto","created_at":"2025-10-17 02:22:16","extension":"xml","order_by":12,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":96838,"visible":true,"origin":"","legend":"","description":"","filename":"88d9de1a91eb4a76a09efac79cfadca41structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-7545687/v1/2119a1ff5a361f7d7d0ee4cb.xml"},{"id":93730910,"identity":"eb12cd64-cfe2-4a91-9bbf-e04d50e78197","added_by":"auto","created_at":"2025-10-17 02:22:16","extension":"html","order_by":13,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":131048,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7545687/v1/41d162cf67fb2a40eb37b286.html"},{"id":93732348,"identity":"e9b043f0-7c1e-4579-8310-74de93c5823c","added_by":"auto","created_at":"2025-10-17 02:30:15","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":105614,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTreatment strategy per line of palliative treatment in patients with \u003c/strong\u003e\u003cem\u003e\u003cstrong\u003erare ALK \u003c/strong\u003e\u003c/em\u003e\u003cstrong\u003efusions. *\u003c/strong\u003e: 5 patients did not receive any antineoplastic treatment. \u003cem\u003eOther:\u003c/em\u003e 1\u003csup\u003est\u003c/sup\u003e line: 1x Pembrolizumab, 1x Capecitabine/Temozolomide, 1x investigational medication, 2\u003csup\u003end\u003c/sup\u003e line:\u0026nbsp; 1x Docetaxel/Ramucirumab, 1x Pembrolizumab, 3\u003csup\u003erd\u003c/sup\u003e line: 1x Docetaxel, 4\u003csup\u003eth\u003c/sup\u003e line: 1x Docetaxel/Ramucirumab.\u003c/p\u003e","description":"","filename":"floatimage119.png","url":"https://assets-eu.researchsquare.com/files/rs-7545687/v1/895460e5a9aaac5e8072ba07.png"},{"id":93730906,"identity":"e67106bf-e506-427b-9dae-bb0a8f61194b","added_by":"auto","created_at":"2025-10-17 02:22:15","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":420844,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eDisease control rate (DCR) and objective response rate (ORR) of first ALK inhibitor in patients with \u003c/strong\u003e\u003cem\u003e\u003cstrong\u003erare ALK\u003c/strong\u003e\u003c/em\u003e\u003cstrong\u003e fusions.\u003c/strong\u003e \u003cstrong\u003eA:\u003c/strong\u003e DCR and ORR in patients with \u003cem\u003erare ALK\u003c/em\u003e fusions (n=42) for first treatment with ALK TKI, irrespectively of treatment line. \u003cstrong\u003eB\u003c/strong\u003e: ORR to first ALK TKI by fusion partner in patients with \u003cem\u003erare ALK\u003c/em\u003efusions. The size of the bubble represents the number of patients in the subgroup, respectively.\u003c/p\u003e","description":"","filename":"floatimage214.png","url":"https://assets-eu.researchsquare.com/files/rs-7545687/v1/0cae0553d26dfaceff332559.png"},{"id":93732351,"identity":"fc6b88fd-0e73-4f37-9b05-010a6d4b4a03","added_by":"auto","created_at":"2025-10-17 02:30:16","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":351225,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eEfficacy of first-line TKI. \u003c/strong\u003eKaplan-Meier plots with 95% confidence intervals for progression-free survival and overall survival in patients with \u003cem\u003erare ALK\u003c/em\u003e fusions as compared to EML4::ALK fusions during first-line therapy with ALK inhibitors in advanced NSCLC.\u003c/p\u003e","description":"","filename":"floatimage315.png","url":"https://assets-eu.researchsquare.com/files/rs-7545687/v1/7b206f05a40ed2887d4f59f7.png"},{"id":93730913,"identity":"0d9852f8-99dd-42a2-bfaa-ca8c7e8fbbc4","added_by":"auto","created_at":"2025-10-17 02:22:16","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":278144,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFirst-line chemotherapy vs TKI in patients with \u003c/strong\u003e\u003cem\u003e\u003cstrong\u003erare ALK \u003c/strong\u003e\u003c/em\u003e\u003cstrong\u003efusions. \u003c/strong\u003eKaplan-Meier-Curves with 95% confidence intervals for progression-free survival and overall survival in patients with \u003cem\u003erare ALK\u003c/em\u003e fusions to first-line therapy with platinum-based chemotherapy (grey) versus ALK TKI (red) in advanced NSCLC.\u003c/p\u003e","description":"","filename":"floatimage43.png","url":"https://assets-eu.researchsquare.com/files/rs-7545687/v1/cb62e3c09659917298e60c1b.png"},{"id":93732835,"identity":"9c135946-7c43-44a3-8c54-2bcb6a5a43a1","added_by":"auto","created_at":"2025-10-17 02:38:17","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2080978,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7545687/v1/6606c2a7-e466-4913-9967-6c14778977f8.pdf"},{"id":93730905,"identity":"4811c8da-326f-46d6-8310-8f6c9bfffdb2","added_by":"auto","created_at":"2025-10-17 02:22:15","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":251158,"visible":true,"origin":"","legend":"\u003cp\u003eSupplements.docx (6 figures and/or tables).\u003c/p\u003e","description":"","filename":"Supplements.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7545687/v1/59db532c2aae14913fb4360f.pdf"}],"financialInterests":"Competing interest reported. MEL: Honoraria: AstraZeneca. FCS: Advisory Board / Consultancy: Johnson/Johnson, BMS, Boehringer Ingelheim, AstraZeneca, Pfizer, MSD, Roche. Honoraria: Johnson/Johnson, Takeda, AstraZeneca, Lilly, Pfizer, Novartis, Accord Healthcare, Thieme, German Society for Thoracic Surgery, CME Verlag, GWT-TUD. Travel Expenses: Johnson\u0026Johnson, AstraZeneca, Lilly, Takeda. Research Funding: Roche. LR: Advisory Board / Consultancy: Amgen, Johnson\u0026Johnson. Travel Expenses: Amgen. DKG: Honoraria: AstraZeneca, Boehringer Ingelheim, BMS, Roche, MSD, Pfizer, GSK, Novartis, Janssen, Takeda. Speakers’ Bureau: Daiichi Sankyo, Boehringer Ingelheim. Travel Expenses: Takeda, Pfizer, AstraZeneca, Johnson\u0026Johnson. Daiichi Sankyo. Research Funding: Gilead. OI: Honoraria: Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Johnson\u0026Johnson, Merck Sharp \u0026 Dohme, Pfizer, and Roche. Advisory Board / Consultancy: Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Johnson\u0026Johnson, Merck Sharp \u0026 Dohme, Pfizer, and Roche. Speakers’ Bureau: Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Menarini, Merck Sharp \u0026 Dohme, Pfizer, and Roche. Research Funding: Amgen and AstraZeneca. Travel Expenses: Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Merck Sharp \u0026 Dohme, Pfizer, and Roche. AS: Advisory Board / Consultancy: Amgen, Astellas Pharma, AstraZeneca, Bayer, Bristol-Myers Squibb, Illumina, Incyte, Janssen, Lilly, MSD, Novartis, SERVIER, Takeda, Thermo Fisher Scientific. Speakers' Bureau: Astellas Pharma, AstraZeneca, Bayer, Bristol-Myers Squibb, Illumina, MSD, Novartis, Roche, SERVIER, Thermo Fisher Scientific. Research Funding: Bayer, Bristol-Myers Squibb, Chugai Pharma, Incyte. KMF: Honoraria: AstraZeneca. AR: Advisory Board / Consultancy: AbbVie, AstraZeneca/MedImmune, Boehringer Ingelheim, Bristol-Myers Squibb, Daichi Sankyo, GlaxoSmithKline, Lilly, MSD, Novartis, Pfizer, Roche/Genentech. Speakers' Bureau: Bristol-Myers Squibb, Lilly, MSD, Roche/Genentech. Uncompensated Relationships: Roche/Genentech. IG: Travel Expenses: Novartis, AstraZeneca. BE: Honoraria: AstraZeneca. Advisory Board / Consultancy: Sanofi. CS: Honoraria: AstraZeneca. SIR: Honoraria: Amgen (Inst), AstraZeneca (Inst), Bayer (Inst), Boehringer Ingelheim (Inst), Bristol-Myers Squibb (Inst), Eisai (Inst), Janssen Oncology (Inst), Lilly (Inst), Merck Serono (Inst), MSD Oncology (Inst), Novartis (Inst), Otsuka (Inst), Pfizer (Inst), PharmaMar (Inst), Roche Pharma AG (Inst), Sanofi (Inst), Takeda (Inst). Consulting or Advisory Role: Amgen (Inst), AstraZeneca (Inst), Boehringer Ingelheim (Inst), Bristol-Myers Squibb (Inst), Eisai (Inst), Lilly (Inst), Merck Serono (Inst), MSD Oncology (Inst), Novartis (Inst), Otsuka (Inst), Pfizer (Inst), PharmaMar (Inst), Roche Pharma AG (Inst), Takeda (Inst). Speakers' Bureau: Amgen (Inst), AstraZeneca (Inst), AstraZeneca (Inst), Roche Pharma AG (Inst), Sanofi/Aventis (Inst), Takeda (Inst). Research Funding: Abbvie (Inst), AstraZeneca (Inst), Boehringer Ingelheim (Inst), Bristol-Myers Squibb (Inst), Merck Serono (Inst), Roche Pharma AG (Inst). Travel, Accommodations, Expenses: Amgen (Inst), Amgen (Inst), AstraZeneca (Inst), Boehringer Ingelheim (Inst), Bristol-Myers Squibb (Inst), MSD Oncology (Inst), Roche Pharma AG (Inst), Sanofi; Takeda (Inst). Other Relationship: Federal Drug Commission of the Swiss Federal Office of Public Health, Swiss Group for Clinical Cancer Research (SAKK) (Inst). CG: Honoraria: Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Merck Sharp \u0026 Dohme, Pfizer, Roche. Consulting or Advisory Role: Boehringer Ingelheim, Merck Sharp \u0026 Dohme, Novartis, Pfizer, Roche. KA: Consulting or Advisory Role: AstraZeneca, BeiGene, Bristol-Myers Squibb, MSD, Roche, Takeda. KM: Honoraria: Amgen, AstraZeneca, Bristol-Myers Squibb, Janssen, MSD, Pfizer, Takeda. Consulting or Advisory Role: Amgen, AstraZeneca, Bristol-Myers Squibb, Janssen, MSD, Pfizer, Takeda. UJ: Honoraria: AstraZeneca, Boehringer Ingelheim, MSD Oncology, Pfizer, Roche, Takeda. CFW: Honoraria: Alvotech, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai Pharma, Lilly, Merck, Merck Sharp \u0026 Dohme, Mylan/Viatris, Novartis, Pfizer, Roche, Takeda. Consulting or Advisory Role: Alvotech, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai/Roche, Lilly, Merck, MSD, Mylan/Viatris, Novartis/Ipsen, Pfizer, Roche, Takeda, Vifor Pharma. Travel Expenses: AstraZeneca, Bristol-Myers Squibb, Ipsen, Janssen, Lilly. TRO: Advisory Board / Consultancy: AstraZeneca, BMS GmbH \u0026 Co. KG, Boehringer Ingelheim, Daiichi Sankyo Europe GmbH, Johnson \u0026 Johnson/Janssen, Merck KGaA, Pfizer, Pierre Fabre, Roche. Travel Expenses: AstraZeneca, Daiichi Sankyo Europe Gmb. LAM: Advisory Board / Consultancy: Amgen, AstraZeneca, BMS, Merck, MSD, Novartis, Pfizer, Roche Pharma, Regeneron, Janssen, Daichii-Sankyo. Research funding: AstraZeneca, Gilead. Honoraria: Merck, AstraZeneca. Expert testimony: BMS. Travel and accommodations: Sanofi, AstraZeneca, and Roche. MW: Honoraria / Advisory Board / Consultancy: Amgen, AstraZeneca, Daiichi Sankyo, GlaxoSmithKline, Janssen, Novartis, Pfizer, Roche, Takeda. Research funding: Bristol-Myers Squibb, Takeda. MF: Research funding: AstraZeneca, BMS, MSD, and Roche. Honoraria / Consultancy: AstraZeneca, MSD, Roche, BMS, AstraZeneca, MSD, Roche, BMS. WK: Honoraria: MSD, Bristol-Myers Squibb, Novartis, and AstraZeneca. MI: Honoraria / Advisory Board: Amgen, AstraZeneca, Astellas Pharma, Bayer, Boehringer Ingelheim, Janssen, Merck Sharp \u0026 Dohme, Pfizer, Roche, and Takeda. SMB: Honoraria / Advisory Board: AstraZeneca, Novartis, Roche, BMS, Illumina, DLS, Daiichi-Sankyo, QuIP, Stemline. Research Funding: AstraZeneca, Roche, Zytovision QuIP. CW: Honoraria: AstraZeneca. DEA: Honoraria: Roche, AstraZeneca, MSD, Pfizer. MT: Honoraria: Amgen, AstraZeneca, BeiGene, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Chugai Pharma, Daiichi Sankyo Europe GmbH, GlaxoSmithKline, Janssen Oncology, Lilly, Merck, MSD, Novartis, Pfizer, Roche, Sanofi, Takeda. Consulting or Advisory Role: Amgen, AstraZeneca, BeiGene, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Chugai Pharma, Daiichi Sankyo Europe GmbH, GlaxoSmithKline, Janssen Oncology, Lilly, Merck, MSD, Novartis, Pfizer, Roche, Sanofi, Takeda. Research Funding: AstraZeneca (Inst), Bristol-Myers Squibb (Inst), Merck (Inst), Roche (Inst), Takeda (Inst). Travel, Accommodations, Expenses: Astrazeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo Europe GmbH, Janssen Oncology, Lilly, Merck, MSD, Novartis, Pfizer, Roche, Sanofi, Takeda. MJH: Consulting or Advisory Role: AstraZeneca/Daiichi Sankyo, Lilly, Roche, Takeda. Speakers' Bureau: Lilly, MSD Oncology, Novartis, Roche. PC: Honoraria: AstraZeneca, Boehringer Ingelheim, Chugai Pharma, Daiichi Sankyo/Astra Zeneca, Gilead Sciences, Merck Serono, Novartis, Pfizer, Roche, Takeda. Research Funding: Amgen (Inst), AstraZeneca (Inst), Boehringer Ingelheim (Inst), Merck Serono (Inst), Roche (Inst), Takeda (Inst). MW: Honoraria: Amgen, BMS GmbH \u0026 Co. KG, Boehringer Ingelheim, GWT, Janssen, Lilly, Merck Serono, Merck Serono, Novartis, Pfizer, SYNLAB. Consulting or Advisory Role: Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo Europe GmbH, ImCheck therapeutics, immatics, ISA Pharmaceuticals, Lilly, Novartis, PharmaMar, Regeneron, Tacalyx, Zymeworks. Research Funding: Roche (Inst). Travel, Accommodations, Expenses: Amgen, AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo Europe GmbH, GEMoaB, immatics, Iovance Biotherapeutics, Janssen Oncology, Merck Serono, Pfizer, Sanofi/Aventis. \nThe other authors (KS, AR, AT, SH, SB, RS, KS, RL, SS, UW, SSF, HS, RV) have nothing to declare.","formattedTitle":"Efficacy of targeted therapy in lung cancer with rare ALK fusions","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eThe frequency of \u003cem\u003eAnaplastic Lymphoma Kinase (ALK)\u003c/em\u003e fusions in non-small cell lung cancer (ALK\u0026thinsp;+\u0026thinsp;NSCLC) ranges between 3\u0026ndash;5%. Affected patients are predominantly non-smokers and considerably younger than the general NSCLC population. [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e], [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e] It has been clearly shown that treatment with an ALK-specific tyrosine kinase inhibitor (TKI) is superior to platinum-based combination therapy in these patients. [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e] More recently, first-line treatment with the 3rd generation TKI lorlatinib has been associated with an unprecedented 5-year progression-free survival (PFS) rate of 60%. [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/p\u003e\u003cp\u003e\u003cem\u003eEchinoderm Microtubule Associated Protein-Like 4 (EML4)\u003c/em\u003e is the ALK fusion partner in 80%-90% of ALK\u0026thinsp;+\u0026thinsp;NSCLC. [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e] In the remaining 10%-20%, ALK fusions involve a heterogeneous group of over 90 different partner genes [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Evidence regarding the optimal treatment of patients with these rare ALK fusions (\u003cem\u003erare ALK\u003c/em\u003e) is currently limited to case reports and small case series. [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] Crizotinib was the TKI used in most of these reports and showed significant benefit in some, but not all cases [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Considerable uncertainty therefore remains on how to treat patients with \u003cem\u003erare ALK\u003c/em\u003e in the palliative first-line setting.\u003c/p\u003e\u003cp\u003eHere, we report a large international real-world analysis of \u003cem\u003erare ALK\u003c/em\u003e fusion positive NSCLC treated with second and third generation TKI and compare their characteristics and outcome to an EML4::ALK positive control cohort.\u003c/p\u003e"},{"header":"RESULTS","content":"\u003cp\u003e\u003cstrong\u003eALK fusion prevalence and patient characteristics\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn an international, retrospective, multicenter approach, we collected data from 26,152 NSCLC patients (62% adenocarcinoma) that underwent local NGS-testing capable of detecting both EML4::ALK and \u003cem\u003erare ALK\u003c/em\u003e fusions. An EML4::ALK fusion was identified in 509 (1.9%) and a \u003cem\u003erare ALK\u003c/em\u003e fusion in 55 (0.2%) patients. Sufficient clinical data was available for 242 and 28 patients, respectively. An additional 119 and 20 cases, respectively, were contributed from other centers that did not report the total number of NSCLC samples tested at their site. In the \u003cem\u003erare ALK\u003c/em\u003e cohort, seven patients were excluded due to early-stage disease (\u003cem\u003eN\u003c/em\u003e=2), non-validation of the ALK fusion (sequencing artifact, \u003cem\u003eN\u003c/em\u003e=1), concurrent other driver alteration (\u003cem\u003eN\u003c/em\u003e=3), and less than three months follow-up (\u003cem\u003eN\u003c/em\u003e=1). In the control cohort, 84 cases were excluded for not meeting eligibility criteria as follows: early-stage disease (\u003cem\u003eN\u003c/em\u003e=8), implausible data (e.g., diagnosis date after initial treatment, \u003cem\u003eN\u003c/em\u003e=33), and lack of follow-up (\u003cem\u003eN\u003c/em\u003e=43). In the entire cohort, 277 (EML4::ALK) and 51 (\u003cem\u003erare ALK\u003c/em\u003e) patients met the eligibility criteria and were hence used for further analyses (see \u003cstrong\u003eSupplement 1\u0026nbsp;\u003c/strong\u003efor the study flowchart).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCompared to the EML4::ALK cohort, patients with \u003cem\u003erare ALK\u003c/em\u003e fusions tended to be older (median age 66 vs 59 years, p=0.04) and were more likely to be current or former smokers (59% vs 35%, p=0.006). Smokers with \u003cem\u003erare ALK\u003c/em\u003e fusions reported more pack years than those with EML4::ALK (14.7 vs. 6.7 pack years, p=0.009). Squamous histology was infrequently reported in the EML4::ALK cohort (1%) but occurred in 10% of the \u003cem\u003erare ALK\u003c/em\u003e patients (see \u003cstrong\u003eTable 1\u0026nbsp;\u003c/strong\u003efor full patient characteristics).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWe detected a total of 21 different fusion partners of which 15 occurred only once (non-recurrent \u003cem\u003erare ALK\u003c/em\u003e fusions). The most common fusions were KIF5B::ALK (12/51, 24%), HIP1::ALK (6/51, 12%), GCC2::ALK (5/51, 10%) and KLC1::ALK (5/51, 10%). In all \u003cem\u003erare\u003c/em\u003e ALK fusions reported, ALK was the 3\u0026rsquo; fusion partner preserving an intact tyrosine kinase domain (exons 20 to 29). A complete list of fusions with breakpoints is provided in \u003cstrong\u003eSupplement 2\u003c/strong\u003e. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTKIs, predominately alectinib, were used as first line of palliative treatment in nearly all patients with EML4::ALK (96%) but only in 71 % of patients with \u003cem\u003erare ALK\u003c/em\u003e. In the latter group, 14% of patients received platinum-based chemotherapy and 10% best supportive care as the primary treatment approach. In contrast, none of the patients with EML4::ALK was managed with chemotherapy in the palliative first-line setting and only 4% were deemed unsuitable for any tumor-directed treatment. Of note, 18% of the subjects in the \u003cem\u003erare ALK\u003c/em\u003e group never received a TKI during the course of their disease (\u003cstrong\u003eTable 1, Figure 1\u003c/strong\u003e).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1. Patient characteristics.\u0026nbsp;\u003c/strong\u003eIn case of missing data, the number of individuals with available data is indicated next to the respective variable. Where data were completely available, no indication was made. CNS: Central nervous system. NA = not available. Other therapy included: pembrolizumab (N=1), capecitabin + temozolomide (N=1), erlotinib + onartuzumab (N=1). \u0026nbsp;*difference statistically significant by t-test or Pearson Chi-square at alpha 0.05.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" align=\"\" width=\"604\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 395px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCharacteristics\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eEML4::ALK\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eRare ALK\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 395px;\"\u003e\n \u003cp\u003eTotal number of patients\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e277\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e51\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 395px;\"\u003e\n \u003cp\u003eAge, y, median (25\u003csup\u003eth\u003c/sup\u003e; 75\u003csup\u003eth\u003c/sup\u003e percentile)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e59 (49; 69)*\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e66 (53; 72)*\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 395px;\"\u003e\n \u003cp\u003eSex (\u003cem\u003eN\u003c/em\u003e=277, 51), \u003cem\u003eN\u003c/em\u003e (%)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Female\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Male\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e143 (52)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e134 (48)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e21 (41)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e30 (59)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 395px;\"\u003e\n \u003cp\u003eSmoking (\u003cem\u003eN\u003c/em\u003e=266, 49), \u003cem\u003eN\u003c/em\u003e (%)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Active Smoker\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Former Smoker\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Never Smoker\u003c/p\u003e\n \u003cp\u003ePack years in smokers (N = 249, 48), median\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e32 (12)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e63 (23)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e161 (58)*\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e6,7*\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e11 (22)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e19 (37)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e19 (37)*\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e14,7*\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 395px;\"\u003e\n \u003cp\u003eCNS metastases (\u003cem\u003eN\u003c/em\u003e=276, 51), \u003cem\u003eN\u003c/em\u003e (%)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;CNS metastases at first diagnosis\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;CNS metastasis at any time point\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eNA\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e104 (38)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e11 (22)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e19 (37)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 395px;\"\u003e\n \u003cp\u003eHistology at first diagnosis (\u003cem\u003eN\u003c/em\u003e=277, 51), \u003cem\u003eN\u003c/em\u003e (%)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Adenocarcinoma\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Squamous-cell carcinoma\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Adenosquamous carcinoma\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Undifferentiated carcinoma NOS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e261 (94)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e4 (1)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e4 (1)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e5 (2)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e45 (88)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e5 (10)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e1 (2)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 395px;\"\u003e\n \u003cp\u003eFirst line treatment in advanced stage (\u003cem\u003eN\u003c/em\u003e=264, 51), \u003cem\u003eN\u003c/em\u003e (%)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Crizotinib\u003cbr\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Brigatinib\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Ceritinib\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Alectinib\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Lorlatinib\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Platinum based chemotherapy\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Other therapy\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;No therapy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e30 (11)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e50 (19)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e3 (1)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e149 (56)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e22 (8)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e0\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e0 (0)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e10 (4)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e5 (10)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e2 (4)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e0 (0)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e24 (47)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e5 (10)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e7 (14)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e3 (6)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e5 (10)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eTreatment outcome\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOverall survival for the entire cohort irrespective of treatment was shorter in patients with \u003cem\u003erare ALK\u003c/em\u003e as opposed to EML4::ALK fusions (median 27 months vs 57 months, HR 1.6, 95% CI 0.9-2.6, p=0.08; \u003cstrong\u003eSupplement 3\u003c/strong\u003e). However, when analyzing response to the first TKI ever received, efficacy of ALK inhibitors in patients with \u003cem\u003erare ALK\u003c/em\u003e was considerable with an objective response rate (ORR) of 71% (95% CI 56%-83%) and a disease control rate (DCR) of 88% (95% CI 73%-96%) (\u003cstrong\u003eFigure 2A).\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eResponses to TKI were observed in all types of recurrent \u003cem\u003erare ALK\u003c/em\u003e fusions (CLIP::ALK, DCTN1::ALK, GCC2::ALK, HIP1::ALK, KLC1::ALK) and in the majority (7/9) of the non-recurrent fusions. Response rates ranged between 40% and 100% in the former group (\u003cstrong\u003eFigure 2B\u003c/strong\u003e). In the latter group, the two non-responding patients (ETV6::ALK, SFTB::ALK) achieved prolonged disease stabilization beyond six months upon first exposure to an TKI. There was no evident association between the likelihood of response to a TKI and the specific exonic breakpoint at which the ALK fusion occurred (\u003cstrong\u003eSupplement 4\u003c/strong\u003e). Among responders (n=30), all patients tested for ALK expression by immunohistochemistry (IHC) were IHC positive (19/19). Among non-responders (N=12), 9/12 tested patients were IHC positive. For two of them, ALK FISH was available and tested positive (\u003cstrong\u003eSupplement 5\u003c/strong\u003e).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWhen focusing on patients receiving an ALK inhibitor as first-line therapy, ORR was similar between EML4::ALK (85%, 95% CI 79-89) and rare ALK (74%, 95% CI 56-87; p=0.9) groups. \u0026nbsp;Median PFS was 25 months in the former and 23 months and the latter group (HR 0.9, 95% CI 0.6-1.5, p=0.7) with 53% (132/247) and 50% (18/36) of PFS events having occurred, respectively (\u003cstrong\u003eFigure\u003c/strong\u003e \u003cstrong\u003e3A\u003c/strong\u003e). Overall survival (OS) was immature (34% and 31 % of events having occurred in EML4::ALK and rare ALK, respectively). Nevertheless, survival curves were largely overlapping\u0026nbsp;(median OS 57 vs 40 months, HR 0.9, 96% CI 0.5-1.6, p=0.6) for patients with EML4::ALK and\u003cem\u003e\u0026nbsp;rare ALK\u003c/em\u003e fusions receiving a TKI as first-line therapy (\u003cstrong\u003eFigure 3B\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003eIn contrast, the use of platinum-based chemotherapy in palliative first-line was associated with a significantly reduced PFS compared to treatment with TKI in patients with \u003cem\u003erare ALK\u003c/em\u003e (HR 3.1, 95% CI 1.2-8, p = 0.02, \u003cstrong\u003eFigure\u003c/strong\u003e \u003cstrong\u003e4A\u003c/strong\u003e). \u0026nbsp;In addition, OS tended to be inferior in these patients (median 24 months vs 40 months for platinum vs targeted therapy, HR 2, 95% CI 0.7-5.9) although this trend did not reach statistical significance (p=0.2; \u003cstrong\u003eFigure 4B\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003eBeyond treatment with platinum-based chemotherapy, non-adenocarcinoma histology was also associated with shorter PFS in patients with \u003cem\u003erare ALK\u003c/em\u003e fusions (HR 9.6, 95% CI 2.6-36.3, p\u0026lt;0.01). A history of smoking and an ECOG performance status of 2-3 showed a statistically non-significant trend towards impaired PFS (\u003cstrong\u003eSupplement 6\u003c/strong\u003e).\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThe broad application of NGS gene fusion assays has led to an increasing number of \u003cem\u003erare ALK\u003c/em\u003e fusion partners being identified. Little is known on the specific efficacy of TKIs in this subgroup, with most of the evidence being derived from case reports or small case series[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. It has been described for other actionable genomic alterations in NSCLC that rare and atypical alterations may be generally insensitive to standard targeted therapy (EGFR Exon 20 insertions[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]) or in itself very heterogeneous (BRAF non-V600 mutations[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e], [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]).\u003c/p\u003e\u003cp\u003eHere, we describe a cohort of patients with \u003cem\u003erare ALK\u003c/em\u003e fusions and compare characteristics and outcome to a group of EML4::ALK positive NSCLC treated at the same set of institutions within the same period. The observed frequency of ALK fusions (3.5% in adenocarcinoma, 1.9% in unselected NSCLC) is in line with previous reports (2\u0026ndash;8%) [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e], [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e], [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eIn the overall cohort, median OS was about 30 months shorter in \u003cem\u003erare ALK\u003c/em\u003e compared to EML4::ALK fusion positive patients (27 vs. 57 months). This might relate to differences both in tumor biology and in patient characteristics, especially to the higher proportion of current or former smokers and the higher median age within the \u003cem\u003erare ALK\u003c/em\u003e cohort. It is, however, notable that fewer patients with \u003cem\u003erare ALK\u003c/em\u003e fusions received a TKI as first line of palliative treatment (71% vs. 96%). The use of a platinum-doublet regimen in this group and setting was associated with a significantly inferior PFS compared to a TKI (HR 3.1, 95% CI 1.2-8, p\u0026thinsp;=\u0026thinsp;0.02). The median PFS with chemotherapy (5 months) aligned well with real-world reports on chemotherapy treated unselected ALK fusion positive patients[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Another notable difference between the \u003cem\u003erare\u003c/em\u003e ALK and EML4::ALK cohort was the higher proportion of patients assigned to best supportive care in the former (10% vs. 4%).\u003c/p\u003e\u003cp\u003eWhen focusing on those individuals who received a TKI (mainly alectinib) as their first line of treatment, ORR and PFS did not differ significantly between \u003cem\u003erare ALK\u003c/em\u003e and EML4::ALK patients (ORR 74% vs. 85%, median PFS 23 vs. 25 months). Along the same lines, a similar efficacy has been described for crizotinib in a smaller Chinese single center study comparing 11 \u003cem\u003erare ALK\u003c/em\u003e to 49 EML4::ALK fusion positive patients[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eWe observed clinical activity of ALK inhibitors across all fusion partners, which suggests that \u003cem\u003erare ALK\u003c/em\u003e fusions as a group should be seen as TKI-sensitive in NSCLC provided the individual rearrangement preserves the tyrosine kinase domain and passes quality controls of the applied assay. ALK IHC did not allow for predicting response in \u003cem\u003erare\u003c/em\u003e ALK as all but three tested patients were positive.\u003c/p\u003e\u003cp\u003eOur study has several limitations inherent to its multicenter retrospective design. First, the exact estimation of fusion frequency is limited by differences in the assays used across 29 different institutions. In addition, the differential outcome between TKI and chemotherapy-treated \u003cem\u003erare ALK\u003c/em\u003e patients might be due to selection bias, with patients presenting with an aggressive disease phenotype being more likely to receive chemotherapy upfront. The median PFS observed in our first-line TKI-treated \u003cem\u003erare ALK\u003c/em\u003e and EML4::ALK cohorts compares unfavorably to the alectinib arm of the phase III ALEX trial (23 vs. 25 vs. 35 months). It is, however, similar to recently published real world data [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Finally, we lack comprehensive data on the efficacy of third generation ALK inhibitors since most patients were treated before lorlatinib became widely available and a standard-of-care first-line approach[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eAcknowledging these limitations and in the absence of prospective evidence, we conclude that our study supports the use of TKIs as first line of treatment in NSCLC with \u003cem\u003erare ALK\u003c/em\u003e fusions.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\u003ch2\u003eStudy design\u003c/h2\u003e\u003cp\u003eWe conducted a retrospective, multicenter chart analysis among 29 international lung cancer centers from 6 countries (Germany, Switzerland, Austria, Greece, Slovenia, Israel). Adult patients were eligible for inclusion if they had (1) histologic diagnosis of NSCLC in advanced stage without curative treatment options, (2) an ALK fusion as detected by next generation sequencing (NGS), and (3) follow-up of at least three months after start of palliative therapy. Patients with additional driver alterations were excluded. Data were collected for two cohorts: (a) the \u003cem\u003erare ALK\u003c/em\u003e cohort (defined as any ALK fusion with a partner other than EML4) for which a comprehensive dataset was compiled including patient characteristics, detailed NGS findings as reported by clinical routine testing, and clinical outcomes across all lines of therapy, and (b) and a control cohort of patients with EML4::ALK fusions in which we collected a reduced data set focused on key patient characteristics and first-line targeted therapy. Overall, the dataset was largely complete, though some variables (e.g., ECOG performance status, TP53 status) were occasionally missing at random.\u003c/p\u003e\u003cp\u003eIn addition to individual patient data, we requested institution-level molecular testing data. Centers reported the total number of NSCLC patients (all histologic subtypes) tested with an NGS assay capable of detecting ALK fusions, and among those patients the frequency of EML4::ALK and \u003cem\u003erare ALK\u003c/em\u003e fusions.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003eAnalysis of patient characteristics and clinical endpoints\u003c/h2\u003e\u003cp\u003ePatient characteristics were analyzed with appropriate descriptive statistics and compared with t-test at alpha 0.05 or Pearson\u0026rsquo;s chi-squared test. Evaluation of treatment response was performed at the individual centers according to the Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST), assessed by the investigator or local radiologist without central review. 95% confidence intervals for objective response rate (ORR) were calculated using the Wilson method.\u003c/p\u003e\u003cp\u003eProgression-free survival (PFS) was analyzed using Kaplan-Meier estimates, calculated from the start of therapy to the date of progression, initiation of a new systemic anti-cancer therapy, or death. Data were censored at the date of last follow-up if none of these events had occurred at the time of analysis. Overall survival (OS) was assessed using Kaplan-Meier estimates, calculated from start of therapy until date of death. For patients who were alive at their latest follow-up, data were censored accordingly. We performed Cox-regression analyses and estimated hazard ratios to compare survival outcomes.\u003c/p\u003e\u003cp\u003eStatistical analyses were performed with IBM SPSS Statistics (version 30.0) and R (R version 4.4.1, R Foundation for Statistical Computing). The figures and tables were generated using R and Microsoft Office 2019.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eDeclaration of potential conflicts of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMEL\u003c/strong\u003e: Honoraria: AstraZeneca. \u0026nbsp;\u003cstrong\u003eFCS\u003c/strong\u003e: Advisory Board / Consultancy: Johnson/Johnson, BMS, Boehringer Ingelheim, AstraZeneca, Pfizer, MSD, Roche. Honoraria: Johnson/Johnson, Takeda, AstraZeneca, Lilly, Pfizer, Novartis, Accord Healthcare, Thieme, German Society for Thoracic Surgery, CME Verlag, GWT-TUD. Travel Expenses: Johnson\u0026amp;Johnson, AstraZeneca, Lilly, Takeda. Research Funding: Roche. \u003cstrong\u003eLR\u003c/strong\u003e: Advisory Board / Consultancy: \u0026nbsp;Amgen, Johnson\u0026amp;Johnson. Travel Expenses: Amgen. \u003cstrong\u003eDKG:\u0026nbsp;\u003c/strong\u003eHonoraria: AstraZeneca, Boehringer Ingelheim, BMS, Roche, MSD, Pfizer, GSK, Novartis, Janssen, Takeda. Speakers\u0026rsquo; Bureau: Daiichi Sankyo, Boehringer Ingelheim. Travel Expenses: Takeda, Pfizer, AstraZeneca, Johnson\u0026amp;Johnson. Daiichi Sankyo. Research Funding: Gilead. \u003cstrong\u003eOI:\u0026nbsp;\u003c/strong\u003eHonoraria: Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Johnson\u0026amp;Johnson, Merck Sharp \u0026amp; Dohme, Pfizer, and Roche\u003cstrong\u003e.\u0026nbsp;\u003c/strong\u003eAdvisory Board / Consultancy: Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Johnson\u0026amp;Johnson, Merck Sharp \u0026amp; Dohme, Pfizer, and Roche. Speakers\u0026rsquo; Bureau: Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Menarini, Merck Sharp \u0026amp; Dohme, Pfizer, and Roche. Research Funding: Amgen and AstraZeneca. Travel Expenses: Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Merck Sharp \u0026amp; Dohme, Pfizer, and Roche. \u003cstrong\u003eAS:\u003c/strong\u003e Advisory Board / Consultancy: Amgen, Astellas Pharma, AstraZeneca, Bayer, Bristol-Myers Squibb, Illumina, Incyte, Janssen, Lilly, MSD, Novartis, SERVIER, Takeda, Thermo Fisher Scientific. Speakers\u0026apos; Bureau: Astellas Pharma, AstraZeneca, Bayer, Bristol-Myers Squibb, Illumina, MSD, Novartis, Roche, SERVIER, Thermo Fisher Scientific. Research Funding: Bayer, Bristol-Myers Squibb, Chugai Pharma, Incyte. \u003cstrong\u003eKMF:\u003c/strong\u003e Honoraria: AstraZeneca. \u003cstrong\u003eAR\u003c/strong\u003e: Advisory Board / Consultancy: AbbVie, AstraZeneca/MedImmune, Boehringer Ingelheim, Bristol-Myers Squibb, Daichi Sankyo, GlaxoSmithKline, Lilly, MSD, Novartis, Pfizer, Roche/Genentech. Speakers\u0026apos; Bureau: Bristol-Myers Squibb, Lilly, MSD, Roche/Genentech. Uncompensated Relationships: Roche/Genentech. \u003cstrong\u003eIG\u003c/strong\u003e: Travel Expenses: Novartis, AstraZeneca. \u003cstrong\u003eBE:\u0026nbsp;\u003c/strong\u003eHonoraria: AstraZeneca. Advisory Board / Consultancy: Sanofi. \u003cstrong\u003eCS:\u0026nbsp;\u003c/strong\u003eHonoraria: AstraZeneca. \u003cstrong\u003eSIR:\u003c/strong\u003e Honoraria: Amgen (Inst), AstraZeneca (Inst), Bayer (Inst), Boehringer Ingelheim (Inst), Bristol-Myers Squibb (Inst), Eisai (Inst), Janssen Oncology (Inst), Lilly (Inst), Merck Serono (Inst), MSD Oncology (Inst), Novartis (Inst), Otsuka (Inst), Pfizer (Inst), PharmaMar (Inst), Roche Pharma AG (Inst), Sanofi (Inst), Takeda (Inst). Consulting or Advisory Role: Amgen (Inst), AstraZeneca (Inst), Boehringer Ingelheim (Inst), Bristol-Myers Squibb (Inst), Eisai (Inst), Lilly (Inst), Merck Serono (Inst), MSD Oncology (Inst), Novartis (Inst), Otsuka (Inst), Pfizer (Inst), PharmaMar (Inst), Roche Pharma AG (Inst), Takeda (Inst). Speakers\u0026apos; Bureau: Amgen (Inst), AstraZeneca (Inst), AstraZeneca (Inst), Roche Pharma AG (Inst), Sanofi/Aventis (Inst), Takeda (Inst). Research Funding: Abbvie (Inst), AstraZeneca (Inst), Boehringer Ingelheim (Inst), Bristol-Myers Squibb (Inst), Merck Serono (Inst), Roche Pharma AG (Inst). Travel, Accommodations, Expenses: Amgen (Inst), Amgen (Inst), AstraZeneca (Inst), Boehringer Ingelheim (Inst), Bristol-Myers Squibb (Inst), MSD Oncology (Inst), Roche Pharma AG (Inst), Sanofi; Takeda (Inst). Other Relationship: Federal Drug Commission of the Swiss Federal Office of Public Health, Swiss Group for Clinical Cancer Research (SAKK) (Inst). \u003cstrong\u003eCG\u003c/strong\u003e: Honoraria: Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Merck Sharp \u0026amp; Dohme, Pfizer, Roche. Consulting or Advisory Role: Boehringer Ingelheim, Merck Sharp \u0026amp; Dohme, Novartis, Pfizer, Roche. \u003cstrong\u003eKA\u003c/strong\u003e: Consulting or Advisory Role: AstraZeneca, BeiGene, Bristol-Myers Squibb, MSD, Roche, Takeda. \u003cstrong\u003eKM\u003c/strong\u003e: Honoraria: Amgen, AstraZeneca, Bristol-Myers Squibb, Janssen, MSD, Pfizer, Takeda. Consulting or Advisory Role: Amgen, AstraZeneca, Bristol-Myers Squibb, Janssen, MSD, Pfizer, Takeda. \u003cstrong\u003eUJ:\u003c/strong\u003e Honoraria: AstraZeneca, Boehringer Ingelheim, MSD Oncology, Pfizer, Roche, Takeda. \u003cstrong\u003eCFW\u003c/strong\u003e: Honoraria: Alvotech, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai Pharma, Lilly, Merck, Merck Sharp \u0026amp; Dohme, Mylan/Viatris, Novartis, Pfizer, Roche, Takeda. Consulting or Advisory Role: Alvotech, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai/Roche, Lilly, Merck, MSD, Mylan/Viatris, Novartis/Ipsen, Pfizer, Roche, Takeda, Vifor Pharma. Travel Expenses: AstraZeneca, Bristol-Myers Squibb, Ipsen, Janssen, Lilly. \u003cstrong\u003eTRO\u003c/strong\u003e: Advisory Board / Consultancy: AstraZeneca, BMS GmbH \u0026amp; Co. KG, Boehringer Ingelheim, Daiichi Sankyo Europe GmbH, Johnson \u0026amp; Johnson/Janssen, Merck KGaA, Pfizer, Pierre Fabre, Roche. Travel Expenses: AstraZeneca, Daiichi Sankyo Europe Gmb. \u003cstrong\u003eLAM\u003c/strong\u003e: Advisory Board / Consultancy: Amgen, AstraZeneca, BMS, Merck, MSD, Novartis, Pfizer, Roche Pharma, Regeneron, Janssen, Daichii-Sankyo. Research funding: AstraZeneca, Gilead. Honoraria: Merck, AstraZeneca. Expert testimony: BMS. Travel and accommodations: Sanofi, AstraZeneca, and Roche. \u003cstrong\u003eMW\u003c/strong\u003e: Honoraria / Advisory Board / Consultancy: Amgen, AstraZeneca, Daiichi Sankyo, GlaxoSmithKline, Janssen, Novartis, Pfizer, Roche, Takeda. Research funding: Bristol-Myers Squibb, Takeda. \u003cstrong\u003eMF:\u0026nbsp;\u003c/strong\u003eResearch funding:\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eAstraZeneca, BMS, MSD, and Roche. Honoraria / Consultancy: AstraZeneca, MSD, Roche, BMS, AstraZeneca, MSD, Roche, BMS.\u003cstrong\u003e\u0026nbsp;WK\u003c/strong\u003e: Honoraria: MSD, Bristol-Myers Squibb, Novartis, and AstraZeneca. \u003cstrong\u003eMI:\u0026nbsp;\u003c/strong\u003eHonoraria / Advisory Board: Amgen, AstraZeneca, Astellas Pharma, Bayer, Boehringer Ingelheim, Janssen, Merck Sharp \u0026amp; Dohme, Pfizer, Roche, and Takeda.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eSMB:\u003c/strong\u003e Honoraria / Advisory Board: AstraZeneca, Novartis, Roche, BMS, Illumina, DLS, Daiichi-Sankyo, QuIP, Stemline. Research Funding: AstraZeneca, Roche, Zytovision QuIP. \u003cstrong\u003eCW:\u0026nbsp;\u003c/strong\u003eHonoraria: AstraZeneca. \u003cstrong\u003eDEA\u003c/strong\u003e: Honoraria: Roche, AstraZeneca, MSD, Pfizer. \u003cstrong\u003eMT\u003c/strong\u003e: Honoraria: Amgen, AstraZeneca, BeiGene, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Chugai Pharma, Daiichi Sankyo Europe GmbH, GlaxoSmithKline, Janssen Oncology, Lilly, Merck, MSD, Novartis, Pfizer, Roche, Sanofi, Takeda. Consulting or Advisory Role: Amgen, AstraZeneca, BeiGene, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Chugai Pharma, Daiichi Sankyo Europe GmbH, GlaxoSmithKline, Janssen Oncology, Lilly, Merck, MSD, Novartis, Pfizer, Roche, Sanofi, Takeda. Research Funding: AstraZeneca (Inst), Bristol-Myers Squibb (Inst), Merck (Inst), Roche (Inst), Takeda (Inst). Travel, Accommodations, Expenses: Astrazeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo Europe GmbH, Janssen Oncology, Lilly, Merck, MSD, Novartis, Pfizer, Roche, Sanofi, Takeda. \u003cstrong\u003eMJH\u003c/strong\u003e: Consulting or Advisory Role: AstraZeneca/Daiichi Sankyo, Lilly, Roche, Takeda. Speakers\u0026apos; Bureau: Lilly, MSD Oncology, Novartis, Roche. \u003cstrong\u003ePC\u003c/strong\u003e: Honoraria: AstraZeneca, Boehringer Ingelheim, Chugai Pharma, Daiichi Sankyo/Astra Zeneca, Gilead Sciences, Merck Serono, Novartis, Pfizer, Roche, Takeda. Research Funding: Amgen (Inst), AstraZeneca (Inst), Boehringer Ingelheim (Inst), Merck Serono (Inst), Roche (Inst), Takeda (Inst). \u003cstrong\u003eMW\u003c/strong\u003e: Honoraria: Amgen, BMS GmbH \u0026amp; Co. KG, Boehringer Ingelheim, GWT, Janssen, Lilly, Merck Serono, Merck Serono, Novartis, Pfizer, SYNLAB. Consulting or Advisory Role: Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo Europe GmbH, ImCheck therapeutics, immatics, ISA Pharmaceuticals, Lilly, Novartis, PharmaMar, Regeneron, Tacalyx, Zymeworks. Research Funding: Roche (Inst). Travel, Accommodations, Expenses: Amgen, AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo Europe GmbH, GEMoaB, immatics, Iovance Biotherapeutics, Janssen Oncology, Merck Serono, Pfizer, Sanofi/Aventis.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe other authors (KS, AR, AT, SH, SB, RS, KS, RL, SS, UW, SSF, HS, RV) have nothing to declare.\u0026nbsp;\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eInformed consent / Ethics committee\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was carried out in accordance with the Code of Ethics of the World Medical Association (Declaration of Helsinki) and was approved by the ethics committee of the Technische Universit\u0026auml;t Dresden, Germany (BO-EK-253062024). Informed consent was obtained if required by law.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDATA AVAILABILITY\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eInformed consent of participating patients does not cover unrestricted publication of complete data. Upon request to the corresponding author, anonymized data can be made available if intended use is in compliance with informed consent.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding and Acknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. The authors thank the Stiftung Deutsche Krebshilfe (DKH) that generously funded the National Network Genomic Medicine Lung Cancer (nNGM), which is the structural framework supporting this multicentric collaboration.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe authors would like to thank the nNGM main investigators in their role as non-author contributors for making possible this collaborative effort: Prof. David Horst (Charit\u0026eacute; Universit\u0026auml;tsmedizin, Berlin), Prof. Ulrich Keilholz (Charit\u0026eacute; Universit\u0026auml;tsmedizin, Berlin), Prof. Thomas Mairinger (Lungenklinik Heckeshorn, Helios Klinikum Emil von Behring, Berlin), Prof. Maike de Wit (Vivantes Klinikum Neuk\u0026ouml;lln, Berlin), Prof. Hubert Schorle (University Hospital Bonn), Prof. Martin Wermke (TU Dresden, University Hospital Carl Gustav Carus, Dresden), Univ.-Prof. Irene Esposito (University Hospital D\u0026uuml;sseldorf), Prof. Arndt Hartmann (University Hospital Erlangen), Univ.-Prof. Martin Schuler (Universit\u0026auml;tsmedizin Essen, University Hospital), Dr. Martin Sebastian (University Hospital Frankfurt), Prof. Martin Werner (University Hospital Freiburg), Prof. Stefan Gattenl\u0026ouml;hner (University Hospital Gie\u0026szlig;en), Prof. Philipp Str\u0026ouml;bel (University Hospital G\u0026ouml;ttingen), Prof. Claudia Wickenhauser (University Medicine Halle), Prof. Carsten Bokemeyer (University Hospital Hamburg Eppendorf), Prof. Ludwig Wilkens (KRH Klinikum Hannover), Prof. Ulrich Lehmann (Medizinische Hochschule Hannover), Prof. Albrecht Stenzinger (University Hospital Heidelberg), Prof. Andrea Tannapfel (Ruhr-Universit\u0026auml;t Bochum, Lungenklinik Hemer), Univ.-Prof. J\u0026uuml;rgen Wolf (University Hospital Cologne), Prof. Jutta Kirfel (Universit\u0026auml;tsklinikum Schleswig-Holstein), Univ.-Prof. Wilfried Roth (University Hospital Mainz, Germany), Prof. Frederick Klauschen (Ludwig-Maximilians-Universit\u0026auml;t Munich, Germany), Dipl.-Biol. Nicole Pfarr (TUM Klinikum rechts der Isar, Munich), Dr. Lukas Heukamp (Pius Hospital Oldenburg), Prof. Matthias Evert (University Hospital Regensburg), Prof. Falko Fend (University Hospital T\u0026uuml;bingen), Prof. Stephan Stilgenbauer (University Hospital Ulm), Prof. Ralf Christian Bargou (University Hospital W\u0026uuml;rzburg).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions (CREDIT)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eM. E. Le\u0026szlig;mann, F. C. Saalfeld: Conceptualization, Data curation, Formal analysis, Methodology, Project administration, Roles/Writing - original draft.\u003c/p\u003e\n\u003cp\u003eP. Christopoulos, M. Wermke: Conceptualization, Methodology, Resources, Supervision, Validation, Roles/Writing - original draft.\u003c/p\u003e\n\u003cp\u003eL. Ruge, D. Kauffmann-Guerrero, O. Illini, A. Stenzinger, K. Minuth-Fuchs, A. Rittmeyer, I. Goetting, K. Schildknecht, B. Eul, C. Schubart, S. I. Rothschild, C. Groh\u0026eacute;, K. Armster, K. Mohorčič, U. Janžič, C. F. Waller, T. R. Overbeck, R. Vesce, H. Schulte, L. A. Mauti, S. Stephan-Falkenau, M. Wiesweg, M. Faehling, U. Gerstenmaier, S. Schmid, W. Kian, R. Lozynskyy\u003cstrong\u003e,\u0026nbsp;\u003c/strong\u003eM. Ivanović,\u0026nbsp;K. Syrigos, R. Simon, S. Merkelbach-Bruse,\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eC. Wenzel, S. Br\u0026uuml;ckmann, S. Herold, D. E. Aust, M. Thomas, M. J. Hochmair, A. Tufman, A. Rasokat: Data curation, Investigation, Writing - review \u0026amp; editing.\u003c/p\u003e\n\u003cp\u003eNational Network Genomic Medicine Lung Cancer (nNGM): Resources.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eW. Xia, J. Yang, H. Li, L. Li, und J. Liu, \u0026bdquo;Comparing Genomic Profiles of ALK Fusion-Positive and ALK Fusion-Negative Nonsmall Cell Lung Cancer Patients\u0026ldquo;, \u003cem\u003eGlob. Med. Genet.\u003c/em\u003e, Bd. 11, Nr. 02, S. 175\u0026ndash;186, Juni 2024, doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1055/s-0044-1787301\u003c/span\u003e\u003cspan address=\"10.1055/s-0044-1787301\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eA. T. Shaw \u003cem\u003eu. a.\u003c/em\u003e, \u0026bdquo;Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK\u0026ldquo;, \u003cem\u003eJ. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol.\u003c/em\u003e, Bd. 27, Nr. 26, S. 4247\u0026ndash;4253, Sep. 2009, doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1200/JCO.2009.22.6993\u003c/span\u003e\u003cspan address=\"10.1200/JCO.2009.22.6993\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eM. Takeda, I. Okamoto, K. Sakai, H. Kawakami, K. Nishio, und K. Nakagawa, \u0026bdquo;Clinical outcome for \u003cem\u003eEML4-ALK\u003c/em\u003e-positive patients with advanced non-small-cell lung cancer treated with first-line platinum-based chemotherapy\u0026ldquo;, \u003cem\u003eAnn. Oncol.\u003c/em\u003e, Bd. 23, Nr. 11, S. 2931\u0026ndash;2936, Nov. 2012, doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1093/annonc/mds124\u003c/span\u003e\u003cspan address=\"10.1093/annonc/mds124\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eB. J. Solomon \u003cem\u003eu. a.\u003c/em\u003e, \u0026bdquo;Lorlatinib Versus Crizotinib in Patients With Advanced ALK-Positive Non\u0026ndash;Small Cell Lung Cancer: 5-Year Outcomes From the Phase III CROWN Study\u0026ldquo;, \u003cem\u003eJ. Clin. Oncol.\u003c/em\u003e, S. JCO.24.00581, Mai 2024, doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1200/JCO.24.00581\u003c/span\u003e\u003cspan address=\"10.1200/JCO.24.00581\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eJ. S. Ross \u003cem\u003eu. a.\u003c/em\u003e, \u0026bdquo;ALK Fusions in a Wide Variety of Tumor Types Respond to Anti-ALK Targeted Therapy\u0026ldquo;, \u003cem\u003eThe Oncologist\u003c/em\u003e, Bd. 22, Nr. 12, S. 1444\u0026ndash;1450, Dez. 2017, doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1634/theoncologist.2016-0488\u003c/span\u003e\u003cspan address=\"10.1634/theoncologist.2016-0488\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eS.-H. I. Ou, V. W. Zhu, und M. Nagasaka, \u0026bdquo;Catalog of 5\u0026rsquo; Fusion Partners in \u003cem\u003eALK\u003c/em\u003e-positive NSCLC Circa 2020\u0026ldquo;, \u003cem\u003eJTO Clin. Res. Rep.\u003c/em\u003e, Bd. 1, Nr. 1, S. 100015, M\u0026auml;rz 2020, doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.jtocrr.2020.100015\u003c/span\u003e\u003cspan address=\"10.1016/j.jtocrr.2020.100015\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eY. Xiang \u003cem\u003eu. a.\u003c/em\u003e, \u0026bdquo;Therapeutic Advances of Rare ALK Fusions in Non-Small Cell Lung Cancer\u0026ldquo;, \u003cem\u003eCurr. Oncol.\u003c/em\u003e, Bd. 29, Nr. 10, S. 7816\u0026ndash;7831, Okt. 2022, doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3390/curroncol29100618\u003c/span\u003e\u003cspan address=\"10.3390/curroncol29100618\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eW. Li \u003cem\u003eu. a.\u003c/em\u003e, \u0026bdquo;Potential Unreliability of Uncommon ALK, ROS1, and RET Genomic Breakpoints in Predicting the Efficacy of Targeted Therapy in NSCLC\u0026ldquo;, \u003cem\u003eJ. Thorac. Oncol.\u003c/em\u003e, Bd. 16, Nr. 3, S. 404\u0026ndash;418, M\u0026auml;rz 2021, doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.jtho.2020.10.156\u003c/span\u003e\u003cspan address=\"10.1016/j.jtho.2020.10.156\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eJ. Naidoo \u003cem\u003eu. a.\u003c/em\u003e, \u0026bdquo;Epidermal growth factor receptor exon 20 insertions in advanced lung adenocarcinomas: Clinical outcomes and response to erlotinib\u0026ldquo;, \u003cem\u003eCancer\u003c/em\u003e, Bd. 121, Nr. 18, S. 3212\u0026ndash;3220, Sep. 2015, doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1002/cncr.29493\u003c/span\u003e\u003cspan address=\"10.1002/cncr.29493\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eC. Kropf-Sanchen \u003cem\u003eu. a.\u003c/em\u003e, \u0026bdquo;Response to targeted and immune therapy in patients with NSCLC and BRAF non-V600E mutations: A retrospective, multicenter analysis within the national Network Genomic Medicine Lung Cancer (nNGM) in Germany.\u0026ldquo;, \u003cem\u003eJ. Clin. Oncol.\u003c/em\u003e, Bd. 42, Nr. 16_suppl, S. 8591\u0026ndash;8591, Juni 2024, doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1200/JCO.2024.42.16_suppl.8591\u003c/span\u003e\u003cspan address=\"10.1200/JCO.2024.42.16_suppl.8591\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eA. Zaman, W. Wu, und T. G. Bivona, \u0026bdquo;Targeting Oncogenic BRAF: Past, Present, and Future\u0026ldquo;, \u003cem\u003eCancers\u003c/em\u003e, Bd. 11, Nr. 8, S. 1197, Aug. 2019, doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3390/cancers11081197\u003c/span\u003e\u003cspan address=\"10.3390/cancers11081197\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eP. Hofman, \u0026bdquo;ALK in Non-Small Cell Lung Cancer (NSCLC) Pathobiology, Epidemiology, Detection from Tumor Tissue and Algorithm Diagnosis in a Daily Practice\u0026ldquo;, \u003cem\u003eCancers\u003c/em\u003e, Bd. 9, Nr. 8, Art. Nr. 8, Aug. 2017, doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3390/cancers9080107\u003c/span\u003e\u003cspan address=\"10.3390/cancers9080107\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eF. Barlesi \u003cem\u003eu. a.\u003c/em\u003e, \u0026bdquo;Routine molecular profiling of patients with advanced non-small-cell lung cancer: results of a 1-year nationwide programme of the French Cooperative Thoracic Intergroup (IFCT)\u0026ldquo;, \u003cem\u003eThe Lancet\u003c/em\u003e, Bd. 387, Nr. 10026, S. 1415\u0026ndash;1426, Apr. 2016, doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/S0140-6736(16)00004-0\u003c/span\u003e\u003cspan address=\"10.1016/S0140-6736(16)00004-0\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eN. Frost \u003cem\u003eu. a.\u003c/em\u003e, \u0026bdquo;Lung Cancer in Germany\u0026ldquo;, \u003cem\u003eJ. Thorac. Oncol.\u003c/em\u003e, Bd. 17, Nr. 6, S. 742\u0026ndash;750, Juni 2022, doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.jtho.2022.03.010\u003c/span\u003e\u003cspan address=\"10.1016/j.jtho.2022.03.010\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eY. Li \u003cem\u003eu. a.\u003c/em\u003e, \u0026bdquo;Response to crizotinib in advanced ALK -rearranged non-small cell lung cancers with different ALK -fusion variants\u0026ldquo;, \u003cem\u003eLung Cancer\u003c/em\u003e, Bd. 118, S. 128\u0026ndash;133, Apr. 2018, doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.lungcan.2018.01.026\u003c/span\u003e\u003cspan address=\"10.1016/j.lungcan.2018.01.026\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eQ. Zhang \u003cem\u003eu. a.\u003c/em\u003e, \u0026bdquo;Real-World Comparative Effectiveness of First-Line Alectinib Versus Crizotinib in Patients With Advanced \u003cem\u003eALK\u003c/em\u003e-Positive NSCLC With or Without Baseline Central Nervous System Metastases\u0026ldquo;, \u003cem\u003eJTO Clin. Res. Rep.\u003c/em\u003e, Bd. 4, Nr. 4, S. 100483, Apr. 2023, doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.jtocrr.2023.100483\u003c/span\u003e\u003cspan address=\"10.1016/j.jtocrr.2023.100483\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eA. T. Shaw \u003cem\u003eu. a.\u003c/em\u003e, \u0026bdquo;First-Line Lorlatinib or Crizotinib in Advanced ALK-Positive Lung Cancer\u0026ldquo;, \u003cem\u003eN. Engl. J. Med.\u003c/em\u003e, Bd. 383, Nr. 21, S. 2018\u0026ndash;2029, Nov. 2020, doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1056/NEJMoa2027187\u003c/span\u003e\u003cspan address=\"10.1056/NEJMoa2027187\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\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":"npj-precision-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"npjprecisiononcology","sideBox":"Learn more about [npj Precision Oncology](http://www.nature.com/npjprecisiononcology/)","snPcode":"41698","submissionUrl":"https://submission.springernature.com/new-submission/41698/3","title":"npj Precision Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"NPJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Rare ALK fusion, EML4::ALK, Non-small cell lung cancer (NSCLC), Targeted therapy","lastPublishedDoi":"10.21203/rs.3.rs-7545687/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7545687/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eParadigms about anaplastic lymphoma kinase (ALK)-driven non-small cell lung cancer (NSCLC) have been shaped by EML4::ALK. There is little evidence on the remaining patients, presenting with a plethora of other fusion partners (\u003cem\u003erare ALK\u003c/em\u003e). We compared real-world data of patients with advanced NSCLC and \u003cem\u003erare ALK\u003c/em\u003e fusions to patients with EML4::ALK fusions. Patients with \u003cem\u003erare ALK\u003c/em\u003e fusions (n\u0026thinsp;=\u0026thinsp;51) were older and more likely to have a history of smoking. Overall survival (OS) tended to be shorter. Tyrosine kinase inhibitors (TKI) were used less and chemotherapies more frequently as first-line palliative treatment. Patients with \u003cem\u003erare ALK\u003c/em\u003e fusions had a significantly shorter progression-free survival (PFS) when treated with first-line platinum-based chemotherapy as opposed to TKI. There was, however, no PFS difference between \u003cem\u003erare ALK\u003c/em\u003e and EML4::ALK positive patients receiving TKI as first-line treatment. Taken together, patients with advanced NSCLC harboring \u003cem\u003erare ALK\u003c/em\u003e fusions derive comparable benefit from TKI as patients with EML4::ALK.\u003c/p\u003e","manuscriptTitle":"Efficacy of targeted therapy in lung cancer with rare ALK fusions","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-17 02:22:10","doi":"10.21203/rs.3.rs-7545687/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-11-11T20:06:48+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-11-10T17:58:38+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"30977915041367960088072474650460585960","date":"2025-10-27T22:37:39+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-10-14T20:46:16+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"335239103701641737036132617030035371584","date":"2025-10-13T20:57:22+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-10-05T18:22:35+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-10-04T20:26:08+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-09-22T17:34:26+00:00","index":"","fulltext":""},{"type":"submitted","content":"npj Precision Oncology","date":"2025-09-05T15:34:18+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"npj-precision-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"npjprecisiononcology","sideBox":"Learn more about [npj Precision Oncology](http://www.nature.com/npjprecisiononcology/)","snPcode":"41698","submissionUrl":"https://submission.springernature.com/new-submission/41698/3","title":"npj Precision Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"NPJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"c64adaf2-e526-4561-9392-cf9b78825f3a","owner":[],"postedDate":"October 17th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":56366549,"name":"Biological sciences/Cancer"},{"id":56366550,"name":"Health sciences/Oncology"}],"tags":[],"updatedAt":"2026-05-07T17:39:40+00:00","versionOfRecord":[],"versionCreatedAt":"2025-10-17 02:22:10","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7545687","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7545687","identity":"rs-7545687","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}