Determining Line of Therapy from Real-World Data in Non-Small Cell Lung Cancer

Introduction Determining lines of therapy (LOT) using real-world data is crucial to inform clinical decisions and support clinical research. Existing rules for determining LOT in patients with metastatic non-small cell lung cancer (mNSCLC) do not incorporate the growing number of targeted therapies used in treatment today. Therefore, we propose rules for determining LOT from real-world data of patients with mNSCLC treated with targeted therapies. Methods LOT rules were developed through expert consensus using a real-world cohort of 550 patients with ALK + or ROS1 + mNSCLC in the multi-institutional, electronic medical record-based Academic Thoracic Oncology Medical Investigators Consortium’s (ATOMIC) Driver Mutation Registry. Rules were subsequently modified based on a review of appropriate LOT determination. These resulting rules were then applied to an independent cohort of patients with EGFR + mNSCLC to illustrate their use. Results Six rules for determining LOTs were developed. Among 1133 patients with EGFR mutations and mNSCLC, a total of 3168 regimens were recorded with a median of 2 regimens per patient (IQR, 1-4; range, 1-13). After applying our rules, there were 2834 total LOTs with a median of 2 LOTs per patient (IQR, 1-3; range, 1-11). Rules 1-3 kept 11% of regimen changes from advancing the LOT. When compared to previously published rules, LOT assignments differed 5.7% of the time, mostly in LOTs with targeted therapy. Conclusion These rules provide an updated framework to evaluate current treatment patterns, accounting for the increased use of targeted therapies in patients with mNSCLC and promote standardization of methods for determining LOT from real-world data. Key Points ### Competing Interest Statement CBG, WH, AC, GL, DP, GLBM, AH, WS, JD, KLM, VV, DRC: No conflicts of interest associated with current work. JER: Advisory Board / Consultant:Genentech/Roche, Sanofi/Genzyme, Personalis, Guardant, Astrazeneca, BMS, Arcus, Abbvie, Daiichi Sankyo. Research Funding (to institution): Genentech/Roche, Verastem, Nuvalent, Mesothelioma Applied Research Foundation, LUNGevity Foundation. Honoraria/Speaking Fees: Astrazeneca, Merck WI: Consultant for OncLive, Clinical Care Options, Chardan, Cello Health, Curio Science. Advisory Board/DSMC for Genentech, Mirati, Outcomes Insights, Jazz Pharmaceuticals, GI Therapeutics, Takeda, AstraZeneca, Sanofi, Janssen, Amgen, Bristol Myers Squibb, NovoCure. SVL: Advisory Board / Consultant for Abbvie, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Catalyst, Daiichi Sankyo, Eisai, Elevation Oncology, Genentech/Roche, Gilead, Guardant Health, Janssen, Jazz Pharmaceuticals, Merck, Merus, Mirati, Novartis, Regeneron, Sanofi, Takeda, Turning Point Therapeutics. Research grant (to institution) from Alkermes, Elevation Oncology, Genentech, Gilead, Merck, Merus, Nuvalent, RAPT, Turning Point Therapeutics. Data Safety Monitoring Board for Candel Therapeutics. TP: Advisory Role (advisory boards or consultations) in last 3 years: Astrazeneca, Biocept, Boehringer Ingelheim, Bristol-Myers Squibb, Bicara, Caris, Guardant Health, Guidepoint, EMD Soreno, Janssen, Jazz Pharamceuticals, Mirati Therapeutics, Natera, Pfizer, Sanofi, Regeneron, Roche/Genentech, Takeda. Advisory Committees: Elevation Oncology (DSMB). Research Funding: EMD Soreno, Janssen, Gilead JN: Stock/Ownership interests in Epic Sciences, Cansera, Quantagene, Indee P/L. Consulting for AstraZeneca, Naveris, Aadi biosciences, Bioatla, Mindmed, ANP Technologies. Research funding to institution from Merck, Genentech. Patent pending on movement and unexpected healthcare encounters. KAM has received consulting/advisory fees from AstraZeneca, Amgen, Janssen, Mirati Therapeutics, Daiichi Sankyo/Lilly and Puma Biotechnology, as well as Honoraria from AstraZeneca. KAM receives research funding to Johns Hopkins University from Bristol-Myers Squibb and Mirati Therapeutics. V.K.L. reports serving in a consultant/advisory role for Seattle Genetics, Bristol-Myers Squibb, AstraZeneca, Guardant Health, Takeda, and Anheart Therapeutics, and has received research funding from BMS, Merck, Seattle Genetics, Astra Zeneca LCV reports researching funding from Janssen, BMS, Merck, Regeneron, GSK, AstraZeneca, BioAtla, Black Daimon Therapeutics, Jazz, Genentech, Beigene. Consulting fees from Takeda, Janssen, Intervenn Biosciences, Sanofi, Daiichi Sankyo, Jazz, BMS, Gilead. CA reports receiving institutional research funding from AstraZeneca, Genentech, Incyte, Macrogenics, Medimmune, and Merck Sharp & Dohme, and receiving consultation fees from Genentech, Lilly, Celgene Merck, AstraZeneca, Blueprint Genetics, Shionogi, Daiichi Sankyo/ Astra Zeneca, Regeneron/ Sanofi, Eisai, BeiGene, Turning Point, Pfizer, Janssen, Boehringer Ingelheim. LS reports research funding from Blueprint (Inst), Seagen (Inst), IO Biotech (Inst), Erasca (Inst). Consulting with Sanofi Genzyme, Regeneron, GenMab, Seagen, and Bayer. MEM reports researching funding from Eli Lilly (Inst), AstraZeneca (Inst), Merck (Inst), Genentech (Inst) consulting role with Astra Zeneca, Novocure, Boehringer Ingelheim, Janssen, Takeda, Blueprint Pharmaceuticals, Bayer, Bristol Myers Squibb, Ikena; Honorarium from Thermo Fisher; stock in Merck, Johnson & Johnson. ### Funding Statement This work is supported in part by grants from Takeda, AstraZeneca and LUNGevity. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study was approved by the University of Pennsylvania Institutional Review Board (IRB #829009). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data produced in the present study are available upon reasonable request to the authors.