Consolidation ALK Tyrosine Kinase Inhibitors Versus Durvalumab or Observation After Chemoradiation in Unresectable Stage III ALK-Positive NSCLC.

Introduction: Patients with advanced ALK-positive NSCLC typically have poor response to immunotherapy; the benefit of consolidation durvalumab in patients with unresectable stage III ALK-positive NSCLC remains unclear. Herein, we compare the efficacy and safety of consolidation ALK tyrosine kinase inhibitor (TKI) versus durvalumab or observation after concurrent chemoradiation.
Methods: We conducted a retrospective study using a multicenter study of 17 institutions globally. Patients with unresectable stage III ALK-positive NSCLC treated between 2015 and 2022 were included. Patients received ALK TKI, durvalumab, or observation after concurrent chemoradiation. Real-world progression-free survival (rwPFS) and overall survival (OS) were estimated using Kaplan-Meier method. Treatment-related adverse events (trAEs) were classified by Common Terminology Criteria for Adverse Events version 5.0. Outcomes were assessed by multivariable Cox regression analysis.
Results: A total of 67 patients were included, of whom 39 (58%) were female. Median age was 57 (interquartile range: 49-67) years. Furthermore, 15 received consolidation ALK TKI, 30 received durvalumab, and 22 underwent observation. Baseline characteristics were similar across the three groups other than differences in race. After adjusting for stage, age, and nodal status, median rwPFS was significantly longer for ALK TKI (rwPFS not reached, 95% confidence interval [CI]: 22.7- not reached) versus durvalumab (11.3 mo, 95% CI: 8.9-18.5, hazard ratio [HR] = 0.12, 95% CI: 0.026-0.5, p-adjusted [p-adj] = 0.006) or observation (7.2 mo, 95% CI: 3.4-10.6, HR = 0.04, 95% CI: 0.009-0.2, p-adj < 0.0001). Durvalumab significantly improved median rwPFS compared with observation (HR = 0.37, 95% CI: 0.19-0.71, p-adj = 0.002). Median OS in the ALK TKI and durvalumab cohorts was significantly improved compared with patients on observation (ALK TKI-observation: p = 0.04; durvalumab-observation: p = 0.03). TrAE of any grade occurred in eight (53%) and 11 (37%) patients treated with ALK TKI and durvalumab, respectively. Grade greater than or equal to three trAEs occurred in 27% (n = 4) of patients treated with ALK TKI and 6.7% of patients treated with durvalumab.
Conclusions: Patients with ALK-positive NSCLC experience significantly improved rwPFS when treated with consolidation ALK TKI therapy, surpassing outcomes found with either durvalumab or observation. Although both ALK TKI therapy and durvalumab offer an extension in OS compared with observation alone, it seems that ALK TKI therapy is the superior choice, underscoring its pivotal role in enhancing patient survival.
Competing Interests: Disclosure Dr. Nassar receives honoraria from OncLive, TEMPUS, and Korean Society for Medical Oncology and consulting fees from Guidepoint Global and Putnam Associates. Dr. Goldberg receives research funding from AstraZeneca, Boehringer Ingelheim, and Mirati; is an advisory board member for AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Genentech, Amgen, Blueprint Medicine, Sanofi Genzyme, Daiichi Sankyo, Takeda, Janssen, Summit Therapeutics, Merck, Regeneron, and Eli Lilly; and receives honoraria for lectures for Amgen and AstraZeneca. Dr. Naqash receives funding to institution for trials he is PI on Loxo@Lilly, Surface Oncology, ADC Therapeutics, IGM Biosciences, EMD Serono, Aravive, Nikang Therapeutics, Inspirna, Exelexis, Revolution Medicine, Jacobio, Pionyr, Jazz Pharmaceuticals, NGM Biopharmaceuticals, Immunocore, Phanes Therapeutics, Deka, Kymera, IDEAYA, IGM Biosciences, Selexine, and Chipscreen Biosciences; receives consultant editor compensation from JCO Precision Oncology; receives travel compensation from SITC, American Association for Cancer Reasearch, Conquer Cancer Foundation, BinayTara Foundation, Foundation Med, Caris Life Sciences, Sarah Cannon Research Institute, Jazz Pharmaceuticals, ASCO, and ASTRO; serves on the advisory board of Foundation Med and NGM Biosciences; receives current research grant support from Swog Hope Foundation, FDA Broad Agency Award, and OSCTR; and has genomics research agreements from Tempus, Caris, and Foundation One. Dr. Kim receives institutional funding from Loxo@Lilly, AstraZeneca, Boehringer Ingelheim, Genentech, Bristol-Myers Squibb, DynamiCure, Seagen, Genmab, and Nykode Therapeutics. Dr. Reuss reports serving on the advisory board/as consultant of Sanofi/Genzyme, Personalis, Guardant, AstraZeneca, Bristol-Myers Squibb, Arcus, AbbVie, Daiichi Sankyo, Catalym, Seagen, Gilead, Janssen, Novocure, Regeneron, and Summit Therapeutics; receiving research funding (to institution) from Genentech/Roche, Verastem, Nuvalent, and Exelixis; and receiving honoraria from Merck and AstraZeneca. Dr. Cortellini reports receiving grants for consultancies/advisory boards from Merck Sharp & Dohme, Bristol-Myers Squibb, OncoC4, IQVIA, AstraZeneca, Regeneron, Access Infinity, Ardelis Health, Alpha Sight, Guidepoint, and Roche; receiving speaker fees from AstraZeneca, Pierre-Fabre, Merck Sharp & Dohme, and Sanofi/Regeneron; having writing/editorial activity for Bristol-Myers Squibb and Merck Sharp & Dohme; and receiving travel support from Sanofi/Regeneron and Merck Sharp & Dohme. Dr. Marron currently or has previously served on advisory and/or data safety monitoring boards for Rockefeller University, Regeneron, AbbVie, Merck, Bristol-Myers Squibb, Boehringer Ingelheim, Atara, AstraZeneca, Genentech, Celldex, Chimeric, DrenBio, Glenmark, Simcere, Surface, G1 Therapeutics, NGMbio, DBV Technologies, Arcus, Fate, Ono, Larkspur, Avammune, and Astellas; and has received research grants from Regeneron, Genentech, Bristol-Myers Squibb, Merck, and Boehringer Ingelheim. Dr. Fitzgerald receives institutional research funding from Genentech/Roche, PPD, and bioatla and travel funding from IASLC. Dr. Dilling has served on the advisory boards for AstraZeneca and is a member of the NCCN Non–Small Cell Lung Cancer Panel. Dr. Bar is an advisor of AbbVie, Amgen, AstraZeneca, Bayer, Merck Sharp & Dohme, Merck-Serono, Roche, and Takeda; has writing/speaker engagement for Bristol-Myers Squibb, Medison, and Pfizer, and has received research funding from Immunai, OncoHost, Merck Sharp & Dohme, AstraZeneca, Roche, and AbbVie. Dr. Aredo reports receiving consulting fees from AstraZeneca. Dr. Lin has served as a compensated consultant for Genentech, C4 Therapeutics, Blueprint Medicines, Nuvalent, Bayer, Elevation Oncology, Novartis, Mirati Therapeutics, AnHeart Therapeutics, CLaiM Therapeutics, Ellipses, AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo, Yuhan, Merus, Regeneron, Pfizer, and Turning Point Therapeutics; received institutional research funds from Hengrui Therapeutics, Turning Point Therapeutics, Neon Therapeutics, Relay Therapeutics, Bayer, Elevation Oncology, Roche, Linnaeus Therapeutics, Nuvalent, and Novartis; and has received travel support from Pfizer and Merus. Dr. Kwiatkowski receives research funding from AADI and Genentech; and consults for Genentech, AADI, Expertconnect, Guidepoint, Bridgebio, Slingshot Insights, William Blair, MEDACorp, and Radyus Research. Dr. Yu has done consulting for AstraZeneca, Daiichi, Janssen, Amgen, Black Diamond, Blueprint, Cullinan, Takeda, and Taiho. Dr. Feng reports receiving speaker honoraria from AstraZeneca Canada. Dr. Velazquez reports receiving consulting fees from AstraZeneca, Merus, Novocure, and Regeneron.
(Crown Copyright © 2024. Published by Elsevier Inc. All rights reserved.)