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Clinical Trial
. 2023 Mar;165(3):828-839.e5.
doi: 10.1016/j.jtcvs.2022.10.007. Epub 2022 Oct 8.

Surgical results of the Lung Cancer Mutation Consortium 3 trial: A phase II multicenter single-arm study to investigate the efficacy and safety of atezolizumab as neoadjuvant therapy in patients with stages IB-select IIIB resectable non-small cell lung cancer

Valerie W Rusch  1 , Alan Nicholas  2 , G Alexander Patterson  3 , Salama N Waqar  3 , Eric M Toloza  4 , Eric B Haura  4 , Dan J Raz  5 , Karen L Reckamp  5 , Robert E Merritt  6 , Dwight H Owen  6 , David J Finley  7 , Ciaran J McNamee  8 , Justin D Blasberg  9 , Edward B Garon  10 , John D Mitchell  11 , Robert C Doebele  11 , Frank Baciewicz  12 , Misako Nagasaka  13 , Harvey I Pass  14 , Katja Schulze  2 , Ann Johnson  2 , Paul A Bunn  11 , Bruce E Johnson  15 , Mark G Kris  16 , David J Kwiatkowski  8 , Ignacio I Wistuba  17 , Jamie E Chaft  16 , David P Carbone  6 , Jay M Lee  10
Affiliations
Clinical Trial

Surgical results of the Lung Cancer Mutation Consortium 3 trial: A phase II multicenter single-arm study to investigate the efficacy and safety of atezolizumab as neoadjuvant therapy in patients with stages IB-select IIIB resectable non-small cell lung cancer

Valerie W Rusch et al. J Thorac Cardiovasc Surg. 2023 Mar.

Abstract

Objective: Multimodality treatment for resectable non-small cell lung cancer has long remained at a therapeutic plateau. Immune checkpoint inhibitors are highly effective in advanced non-small cell lung cancer and promising preoperatively in small clinical trials for resectable non-small cell lung cancer. This large multicenter trial tested the safety and efficacy of neoadjuvant atezolizumab and surgery.

Methods: Patients with stage IB to select IIIB resectable non-small cell lung cancer and Eastern Cooperative Oncology Group performance status 0/1 were eligible. Patients received atezolizumab 1200 mg intravenously every 3 weeks for 2 cycles or less followed by resection. The primary end point was major pathological response in patients without EGFR/ALK+ alterations. Pre- and post-treatment computed tomography, positron emission tomography, pulmonary function tests, and biospecimens were obtained. Adverse events were recorded by Common Terminology Criteria for Adverse Events v.4.0.

Results: From April 2017 to February 2020, 181 patients were entered in the study. Baseline characteristics were mean age, 65.1 years; female, 93 of 181 (51%); nonsquamous histology, 112 of 181 (62%); and clinical stages IIB to IIIB, 147 of 181 (81%). In patients without EGFR/ALK alterations who underwent surgery, the major pathological response rate was 20% (29/143; 95% confidence interval, 14-28) and the pathological complete response rate was 6% (8/143; 95% confidence interval, 2-11). There were no grade 4/5 treatment-related adverse events preoperatively. Of 159 patients (87.8%) undergoing surgery, 145 (91%) had pathologic complete resection. There were 5 (3%) intraoperative complications, no intraoperative deaths, and 2 postoperative deaths within 90 days, 1 treatment related. Median disease-free and overall survival have not been reached.

Conclusions: Neoadjuvant atezolizumab in resectable stage IB to IIIB non-small cell lung cancer was well tolerated, yielded a 20% major pathological response rate, and allowed safe, complete surgical resection. These results strongly support the further development of immune checkpoint inhibitors as preoperative therapy in locally advanced non-small cell lung cancer.

Keywords: immunotherapy; lung cancer; neoadjuvant therapy.

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Conflict of interest statement

Conflict of Interest Statement

V.W.R. is a member of the Data Safety and Monitoring Committee for the MARS2 trial (UK), serves as Co-Chair of the National Cancer Institute Thoracic Staging Malignancy Committee, and reports institutional funding from Genentech. A.N. is an employee of Genentech and reports stock ownership with Roche. S.N.W. reports research support grants from AbbVie Inc, Ariad Pharmaceuticals, Genentech, ImmunoMedics, Inc, Millennium Pharmaceuticals Inc, Roche, Astellas Pharma Inc, Daiichi Sankyo, Cullinan Pearl, Verastem Inc, GlaxoSmithKline/GSK, Janssen Research & Development, LLC, Elevation Oncology, Daiichi Sankyo, Genentech, Loxo Oncology, Takeda Pharmaceuticals Company Limited, grant from the SWOG Clinical Trials Partnership, honorarium from ASCO, and Chair of Data Safety Monitoring Board for the Hoosier Cancer Research Network. E.M.T. reports honoraria from Intuitive Surgical. E.B.H. serves in a consulting or advisory role to Amgen, Ellipses Pharma, Janssen Oncology, Janssen Research & Development, and Revolution Medicines; reports research funding (paid to his institution) from AstraZeneca, Genentech, Incyte, Janssen, Novartis, Revolution Medicines, and Spectrum Pharmaceuticals; and reports patents, royalties, or other intellectual property from Protein-Protein Interactions as Biomarkers Patent. K.L.R. reports personal fees from Amgen, Calithera, AstraZeneca, Blueprint, Boehringer Ingelheim, Daiichi Sankyo, EMD Soreno, Genentech, GlaxoSmithKline, Janssen, Lilly, Merck KGA, Mirati, Takeda, Tesaro, and nonfinancial support from Seattle Genetics; research support to institution from CALITHERA, Blueprint, Daiichi Sankyo, Genentech, Elevation Oncology, and Janssen outside the submitted work. R.E.M. reports speaker fees from Intuitive Surgical. D.H.O. reports funding to his institution from Genentech, Merck, Pfizer, Palobiofarma, and Bristol Myers Squibb. E.B.G. reports grant and research support from ABL Bio, AstraZeneca, Bristol Myers Squibb, Dynavax Technologies, EMD Serono, Genentech, Iovance Biotherapeutics, Eli Lilly & Co, Merck, Mirati Therapeutics, Neon Therapeutics, and Novartis; and consulting or advisory roles with ABL Bio, Boehringer Ingelheim, Bristol Myers Squibb, Dracen Pharmaceuticals, Eisai, Eli Lilly, EMD Serono, Gilead, GSK, Merck, Natera, Novartis, Personalis, Regeneron, Sanofi, Shionogi, and Xilio Therapeutics. R.C.D. is an employee and shareholder of Rain Therapeutics and has received consulting fees, travel reimbursement, and licensing fees from Genentech/Roche; and has received funding from the National Institutes of Health/National Cancer Institute University of Colorado Lung SPORE (5P50CA058187). M.N. reports honoraria from Astra Zeneca (ad-board), Caris Life Sciences (consultant), Lilly (consultant), Daiichi Sankyo (ad-board), Takeda (speaker), Novartis (ad-board), EMD Serono (ad-board), Blueprint Medicines (speaker), Janssen (ad-board), Pfizer (ad-board), Genentech (ad-board), and has received travel support from AnHeart Therapeutics. H.I.P. is a member of the Genentech Steering Committee for IMPOWER030 and the SKYSCRAPER Trial. K.S. is an employee of Genentech and reports stock ownership with Roche. A.J. is an employee of Genentech and reports stock ownership with Roche. P.A.B. is on Advisory or Data Safety Monitoring Boards for BMS and Merck, and reports membership on the Board of Directors for Verastem, Inc., with funding to his institution. B.E.J. reports consultant fees from Checkpoint Therapeutics, Genentech, Hummingbird Diagnostics and Hengrui Therapeutics. M.G.K. reports speaking fees from AstraZeneca and Pfizer, consultant fees for Janssen, and in-kind support for medical writing from Hoffman-La Roche. D.J.K. serves as an advisor to AstraZeneca and Genentech/Roche and reports research funding from AADi. I.I.W. reports grants and personal fees from Genentech/Roche, Bayer, Bristol-Myers Squibb, AstraZeneca, Pfizer, HTG Molecular, GlaxoSmithKline, Guardant Health, Merck, Novartis, Sanofi, and Amgen; personal fees from Asuragen, Flame, Daiichi Sankyo, Oncocyte, MSD, and Platform Health; grants from Adaptive, Adaptimmune, EMD Serono, Takeda, Karus, Johnson & Johnson, 4D, Iovance, and Akoya, outside the submitted work. J.E.C. serves as an advisor to Genentech/Roche, AstraZeneca/MedImmune, Merck, Bristol Myers Squibb, Flame Biosciences, Janssen Oncology, Guardant Health, Regeneron/Sanofi, and Novartis; and reports research funding from Genentech/Roche, Bristol Myers Squibb, AstraZeneca/MedImmune, and Merck. D.P.C. serves in a consultant or advisory role to AbbVie, Agenus, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, EMD Serono, Genentech/Roche, Helsinn Healthcare, Incyte, Inivata, Inovio Pharmaceuticals, Janssen, Kyowa Hakko Kirin, Merck, Novartis, Pfizer, prIME Oncology, and Takeda, and research funding from Bristol Myers Squibb and Genentech. J.M.L. reports grants, consulting fees, and honoraria from AstraZeneca, BMS, Genentech, and Novartis, and leadership roles at AstraZeneca, Genentech, and Novartis. All other authors reported no conflicts of interest.

The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest.

Figures

FIGURE 1.
FIGURE 1.
Study overview. A, Design. B, Protocol mandated timing of surgery in relationship to neoadjuvant therapy. aT4 due to mediastinal organ invasion and N3 disease were excluded. bMandatory: Driver mutations were removed. CT, Computed tomography; PET, positron emission tomography; SOC, standard of care; q3m, every 3 months; NSCLC, non–small cell lung cancer; C, cycle.
FIGURE 2.
FIGURE 2.
Association between pretreatment clinical stage and final pathologic stage at resection. Figure reflects patients with both clinical stage and pathologic stage per American Joint Commission on Cancer 8th edition staging system. Four patients did not have a pathologic stage evaluation.
FIGURE 3.
FIGURE 3.
Surgical overview in patients who underwent surgery (n = 159). A, Surgical approach used. B, Extent of resection. C, Completeness of resection. Five of the patients who underwent lobectomy had sleeve lobectomies (4 bronchial, 1 bronchial and vascular). VATS, Video-assisted thoracoscopic surgery.
FIGURE 4.
FIGURE 4.
Pre- and postoperative treatment-related AEs. A, AEs considered to be immune-related are summarized. B, One patient had hypothyroidism preoperatively and postoperatively. irAE, Immune-related adverse event; TRAE, treatment-related adverse event; AST, aspartate aminotransferase; ALT, alanine aminotransferase.
FIGURE 4.
FIGURE 4.
Pre- and postoperative treatment-related AEs. A, AEs considered to be immune-related are summarized. B, One patient had hypothyroidism preoperatively and postoperatively. irAE, Immune-related adverse event; TRAE, treatment-related adverse event; AST, aspartate aminotransferase; ALT, alanine aminotransferase.
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Comment in

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