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Translational Therapeutics

Immune biomarkers and response to checkpoint inhibition of BRAFV600 and BRAF non-V600 altered lung cancers

Abstract

Background

While 2–4% of lung cancers possess alterations in BRAF, little is known about the immune responsiveness of these tumours.

Methods

Clinical and genomic data were collected from 5945 patients with lung cancers whose tumours underwent next-generation sequencing between 2015 and 2018. Patients were followed through 2020.

Results

In total, 127 patients with metastatic BRAF-altered lung cancers were identified: 29 tumours had Class I mutations, 59 had Class II/III alterations, and 39 had variants of unknown significance (VUS). Tumour mutation burden was higher in Class II/III than Class I-altered tumours (8.8 mutations/Mb versus 4.9, P < 0.001), but this difference was diminished when stratified by smoking status. The overall response rate to immune checkpoint inhibitors (ICI) was 9% in Class I-altered tumours and 26% in Class II/III (P = 0.25), with median time on treatment of 1.9 months in both groups. Among patients with Class I–III-altered tumours, 36-month HR for death in those who ever versus never received ICI was 1.82 (1.17–6.11). Nine patients were on ICI for >2 years (two with Class I mutations, two with Class II/III alterations, and five with VUS).

Conclusions

A subset of patients with BRAF-altered lung cancers achieved durable disease control on ICI. However, collectively no significant clinical benefit was seen.

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Fig. 1: Overall survival of patients with lung cancers according to the type of BRAF alteration.
Fig. 2: Response to ICI according to BRAF mutation class, TMB and PD-L1 status.
Fig. 3: Time on ICI (in years) among patients with BRAF-altered lung cancer.

Data availability

All genomic data from sequenced tumours are included in the cBioportal for Cancer Genomics repository (http://cbioportal.org/msk-impact). Relevant clinical data are included in the manuscript.

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Acknowledgements

YRMG gratefully acknowledges receipt of the Kristina M. Day Young Investigator Award from Conquer Cancer, the ASCO Foundation. She has received training as part of an institutional K30 grant from the National Cancer Institute (CTSA #UL1TR00457). The authors acknowledge funding for Memorial Sloan Kettering Cancer Center received through the NIH/NCI institutional P30 CA008748 grant. The authors appreciate the editorial and administrative contributions of Clare Wilhelm, Reeja Thomas and Jessica Moore.

Funding

This research was supported in part by the National Cancer Institute of the National Institutes of Health P30 CA008748.

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Authors and Affiliations

Authors

Contributions

MO and BTL conceived of/ designed the study. YRMG, TP, SM, DH, AJP, DL and MO acquired the data. All authors were involved in data analysis and/or interpretation. YRMG and MO drafted the manuscript. All authors approved the final version of the manuscript.

Corresponding author

Correspondence to Michael Offin.

Ethics declarations

Ethics approval and consent to participate

This study was approved by the institutional review board of Memorial Sloan Kettering Cancer Center.

Consent to publish

Not applicable.

Competing interests

MSK was awarded grants from the National Institutes of Health/National Cancer Institute during the conduct of the study. YRMG acknowledges receipt of travel, accommodation, and expenses from AstraZeneca. MGK reports personal fees from AstraZeneca, Pfizer, Regeneron, Daiichi Sankyo, outside the submitted work; he has received honoraria for participation in educational programs from WebMD, OncLive, Physicians Education Resources, Prime Oncology, Intellisphere, Creative Educational Concepts, Peerview, i3 Health, Paradigm Medical Communications, AXIS, Carvive Systems, AstraZeneca, and Research to Practice. Funds for travel and lodging, and food and beverage have been provided by AstraZeneca, Pfizer, Regeneron, and Genentech. Dr. Kris is an employee of Memorial Sloan Kettering. Memorial Sloan Kettering has received research funding from The National Cancer Institute (USA), The Lung Cancer Research Foundation, Genentech Roche, and PUMA Biotechnology for research conducted by Dr. Kris. Memorial Sloan Kettering has an institutional agreement with IBM for Watson For Oncology and receives royalties from IBM. MSK has licensed testing for EGFR T790M to MolecularMD. PKP reports grants and personal fees from Celgene; personal fees from Takeda, Abbvie, Lilly, Boehringer Ingelheim, EMD Serono, Calithera, Bicara, Xencor, GlaxoSmithKline, AstraZeneca, outside the submitted work. GJR reports grants from Novartis, Roche, Genentech, Millennium, GlaxoSmithKline, Pfizer, Infinity Pharmaceuticals, ARIAD; non-financial support from Merck Sharp & Dohme, outside the submitted work. In addition, Dr. Riely has a patent US20170273982A1 pending, and a patent WO2017164887A8 pending. HAY reports grants and personal fees from AstraZeneca and Daiichi; grants and non-financial support from Lilly, grants from Novartis, Pfizer, and Cullinan; personal fees from Blueprint Medicine, Janssen, outside the submitted work. In addition, Dr. Yu has a patent US20170273982A1 pending, and a patent WO2017164887A1 pending. CMR reports personal fees from AbbVie, Amgen, Ascentage, AstraZeneca, Bicycle, Celgene, Daiichi Sankyo, Genentech/Roche, Ipsen, Jansen, Jazz, Lilly/Loxo, Pfizer, PharmaMar, Syros, Vavotek, Bridge Medicines, Harpoon Therapeutics, and Earli outside the submitted work. M.D.H. reports personal fees from AstraZeneca/MedImmune; grants and personal fees from Bristol-Myers Squibb; personal fees from Merck, Genentech/Roche, Novartis, Janssen Pharmaceuticals, Nektar, Syndax Pharmaceuticals, Mirati Therapeutics, Shattuck Labs, outside the submitted work. In addition, Dr. Hellmann has a patent PCT/US2015/062208 pending and Stock and Other Ownership Interests: Shattuck Labs; Dr. Hellman is a Damon Runyon Clinical Investigator supported (in part) by the Damon Runyon Cancer Research Foundation (CI-98-18) and is a member of the Parker Institute for Cancer Immunotherapy. LWB reports personal fees from Amgen, Jazz Pharmaceuticals, Heron, Pfizer, outside the submitted work. PL reports research support to MSK from Mirati, Revolution Medicines, Amgen and Strategia during the conduct of the study. Dr Lito is listed as an inventor on patent applications filed by MSKCC describing therapeutic interventions for BRAF or KRAS mutant tumours. Dr. Lito is supported in part by the NIH/NCI (1R01CA230745-01 and 1R01CA230267-01A1), the Pew Charitable Trusts and the Damon Runyon Cancer Research Foundation. AD reports personal fees from Ignyta/Genentech/Roche, Loxo/Bayer/Lilly, Takeda/Ariad/Millenium, TP Therapeutics, AstraZeneca, Blueprint Medicines, Helsinn, Beigene, BergenBio, Hengrui Therapeutics, Exelixis, Tyra Biosciences, Verastem, MORE Health, Abbvie, 14ner/Elevation Oncology, Remedica Ltd., ArcherDX, Monopteros, Elevation Oncology, Novartis, EMD Serono, Melendi, Faculty RTP, Repare RX, Pfizer, Liberum, outside the submitted work; and Associated research paid to MSK from Pfizer, Exelixis, GlaxoSmithKline, Teva, Taiho, PharmaMar; research from Foundation Medicine; royalties from Wolters Kluwer; other support from Merck, Puma, Merus, Boehringer Ingelheim; Únd CME honoraria from Medscape, OncLive, PeerVoice, Physicians Education Resources, Targeted Oncology, Research to Practice, Axis, Peerview Institute, Paradigm Medical Communications, WebMD, MJH Life Sciences, Med Learning, Imedex, Answers in CME, Medscape, Clinical Care Options. DL reports personal fees from Pfizer, Heron Therapeutics, outside the submitted work. BTL reports non-financial support from Amgen, Genentech, and Boehringer Ingelheim; grants and non-financial support from Lilly, AstraZeneca, Daiichi Sankyo; grants and personal fees from Guardant Health, Hengrui Therapeutics, MORE Health; grants from Amgen, Illumina, GRAIL, Bolt Biotherapeutics; personal fees from Resolution Bioscience, Jiangsu Hengrui Medicine, outside the submitted work; Dr. Li is an inventor on two institutional patents at MSK and has intellectual property rights as a book author at Karger Publishers. The remaining authors declare no competing interests.

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Murciano-Goroff, Y.R., Pak, T., Mondaca, S. et al. Immune biomarkers and response to checkpoint inhibition of BRAFV600 and BRAF non-V600 altered lung cancers. Br J Cancer 126, 889–898 (2022). https://doi.org/10.1038/s41416-021-01679-1

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