While 2–4% of lung cancers possess alterations in BRAF, little is known about the immune responsiveness of these tumours.
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.
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).
A subset of patients with BRAF-altered lung cancers achieved durable disease control on ICI. However, collectively no significant clinical benefit was seen.
This is a preview of subscription content, access via your institution
Subscribe to Journal
Get full journal access for 1 year
only $4.96 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
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.
Chen D, Zhang LQ, Huang JF, Liu K, Chuai ZR, Yang Z, et al. BRAF mutations in patients with non-small cell lung cancer: a systematic review and meta-analysis. PLoS ONE. 2014;9:e101354.
Paik PK, Arcila ME, Fara M, Sima CS, Miller VA, Kris MG, et al. Clinical characteristics of patients with lung adenocarcinomas harboring BRAF mutations. J Clin Oncol. 2011;29:2046–51.
Cardarella S, Ogino A, Nishino M, Butaney M, Shen J, Lydon C, et al. Clinical, pathologic, and biologic features associated with BRAF mutations in non-small cell lung cancer. Clin Cancer Res. 2013;19:4532–40.
Marchetti A, Felicioni L, Malatesta S, Grazia Sciarrotta M, Guetti L, Chella A, et al. Clinical features and outcome of patients with non-small-cell lung cancer harboring BRAF mutations. J Clin Oncol. 2011;29:3574–9.
Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417:949–54.
Lin Q, Zhang H, Ding H, Qian J, Lizaso A, Lin J, et al. The association between BRAF mutation class and clinical features in BRAF-mutant Chinese non-small cell lung cancer patients. J Transl Med. 2019;17:298.
Jordan EJ, Kim HR, Arcila ME, Barron D, Chakravarty D, Gao J, et al. Prospective comprehensive molecular characterization of lung adenocarcinomas for efficient patient matching to approved and emerging therapies. Cancer Discov. 2017;7:596–609.
Dankner M, Rose AAN, Rajkumar S, Siegel PM, Watson IR. Classifying BRAF alterations in cancer: new rational therapeutic strategies for actionable mutations. Oncogene. 2018;37:3183–99.
Baik CS, Myall NJ, Wakelee HA. Targeting BRAF-mutant non-small cell lung cancer: from molecular profiling to rationally designed therapy. Oncologist. 2017;22:786–96.
Litvak AM, Paik PK, Woo KM, Sima CS, Hellmann MD, Arcila ME, et al. Clinical characteristics and course of 63 patients with BRAF mutant lung cancers. J Thorac Oncol. 2014;9:1669–74.
Villaruz LC, Socinski MA, Abberbock S, Berry LD, Johnson BE, Kwiatkowski DJ, et al. Clinicopathologic features and outcomes of patients with lung adenocarcinomas harboring BRAF mutations in the Lung Cancer Mutation Consortium. Cancer. 2015;121:448–56.
Kinno T, Tsuta K, Shiraishi K, Mizukami T, Suzuki M, Yoshida A, et al. Clinicopathological features of nonsmall cell lung carcinomas with BRAF mutations. Ann Oncol. 2014;25:138–42.
Yao Z, Yaeger R, Rodrik-Outmezguine VS, Tao A, Torres NM, Chang MT, et al. Tumours with class 3 BRAF mutants are sensitive to the inhibition of activated RAS. Nature. 2017;548:234–8.
Yao Z, Torres NM, Tao A, Gao Y, Luo L, Li Q, et al. BRAF mutants evade ERK-dependent feedback by different mechanisms that determine their sensitivity to pharmacologic inhibition. Cancer Cell. 2015;28:370–83.
Fontana E, Valeri N. Class(y) dissection of BRAF heterogeneity: beyond non-V600. Clin Cancer Res. 2019;25:6896–8.
Dagogo-Jack I, Martinez P, Yeap BY, Ambrogio C, Ferris LA, Lydon C, et al. Impact of BRAF mutation class on disease characteristics and clinical outcomes in BRAF-mutant lung cancer. Clin Cancer Res. 2019;25:158–65.
Tissot C, Couraud S, Tanguy R, Bringuier PP, Girard N, Souquet PJ. Clinical characteristics and outcome of patients with lung cancer harboring BRAF mutations. Lung Cancer. 2016;91:23–8.
Cui G, Liu D, Li W, Fu X, Liang Y, Li Y, et al. A meta-analysis of the association between BRAF mutation and nonsmall cell lung cancer. Medicine. 2017;96:e6552.
Planchard D, Besse B, Groen HJM, Souquet PJ, Quoix E, Baik CS, et al. Dabrafenib plus trametinib in patients with previously treated BRAF(V600E)-mutant metastatic non-small cell lung cancer: an open-label, multicentre phase 2 trial. Lancet Oncol. 2016;17:984–93.
Mazieres J, Cropet C, Montané L, Barlesi F, Souquet PJ, Quantin X, et al. Vemurafenib in non-small-cell lung cancer patients with BRAF(V600) and BRAF(nonV600) mutations. Ann Oncol. 2020;31:289–94.
Planchard D, Kim TM, Mazieres J, Quoix E, Riely G, Barlesi F, et al. Dabrafenib in patients with BRAF(V600E)-positive advanced non-small-cell lung cancer: a single-arm, multicentre, open-label, phase 2 trial. Lancet Oncol. 2016;17:642–50.
Planchard D, Smit EF, Groen HJM, Mazieres J, Besse B, Helland A, et al. Dabrafenib plus trametinib in patients with previously untreated BRAF(V600E)-mutant metastatic non-small-cell lung cancer: an open-label, phase 2 trial. Lancet Oncol. 2017;18:1307–16.
Subbiah V, Puzanov I, Blay JY, Chau I, Lockhart AC, Raje NS, et al. Pan-cancer efficacy of vemurafenib in BRAF (V600)-mutant non-melanoma cancers. Cancer Discov. 2020;10:657–63.
National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology. Non-small cell lung cancer (version 2.2021) 2020. Available from: https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf.
Dagogo-Jack I. Durable response to dabrafenib combined with trametinib in a patient with NSCLC harboring a BRAF G469A mutation. J Thorac Oncol. 2020;15:e174–e6.
Negrao MV, Raymond VM, Lanman RB, Robichaux JP, He J, Nilsson MB, et al. Molecular landscape of BRAF-mutant NSCLC reveals an association between clonality and driver mutations and identifies targetable non-V600 driver mutations. J Thorac Oncol. 2020;15:1611–23.
Dudnik E, Peled N, Nechushtan H, Wollner M, Onn A, Agbarya A, et al. BRAF mutant lung cancer: programmed death ligand 1 expression, tumor mutational burden, microsatellite instability status, and response to immune check-point inhibitors. J Thorac Oncol. 2018;13:1128–37.
Guisier F, Dubos-Arvis C, Viñas F, Doubre H, Ricordel C, Ropert S, et al. Efficacy and safety of anti-PD-1 immunotherapy in patients with advanced NSCLC with BRAF, HER2, or MET mutations or RET translocation: GFPC 01-2018. J Thorac Oncol. 2020;15:628–36.
Mansuet-Lupo A, Alifano M, Pécuchet N, Biton J, Becht E, Goc J, et al. Intratumoral immune cell densities are associated with lung adenocarcinoma gene alterations. Am J Respir Crit Care Med. 2016;194:1403–12.
Rihawi K, Giannarelli D, Galetta D, Delmonte A, Giavarra M, Turci D, et al. BRAF mutant NSCLC and immune checkpoint inhibitors: results from a real-world experience. J Thorac Oncol. 2019;14:e57–e9.
Gainor JF, Shaw AT, Sequist LV, Fu X, Azzoli CG, Piotrowska Z, et al. EGFR mutations and ALK rearrangements are associated with low response rates to PD-1 pathway blockade in non-small cell lung cancer: a retrospective analysis. Clin Cancer Res. 2016;22:4585–93.
Berghoff AS, Bellosillo B, Caux C, de Langen A, Mazieres J, Normanno N, et al. Immune checkpoint inhibitor treatment in patients with oncogene- addicted non-small cell lung cancer (NSCLC): summary of a multidisciplinary round-table discussion. ESMO Open. 2019;4:e000498.
Lee CK, Man J, Lord S, Links M, Gebski V, Mok T, et al. Checkpoint inhibitors in metastatic EGFR-mutated non-small cell lung cancer—a meta-analysis. J Thorac Oncol. 2017;12:403–7.
Rizvi H, Sanchez-Vega F, La K, Chatila W, Jonsson P, Halpenny D, et al. Molecular determinants of response to anti-programmed cell death (PD)-1 and anti-programmed death-ligand 1 (PD-L1) blockade in patients with non-small-cell lung cancer profiled with targeted next-generation sequencing. J Clin Oncol. 2018;36:633–41.
Spigel DR, Schrock AB, Fabrizio D, Frampton GM, Sun J, He J, et al. Total mutation burden (TMB) in lung cancer (LC) and relationship with response to PD-1/PD-L1 targeted therapies. J Clin Oncol. 2016;34:9017–9017.
Nagahashi M, Sato S, Yuza K, Shimada Y, Ichikawa H, Watanabe S, et al. Common driver mutations and smoking history affect tumor mutation burden in lung adenocarcinoma. J Surg Res. 2018;230:181–5.
Offin M, Rizvi H, Tenet M, Ni A, Sanchez-Vega F, Li BT, et al. Tumor mutation burden and efficacy of EGFR-tyrosine kinase inhibitors in patients with EGFR-mutant lung cancers. Clin Cancer Res. 2019;25:1063–9.
Mazieres J, Drilon A, Lusque A, Mhanna L, Cortot AB, Mezquita L, et al. Immune checkpoint inhibitors for patients with advanced lung cancer and oncogenic driver alterations: results from the IMMUNOTARGET registry. Ann Oncol. 2019;30:1321–8.
Cheng DT, Mitchell TN, Zehir A, Shah RH, Benayed R, Syed A, et al. Memorial Sloan Kettering-integrated mutation profiling of actionable cancer targets (MSK-IMPACT): a hybridization capture-based next-generation sequencing clinical assay for solid tumor molecular oncology. J Mol Diagn. 2015;17:251–64.
Samstein RM, Lee CH, Shoushtari AN, Hellmann MD, Shen R, Janjigian YY, et al. Tumor mutational load predicts survival after immunotherapy across multiple cancer types. Nat Genet. 2019;51:202–6.
Vokes NI, Liu D, Ricciuti B, Jimenez-Aguilar E, Rizvi H, Dietlein F, et al. Harmonization of tumor mutational burden quantification and association with response to immune checkpoint blockade in non-small-cell lung cancer. JCO Precis Oncol. 2019;3:1–12.
Hellmann MD, Ciuleanu TE, Pluzanski A, Lee JS, Otterson GA, Audigier-Valette C, et al. Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden. N. Engl J Med. 2018;378:2093–104.
Gaule P, Smithy JW, Toki M, Rehman J, Patell-Socha F, Cougot D, et al. A quantitative comparison of antibodies to programmed cell death 1 ligand 1. JAMA Oncol. 2017;3:256–9.
Gandhi L, Rodríguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, et al. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N. Engl J Med. 2018;378:2078–92.
Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N. Engl J Med. 2016;375:1823–33.
Shen R, Martin A, Ni A, Hellmann M, Arbour KC, Jordan E, et al. Harnessing clinical sequencing data for survival stratification of patients with metastatic lung adenocarcinomas. JCO Precis Oncol. 2019;3:1–9.
Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Lao CD, et al. Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. N. Engl J Med. 2019;381:1535–46.
Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, et al. Pembrolizumab versus ipilimumab in advanced melanoma. N. Engl J Med. 2015;372:2521–32.
Planchard D, Besse B, Groen HJM, Souquet P-J, Quoix E, Baik CS, et al. Dabrafenib plus trametinib in patients with previously treated BRAF(V600E)-mutant metastatic non-small cell lung cancer: an open-label, multicentre phase 2 trial. Lancet Oncol. 2016;17:984–93.
Zehir A, Benayed R, Shah RH, Syed A, Middha S, Kim HR, et al. Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients. Nat Med. 2017;23:703–13.
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.
This research was supported in part by the National Cancer Institute of the National Institutes of Health P30 CA008748.
Ethics approval and consent to participate
This study was approved by the institutional review board of Memorial Sloan Kettering Cancer Center.
Consent to publish
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.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
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