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Vemurafenib in non-small-cell lung cancer patients with BRAFV600 and BRAFnonV600 mutations. ​

Literature Information ​

DOI10.1016/j.annonc.2019.10.022
PMID31959346
JournalAnnals of oncology : official journal of the European Society for Medical Oncology
Impact Factor65.4
JCR QuartileQ1
Publication Year2020
Times Cited82
KeywordsBRAF, basket trial, biomarker, lung cancer, personalised therapy
Literature TypeJournal Article, Research Support, Non-U.S. Gov't
ISSN0923-7534
Pages289-294
Issue31(2)
AuthorsJ Mazieres, C Cropet, L Montané, F Barlesi, P J Souquet, X Quantin, C Dubos-Arvis, J Otto, L Favier, V Avrillon, J Cadranel, D Moro-Sibilot, I Monnet, V Westeel, J Le Treut, E Brain, J Trédaniel, M Jaffro, S Collot, G R Ferretti, C Tiffon, C Mahier-Ait Oukhatar, J Y Blay

TL;DR ​

The AcSé vemurafenib trial evaluated the efficacy of vemurafenib in treating non-small-cell lung cancer (NSCLC) patients with BRAF mutations, revealing that while 44.9% of patients with the BRAFV600 mutation responded to treatment, those with BRAFnonV600 mutations showed no clinical benefit. These findings underscore the necessity of routine biomarker screening for BRAFV600 mutations in NSCLC to guide targeted therapy effectively.

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BRAF · basket trial · biomarker · lung cancer · personalised therapy

Abstract ​

BACKGROUND BRAF mutations occurring in 1%-5% of patients with non-small-cell lung cancer (NSCLC) are therapeutic targets for these cancers but the impact of the exact mutation on clinical activity is unclear. The French National Cancer Institute (INCA) launched the AcSé vemurafenib trial to assess the efficacy and safety of vemurafenib in cancers with various BRAF mutations. We herein report the results of the NSCLC cohort.

PATIENTS AND METHODS Tumour samples were screened for BRAF mutations in INCA-certified molecular genetic centres. Patients with BRAF-mutated tumours progressing after ≥1 line of treatment were proposed vemurafenib 960 mg twice daily. Between October 2014 and July 2018, 118 patients were enrolled in the NSCLC cohort. The primary outcome was the objective response rate (ORR) assessed every 8 weeks (RECIST v1.1). A sequential Bayesian approach was planned with an inefficacy bound of 10% for ORR. If no early stopping occurred, the treatment was of interest if the estimated ORR was ≥30% with a 90% probability. Secondary outcomes were tolerance, response duration, progression-free survival (PFS), and overall survival (OS).

RESULTS Of the 118 patients enrolled, 101 presented with a BRAFV600 mutation and 17 with BRAFnonV600 mutations; the median follow-up was 23.9 months. In the BRAFnonV600 cohort, no objective response was observed and this cohort was stopped. In the BRAFV600 cohort, 43/96 patients had objective responses. The mean Bayesian estimated success rate was 44.9% [95% confidence intervals (CI) 35.2%-54.8%]. The ORR had a 99.9% probability of being ≥30%. Median response duration was 6.4 months, median PFS was 5.2 months (95% CI 3.8-6.8), and OS was 10 months (95% CI 6.8-15.7). The vemurafenib safety profile was consistent with previous publications.

CONCLUSION Routine biomarker screening of NSCLC should include BRAFV600 mutations. Vemurafenib monotherapy is effective for treating patients with BRAFV600-mutated NSCLC but not those with BRAFnonV600 mutations.

TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT02304809.

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Primary Questions Addressed ​

  1. What are the long-term outcomes for patients with BRAFV600 mutations treated with vemurafenib compared to those with other mutations in NSCLC?
  2. How does the efficacy of vemurafenib in NSCLC patients with BRAFV600 mutations compare to other targeted therapies available for lung cancer?
  3. What factors contribute to the lack of objective response in patients with BRAFnonV600 mutations receiving vemurafenib?
  4. Are there specific biomarkers that can predict the response to vemurafenib in NSCLC patients with BRAFV600 mutations?
  5. How do the side effects of vemurafenib in the NSCLC cohort compare to its effects in other cancer types where it is used?

Key Findings ​

Key Insights ​

  1. Research Background and Purpose: BRAF mutations are found in 1%-5% of non-small-cell lung cancer (NSCLC) patients and represent potential therapeutic targets. However, the specific effects of different BRAF mutations on treatment responses remain unclear. The French National Cancer Institute (INCA) initiated the AcSé vemurafenib trial to evaluate the efficacy and safety of vemurafenib, a targeted therapy, in NSCLC patients harboring various BRAF mutations. This study specifically reports findings from the NSCLC cohort.

  2. Main Methods and Findings: A total of 118 patients with BRAF-mutated NSCLC who had progressed after at least one line of treatment were enrolled in the trial from October 2014 to July 2018. All patients were first screened for BRAF mutations in INCA-certified molecular genetic centers. Patients received vemurafenib at a dose of 960 mg twice daily. The primary outcome measured was the objective response rate (ORR) assessed every eight weeks using RECIST v1.1 criteria. Secondary outcomes included treatment tolerance, response duration, progression-free survival (PFS), and overall survival (OS).

    Among the enrolled patients, 101 had BRAFV600 mutations, and 17 had BRAFnonV600 mutations. The results showed that no objective responses occurred in the BRAFnonV600 cohort, leading to its early termination. In contrast, the BRAFV600 cohort exhibited a significant treatment response, with 43 out of 96 patients achieving objective responses, yielding an estimated ORR of 44.9% (95% CI: 35.2%-54.8%). The median response duration was 6.4 months, median PFS was 5.2 months (95% CI: 3.8-6.8), and the median OS was 10 months (95% CI: 6.8-15.7). The safety profile of vemurafenib was consistent with existing literature, indicating manageable side effects.

  3. Core Conclusion: The study concludes that vemurafenib monotherapy is effective for patients with BRAFV600-mutated NSCLC, demonstrating a clinically significant response rate and favorable survival metrics. However, it is ineffective for those with BRAFnonV600 mutations, emphasizing the necessity of distinguishing between these mutation types in treatment considerations.

  4. Research Significance and Impact: This research underscores the critical importance of routine biomarker screening for BRAFV600 mutations in NSCLC, as it can inform treatment decisions and optimize patient outcomes. The findings advocate for targeted therapy in the appropriate patient subset, potentially influencing clinical practice guidelines and improving therapeutic strategies for BRAF-mutated lung cancer. By establishing the efficacy of vemurafenib specifically in the BRAFV600 cohort, the study contributes to the growing body of evidence supporting personalized medicine in oncology, paving the way for more effective management of NSCLC based on genetic profiling.

Literatures Citing This Work ​

  1. Secondary Resistant Mutations to Small Molecule Inhibitors in Cancer Cells. - Abdulaziz B Hamid;Ruben C Petreaca - Cancers (2020)
  2. Current status and future outlook for patient-derived cancer models from a rare cancer research perspective. - Tadashi Kondo - Cancer science (2021)
  3. A highly sensitive and specific real-time quantitative PCR for BRAF V600E/K mutation screening. - Jrhau Lung;Ming-Szu Hung;Yu-Ching Lin;Yuan Yuan Jiang;Yu-Hung Fang;Ming-Shian Lu;Ching-Chuan Hsieh;Chia-Siu Wang;Feng-Che Kuan;Chang-Hsien Lu;Ping-Tsung Chen;Chieh-Mo Lin;Yen-Li Chou;Chin-Kuo Lin;Tsung-Ming Yang;Fen Fen Chen;Paul Yann Lin;Meng-Jer Hsieh;Ying Huang Tsai - Scientific reports (2020)
  4. Construction and Validation of a Protein Prognostic Model for Lung Squamous Cell Carcinoma. - Xisheng Fang;Xia Liu;Chengyin Weng;Yong Wu;Baoxiu Li;Haibo Mao;Mingmei Guan;Lin Lu;Guolong Liu - International journal of medical sciences (2020)
  5. First line Immunotherapy for Non-Small Cell Lung Cancer. - Nicola J Nasser;Miguel Gorenberg;Abed Agbarya - Pharmaceuticals (Basel, Switzerland) (2020)
  6. Current Targeted Therapies for the Fight against Non-Small Cell Lung Cancer. - Lisa Maria Mustachio;Jason Roszik - Pharmaceuticals (Basel, Switzerland) (2020)
  7. Up-regulation of VANGL1 by IGF2BPs and miR-29b-3p attenuates the detrimental effect of irradiation on lung adenocarcinoma. - Chun-Cheng Hao;Cui-Yang Xu;Xin-Yu Zhao;Jia-Ning Luo;Gang Wang;Li-Hong Zhao;Xiaofeng Ge;Xiao-Feng Ge - Journal of experimental & clinical cancer research : CR (2020)
  8. BRAF: A Two-Faced Janus. - Pasquale Pisapia;Francesco Pepe;Antonino Iaccarino;Roberta Sgariglia;Mariantonia Nacchio;Gianluca Russo;Gianluca Gragnano;Umberto Malapelle;Giancarlo Troncone - Cells (2020)
  9. Immunotherapy Benefit in a Patient With Non-Small Cell Lung Cancer and a Rare BRAF Mutation. - Rebekah Rittberg;Shantanu Banerji;Susan Green;Gefei Qing;David E Dawe - Cureus (2020)
  10. Genomic characteristics of driver genes in Chinese patients with non-small cell lung cancer. - Xiaoyan Si;Ruili Pan;Shaohua Ma;Lin Li;Li Liang;Ping Zhang;Yuping Chu;Hanping Wang;Mengzhao Wang;Xiaotong Zhang;Li Zhang - Thoracic cancer (2021)

... (72 more literatures)

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