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Dabrafenib plus trametinib in patients with previously treated BRAF(V600E)-mutant metastatic non-small cell lung cancer: an open-label, multicentre phase 2 trial.

ABSTRACT: BACKGROUND:BRAF mutations act as an oncogenic driver via the mitogen-activated protein kinase (MAPK) pathway in non-small cell lung cancer (NSCLC). BRAF inhibition has shown antitumour activity in patients with BRAF(V600E)-mutant NSCLC. Dual MAPK pathway inhibition with BRAF and MEK inhibitors in BRAF(V600E)-mutant NSCLC might improve efficacy over BRAF inhibitor monotherapy based on observations in BRAF(V600)-mutant melanoma. We aimed to assess the antitumour activity and safety of dabrafenib plus trametinib in patients with BRAF(V600E)-mutant NSCLC. METHODS:In this phase 2, multicentre, non-randomised, open-label study, we enrolled adult patients (aged ?18 years) with pretreated metastatic stage IV BRAF(V600E)-mutant NSCLC who had documented tumour progression after at least one previous platinum-based chemotherapy and had had no more than three previous systemic anticancer therapies. Patients with previous BRAF or MEK inhibitor treatment were ineligible. Patients with brain metastases were allowed to enrol only if the lesions were asymptomatic, untreated (or stable more than 3 weeks after local therapy if treated), and measured less than 1 cm. Enrolled patients received oral dabrafenib (150 mg twice daily) plus oral trametinib (2 mg once daily) in continuous 21-day cycles until disease progression, unacceptable adverse events, withdrawal of consent, or death. The primary endpoint was investigator-assessed overall response, which was assessed by intention to treat in the protocol-defined population (patients who received second-line or later treatment); safety was also assessed in this population and was assessed at least once every 3 weeks, with adverse events, laboratory values, and vital signs graded according to the Common Terminology Criteria for Adverse Events version 4.0. The study is ongoing but no longer recruiting patients. This trial is registered with ClinicalTrials.gov, number NCT01336634. FINDINGS:Between Dec 20, 2013, and Jan 14, 2015, 59 patients from 30 centres in nine countries across North America, Europe, and Asia met eligibility criteria. Two patients who had previously been untreated due to protocol deviation were excluded; thus, 57 eligible patients were enrolled. 36 patients (63·2% [95% CI 49·3-75·6]) achieved an investigator-assessed overall response. Serious adverse events were reported in 32 (56%) of 57 patients and included pyrexia in nine (16%), anaemia in three (5%), confusional state in two (4%), decreased appetite in two (4%), haemoptysis in two (4%), hypercalcaemia in two (4%), nausea in two (4%), and cutaneous squamous cell carcinoma in two (4%). The most common grade 3-4 adverse events were neutropenia in five patients (9%), hyponatraemia in four (7%), and anaemia in three (5%). Four patients died during the study from fatal adverse events judged to be unrelated to treatment (one retroperitoneal haemorrhage, one subarachnoid haemorrhage, one respiratory distress, and one from disease progression that was more severe than typical progression, as assessed by the investigator). INTERPRETATION:Dabrafenib plus trametinib could represent a new targeted therapy with robust antitumour activity and a manageable safety profile in patients with BRAF(V600E)-mutant NSCLC. FUNDING:GlaxoSmithKline.

SUBMITTER: Planchard D

PROVIDER: S-EPMC4993103 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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Dabrafenib plus trametinib in patients with previously treated BRAF(V600E)-mutant metastatic non-small cell lung cancer: an open-label, multicentre phase 2 trial.

Planchard David D Besse Benjamin B Groen Harry J M HJM Souquet Pierre-Jean PJ Quoix Elisabeth E Baik Christina S CS Barlesi Fabrice F Kim Tae Min TM Mazieres Julien J Novello Silvia S Rigas James R JR Upalawanna Allison A D'Amelio Anthony M AM Zhang Pingkuan P Mookerjee Bijoyesh B Johnson Bruce E BE

The Lancet. Oncology 20160606 7

<h4>Background</h4>BRAF mutations act as an oncogenic driver via the mitogen-activated protein kinase (MAPK) pathway in non-small cell lung cancer (NSCLC). BRAF inhibition has shown antitumour activity in patients with BRAF(V600E)-mutant NSCLC. Dual MAPK pathway inhibition with BRAF and MEK inhibitors in BRAF(V600E)-mutant NSCLC might improve efficacy over BRAF inhibitor monotherapy based on observations in BRAF(V600)-mutant melanoma. We aimed to assess the antitumour activity and safety of dabr ...[more]

PMID: 27283860

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Project description:BackgroundDabrafenib plus trametinib improves clinical outcomes in BRAFV600-mutant metastatic melanoma without brain metastases; however, the activity of dabrafenib plus trametinib has not been studied in active melanoma brain metastases. Here, we report results from the phase 2 COMBI-MB trial. Our aim was to build on the current body of evidence of targeted therapy in melanoma brain metastases through an evaluation of dabrafenib plus trametinib in patients with BRAFV600-mutant melanoma brain metastases.MethodsThis ongoing, multicentre, multicohort, open-label, phase 2 study evaluated oral dabrafenib (150 mg twice per day) plus oral trametinib (2 mg once per day) in four patient cohorts with melanoma brain metastases enrolled from 32 hospitals and institutions in Europe, North America, and Australia: (A) BRAFV600E-positive, asymptomatic melanoma brain metastases, with no previous local brain therapy, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; (B) BRAFV600E-positive, asymptomatic melanoma brain metastases, with previous local brain therapy, and an ECOG performance status of 0 or 1; (C) BRAFV600D/K/R-positive, asymptomatic melanoma brain metastases, with or without previous local brain therapy, and an ECOG performance status of 0 or 1; and (D) BRAFV600D/E/K/R-positive, symptomatic melanoma brain metastases, with or without previous local brain therapy, and an ECOG performance status of 0, 1, or 2. The primary endpoint was investigator-assessed intracranial response in cohort A in the all-treated-patients population. Secondary endpoints included intracranial response in cohorts B, C, and D. This study is registered with ClinicalTrials.gov, number NCT02039947.FindingsBetween Feb 28, 2014, and Aug 5, 2016, 125 patients were enrolled in the study: 76 patients in cohort A; 16 patients in cohort B; 16 patients in cohort C; and 17 patients in cohort D. At the data cutoff (Nov 28, 2016) after a median follow-up of 8·5 months (IQR 5·5-14·0), 44 (58%; 95% CI 46-69) of 76 patients in cohort A achieved an intracranial response. Intracranial response by investigator assessment was also achieved in nine (56%; 95% CI 30-80) of 16 patients in cohort B, seven (44%; 20-70) of 16 patients in cohort C, and ten (59%; 33-82) of 17 patients in cohort D. The most common serious adverse events related to study treatment were pyrexia for dabrafenib (eight [6%] of 125 patients) and decreased ejection fraction (five [4%]) for trametinib. The most common grade 3 or worse adverse events, regardless of study drug relationship, were pyrexia (four [3%] of 125) and headache (three [2%]).InterpretationDabrafenib plus trametinib was active with a manageable safety profile in this melanoma population that was consistent with previous dabrafenib plus trametinib studies in patients with BRAFV600-mutant melanoma without brain metastases, but the median duration of response was relatively short. These results provide evidence of clinical benefit with dabrafenib plus trametinib and support the need for additional research to further improve outcomes in patients with melanoma brain metastases.FundingNovartis.

Project description:BackgroundCombined therapy with dabrafenib plus trametinib was approved in several countries for treatment of BRAF V600E-mutant anaplastic thyroid cancer (ATC) based on an earlier interim analysis of 23 response-assessable patients in the ATC cohort of the phase II Rare Oncology Agnostic Research (ROAR) basket study. We report an updated analysis describing the efficacy and safety of dabrafenib plus trametinib in the full ROAR ATC cohort of 36 patients with ∼4 years of additional study follow-up.Patients and methodsROAR (NCT02034110) is an open-label, nonrandomized, phase II basket study evaluating dabrafenib plus trametinib in BRAF V600E-mutant rare cancers. The ATC cohort comprised 36 patients with unresectable or metastatic ATC who received dabrafenib 150 mg twice daily plus trametinib 2 mg once daily orally until disease progression, unacceptable toxicity, or death. The primary endpoint was investigator-assessed overall response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1. Secondary endpoints were duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety.ResultsAt data cutoff (14 September 2020), median follow-up was 11.1 months (range, 0.9-76.6 months). The investigator-assessed ORR was 56% (95% confidence interval, 38.1% to 72.1%), including three complete responses; the 12-month DOR rate was 50%. Median PFS and OS were 6.7 and 14.5 months, respectively. The respective 12-month PFS and OS rates were 43.2% and 51.7%, and the 24-month OS rate was 31.5%. No new safety signals were identified with additional follow-up, and adverse events were consistent with the established tolerability of dabrafenib plus trametinib.ConclusionsThese updated results confirm the substantial clinical benefit and manageable toxicity of dabrafenib plus trametinib in BRAF V600E-mutant ATC. Dabrafenib plus trametinib notably improved long-term survival and represents a meaningful treatment option for this rare, aggressive cancer.

Project description:Background:Previous analysis of COMBI-d (NCT01584648) demonstrated improved progression-free survival (PFS) and overall survival (OS) with combination dabrafenib and trametinib versus dabrafenib monotherapy in BRAF V600E/K-mutant metastatic melanoma. This study was continued to assess 3-year landmark efficacy and safety after??36-month follow-up for all living patients. Patients and methods:This double-blind, phase 3 study enrolled previously untreated patients with BRAF V600E/K-mutant unresectable stage IIIC or stage IV melanoma. Patients were randomized to receive dabrafenib (150?mg twice daily) plus trametinib (2?mg once daily) or dabrafenib plus placebo. The primary endpoint was PFS; secondary endpoints were OS, overall response, duration of response, safety, and pharmacokinetics. Results:Between 4 May and 30 November 2012, a total of 423 of 947 screened patients were randomly assigned to receive dabrafenib plus trametinib (n?=?211) or dabrafenib monotherapy (n?=?212). At data cut-off (15 February 2016), outcomes remained superior with the combination: 3-year PFS was 22% with dabrafenib plus trametinib versus 12% with monotherapy, and 3-year OS was 44% versus 32%, respectively. Twenty-five patients receiving monotherapy crossed over to combination therapy, with continued follow-up under the monotherapy arm (per intent-to-treat principle). Of combination-arm patients alive at 3 years, 58% remained on dabrafenib plus trametinib. Three-year OS with the combination reached 62% in the most favourable subgroup (normal lactate dehydrogenase and?<3 organ sites with metastasis) versus only 25% in the unfavourable subgroup (elevated lactate dehydrogenase). The dabrafenib plus trametinib safety profile was consistent with previous clinical trial observations, and no new safety signals were detected with long-term use. Conclusions:These data demonstrate that durable (?3 years) survival is achievable with dabrafenib plus trametinib in patients with BRAF V600-mutant metastatic melanoma and support long-term first-line use of the combination in this setting.

Project description:PurposePreclinical data suggest the combination of an anti-programmed death receptor 1 antibody plus dabrafenib and trametinib to have superior antitumor activity compared with dabrafenib plus trametinib alone. These observations are supported by translational evidence suggesting that immune checkpoint inhibitors plus targeted therapy may improve treatment outcomes in patients with BRAF V600-mutant metastatic melanoma. COMBI-i is a phase III trial evaluating spartalizumab, an anti-programmed death receptor 1 antibody, in combination with dabrafenib and trametinib (sparta-DabTram), versus placebo plus dabrafenib and trametinib (placebo-DabTram) in patients with BRAF V600-mutant unresectable or metastatic melanoma.MethodsPatients received spartalizumab 400 mg intravenously every 4 weeks plus dabrafenib 150 mg orally twice daily and trametinib 2 mg orally once daily or placebo-DabTram. Participants were age ≥ 18 years with unresectable or metastatic BRAF V600-mutant melanoma. The primary end point was investigator-assessed progression-free survival. Overall survival was a key secondary end point (ClinicalTrials.gov identifier: NCT02967692).ResultsAt data cutoff (July 1, 2020), the median progression-free survival was 16.2 months (95% CI, 12.7 to 23.9 months) in the sparta-DabTram arm versus 12.0 months (95% CI, 10.2 to 15.4 months) in the placebo-DabTram arm (hazard ratio, 0.82 [95% CI, 0.66 to 1.03]; P = .042 [one-sided; nonsignificant]). The objective response rates were 69% (183 of 267 patients) versus 64% (170 of 265 patients), respectively. Grade ≥ 3 treatment-related adverse events occurred in 55% (146 of 267) of patients in the sparta-DabTram arm and 33% (88 of 264) in the placebo-DabTram arm.ConclusionThe study did not meet its primary end point; broad first-line use of sparta-DabTram is not supported by these results. Further biomarker-driven investigation may identify patient subpopulations who could benefit from checkpoint inhibitor plus targeted therapy combinations.

Dataset Information

Dabrafenib plus trametinib in patients with previously treated BRAF(V600E)-mutant metastatic non-small cell lung cancer: an open-label, multicentre phase 2 trial.

Publications

Dabrafenib plus trametinib in patients with previously treated BRAF(V600E)-mutant metastatic non-small cell lung cancer: an open-label, multicentre phase 2 trial.

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