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Clinical Trial
. 2021 May;32(5):652-660.
doi: 10.1016/j.annonc.2021.01.065. Epub 2021 Feb 1.

A phase II randomized trial of cobimetinib plus chemotherapy, with or without atezolizumab, as first-line treatment for patients with locally advanced or metastatic triple-negative breast cancer (COLET): primary analysis

A Brufsky  1 , S B Kim  2 , Ž Zvirbule  3 , A Eniu  4 , J Mebis  5 , J H Sohn  6 , M Wongchenko  7 , S Chohan  8 , R Amin  7 , Y Yan  7 , V McNally  9 , D Miles  10 , S Loi  11
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Free article
Clinical Trial

A phase II randomized trial of cobimetinib plus chemotherapy, with or without atezolizumab, as first-line treatment for patients with locally advanced or metastatic triple-negative breast cancer (COLET): primary analysis

A Brufsky et al. Ann Oncol. 2021 May.
Free article

Abstract

Background: Resistance to standard chemotherapy in metastatic triple-negative breast cancer (mTNBC) is associated with upregulation of the mitogen-activated protein kinase (MAPK) pathway. Cobimetinib, an MAPK/extracellular signal-regulated kinase (MEK) inhibitor, may increase sensitivity to taxanes and programmed death-ligand 1 inhibitors. COLET is a three-cohort phase II study evaluating first-line cobimetinib plus chemotherapy, with or without atezolizumab, in patients with locally advanced or mTNBC.

Patients and methods: Patients were ≥18 years with locally advanced or mTNBC. Following a safety run-in, patients in cohort I were randomized 1:1 to cobimetinib (60 mg, D3-D23 of each 28-day cycle) or placebo, plus paclitaxel (80 mg/m2, D1, 8, and 15). Additional patients were randomized (1:1) to cohort II or III to receive cobimetinib plus atezolizumab (840 mg, D1 and D15) and either paclitaxel (cohort II) or nab-paclitaxel [cohort III (100 mg/m2, D1, D8, and D15)]. Primary endpoints were investigator-assessed progression-free survival (PFS) (cohort I) and confirmed objective response rate (ORR) (cohorts II/III). Safety and tolerability were also assessed.

Results: In the expansion stages, median PFS was 5.5 months for cobimetinib/paclitaxel versus 3.8 months for placebo/paclitaxel in cohort I [hazard ratio 0.73; 95% confidence interval (CI) 0.43-1.24; P = 0.25]. In cohort I, ORR was 38.3% (95% CI 24.40-52.20) for cobimetinib/paclitaxel and 20.9% (95% CI 8.77-33.09) for placebo/paclitaxel; ORRs in cohorts II and III were 34.4% (95% CI 18.57-53.19) and 29.0% (95% CI 14.22-48.04), respectively. Diarrhea was the most common grade ≥3 adverse events across all cohorts.

Conclusions: Cobimetinib added to paclitaxel did not lead to a statistically significant increase in PFS or ORR, although a nonsignificant trend toward a numerical increase was observed. Cobimetinib plus atezolizumab and a taxane did not appear to increase ORR. This demonstrates the potential activity of a combinatorial MEK inhibitor, chemotherapy, and immunotherapy in this difficult-to-treat population.

Keywords: MEK inhibitor; atezolizumab; cobimetinib; programmed death-ligand 1 inhibitor; triple-negative breast cancer.

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Conflict of interest statement

Disclosure AB reports personal fees from Roche, Novartis, Eli Lilly, AstraZeneca, and Pfizer. SBK has received research funding from Novartis, Sanofi-Aventis, Kyowa-Kirin Inc, and Dongkook Pharm Co.; and has participated as a consultant in advisory boards for Novartis, AstraZeneca, Lilly, Enzychem, Dae Hwa Pharmaceutical Co. Ltd, ISU Abxis, and Daiichi Sankyo. ŽZ reports grants and personal fees for the participation in the study from Roche; and grants and personal fees outside the study from Genentech, Halozyme Inc., Roche, AbbVie, and MSD. AE has received research grants from Celltrion, Roche, and Pfizer. JM reports congress fees from Roche. JHS has received institutional research funding from MSD, Roche, Novartis, AstraZeneca, Eli Lilly, Pfizer, Bayer, Contessa, Daiichi Sankyo, and GSK. MW is a salaried employee of Genentech and has stock ownership interest in Roche. SC, YY, and VM are salaried employees and have ownership interests in Roche. RA is an employee of Genentech. DM has received honoraria from Roche, Eisai, and Genomic Health for advisory boards, and from Eisai for presentations. SL has received institutional research funding and nonremunerated consultancy fees from Bristol Myers Squibb, Roche, Genentech, Pfizer, Seattle Genetics, Novartis, Merck, and AstraZeneca; has received institutional research funding from Puma Biotechnology and Eli Lilly; and has received consultancy fees to her institution from Aduro Biotech, G1 Therapeutics, and GSK. Data sharing statement Qualified researchers may request access to individual patient-level data through the clinical study data request platform (https://vivli.org/). Further details on Roche's criteria for eligible studies are available here: https://vivli.org/members/ourmembers/. For further details on Roche's Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents, see here: https://www.roche.com/research_and_development/who_we_are_how_we_work/clinical_trials/our_commitment_to_data_sharing.htm.

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