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
Mené sur des patientes atteintes d'un cancer du sein triple négatif de stade localement avancé ou métastatique, cet essai de phase II évalue l'efficacité, du point de vue de la survie sans progression et du taux de réponse objective, de l'ajout du cobimétinib à une chimiothérapie de première ligne avec ou sans atézolizumab
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, a 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) into 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/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 AE across all cohorts. Conclusions : Cobimetinib added to paclitaxel did not lead to a statistically significant increase in PFS or ORR, although a nonsignificant trend towards 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.
Annals of Oncology 2021