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Title: | 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 | Authors: | Brufsky, A. Kim, S. B. Zvirbule, Z. Eniu, A. MEBIS, Jeroen Sohn, J. H. Wongchenko, M. Chohan, S. Amin, R. Yan, Y. McNally, V Miles, D. Loi, S. |
Issue Date: | 2021 | Publisher: | ELSEVIER | Source: | Annals of oncology, 32 (5) , p. 652 -660 | 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/m(2), 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/m(2), 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. | Notes: | Brufsky, A (corresponding author), Univ Pittsburgh, Dept Med, Div Hematol Oncol, Med Ctr, 300 Halket St,Suite 4628, Pittsburgh, PA 15213 USA.; Loi, S (corresponding author), Peter MacCallum Canc Ctr, Div Clin Med & Res, 305 Grattan St, Melbourne, Vic 3000, Australia. brufskyam@upmc.edu; sherene.loi@petermac.org |
Other: | Brufsky, A (corresponding author), Univ Pittsburgh, Dept Med, Div Hematol Oncol, Med Ctr, 300 Halket St,Suite 4628, Pittsburgh, PA 15213 USA. Loi, S (corresponding author), Peter MacCallum Canc Ctr, Div Clin Med & Res, 305 Grattan St, Melbourne, Vic 3000, Australia. brufskyam@upmc.edu; sherene.loi@petermac.org | Keywords: | cobimetinib;triple-negative breast cancer;MEK inhibitor;atezolizumab;programmed death-ligand 1 inhibitor | Document URI: | http://hdl.handle.net/1942/34426 | ISSN: | 0923-7534 | e-ISSN: | 1569-8041 | DOI: | 10.1016/j.annonc.2021.01.065 | ISI #: | WOS:000640355800011 | Category: | A1 | Type: | Journal Contribution | Validations: | ecoom 2022 |
Appears in Collections: | Research publications |
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