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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

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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.
Author(s)
? Zvirbule김성배A BrufskyA EniuD MilesJ H SohnJ MebisM WongchenkoR AminS ChohanS LoiV McNallyY Yan
Issued Date
2021
Type
Article
Keyword
MEK inhibitoratezolizumabcobimetinibprogrammed death-ligand 1 inhibitortriple-negative breast cancer.
DOI
10.1016/j.annonc.2021.01.065
URI
https://oak.ulsan.ac.kr/handle/2021.oak/8426
https://ulsan-primo.hosted.exlibrisgroup.com/primo-explore/fulldisplay?docid=TN_cdi_crossref_primary_10_1016_j_annonc_2021_01_065&context=PC&vid=ULSAN&lang=ko_KR&search_scope=default_scope&adaptor=primo_central_multiple_fe&tab=default_tab&query=any,contains,A%20phase%20II%20randomized%20trial%20of%20cobimetinib%20plus%20chemotherapy,%20with%20or%20without%20atezolizumab,%20as%20first-line%20treatment%20for%20patients%20with%20locally%20advanced%20or%20metastatic%20triple-negative%20breast%20cancer%20(COLET):%20primary%20analysis&offset=0&pcAvailability=true
Publisher
ANNALS OF ONCOLOGY
Location
영국
Language
영어
ISSN
0923-7534
Citation Volume
32
Citation Number
5
Citation Start Page
652
Citation End Page
660
Appears in Collections:
Medicine > Medicine
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