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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| Název: | 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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| Autoři: | Brufsky, A, Kim, SB, Zvirbule, Z, Eniu, A, Mebis, J, Sohn, JH, Wongchenko, M, Chohan, S, Amin, R, Yan, Y, McNally, V, Miles, D, Loi, S |
| Přispěvatelé: | A Brufsky, S B Kim, A Eniu, J Mebis, J H Sohn, M Wongchenko, S Chohan, R Amin, Y Yan, V McNally, D Miles, S Loi, Sohn, Joo Hyuk |
| Zdroj: | Annals of Oncology. 32:652-660 |
| Informace o vydavateli: | Elsevier BV, 2021. |
| Rok vydání: | 2021 |
| Témata: | atezolizumab, Paclitaxel / adverse effects, Triple Negative Breast Neoplasms* / drug therapy, MEK inhibitor, programmed death-ligand 1 inhibitor, Paclitaxel, Triple Negative Breast Neoplasms, Antibodies, Monoclonal, Humanized, Antibodies, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Piperidines, Monoclonal, Humanized / therapeutic use, Antineoplastic Combined Chemotherapy Protocols / adverse effects, Antineoplastic Combined Chemotherapy Protocols, triple-negative breast cancer, Azetidines, Humans, cobimetinib |
| Popis: | 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 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.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.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. |
| Druh dokumentu: | Article |
| Popis souboru: | application/pdf |
| Jazyk: | English |
| ISSN: | 0923-7534 |
| DOI: | 10.1016/j.annonc.2021.01.065 |
| Přístupová URL adresa: | http://www.annalsofoncology.org/article/S0923753421000934/pdf https://pubmed.ncbi.nlm.nih.gov/33539944 https://findanexpert.unimelb.edu.au/scholarlywork/1504537-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 https://www.ncbi.nlm.nih.gov/pubmed/33539944 https://www.annalsofoncology.org/article/S0923-7534(21)00093-4/fulltext https://europepmc.org/article/MED/33539944 https://pubmed.ncbi.nlm.nih.gov/33539944/ https://www.annalsofoncology.org/article/S0923753421000934/pdf http://hdl.handle.net/1942/34426 |
| Rights: | CC BY NC ND |
| Přístupové číslo: | edsair.doi.dedup.....cd79d91b0da371afcc23e33953fb7318 |
| Databáze: | OpenAIRE |
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Nájsť tento článok vo Web of Science | Abstrakt: | 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 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.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.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. |
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| ISSN: | 09237534 |
| DOI: | 10.1016/j.annonc.2021.01.065 |