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Cobimetinib Plus Vemurafenib in Patients With Solid Tumors With BRAF Mutations: Results From the Targeted Agent and
Funda Meric-Bernstam1, Michael Rothe2, Pam K Mangat2
1University of Texas MD Anderson Cancer Center, Houston, TX.
Purpose:
The Targeted Agent and Profiling Utilization Registry Study is a phase II basket study evaluating antitumor activity of commercially available targeted agents in patients with advanced cancers with genomic alterations known to be drug targets. The results in a cohort of patients with solid tumors with BRAF mutations treated with cobimetinib plus vemurafenib are reported.
Methods:
Eligible patients had measurable disease (RECIST v.1.1), Eastern Cooperative Oncology Group performance status 0-2, adequate organ function, and no standard treatment options. The primary end point was disease control (DC), defined as complete response (CR) or partial response (PR) or stable disease of at least 16-weeks duration (SD16+). Low-accruing histology-specific cohorts with BRAF mutations treated with cobimetinib plus vemurafenib were collapsed into a single histology-pooled cohort for this analysis. The results were evaluated on the basis of a one-sided exact binomial test with a null DC rate of 15% versus 35% (power, .82; α, .10). The secondary end points were objective response (OR), progression-free survival, overall survival, duration of response, duration of stable disease, and safety.
Results:
Thirty-one patients with solid tumors with BRAF mutations were enrolled. Twenty-eight patients were evaluable for efficacy. Patients had tumors with BRAF V600E (n = 26), K601E (n = 2), or other (n = 3) mutations. Two patients with CR (breast and ovarian cancers; V600E), 14 with PR (13 V600E, one N581I), and three with SD16+ (two V600E, one T599_V600insT) were observed with a DC rate of 68% (P < .0001; one-sided 90% CI, 54 to 100) and an OR rate of 57% (95% CI, 37 to 76). Nineteen patients experienced ≥one drug-related grade 3-5 adverse event or serious adverse event including one death attributed to treatment-related kidney injury.
Conclusion:
Cobimetinib plus vemurafenib showed antitumor activity in patients with advanced solid tumors with BRAF V600E mutations; additional study is warranted to confirm the antitumor activity in tumors with non-V600E BRAF mutations.
Insights
Cobimetinib plus vemurafenib demonstrated significant antitumor activity in advanced solid tumors with BRAF V600E mutations. Further research is needed to confirm efficacy in non-V600E BRAF mutations.
Area of Science:
- Oncology
- Genomics
- Pharmacology
Background:
- Targeted therapies offer new treatment avenues for advanced cancers.
- Genomic alterations, such as BRAF mutations, are key targets for precision medicine.
Purpose of the Study:
- To evaluate the antitumor activity of cobimetinib plus vemurafenib in patients with advanced solid tumors harboring BRAF mutations.
- To assess disease control rate (DC) as the primary endpoint in a phase II basket study.
Main Methods:
- A cohort of 31 patients with advanced solid tumors and BRAF mutations were treated with cobimetinib and vemurafenib.
- Disease control (complete response, partial response, or stable disease ≥16 weeks) was the primary efficacy endpoint.
- Safety and other efficacy endpoints including objective response rate (ORR) were also assessed.
Main Results:
- A disease control rate of 68% (P < .0001) was observed in 28 evaluable patients.
- The objective response rate was 57% (95% CI, 37 to 76), with 2 complete responses and 14 partial responses.
- Nineteen patients experienced treatment-related adverse events, including one death due to kidney injury.
Conclusions:
- Cobimetinib plus vemurafenib exhibits notable antitumor activity in advanced solid tumors with BRAF V600E mutations.
- Further investigation is recommended to validate these findings in tumors with non-V600E BRAF mutations.
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