Atezolizumab/Vemurafenib Combo Shows Clinical Activity in BRAF+ Melanoma

Omid Hamid, MD

The combination of atezolizumab (MPDL3280A) and vemurafenib (Zelboraf) yielded durable responses in patients with previously untreated BRAF V600—mutated metastatic melanoma in an ongoing phase Ib study.¹

Atezolizumab, an investigational PD-L1 inhibitor, and vemurafenib, a BRAF-targeted agent, produced an objective response rate (ORR) of 76% (95% CI, 50.1%—93.2%). This included 3 complete responses (CR) and 10 partial responses (PR) among the 17 patients evaluable at the time of data collection.

“The targeted therapy has a great initial response rate and a great palliative benefit, but a not so great long-term durable benefit. The immunotherapy has a low initial response rate, but the ability to have a long-term durability,” said Omid Hamid, MD, who presented the phase Ib data at the Society for Melanoma Research 2015 International Congress. “The study is still accruing, but as we’ve brought the cohorts forward, we are seeing higher response rates and durable responses.”

In the multicenter, open-label, dose-escalation study, patients received atezolizumab combined with vemurafenib concurrently (n = 3) or after a run-in period with vemurafenib alone for 56 days (n = 8) or 28 days (n = 6). Atezolizumab was administered intravenously every 3 weeks at 20 mg/kg or 15 mg/kg or 1200 mg fixed. Vemurafenib was given twice daily at 960 mg during the run-in period and at 720 mg during the combination.

ORR in the concurrent cohort was 33%, with 1 complete response. ORR was 75% and 100% with 1 CR each in the 56- and 28-day vemurafenib run-in cohorts, respectively. The median duration of response in the overall study population was 20.9 months and the median progression-free survival (PFS) was 10.9 months. Patients in the study will continue to receive treatment until they no longer experience clinical benefit as assessed by the investigators.

Overall, the combination was well tolerated with no dose-limiting toxicities or atezolizumab-related treatment discontinuations.

In the overall study population, grade 3 adverse events (AEs) related to atezolizumab occurred in 41% of patients and grade 3 AEs related to vemurafenib occurred in 59% of patients.

Sixty-seven percent of the concurrent cohort experienced a grade 3 AE, with lower rates of 38% and 33% experienced by the 56- and 28-day vemurafenib run-in cohorts, respectively. Serious AEs included pyrexia and dehydration, which were manageable. There were no treatment-related grade 4 AEs or deaths.

“What we initially saw were toxicities of elevated liver enzymes and rash, but the regimen became more tolerable when we had a run-in period of vemurafenib, and then brought the anti—PD-L1 in," said Hamid, who is chief of Translational Research and Immunotherapy and director of Melanoma Therapeutics at The Angeles Clinic. “We tried very hard to limit the toxicity.”

In November 2015, the FDA approved the combination of vemurafenib and MEK inhibitor cobimetinib (Cotellic) as a treatment for patients with BRAF-positive metastatic or unresectable melanoma. Because of this approval, the phase Ib study was amended to include the triplet of vemurafenib, atezolizumab, and cobimetinib.

“We are hoping to continue accrual and show greater benefit with the triplet,” said Hamid. “This data is extremely positive regarding our ability to take targeted agents and combine them with immune agents and checkpoint inhibitors. I think this is a very viable regimen to take forward. The idea of moving from single-agent targeted or immunotherapy into combinations and now triplets is very exciting.”

The vemurafenib/cobimetinib approval was based on the phase III coBRIM study, which found a median PFS of 12.3 months with the combination versus 7.2 months for vemurafenib alone (HR, 0.56; P <.001). At a 17-month analysis, 65% of patients receiving the combination remained alive versus 50% for vemurafenib. The ORR with the combination was 69.6% compared with 50% for vemurafenib alone.²

Toxicities with the triplet combination are not expected to be any less tolerable than the doublet combination has shown thus far, said Hamid.

“There are 2 other similar trials going forward with the triplet combination and, in those trials, we’ve seen toxicity, but it is not significantly higher and there hasn’t been any significant toxicity that isn’t manageable,” said Hamid.

References

1. Hamid O, et al. Preliminary clinical safety, tolerability and activity of atezolizumab (anti-PD-L1) combined with Zelboraf in BRAFv600 metastatic melanoma. Presented at the Society for Melanoma Research 2015 International Congress; November 18-21, 2015; San Francisco, CA.
2. Larkin JMG, Yan Y, McArthur GA, et al. Update of progression-free survival (PFS) and correlative biomarker analysis from coBRIM: Phase III study of cobimetinib (cobi) plus vemurafenib (vem) in advanced BRAF-mutated melanoma. J Clin Oncol. 2015;33 (suppl; abstr 9006).