Atezolizumab Plus Cobimetinib/Vemurafenib Meets PFS Endpoint in Frontline BRAF V600+ Advanced Melanoma

Levi Garraway, MD, PhD

The triplet regimen of atezolizumab (Tecentriq), cobimetinib (Cotellic), and vemurafenib (Zelboraf) was found to improve progression-free survival (PFS) compared with cobimetinib/vemurafenib plus placebo in patients with previously untreated BRAF V600 mutation—positive advanced melanoma, meeting the primary endpoint of the phase III IMspire150 study (NCT02908672).¹

Additionally, data showed that the known safety profile of the 3-drug regimen was consistent of each agent alone. Results of the trial will be presented at an upcoming medical meeting and will also be discussed with the FDA and European Medicines Agency.

"By combining a cancer immunotherapy with targeted therapies, we hope to offer a new approach that improves outcomes for people with advanced, BRAF-mutant melanoma," Levi Garraway, MD, PhD, chief medical officer and head of Global Product Development, Genentech (Roche), stated in a press release. "We look forward to discussing the results with health authorities around the world."

In the, multicenter, double-blind, placebo-controlled, phase III IMspire150 trial, 513 patients with previously untreated BRAF V600 mutation—positive metastatic or unresectable locally advanced melanoma were randomized to receive atezolizumab plus cobimetinib and vemurafenib or cobimetinib/vemurafenib and placebo.

To be eligible for enrollment, patients had histologically confirmed metastatic or unresectable locally advanced melanoma, were treatment-naïve and had BRAF V600 mutation—positive disease, an ECOG performance status of 0 or 1, measurable disease according to RECIST v1.1 criteria, and a life expectancy of ≥18 weeks. Those who had major surgery within 4 weeks of starting study treatment, an active malignancy other than the melanoma, or had untreated or actively progressing central nervous system lesions were excluded from enrollment.

The primary endpoint was investigator-assessed PFS; key secondary endpoints were PFS by an independent review committee, overall survival (OS), objective response rate (ORR), duration of response (DOR), and other safety and pharmacokinetic measures.

Earlier findings of this triplet regimen were presented at the 2016 Society for Melanoma Research Annual Meeting.² In cohort 4 of a phase Ib trial, patients with metastatic or unresectable BRAF-mutant melanoma were treated with atezolizumab in combination with cobimetinib and vemurafenib. The median age was 50 years and patients had not received a prior PD-1 or BRAF/MEK inhibitor. A majority of patients had a normal lactate dehydrogenase (81.5%) and an ECOG performance status of 0 (83%). The stage of disease ranged from IIIc (27%) to M1c (20%).

During a 28-day run-in period, vemurafenib was administered at 960 mg twice daily on days 1 to 21. After the run-in, the vemurafenib dose was reduced to 720 mg twice daily and atezolizumab was administered at 800 mg every 2 weeks. Cobimetinib was given at 60 mg daily on days 1 to 21 across both phases of the study.

At the data cutoff of June 15, 2016, 30 patients had received ≥1 dose of atezolizumab. The response rate with the triplet was 83%, which included 3 complete responses (10%) and 21 partial responses (PRs). Overall, 29 patients were evaluable for response, with 1 patient experiencing primary progressive disease. At the time of the analysis, median DOR and PFS were not yet reached.

Safety findings, which had a median follow-up of 3.9 months, showed that the most common treatment-related adverse events were arthralgia, elevated liver enzymes, nausea, fatigue, flu-like symptoms, maculopapular rash, mucosal inflammation, and photosensitivity.

Grade 3/4 AEs were experienced by 40% of patients treated with the combination, of which 27% were deemed atezolizumab related. There were 3 treatment-related serious AEs, which included 1 patient with elevated creatine phosphokinase, 1 case of sepsis, and 1 patient with diarrhea and alanine aminotransferase/aspartate aminotransferase elevation. These events were resolved with dose interruptions and/or dose reductions.

In 2015, the FDA approved the combination of cobimetinib and vemurafenib in 2015 as a treatment for patients with BRAF-positive metastatic or unresectable melanoma, based on earlier findings of the phase III coBRIM trial.

Five-year findings of coBRIM study were recently presented at the 16th International Congress of the Society for Melanoma Research.³ The study included 495 treatment-naïve patients with BRAF V600E/K—positive unresectable locally advanced or metastatic melanoma. Patient demographics were well balanced across the 2 arms, including disease stage, ECOG performance status, age, and geographic region. More than half of patients had stage IV, M1c melanoma.

Patients were randomized to continuous vemurafenib at 960 mg twice daily plus either placebo (n = 248) or 60 mg of cobimetinib once daily on days 1-21 of a 28-day cycle (n = 247). The primary endpoint of the study was PFS, with secondary endpoints including OS, ORR, and DOR.

The combination induced an ORR of 70% (95% CI, 63-75) with a complete response (CR) rate of 21% and a partial response (PR) rate of 49%. Vemurafenib alone induced an ORR of 50% (95% CI, 43-56) with a CR of 13% and a PR of 37%.

Additionally, the median OS was 22.5 months (95% CI, 20.3-28.8) with the combination compared with 17.4 months (95% CI, 14.5-19.8) for the monotherapy. The 5-years OS rates were 30.8% vs 26.3%, respectively.

The median PFS at 5 years was 12.6 months (95% CI, 9.5-14.8) with cobimetinib/vemurafenib versus 7.2 months (95% CI, 5.6-7.5) with vemurafenib alone. The 5-year PFS rates were 14% versus 10%, respectively.

Patients who responded to the cobimetinib/vemurafenib combination had a superior median OS at 32.1 vs 9.7 months, and OS rate of 37% vs 13% at 5 years. Similarly, those patients had superior median PFS (16.6 vs 3.7 months) and PFS rate (18% vs 4%).

References

1. Genentech announces phase III study results for Tecentriq plus Cotellic and Zelboraf in people with previously untreated BRAF V600 mutation-positive advanced melanoma [news release]. Genentench (Roche). Published December 12, 2019. https://bit.ly/34my7ap. Accessed December 13, 2019.
2. Sullivan RJ, Hamid O, Gonzalez R, et al. Safety and clinical activity of atezolizumab + cobimetinib + vemurafenib in BRAFV600-mutant metastatic melanoma. Presented at: Society for Melanoma Research Annual Meeting; Boston, Massachusetts, November 6-9, 2016.
3. McArthur GA, Dréno B, Larkin J, et al. 5-year survival update of cobimetinib plus vemurafenib BRAF V600 mutation-positive advanced melanoma: final analysis of the coBRIM study. Presented at: the 16th International Congress of the Society for Melanoma Research; November 20-23, 2019; Salt Lake City, UT.