FDA Approves Atezolizumab Plus Cobimetinib/Vemurafenib in BRAF+ Advanced Melanoma

The FDA has approved atezolizumab (Tecentriq) in combination with cobimetinib (Cotellic) and vemurafenib (Zelboraf) in the treatment of patients with BRAF V600 mutation–positive advanced melanoma.¹

“When receiving a cancer immunotherapy combined with targeted therapies, patients with BRAF V600 mutation–positive advanced melanoma were able to live for more than 15 months without their disease worsening,” said Levi Garraway, MD, PhD, chief medical officer and head of Global Product Development of Genentech, stated in a press release. “Today’s FDA approval of this Tecentriq combination represents an important step forward for many patients living with advanced melanoma.”

The approval is based on data from the pivotal phase 3 IMspire150 trial (NCT02908672), in which the addition of atezolizumab to cobimetinib and vemurafenib led to a significant improvement in progression-free survival (PFS) versus placebo plus cobimetinib/vemurafenib in treatment-naïve patients with BRAF V600–mutant advanced melanoma.

Results from the trial were presented during the 2020 AACR Annual Virtual Meeting I and showed that the triplet led to a median PFS of 15.1 months versus 10.6 months with vemurafenib/cobimetinib (HR, 0.78; P = .025); this benefit was reported across all prognostic subgroups analyzed.² The median PFS, when assessed by independent review committee (IRC) was 16.1 months versus 12.3 months with the triplet and the doublet, respectively (log-rank P = .1607).

Objective response rates (ORRs) were found to be comparable between the 2 arms; however, the triplet was found to result in a prolonged median duration of response (DOR) at 21.0 months versus 12.6 months with the doublet.

The double-blinded, placebo-controlled, multicenter, phase 3 trial enrolled treatment-naïve patients with advanced, BRAF V600–mutant melanoma and an ECOG performance score of 0 to 1 who had measurable disease per RECIST v.1.1 criteria.

A total of 514 patients were randomized 1:1 to the triplet or the doublet. Importantly, there was a 28-day run-in with vemurafenib/cobimetinib alone. Although patients in both arms began vemurafenib at 960 mg twice daily and cobimetinib at 60 mg once daily, dosing changed on day 22 of the trial. Specifically, in the triplet arm, the vemurafenib dose dropped to 720 mg twice daily while dosing with the agent stayed the same in the doublet arm of the trial. In cycle 2 and onward, patients were given either atezolizumab or placebo on days 1 and 15 of the 28-day cycle, in addition to the doublet of vemurafenib/cobimetinib.

The primary end point of the trial was PFS per investigator assessment, while key secondary end points included PFS per IRC, ORR, DOR, and overall survival (OS).

At 6 months following randomization, investigators observed no significant difference in PFS between the treatment arms; the PFS rate was 72.8% with the triplet versus 74.2% with the doublet. By 12 months, however, 54.0% of patients on the investigational arm were progression free versus 45.1% on the control arm; notably, these differences in benefit were upheld at 18 months and beyond.

Moreover, additional analyses revealed that all subgroups favored the atezolizumab arm, including those that looked at patient’s age, lactate dehydrogenase levels, markers of disease burden, and extend of disease via organ site.

With regard to responses, the triplet elicited an ORR of 66.3% whereas treatment with the doublet led to an ORR of 65.0%. In the investigational arm, the ORR was comprised of a 15.7% complete response (CR) rate, a 50.6% partial response (PR) rate, and a 22.7% stable disease (SD) rate. The CR, PR, and SD rates in the doublet arm were 17.1%, 48.0%, and 22.8%, respectively.

At 1 year, no difference in OS was observed between the 2 treatment arms. At 2 years, however, the OS was observed to slightly favor the triplet arm at 76.7% compared with 76.1% in the doublet arm. Specifically, the median OS was 28.8 months versus 25.1 months, respectively.

With regard to safety, treatment-related adverse effects (AEs) were reported in at least 15% of patients. Although the rates of these toxicities were comparable between the treatment arms, the following effects were more commonly experienced by those who were given the atezolizumab triplet versus the doublet: pyrexia (37% vs 25%, respectively), arthralgia (36% vs 26%), elevated alanine aminotransferase (21% vs 14%), elevated asparate aminotransferase (22% vs 16%), hyperthyroidism (16% vs 8%), and hypothyroidism (17% vs 6%). All effects reported with the triplet were expected.

Fourteen patients experienced grade 5 AEs (7 on each arm). These toxicities included sepsis (0.9%), septic shock (0.4%), pneumonia (0.4%), hepatic failure (0.4%), hepatitis fulminant (0.4%), and cardiac arrest (0.4%) in the triplet arm. In the doublet arm, cardiac arrest, cardiac failure, left ventricular failure, cerebrovascular accident, hydrocephalus, gastrointestinal hemorrhage, and pulmonary hemorrhage were reported (0.4% each).

References

1. FDA Approves Genentech's Tecentriq plus cotellic and Zelboraf for people with advanced melanoma. News release. Genentech. July 30, 2020. Accessed July 30, 2020. https://bwnews.pr/3gey877.
2. McArthur GA, Stroyakovskiy D, Gogas H, et al. CT012 — Evaluation of atezolizumab (A), cobimetinib (C), and vemurafenib (V) in previously untreated patients with BRAFV600 mutation-positive advanced melanoma: primary results from the phase 3 IMspire150 trial. Presented at: the 2020 AACR Annual Virtual Meeting I; April 27-28, 2020. Abstract CT012.