FDA Approves Atezolizumab Triplet Regimen for Treatment of Advanced BRAF-Mutant Melanoma

The FDA has granted approval to atezolizumab (Tecentriq) in combination with cobimetinib (Cotellic) and vemurafenib (Zelboraf) for the treatment of patients with BRAF V600E-mutated advanced melanoma, Genentech announced in a press release.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, in a statement. “Today’s FDA approval of this atezolizumab combination represents an important step forward for many patients living with advanced melanoma.”

The approval was based on findings from the phase 3 IMspire150 clinical trial, which evaluated the triplet regimen in comparison with cobimetinib plus vemurafenib and placebo. These data were presented during the 2020 AACR Annual Virtual Meeting, demonstrating a significantly improved progression-free survival (PFS) with the addition of atezolizumab.

The median PFS was 15.1 months with the triplet regimen (95% CI, 11.4-18.4) compared with 10.6 months (95% CI, 9.3-12.7) in the placebo arm by investigator assessment (log-rank, P =.0249). This benefit was observed across all prognostic subgroups as well. When PFS was assessed by an independent review committee (IRC), the median was 16.1 months (95% CI, 11.3-18.5) with the triplet versus 12.3 months (95% CI, 10.8-14.7) in the placebo arm (log-rank, P =.1607).²

The objective response rates (ORRs) between the 2 arms appeared similar, and the median duration of response was 21.0 months (95% CI, 15.1-not evaluable [NE]) with the triplet versus 12.6 months in the placebo arm (95% CI, 10.5-16.6). The ORR in the triplet arm was 66.3% versus 65.0% in the placebo arm. With the triplet regimen, the complete response rate was 15.7%, the partial response rate was 50.6%, and the stable disease rate was 22.7% compared with 17.1%, 48.0%, and 22.8% in the placebo arm.

By 24 months, the OS rate was 76.7% with the triplet versus 76.1% in the placebo arm. The median OS with the triplet was 28.8 months (95% CI, 27.4-NE) versus 25.1 months in the placebo arm (95% CI, 22.3-NE).

Atezolizumab did not induce any unexpected toxicities for an anti-PD-L1 agent. Treatment-related adverse events (AEs) occurred in at least 15% of patients. While the rate of treatment-related AEs was similar between the triplet and placebo arms, pyrexia (37% vs 25%), arthralgia (36% vs 26%), elevated alanine aminotransferase (21% vs 14%), elevated aspartate aminotransferase (22% vs 16%), hyperthyroidism (16% vs 8%) and hypothyroidism (17% vs 6%) were the most common in the atezolizumab arm, respectively.

Overall, 14 patients experienced grade 5 AEs, which included 7 patients in each arm. In the triplet arm, grade 5 AEs included sepsis (0.9%), septic shock (0.4%), pneumonia (0.4%), hepatic failure (0.4%), hepatitis fulminant (0.4%), and cardiac arrest (0.4%), while grade 5 AEs in the placebo arm included cardiac arrest, cardiac failure, left ventricular failure, cerebrovascular accident, hydrocephalus, gastrointestinal hemorrhage, and pulmonary hemorrhage.

At 6 months after randomization, there was no difference in PFS between the 2 arms, whereas the PFS rate was 72.8% with the triplet arm and 74.2% in the placebo arm. By 12 months, 54.0% of patients were progression-free in the triplet arm versus 45.1% in the placebo arm. At 18 months and beyond, these differences were maintained.

IMspire150 is a double-blinded, placebo-controlled, multicenter study that enrolled patients with previously untreated, advanced BRAF V600-mutant melanoma (n = 514). Patients had to have an ECOG performance status of 0 or 1 and measurable disease per RECIST v1.1 criteria.

In the trial, a total of 514 patients were randomized in a 1:1 ratio stratified by geographic region and centrally tested lactate dehydrogenase (LDH) level (≤ upper limit of normal [ULN] ULN vs >ULN) to the triplet comprised of atezolizumab plus vemurafenib/cobimetinib or vemurafenib/cobimetinib plus placebo. Importantly, there was a 28-day run-in with vemurafenib plus cobimetinib alone.

Patients in both treatment arms started vemurafenib at 960 mg twice daily and cobimetinib at 60 mg once daily, then the dosing changed on day 22. In the triplet arm, the dose of vemurafenib dropped to 720 mg twice daily at day 22, whereas the dosing stayed at 960 mg twice daily, in the doublet arm. In cycle 2 and beyond, either atezolizumab or placebo was given to patients on days 1 and 15, in addition to the vemurafenib/cobimetinib combination.

The primary end point was investigator-assessed PFS, while secondary end points included PFS as assessed by an IRC, ORR, duration of response, and OS.

The company has an extensive program for the development of atezolizumab, which includes multiple ongoing phase 3 clinical trials and planned clinical trials in lung cancer, genitourinary cancer, skin cancer, breast cancer, gastrointestinal cancer, and gynecological cancers, as well as head and neck cancers. The agent will be evaluated in combination with other agents as well as a monotherapy.¹

_References

_{1. FDA Approves Genentech’s Tecentriq plus Cotellic and Zelboraf for People With Advanced Melanoma. News Release. July 30, 2020. Accessed July 30, 2020. https://bit.ly/33cOoSK}

_{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.}