Atezolizumab Plus Vemurafenib/Cobimetinib Impresses in BRAF V600+ Melanoma

Kristi Rosa
Published: Monday, Apr 27, 2020

Grant A. McArthur, MBBS, PhD

Grant A. McArthur, MBBS, PhD

Treatment with atezolizumab (Tecentriq) in combination with vemurafenib (Zelboraf) and cobimetinib (Cotellic) was found to significantly improve progression-free survival (PFS) and produce durable responses versus vemurafenib and cobimetinib alone in treatment-naïve patients with BRAF V600–mutant advanced melanoma, according to data from the phase 3 IMspire150 trial presented at the 2020 AACR Annual Virtual Meeting I.1

"Atezolizumab combined with vemurafenib and cobimetinib showed a statistically significant and clinically meaningful in PFS via investigator assessment when compared with placebo plus vemurafenib and cobimetinib. At the time of this analysis, the overall survival data are not mature, but did favor the atezolizumab arm," said lead study author Grant A. McArthur, MBBS, PhD, executive director of the Victorian Comprehensive Cancer Centre, inaugural Lorenzo Galli Chair of Melanoma and Skin Cancers at the University of Melbourne, and a senior principal research fellow.

Specifically, the investigator-assessed median PFS with the triplet was 15.1 months (95% CI, 11.4-18.4) versus 10.6 months with vemurafenib/cobimetinib alone (95% CI, 9.3-12.7; log-rank P = .0249); this effect was observed across all prognostic subgroups. Furthermore, the median PFS, when assessed by an independent review committee (IRC), was 16.1 months (95% CI, 11.3-18.5) and 12.3 months (95% CI, 10.8-14.7) with the triplet and the doublet, respectively (log-rank P = .1607).

"Importantly, the addition of atezolizumab to vemurafenib and cobimetinib provided a clinically meaningful improvement in duration of response compared with vemurafenib and cobimetinib alone," added McArthur, who is also head of the Molecular Oncology Laboratory and of the Cancer Therapeutics Program, Cancer Research, and a senior consultant medical oncologist, Cancer Medicine, at the Peter MacCallum Cancer Centre. "Overall, the safety profile was consistent with the known risks for each individual study drug and the vemurafenib plus cobimetinib combination."

Although objective response rates (ORRs) were found to be similar between the arms, the median duration of response (DOR) was prolonged with the triplet at 21.0 months (95% CI, 15.1-not evaluable [NE]) versus 12.6 months with vemurafenib/cobimetinib (95% CI, 10.5-16.6).

Although patients with BRAF-mutant melanoma typically experience high ORRs with BRAF plus MEK combinations, responses are short lived in most patients.2 Immune checkpoint inhibitors are known to provide more durable responses in these patients, but response rates are relatively lower.3-6

"Collectively, these data lead to the hypothesis that combining BRAF and MEK inhibitors with immune checkpoint inhibition might overcome the clinical limitations of individual classes of therapy, and potentially lead to more durable responses," explained McArthur.

To this end, investigators launched the double-blinded, placebo-controlled, multicenter, phase 3 IMspire150 trial, which enrolled patients with previously untreated, advanced BRAF V600-mutant melanoma with ECOG performance scores from 0 to 1, and measurable disease per RECIST v.1.1 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.

Notably, although patients in both arms started vemurafenib at 960 mg twice daily and cobimetinib at 60 mg once daily, the dosing of the agent changed on day 22. The dose of vemurafenib in the triplet arm dropped to 720 mg twice daily at that time point and on, whereas the dosing of the agent stayed the same, at 960 mg twice daily, in the doublet arm. In cycle 2 and onward, either atezolizumab or placebo was given on days 1 and 15 of the 28-day cycle, in addition to vemurafenib/cobimetinib.

The primary end point of the trial was investigator-assessed PFS; key secondary end points included PFS as assessed by an IRC, ORR (confirmed by observations at least 4 weeks apart), DOR, and overall survival (OS).

"Just over 20 patients who were randomized did not receive their allocated treatment in cycle 2; this leads us to an intent-to-treat population for all the efficacy analyses," explained McArthur. "For all the safety analyses, patients who did not receive atezolizumab in the triplet-therapy arm were included in the placebo arm for safety analysis."

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