The addition of the checkpoint inhibitor atezolizumab (Tecentriq) to the 2 targeted therapies—the BRAF inhibitor vemurafenib (Zelboraf) and the MEK inhibitor cobimetinib (Cotellic)—improved progression-free survival (PFS) and the duration of responses compared with the 2 targeted therapies plus placebo in patients with newly diagnosed advanced melanoma and BRAF V600E/K mutation, according to the phase 3 IMspire150 clinical trial. The results were presented at the 2020 American Association for Cancer Research virtual annual meeting by lead investigator Grant A. McArthur, MB BS (Hons), PhD, FRACP, FAHMS, Head, Cancer Therapeutics Program, Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Australia.
The investigator-assessed median PFS was 15.1 months with the triplet therapy versus 10.6 months in the placebo arm (P = .025). The 12-month PFS rate was 54% versus 45.1%, respectively, and the 18-month PFS rate was 43.5% versus 31.6%, respectively. An interim analysis of survival favored the atezolizumab-containing triplet regimen compared with vemurafenib plus cobimetinib and placebo.
“Atezolizumab combined with vemurafenib and cobimetinib showed a statistically significant and clinically significant improvement in investigator-assessed PFS versus placebo plus vemurafenib and cobimetinib. The addition of atezolizumab led to a clinically meaningful improvement in duration of response versus vemurafenib and cobimetinib alone,” Dr McArthur said. “Based on these results, combination therapy with atezolizumab, vemurafenib, and cobimetinib represents a viable treatment option for this group of patients,” he advised.
IMspire150 Clinical Trial
The international IMspire150 trial randomized 514 treatment-naïve patients with BRAF V600E–positive stage IIIc or IV advanced melanoma in a 1:1 ratio to treatment with the triplet regimen versus the 2 targeted therapies. Treatment in the control arm included vemurafenib 960 mg twice daily plus cobimetinib 60 mg daily on days 1 to 21 of a 4-week cycle. The experimental arm received atezolizumab 940 mg on days 1 and 15 of 4-week cycles plus a similar loading dose of vemurafenib plus cobimetinib for cycle 1; during cycle 2, the dose of vemurafenib was lower (720 mg). Treatment was given on days 1 and 15 of each 28-day cycle and was continued until disease progression, unacceptable toxicity, or death.
The baseline demographic and clinical characteristics were well-balanced between the 2 arms. Almost all the patients (94%) had metastatic disease.
The objective response rates were similar in both groups, but treatment with atezolizumab extended the median duration of response to 21 months versus 12.6 months, respectively. “This was a clinically meaningful difference,” Dr McArthur emphasized.
An independent review committee assessment of PFS did not show a significant difference between the treatment arms, which had a median PFS of 16.1 months with the triplet versus 12.3 months with the doublet. At 6 months, 12 months, and 18 months, a landmark analysis favored the atezolizumab-containing arm over the doublet.
All subgroup analyses of PFS favored the experimental arm, including age, lactate dehydrogenase levels, disease burden, and extent of disease by organ site.
The overall survival data were not mature at the time of analysis, but an interim analysis numerically favored the triplet therapy.
No unexpected side effects were reported. The treatment-related adverse events seen in ≥30% of patients in the experimental arm versus the controls included increased serum creatinine phosphatase levels (51.3% vs 44.8%, respectively), diarrhea (42.2% vs 46.6%, respectively), rash (40.9% in both arms), arthralgia (39.1% vs 28.1%, respectively), pyrexia (38.7% vs 26%, respectively), increased alanine aminotransferase (ALT; 33.9% vs 22.8%, respectively), and increased lipase (32.2% vs 27.4%, respectively).
The grades 3 and 4 treatment-related adverse events in >10% of patients included increased lipase (20.4% vs 20.6%, respectively), increased serum creatinine phosphatase (20% vs 14.9%, respectively), increased ALT (13% vs 8.9%, respectively), and maculopapular rash (12.6% vs 9.6%, respectively).
Commenting on this study, discussant Charles L. Sawyers, MD, Chair, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York City, said, “To me, the biggest question is why is the combination therapy [ie, plus atezolizumab] better. Perhaps the targeted agents prime the microenvironment for immunotherapy, changing the tumor from ‘warm’ to ‘hot.’ It is also possible that the benefit of combination therapy is due to patient-to-patient variability without drug activity or synthesis; that is, the benefit is actually due to the fact that some patients respond well to drug A and some to drug B. Time will tell.”