The addition of the checkpoint inhibitor atezolizumab to two targeted therapies (the BRAF inhibitor vemurafenib and the MEK inhibitor cobimetinib) as initial therapy improved outcomes compared with the two targeted therapies plus placebo in patients with newly diagnosed BRAF V600E/K–mutant advanced melanoma. Specifically, the triplet combination improved progression-free survival, led to more durable responses, and increased the duration of response versus targeted therapies plus placebo, according to the primary results of the phase III IMspire150 trial presented during the opening clinical plenary session of the 2020 American Association for Cancer Research (AACR) Virtual Annual Meeting.1
The triplet combination led to an investigator-assessed median progression-free survival of 15.1 months vs 10.6 months for those in the placebo arm (P = .025). Investigator-assessed progression-free survival favored the triplet over the two targeted therapies at 12 months and at 18 months. The 12-month progression-free survival was 54% vs 45%, respectively, and the 18-month progression-free survival was 43.5% vs 31.6%, respectively. Although the data are still immature, an interim analysis of overall survival favored the atezolizumab-containing arm compared with vemurafenib/cobimetinib plus placebo.
“Patients with advanced BRAF-mutated melanoma can be treated with a BRAF inhibitor/MEK inhibitor combination, with high response rates. However, responses are short-lived. Immune checkpoint inhibitors, in contrast, provide more durable responses, but response rates are lower. Preclinical and translational data suggest that combining these two targeted therapies with a checkpoint inhibitor might overcome the limitations of each class and potentially lead to more durable responses,” explained Grant A. McArthur, MBBS, PhD, of the Peter MacCallum Cancer Centre, Melbourne, Australia.
Grant A. McArthur, MBBS, PhD
“Atezolizumab combined with vemurafenib and cobimetinib showed a statistically significant and clinically significant improvement in investigator-assessed progression-free survival vs placebo plus vemurafenib and cobimetinib. The addition of atezolizumab led to a clinically meaningful improvement in the duration of response vs vemurafenib and cobimetinib alone.
Based on these results, combination therapy with atezolizumab, vemurafenib, and cobimetinib represents a viable treatment option for this group of patients,” stated Dr. McArthur.
The international IMspire150 trial randomly assigned 514 treatment-naive patients 1:1 to treatment with the triplet combination vs the two targeted therapies. The control arm received vemurafenib at 960 mg twice daily plus cobimetinib at 60 mg/d on days 1 to 21 of a 4-week cycle. The experimental arm received atezolizumab at 840 mg on days 1 and 15 of 4-week cycles plus a similar loading dose of vemurafenib/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 continued until disease progression, death, or unacceptable toxicity.
Patients enrolled in the trial had unresectable stage IIIc or IV melanoma, and their tumors were BRAF V600–positive. Baseline characteristics were well balanced between the two arms. The median age of patients was 54 years, 58% were male, all had good a performance status, and 79% were treated in Europe. Almost all patients (94%) had metastatic disease. Elevated lactate dehydrogenase (LDH) levels were present in one-third of patients.
The immunotherapy/targeted therapies combination significantly prolonged a number of parameters vs placebo/targeted therapies. Progression-free survival was 15.1 months vs 10.6 months, respectively, for a 22% reduction (P =.025). Although objective response rates were similar in both groups, the median duration of response was 21.0 months vs 12.6 months, respectively. “This was a clinically meaningful difference,” Dr. McArthur noted.
Although investigator-assessed progression-free survival showed a significant difference favoring the triplet arm, an independent review committee assessment of progression-free survival did not show significance: median of 16.1 months for the triplet vs 12.3 months for the doublet. At 6 months, 12 months, and 18 months, landmark analysis favored the atezolizumab-containing arm over the doublet. Progression-free survival in all subgroups favored the experimental arm, including age, LDH level, disease burden, and extent of disease by organ site.
Overall survival data were not mature at the time of this analysis, but interim analysis showed survival of 28.8 months with the triplet vs 25.1 months with the doublet. At 2 years, the overall survival rate was 60.4% vs 53.1%, respectively.
The side-effect profile was consistent with what is known about each of the components of therapies used in the trial. Treatment-related adverse events that occurred in 30% or more of patients in the immunotherapy-containing arm vs the targeted-therapies arm included increased serum creatinine phosphatase (CPK) levels (51.3% vs 44.8%, respectively), diarrhea (42.2% vs 46.6%), rash (40.9% in both arms), arthralgia (39.1% vs 28.1%), pyrexia (38.7% vs 26%), increased alanine aminotransferase (ALT, 33.9% vs 22.8%), and increased lipase (32.2% vs 27.4%).
More serious grade 3 and 4 treatment-related adverse events occurring in the immunotherapy-containing arm vs the targeted-therapies arm in more than 10% of patients included increased lipase (20.4% vs 20.6%, respectively), increased serum CPK (20% vs 14.9%), increased ALT (13% vs 8.9%), and maculopapular rash (12.6% vs 9.6%).
The incidence of serious treatment-related adverse events was similar between the two groups: 33.5% vs 28.8%, respectively. Treatment discontinuations due to adverse events were reported in 12.6% and 15.7%, respectively. Treatment-related deaths occurred in seven patients in each arm.
DISCLOSURE: Dr. McArthur has received institutional funding from Array BioPharma, Roche, and Genentech.
1. McArthur GA, Stroyakovskiy D, Gogas H, et al: Evaluation of atezolizumab, cobimetinib, and vemurafenib in previously untreated patients with BRAF V600 mutation-positive advanced melanoma: Primary results from the phase 3 IMspire150 trial. 2020 AACR Virtual Annual Meeting. Abstract CT012. Presented April 27, 2020.
Charles Sawyers, MD
“The hypothesis of combining kinase inhibitors with checkpoint inhibitors could be a fantastic idea,” said formal study discussant Charles Sawyers, MD, of Memorial Sloan Kettering Cancer Center, New York. “This trial [IMspire150] is positive, and that is great news. Triple ...