Atezolizumab Plus Vemurafenib/Cobimetinib Impresses in BRAF V600+ Melanoma

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."

Baseline characteristics were similar between arms. In the triplet arm, the median age of patients was 54 years (range, 22-87); 58.6% were male, and 94.9% were white. Notably, 79.3% of patients enrolled on the trial were from Europe. Overall, patients enrolled on the trial had a good performance status: 76.2% had an ECOG performance status of 0, while 23.8% had an ECOG performance status of 1. Importantly, LDH was elevated in approximately 33% of patients in both arms of the study.

Interestingly, at 6 months following randomization, no difference in PFS was observed between the arms at 72.8% with the triplet arm and 74.2% with the doublet regimen. However, by 12 months, 54.0% of patients were free from progression in the atezolizumab arm versus 45.1% of those in the placebo arm. These differences were maintained at 18 months and beyond, according to McArthur.

"With respect to outcomes by subgroups, all subgroups favored the atezolizumab arm, including subgroups that looked at patient's age, LDH levels, and also markers of disease burden and extent of disease by organ site," noted McArthur.

Results showed that the ORRs were similar between the arms, at 66.3% in the triplet arm versus 65.0% in the doublet arm. In the triplet 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. In the doublet arm, the CR rate was 17.1%, the PR rate was 48.0%, and the SD rate was 22.8%.

At 12 months, no difference in OS was observed between the arms; however, by 24 months, the OS rate slightly favored the atezolizumab arm at 76.7% versus 76.1% in the placebo arm. Specifically, the median OS with the triplet was 28.8 months (95% CI, 27.4-NE) versus 25.1 months with the doublet (95% CI, 22.3-NE).

"Ongoing follow up is critical to determine whether these curves will separate with time," noted McArthur.

With regard to safety, treatment-related adverse events (AEs) occurred in at least 15% of patients. The rate of treatment-related AEs was similar between the 2 arms; however, pyrexia (37% with triplet vs 25% with doublet), arthralgia (36% vs 26%, respectively), elevated alanine aminotransferase (21% vs 14%), elevated aspartate aminotransferase (22% vs 16%), hyperthyroidism (16% vs 8%) and hypothyroidism (17% vs 6%) were all more common in the atezolizumab arm. Regardless, these are all expected toxicities for an anti¬—PD-L1 agent, noted McArthur.

"An important indicator of the overall tolerability of a therapy is the rate of treatment discontinuation because of treatment-related AEs," said McArthur. "Interestingly, this was very similar between the 2 arms of the trial, being just less than 13% in the atezolizumab arm and just less than 16% in the placebo arm."

A total of 14 patients experienced grade 5 AEs, experienced by 7 patients in each arm. These events 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. Cardiac arrest, cardiac failure, left ventricular failure, cerebrovascular accident, hydrocephalus, gastrointestinal hemorrhage, and pulmonary hemorrhage were observed with the doublet arm (0.4% each).

Based on these data, the investigators concluded that the triplet combination represents a viable treatment option for patients with BRAF V600—mutant advanced melanoma.

References

1. 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.
2. Kakadia S, Yarlagadda N, Awad R, et al. Mechanisms of resistance to BRAF and MEK inhibitors and clinical update of US Food and Drug Administration—approved targeted therapy in advanced melanoma. Onco Targets Ther. 2018;11:7095-71077. doi: 10.2147/OTT.S182721
3. Frederick DT, Piris A, Cogdill AP, et al. BRAF inhibition is associated with advanced melanoma antigen expression and a more favorable tumor microenvironment in patients with metastatic melanoma. Clin Cancer Res. 2013;19(5):1225-1231. doi: 10.1158/1078-0432.CCR-12-1630
4. Pelster MS, Amaria RN. Combined targeted therapy and immunotherapy in melanoma: a review of the impact on the tumor microenvironment and outcomes of early clinical trials. Ther Adv Med Oncol. 2019;11:1758835919830826. doi: 10.1177/1758835919830826
5. Wilmott JS, Long GV, Howle JR, et al. Selective BRAF inhibitors include marked T-cell infiltration into human metastatic melanoma. Clin Cancer Res. 2012;18(5):1386-1394. doi: 10.1158/1078-0432.CCR-11-2479
6. Ascierto PA, Dummer R. Immunological effects of BRAF+MEK inhibition. Oncoimmunology. 2018;7(9):e1468955. doi: 10.1080/2162402X.2018.1468955

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