Cobimetinib Combinations Yield Responses in High-Risk Melanoma

“We saw that about two-thirds of the patients in one arm of the trial had no remaining tumor at all at the time of their surgery,” according to Matthew S. Block, MD, PhD.

Neoadjuvant treatment with cobimetinib (Cotellic) plus atezolizumab (Tecentriq) with or without vemurafenib (Zelboraf) showed promising outcomes in patients with high-risk resectable stage III melanoma, according to findings from the phase 2 NeoACTIVATE trial (NCT03554083) published in Nature Communications.¹

Of 15 patients included in cohort A—which included those with BRAF-mutated disease who received vemurafenib plus cobimetinib and atezolizumab—4 had a complete radiographic response, 6 had partial responses, and 1 had stable disease. Additionally, the major pathologic complete response (pCR) rate was 66.7% (90% CI, 42.3%-85.8%), and the pCR was 86.7%.

Among 15 patients in cohort B—which included those without BRAF mutations who received cobimetinib/atezolizumab only—partial radiographic responses occurred in 4 patients, 4 had stable disease, and progressive disease occurred in 1 patient. Data showed a major pCR rate of 13.3% (90% CI, 2.4%-36.3%) in this cohort, and a pCR rate of 53.3%.

“We saw that about two-thirds of the patients in one arm of the trial had no remaining tumor at all at the time of their surgery,” senior study author Matthew S. Block, MD, PhD, an immunologist and medical oncologist at Mayo Clinic Comprehensive Cancer Center and leader of the Stand Up To Cancer (SU2C) Catalyst Research Team, said in a news release on these findings.²

Investigators reported that accrual to the trial was not interrupted due to toxicity. Common adverse effects (AEs) in cohort A included rash (53.3%), hypertension (13.3%), and hyperglycemia (13.3%). There were no patients in cohort A who had delays in surgical treatment due to toxicity, although 1 patient went off protocol following surgery due to grade 3 pneumonitis.

In cohort B, no patients had delayed surgical treatment due to toxicity. Frequent AEs during neoadjuvant therapy included alanine aminotransferase increases (20%), hypertension (20%), and infection (13.3%).

“We believe these results support the concept that a short course of certain drug combinations given before surgery can help a substantial number of patients,” said lead study author Tina J. Hieken, MD, clinical lead for the Research Team and a surgical oncologist at Mayo Clinic Comprehensive Cancer Center.²

In the open-label, multi-center NeoACTIVATE trial, patients received treatment across 3 arms. Patients in cohort A received oral vemurafenib plus oral cobimetinib and intravenous atezolizumab as part of 28-day cycles as neoadjuvant therapy. Patients in cohort B received cobimetinib plus atezolizumab. In cohort C, patients will receive atezolizumab in combination with tiragolumab; investigators anticipate completing enrollment for this cohort within the next few months.

The trial’s primary end points include pCR in patients with BRAF-mutant or BRAF wild-type disease and recurrence-free survival (RFS).³ Secondary end points include the incidence of AEs per Common Terminology Criteria for Adverse Events criteria and changes in PET/CT results.

Patients 18 years and older with histologically confirmed, clinically detected, recurrent or dual basin nodal metastatic melanoma are eligible for enrollment on the trial. Additional eligibility criteria include having surgically resectable disease; an ECOG performance status of 0 or 1; a minimum life expectancy of 26 weeks; and adequate platelet, hemoglobin, bilirubin, and absolute neutrophil counts.

Those with prior systemic therapy for melanoma or major surgery within 4 weeks prior to registration are ineligible for study entry. Patients are also unsuitable for enrollment if they have prior radiotherapy, an active malignancy apart from melanoma within 3 years of registration, prior allogeneic stem cell or solid organ transplantation, and history of autoimmune disease requiring management with immunosuppressive therapy.

“We’re very excited that this research team’s work is helping us learn more about the potential promise of these therapies. We hope that these promising results will transform into therapies that can help many patients with melanoma,” Ira Mellman, vice president of cancer immunology at Genentech, concluded.²

References

1. Hieken TJ, Nelson GD, Flotte TJ, et al. Neoadjuvant cobimetinib and atezolizumab with or without vemurafenib for high-risk operable stage III melanoma: the Phase II NeoACTIVATE trial. Nat Commun. 2024;15(1):1430. doi:10.1038/s41467-024-45798-8
2. First-of-its-kind clinical trial eliminated or shrunk melanoma tumors in 70% of patients. News release. Stand Up To Cancer. July 11, 2024. Accessed July 15, 2024. https://tinyurl.com/2x35net3
3. Vemurafenib, cobimetinib, atezolizumab, and tiragolumab in treating patients with high-risk stage III melanoma. ClinicalTrials.gov. Accessed July 15, 2024. https://tinyurl.com/4fb6vstr