Neoadjuvant Immunotherapy Trial Sees High pCR Rates in Stage III Melanoma

Microscopic image of melanoma

Neoadjuvant immunotherapy consisting of cobimetinib (Cotellic) and atezolizumab (Tecentriq) with or without vemurafenib (Zelboraf) followed by therapeutic lymph node dissection (TLND) led to robust pathologic complete response (pCR) and major pathologic response (mPR) rates in patients with resected stage III melanoma, according to findings from the phase 2 NeoACTIVATE trial (NCT03554083).¹

A total of 30 patients were included in the trial; 15 patients with a BRAF mutation comprised cohort A. These patients received 12 weeks of neoadjuvant treatment with vemurafenib, the MEK inhibitor cobimetinib, and the PD-L1 inhibitor atezolizumab followed by TLND and 24 weeks of adjuvant atezolizumab. Ten patients (66.7%; 95% CI, 42.3%-85.8%) in cohort A had a pCR, 0 patients had a near-pCR, 3 had a partial pathologic response (pPR), and 2 had a pathologic nonresponse (pNR).

In cohort B, 15 patients with BRAF wild-type disease were included and received 12 weeks of cobimetinib plus atezolizumab, followed by TLND and 24 weeks of atezolizumab. Two patients (13.3%; 90% CI, 2.4%-36.3%) had a pCR, 3 had a near-pCR, 3 had a pPR, and 5 had a pNR.

“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 Tina J. Hieken, MD, clinical lead for the research team, surgical oncologist at Mayo Clinic Comprehensive Cancer Center, and first author of the study, in a press release.²

In cohort A, 11 patients had dose modifications and 12 had dose omissions, most frequently due to cutaneous toxicity.¹ One patient discontinued treatment protocol due to grade 3 pneumonitis. Grade 3 or 4 adverse events (AEs) were reported in 11 patients in cohort A, and the most experienced AEs were rash (53.5%), hypertension (13.3%), and hyperglycemia (13.3%). Surgical treatment was not delayed in any patients due to toxicity.

In cohort B, 7 patients experienced dose modifications and 13 had a dose omission. The most common causes were for cutaneous toxicity or elevated liver enzymes. Grade 3 or 4 AEs were observed in 8 patients. Surgical treatment was not delayed in any patients due to toxicity. The most common AEs in this cohort were increased alanine aminotransferase (20%), hypertension (20%), and infection (13.3%).

Surgical outcomes served as an exploratory secondary outcome measure. There were no reported significant AEs of the neoadjuvant combination therapy on TLND. Grade 2 complications were observed in 29% of patients through 60 days after operation; these included 6 cases of seroma and 2 cases of surgical site infection.

“Little data exist on the impact of neoadjuvant therapy on the technical aspects of operation and whether complication rates associated with TLND might be higher following various neoadjuvant regimens. Our acceptably low surgical complication rate provides reassurance that these combinatorial regimens do not preclude safe operation,” the study authors wrote.

REFERENCES:

1. Hieken T, Nelson G, Flotte T, et al. Neoadjuvant cobimetinib and atezolizumab with or without vemurafenib for high-risk operable stage III melanoma: the phase II NeoACTIVATE trial. Nature Comm. 2024, 15:1430. 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/knbr9fep