Michael Andrew Postow

2A– Baseline Information by Response. 2B - Primary site, TMB, & driver mutations by doublet response

Purpose:Mucosal melanoma is a rare subtype of melanoma with inferior response rates and outcomes to immunotherapy. Vascular endothelial growth factor (VEGF) signaling may contribute to immune resistance and represents a potential therapeutic target. We evaluated nivolumab plus axitinib in untreated, advanced mucosal melanoma in a Western population and explored escalation to triplet strategies for PD-1–refractory disease. Patients and Methods:In this single-center, investigator-initiated phase II study, patients with previously untreated unresectable or metastatic mucosal melanoma received nivolumab every 4 weeks and axitinib twice daily. The primary endpoint was objective response rate (ORR) per RECIST v1.1. A sequential phase Ib exploratory cohort evaluated treatment intensification with the addition of ipilimumab or stereotactic body radiotherapy (SBRT) at progression, with safety as the primary endpoint. Results:Among 20 evaluable patients, the ORR was 45% [95% confidence interval (CI), 23–68], including 4 complete responses (20%) and 5 partial responses (25%). The median duration of response was 21 months [95% CI, 8.6–Not Reached (NR)]. The median progression-free survival was 6.4 months (95% CI, 3.5–NR); the median overall survival was not reached. Grade 3 to 5 treatment-related adverse events occurred in 67%, including two treatment-related deaths. Seven patients received triplet therapy (ipilimumab, n = 5; SBRT, n = 2), with no unexpected toxicities observed. Conclusions:Nivolumab plus axitinib demonstrated meaningful activity in advanced mucosal melanoma and warrants further evaluation in randomized studies. The addition of ipilimumab or SBRT after progression was feasible and may inform future studies, including biomarker-directed intensification to triplet strategies.

Consort Diagram– Patient Disposition

Adverse Events of Special Interest (AESI)

Doublet Treatment Related Adverse Events by Grade

5A. Triplet with Ipilimumab treatment related AEs. 5B. Triplet with SBRT treatment related AEs

Representativeness of Study Participants

Dose hold, reduction and discontinuation data

Neoadjuvant immune checkpoint inhibitors (ICIs) are standard of care for resectable stage IIIB–D melanoma, but knowledge gaps remain regarding optimal treatment type, long-term survival, postsurgical management and clinical, histopathological or molecular subgroups. We analyzed 1,038 patients treated with neoadjuvant ICIs ( n = 735), BRAF and MEK inhibitors (BRAF/MEKis; n = 119) or ICI plus any targeted therapy (ICI + TT; n = 184) from 26 international sites in both trial (755, 72.7%) and nontrial (283, 27.3%) settings. ICI regimens included anti-programmed cell death protein 1 (PD-1) alone (PD-1 alone; n = 242) and anti-PD-1 plus other immuno-oncology agent(s) (PD-1 + IO; n = 489). Outcomes included major pathological response (MPR), recurrence-free survival (RFS) and overall survival (OS). An MPR was achieved in 57.8% of patients with ICIs, 51.4% with BRAF/MEKis and 44.6% with ICI + TT. PD-1 + IO elicited higher MPR rates than PD-1 alone (61.4% versus 49.5%). The 5-year RFS rate was 61.0% with PD-1 alone, 73.9% with PD-1 + IO, 37.4% with BRAF/MEKis and 76.4% with ICI + TT; the 5-year OS rates were 83.3%, 87.5%, 69.8% and 83.9%, respectively. ICI-treated patients with MPR had 5-year OS rates of 98.8% with PD-1 alone and 97.9% with PD-1 + IO and gained no benefit from continuing ICIs into the adjuvant setting. Neoadjuvant ICIs were active in BRAF -mutant melanoma (MPR, 46.3%), acral melanoma (38.1%), in-transit metastases (66.7%) and oligometastases (41.2%), although subgroup sizes and relative effectiveness varied. Survival outcomes were excellent with neoadjuvant ICIs, particularly in patients achieving MPR, but poor with BRAF/MEKis and mixed with ICI + TT. Predictive biomarker-driven trials, effective adjuvant strategies and subgroup-specific research are needed for nonresponders.