Neoadjuvant-adjuvant pembrolizumab in clinical stage IIB/C melanoma.

9502 Background: Neoadjuvant immune checkpoint therapy has shown improvement in event-free survival outcomes in patients with resectable clinical stage III and IV melanoma. Whether there is benefit to neoadjuvant immune therapy in patients with clinical stage IIB/C melanoma is unknown. Methods: In a single arm multicenter investigator-initiated phase 2 trial, patients with clinical stage IIB/C melanoma received a single dose of neoadjuvant pembrolizumab (200 mg intravenously) 3 weeks prior to wide excision and sentinel lymph node (SLN) biopsy followed by 1 year adjuvant pembrolizumab every 3 weeks or until unacceptable toxicity or disease progression. Primary endpoint was SLN positivity rate. A sample size of 63 patients had 80% power detect a 50% difference when compared to a predetermined historical SLN positivity rate in treatment naïve patients (25% Stage IIB and 40% Stage IIC) weighted by proportion of clinical tumor stage in eligible study patients. Secondary endpoint included recurrence-free survival. Safety outcomes, including overall toxicity and immune related adverse events, were also assessed. Results: Of 63 evaluable patients (33 IIB; 30 IIC at initial biopsy), the SLN metastasis rate in the neoadjuvant study group was 27%. 28 patients (44%) had residual primary tumor after single dose pembrolizumab; 4 patients had their primary tumors upstaged to IIC. Compared to a SLN metastasis rate in a historical treatment- naïve cohort based on tumor staging at wide excision (33.1%), there was a 18% reduction in SLN positivity rate in the neoadjuvant group, although this was not statistically significant (p = 0.302). In a subgroup analysis, stage IIC patients in the neoadjuvant study group had a SLN metastasis rate of 16.7% versus 40% (p = 0.009) based on initial biopsy and 23.5% versus 40% (p = 0.0499) based on primary tumor staging at wide excision. With median follow-up of 20.4 months, the 2-year recurrence free-survival in the study group was 84% with median time to recurrence (n = 10) of 9.9 months. Overall treatment-related grade 3/4 adverse events were 14 (22%) with 9 (14%) immune-related adverse events; there was no delay in definite surgery secondary to neoadjuvant treatment. Conclusions: Rate of SLN metastasis among patients with clinical stage IIB/C melanoma undergoing neoadjuvant pembrolizumab did not differ significantly compared to expected historical rates in treatment-naïve patients; however, in a secondary subgroup analysis among patients with clinical stage IIC disease, a decrease in SLN positivity rate was noted. Neoadjuvant therapy in clinical stage IIB/C was safe and feasible, with no significant delay in surgery or new or unexpected toxicities noted in these patients. Translational studies are under way, including flow cytometric and transcriptional studies, that may reveal immunologic determinants of efficacy versus resistance. Clinical trial information: NCT03757689 .