Safety and efficacy of adjuvant anti-PD1 therapy (nivolumab) in combination with vaccine in resected high-risk metastatic melanoma.

Abstract

9056^ Background: Nivolumab (BMS-936558), a fully human monoclonal antibody targeting the programmed death-1 (PD-1) receptor, has demonstrated clinical activity in advanced metastatic melanoma patients (pts). In this phase I study, the safety and activity of nivolumab plus a multipeptide vaccine was investigated as adjuvant therapy in resected stage IIIC and IV melanoma pts. Methods: HLA-A*0201 positive pts with HMB-45, NY-ESO-1, and/or MART-1 positive tumors received nivolumab (1mg/kg, 3mg/kg, or 10mg/kg IV) with a multipeptide vaccine (gp100, MART-1, NY-ESO-1, Montanide ISA 51 VG) every 2 weeks for 12 doses followed by nivolumab maintenance every 3 months (8 doses) or until disease recurrence. The primary objective was safety and determination of maximum tolerated dose (MTD). Secondary objectives were immunologic response and relapse free survival. Results: 33 pts were enrolled: 12 pts at 1mg/kg, 10 pts at 3mg/kg, and 11 pts at 10mg/kg nivolumab. Median age was 47 yrs; 55% male and 52% M1c disease (2 IIIc, 7 M1a, 7 M1b, and 17 M1c pts). As of January 16, 2012, median follow up time was 14 months and median number of doses was 12 (20 pts still receiving therapy). A MTD was not reached. Grade 2-3 related adverse events (AEs) occurred in 27 pts with the most common AEs being fatigue, rash/pruritis, and endocrinopathies. 4 pts experienced grade 3 AEs: (colitis/diarrhea (3), rash (1)). No drug related grade 4 or higher AEs occurred. 7/33 pts have relapsed to date. One pt with biopsy-proven relapse on trial had spontaneous disease regression. Non-relapsing pts had higher pre-treatment PD-1 expression on Treg and TCD4+ cells (p=0.053) and a greater increase in Treg cells after 12 weeks on treatment (p=0.027). Among all pts, treatment led to a rise in Treg cells (p=0.015) and decreased PD-1 expression on TCD4+ and TCD8+cells (p=0.014 and p<0.001, respectively). Conclusions: Nivolumab is well tolerated in combination with vaccine and preliminary data demonstrates immunologic and clinical activity as adjuvant therapy, justifying a randomized phase III study in resected high risk melanoma pts. Clinical trial information: NCT01176474.