Background: Pembrolizumab is a potent, highly selective, humanized monoclonal antibody against PD-1 that has shown robust antitumor activity against several advanced malignancies. In phase 1 testing, combination therapy with the anti–PD-1 antibody nivolumab and full-dose IPI (3 mg/kg) was seemingly associated with improved response rates but also increased toxicities (NEJM 2013;369:122-33). Here, we report the phase 1 data of concurrent administration of pembrolizumab and low-dose IPI in pts with advanced MEL or RCC. Methods: KEYNOTE-029 (NCT02089685) is a phase 1/2 study of pembrolizumab plus IPI or pegylated interferon alfa-2b (PEG-IFN). Assessment of the safety and tolerability of pembrolizumab plus PEG-IFN is ongoing. Safety and tolerability of pembrolizumab 2 mg/kg plus low-dose IPI 1 mg/kg every 3 weeks (Q3W) for 4 doses, followed by pembrolizumab 2 mg/kg Q3W for up to 2 years, were assessed. Dose confirmation continued until 18 pts completed the 6-wk observation period (Cycle 1). DLTs were evaluated in pts who completed the first cycle of combination therapy or who discontinued due to a treatment-related AE. The dose would be considered tolerable if ≤6 pts experienced DLTs. Toxicities were graded by CTCAE v4.0. Response is assessed at wk 12, every 6 wk thereafter until wk 30, and every 12 wk thereafter. Results: DLTs were observed in 6 of 19 evaluable pts (2 of 9 RCC pts, 4 of 10 MEL pts). All DLTs were of grade 3 severity. Two pts experienced 2 DLTs each: elevation of pancreatic enzymes and hyperthyroidism in 1 patient and lipase elevation and pneumonitis in another patient. The remaining DLTs were ALT/AST elevation (n = 2), colitis (n = 1), and uveitis (n = 1). Responses have been observed in MEL and RCC pts. Additional safety and preliminary efficacy data will be available for presentation. Conclusions: Pembrolizumab and low-dose IPI combination therapy was considered to have an acceptable safety profile in this initial safety run-in period. Based on these results, we have initiated a protocol-specified, single-arm expansion cohort to further evaluate the safety, tolerability, and preliminary efficacy of this combination in advanced MEL pts. Clinical trial information: NCT02089685