Combined nivolumab and ipilimumab with or without stereotactic body radiation therapy for advanced Merkel cell carcinoma: a randomised, open label, phase 2 trial

Background: Merkel cell carcinoma is among the most aggressive and lethal of primary skin cancers, with a high rate of distant metastasis. Anti-PD1/PDL1 monotherapy is currently standard-of-care for unresectable recurrent or metastatic Merkel cell carcinoma. We assessed treatment with combined nivolumab plus ipilimumab (NIVO/IPI) with or without stereotactic body radiation therapy (SBRT) in patients with advanced Merkel cell carcinoma as a first-line therapy or following prior treatment with anti-PD1/PDL1 monotherapy. Methods: We randomly assigned adults with unresectable Merkel cell carcinoma stratified by prior immune-checkpoint inhibitor (ICI) status to receive nivolumab 240mg intravenously every 2 weeks plus ipilimumab 1mg/kg intravenously every 6 weeks (NIVO/IPI, Arm A) or NIVO/IPI plus stereotactic body radiation therapy (SBRT) to ≥1 lesion (24Gy in 3 fractions at week 2, Arm B). The trial was non-blinded and open label. Patients had to have ≥2 measurable sites of disease so one non-irradiated site could be followed for response. The primary endpoint was objective response rate (ORR). Response was assessed every 12 weeks by immune-related Response Evaluation Criteria in Solid Tumors. Findings: 50 patients (24 ICI naïve, 26 following prior ICI) received ≥1 dose of NIVO/IPI and 24 received SBRT (median follow-up 14.6 months). ORR in ICI naïve patients was 100% [95%CI, 82%-100%], 41% with complete response. ORR in patients with prior ICI exposure was 31% [95%CI, 15%-52%], 15% with complete response. No significant differences in ORR were observed between Arms A and B (72% vs. 52%, p=0.26). Median duration of response was not reached [95%CI, 33.9 months-NE] in the ICI naïve cohort and was 10.8 months [95% CI, 4.9 months-NE] in the prior ICI cohort. The toxicity profile was similar to that previously observed for the study drug dose and schedule. Interpretation: First-line NIVO/IPI in patients with advanced Merkel cell carcinoma demonstrated an exceptionally high ORR with durable responses and an expected safety profile. NIVO/IPI also showed clinical benefit in patients with prior anti-PD1/PDL1 treatment. Addition of SBRT did not improve efficacy of NIVO/IPI. NIVO/IPI represents a new first-line and salvage therapeutic option for advanced Merkel cell carcinoma. Funding: Bristol Myers Squibb Rare Population Malignancy Program clinicaltrials.gov Identifier: NCT03071406