A phase II study to evaluate the need for > two doses of nivolumab + ipilimumab combination (combo) immunotherapy.

Abstract

10003 Background: Standard of care nivolumab (nivo) + ipilimumab (ipi) combo immunotherapy is given for 4 doses in patients (pts) with unresectable stage III/IV melanoma. Whether 4 doses are needed is questionable as retrospective data suggest pts treated with <4 doses of combo due to toxicity can have durable benefit. No prospective trials have evaluated the efficacy of intentionally giving <4 doses of combo in unresectable stage III/IV melanoma. Methods: In this phase 2, multicenter clinical trial (n=60), pts with unresectable stage III/IV melanoma received 2 doses of nivo (1mg/kg) + ipi (3mg/kg) followed by a CT scan at week 6. Pts with complete (CR) or partial responses (PR) by RECIST 1.1 or stable disease without an increase in total measurable tumor burden had protocol defined early favorable anti-tumor effect (FATE) and ceased combo, transitioning to maintenance nivo. Pts without FATE at week 6 received the standard third and fourth doses of combo followed by maintenance nivo. The primary endpoint was response rate by RECIST 1.1 at week 12. Secondary endpoints included additional efficacy assessments and safety. Results: 41 pts (68%) had FATE at week 6. The best overall response rates (CR + PR) by RECIST at week 12 or any time afterwards were 48% (95% CI: 35.2-61.6%) and 53% (95% CI: 40.0-66.3%), respectively. 18%, 58%, 12%, 10% had 1, 2, 3, 4 doses of combo, respectively. With a median follow-up of 11 months, any grade treatment-related toxicity occurred in 100% (57% grade 3-4) of pts. Three pts died due to treatment-related toxicity (2 myocarditis, 1 possible adrenal insufficiency). Among the 19 pts without FATE at week 6 and not selected to de-escalate combo after dose 2, no pts ultimately responded with ongoing combo dosing. Conclusions: The first 2 doses of nivo + ipi appear to drive combo’s response efficacy and toxicity. Early radiographic imaging at week 6 may be able to identify pts who do not respond to combo dosing beyond dose 2. Randomized studies are planned to evaluate 1 dose of combo to see if efficacy is maintained with reduced toxicity. Clinical trial information: NCT03122522.