RELATIVITY-020: Intracranial (IC) activity of nivolumab + relatlimab (NIVO + RELA) in patients (pts) with PD-(L)1 refractory melanoma with melanoma brain metastases (MBM).

9525 Background: NIVO + RELA is an anti-PD-1 + anti-LAG3 combination approved for the treatment of pts with advanced melanoma, but data on activity in pts with MBM are lacking. NIVO + RELA prolonged time to and decreased incidence of development of new brain lesions vs NIVO in RELATIVITY-047 (Tawbi, 2024 ASCO). Preliminary BLUEBONNET data (n = 9) showed a NIVO + RELA IC overall response rate (ORR) of 44% (Phillips, 2024 SNO/ASCO). This post hoc analysis investigated IC activity in pts with PD-(L)1–refractory melanoma treated with NIVO + RELA in the phase I/IIa RELATIVITY-020 trial (NCT01968109). Methods: Pts with anti-PD-(L)1–refractory melanoma treated with NIVO + RELA in RELATIVITY-020 parts C, D, or E with possible IC lesions were included. Brain imaging from these pts (eg, those with stable MBM at baseline) were interpreted by blinded independent central review (BICR) using modified RECIST v1.1 specific to the CNS. Efficacy endpoints for BICR-confirmed pts included confirmed IC response, target IC lesion reduction, and time to IC progression. Results: BICR analysis confirmed 27 pts had ≥ 1 MBM; of these, 59% had an ECOG PS 0, 30% had a BRAF mutation, and 48% had liver lesions. Pts had a median (range) of 2 (1–10) prior therapies, including anti-PD-(L)1 (100%), anti-CTLA-4 (63%, including 44% NIVO + ipilimumab), BRAF/MEKi (26%), and brain radiotherapy (81%, with 26% receiving the radiotherapy < 3 mo prior to first dose). With a minimum follow-up of 54.4 mo, confirmed IC ORR was 22% and clinical benefit rate (CBR) was 63% (table). Median duration of IC response was not reached. Target IC lesions were identified in 17 pts; 14 had both a baseline lesion and ≥ 1 on-treatment brain scan. Median best reduction from baseline for those 14 pts was 19.5%; 6 pts had a reduction ≥ 30%. Median time to IC progression (as first progression) was not reached, with 63% of pts event free for > 3 y (events/N = 7/27). Median overall survival was 21.5 mo (95% CI, 10.9–29.4) with rates of 70% at 1 y and 27% at 3 y (events/N = 22/27). Conclusions: A previous Part D report of this study showed a heavily pre-treated anti-PD-(L)1 refractory melanoma pt population with 12% ORR in response to NIVO + RELA irrespective of tumor location; here a subpopulation of similar pts with IC lesions compared favorably: 22% ORR and 63% CBR per CNS-specific modified RECIST v1.1. Prospective and larger studies are needed to confirm these findings. Clinical trial information: NCT01968109 . NIVO + RELA(N = 27) Confirmed IC ORR, a n (%)(95% CI) 6 (22)(9–42) CR, n (%) 1 (4) PR, n (%) 5 (19) SD, n (%) 11 (41) PD, n (%) 5 (19) UTD, n (%) 5 (19) Confirmed IC CBR, b n (%) 17 (63) Median time to IC response, mo (range) 3.2 (1.7–53.4) Median duration of IC response, mo (95% CI) NR (4.6–NR) a CR+PR; b CR+PR+SD; CR, complete response; IC, intracranial; NR, not reached; PD, progressive disease; PR, partial response; SD stable disease; UTD, unable to determine.