High dose ipilimumab (Ipi) plus temozolomide (TMZ) after progression on standard or low dose Ipi in advanced melanoma.
Authors: Williamson Julie , Hidayatullah Fadlullah Muhammad Zaki , Kovacsovics Magdalena , Gibson Berit , Erickson-Wayman Alyssa , Jamison Debra , Sageser Daniel S. , Swami Umang , Jeter Joanne M. , Bowles Tawnya Lynn , Cannon Donald Maurice , Haaland Ben , Schroeder Joyce , McPherson Jordan P. , Hyngstrom John Robert , Tan Aik-choon , Hu-Lieskovan Siwen 
Published: June 2023

9557

Background: Despite advancements in checkpoint inhibitor-based immunotherapy (IO), patients (pts) with advanced melanoma who have progressed on Ipi + nivolumab (Nivo) continue to have poor prognosis. Several studies support a dose-response activity of Ipi. One promising combination for these pts is Ipi 10mg/kg (Ipi10) + TMZ. TMZ depletes regulatory T cells and suppresses their function, and it may enhance the antitumor activity of Ipi. We studied outcomes of pts with advanced melanoma treated with Ipi10+TMZ in the IO refractory/resistant setting, using a cohort of similar pts treated with Ipi3+TMZ as comparison. Methods: Clinical data of pts with IO refractory melanoma treated with Ipi+TMZ was collected retrospectively following IRB approval. Molecular profiling by WES and RNAseq of tumors harvested throughout one responder’s treatment were analyzed: the primary skin lesion (P1), a liver metastasis (M2) 2 days after low-dose Ipi1+Nivo, and a soft tissue metastasis (M3) after Ipi10+TMZ. Results: Overall 12 pts met eligibility: 6 received Ipi10 and 6 received Ipi3. All pts in Ipi10 cohort had progressed on prior Ipi+Nivo. Two pts (33% ORR) with CNS involvement demonstrated extraordinary near complete responses to Ipi10+TMZ despite progressing on prior therapies, including regular or low dose Ipi+Nivo. With a median follow up of 119 days, pts treated with Ipi10+TMZ had statistically significant longer median progression free survival (PFS) of 144.5 days (range 27–219) vs 44 (26–75) for Ipi3+TMZ, p = 0.04. There is a trend for longer median PFS for pts who had > 1 cycle of treatment, and for those who had progressed on prior Ipi+Nivo. There is a trend for longer median overall survival (OS) of 154.5 days (27–537) with Ipi10 vs 89.5 (26–548) for Ipi3 +TMZ. In those previously exposed to Ipi3+Nivo, median OS in the Ipi10+TMZ group was 154.5 days (27–537) vs 39 (26–55) in Ipi3+TMZ group. WES of one responder’s tumors revealed only 12 shared somatic mutations among P1, M2 and M3, including BRAF V600E, suggesting common lineage but significant clonal evolution. Genes involved in several important immune response pathways were mutated in M2 and M3 but not in P1. RNAseq showed enrichment of inflammatory signatures, including interferon responses in both M2 and M3 compared to P1, and downregulated negative immune regulators such as Wnt and TGFb signaling. M2 is a responding liver lesion to prior Ipi1+Nivo but disease progressed to bones and brain that subsequently responded to Ipi10+TMZ. Conclusions: Ipi10+TMZ demonstrated efficacy including dramatic responses in pts with advanced melanoma refractory to standard or low doses of Ipi + anti-PD1, even with CNS metastases. Molecular data suggest a potential threshold of Ipi dose for activation of sufficient anti-tumor immune response, and higher dose Ipi is required for some pts.