Response to high dose ipilimumab plus temozolomide after progression on standard or low dose ipilimumab in advanced melanoma: a retrospective analysis.

Autor:	Williamson J; University of Utah., Fadlullah MZH; Huntsman Cancer Institute., Kovacsovics-Bankowski M; Huntsman Cancer Institute., Gibson B; Huntsman Cancer Institute., Swami U; Huntsman Cancer Institute., Erickson-Wayman A; Huntsman Cancer Institute., Jamison D; Huntsman Cancer Institute., Sageser D; Huntsman Cancer Institute., Jeter J; Huntsman Cancer Institute., Bowles T; Intermountain Health., Cannon DM; Huntsman Cancer Institute., Haaland B; Huntsman Cancer Institute., Schroeder JD; Huntsman Cancer Institute., Nix D; Huntsman Cancer Institute., Atkinson A; Huntsman Cancer Institute., Hyngstrom J; Huntsman Cancer Institute., McPherson J; Huntsman Cancer Institute., Tan AC; Huntsman Cancer Institute., Hu-Lieskovan S; University of Utah.
Jazyk:	angličtina
Zdroj:	Research square [Res Sq] 2023 Jun 01. Date of Electronic Publication: 2023 Jun 01.
DOI:	10.21203/rs.3.rs-2997157/v1
Abstrakt:	Background: Despite advancements in checkpoint inhibitor-based immunotherapy, patients with advanced melanoma who have progressed on standard dose ipilimumab (Ipi) + nivolumab continue to have poor prognosis. Several studies support a dose-response activity of Ipi, and one promising combination is Ipi 10mg/kg (Ipi10) + temozolomide (TMZ). Methods: We performed a retrospective cohort analysis of patients with advanced melanoma treated with Ipi10+TMZ in the immunotherapy refractory/resistant setting (n = 6), using similar patients treated with Ipi3+TMZ (n = 6) as comparison. Molecular profiling by whole exome sequencing (WES) and RNA-seq of tumors harvested through one responder's treatment was performed. Results: With a median follow up of 119 days, patients treated with Ipi10+TMZ had statistically significant longer median progression free survival of 144.5 days (range 27-219) vs 44 (26-75) in Ipi3+TMZ, p=0.04, and a trend for longer median overall survival of 154.5 days (27-537) vs 89.5 (26-548). All patients in the Ipi10 cohort had progressed on prior Ipi+Nivo. WES revealed only 12 shared somatic mutations including BRAF V600E. RNA-seq showed enrichment of inflammatory signatures, including interferon responses in metastatic lesions after standard dose Ipi + nivo and Ipi10 + TMZ compared to the primary tumor, and downregulated negative immune regulators including Wnt and TGFb signaling. Conclusion: Ipi10+TMZ demonstrated efficacy including dramatic responses in patients with advanced melanoma refractory to prior 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 patients. Competing Interests: Competing interests: JM has received research funding from Hitachi, Ltd. JH has conducted other research projects with funding from Institutional PI trials: BMS, Merck, Amgen, Philogen, Iovance, Morphogenesis, Oncosec, NAtera, Skyline, Takara, LOKON, Checkmate/Regeneron.
Databáze:	MEDLINE
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