1080MO - Sitravatinib plus tislelizumab for metastatic uveal melanoma with liver metastasis: The open-label, multicenter, phase II GEM-2101 trial

Background

Immune checkpoint inhibitors have limited activity in metastatic uveal melanoma (MUM). Modulation of the tumor vasculature and immune microenvironment could increase patient survival, especially in patients with liver metastasis (LM). This study aims to assess the efficacy of the combination of sitravatinib (sitra), a pan-TKI inhibitor (targeting RET, the TAM family (TYRO3, AXL and MER-TK), VEGFR2, and KIT), and tislelizumab (tisle), an anti-PD1 antibody designed to minimize the binding to Fcγ receptors, in patients with MUM and LM.

Methods

This was a single-arm, phase II trial testing sitra and tisle (sitra+tisle) for systemic treatment-naïve patients or after failure to 1st line tebentafusp if HLA-A02:01. Eligible patients had confirmed diagnosis of LM for MUM that is considered adequate for correlative biopsies. Sitra (100 mg p.o. q.d.) and tisle (200 mg q.3-w) were administered until progressive disease (PD), toxicity, or withdrawal. The primary endpoint was ORR according to RECIST 1.1. Image evaluations were performed q.6-w.

Results

From Nov 2022 to Jul 2023, 16 patients were enrolled. Median age was 63 years (range: 49-86). Extrahepatic disease was present in 43.8%, high LDH in 56.2% and high ALP in 31.2%. Median duration of treatment was 6.6 months (95% CI: 3.5-12.2). ORR was 18.8%, with 3 confirmed partial responses. Stable disease was the most common outcome (81.2%), achieving a disease control rate of 100% with a median follow-up of 6.9 months (range: 2.8-13.4). Median PFS was 8.3 months (95% CI: 7.2-NR). The projected 1-year OS rate was 79.6% (95% CI: 61.1-100). Grade 3-4 treatment-related adverse events were reported in 8 (50%) patients, the most common being hypertension (25%) and diarrhea (18.5%). Treatment was discontinued due to toxicity in 3 (18.8%) patients.

Conclusions

Sitra+tisle showed promising activity with a manageable toxicity profile in patients with MUM and LM. The PFS observed is the longest PFS ever reported for systemic treatment in MUM. An update on translational research to understand synergy between both drugs using correlative liver biopsies is underway.

Clinical trial identification

EudraCT: 2021-002474-99; NCT05542342.

Editorial acknowledgement

We acknowledge MFAR Clinical Research staff for their assistance in the development of this abstract.

Legal entity responsible for the study

GEM - Grupo Español Multidisciplinario de Melanoma.

Funding

GEM / Support provided by Mirati Therapeutics – A Bristol Myers Squibb Company and BeiGene.

Disclosure

E. Espinosa: Financial Interests, Personal, Invited Speaker: BMS, MSD, Pierre Fabre, Novartis; Financial Interests, Personal, Advisory Board: MSD, Immunocore; Financial Interests, Personal, Other, assistance to congress: Pierre Fabre. L. de la Cruz Merino: Financial Interests, Personal, Advisory Board: Astra-Zeneca, BMS, MSD, Pierre-Fabré, Novartis; Financial Interests, Personal, Advisory Role: Gilead; Financial Interests, Personal, Expert Testimony: Roche, Incyte; Financial Interests, Institutional, Other, Clinical trials: BMS, Gilead, AstraZeneca, MSD, Novartis, Roche, Pfizer; Non-Financial Interests, Personal, Local PI, PI of Investigator Initiated Trials: BMS; Financial Interests, Personal, Local PI, PI of Investigator Initiated Trials: Celgene-BMS; Non-Financial Interests, Personal, Member of Board of Directors: GETICA cooperative group (Spain); Financial Interests, Personal, Member of Board of Directors: ECO foundation (Spain). A. Berrocal-Jaime: Financial Interests, Personal, Speaker, Consultant, Advisor: BMS, MSD, Roche, Novartis; Financial Interests, Personal, Other, Honoraria, Travel, Accommodations, Expenses: BMS, MSD, Roche, Novartis; Financial Interests, Personal, Expert Testimony: BMS, MSD, Roche, Novartis. J.M. Piulats: Financial Interests, Personal, Advisory Role: BMS, Novartis, Roche, Merck, Janssen, Astellas; Non-Financial Interests, Personal, Other, Travel, Accomodations, Expenses: Janssen, Astellas. All other authors have declared no conflicts of interest.