Safety, efficacy, and biomarker results from an open-label, multicenter, phase 1 study of RP2 alone or combined with nivolumab in a cohort of patients with uveal melanoma.
Authors: Sacco Joseph J , Harrington Kevin Joseph , Olsson-Brown Anna , Chan Tze Y , Nenclares Pablo , Leslie Isla , Bommareddy Praveen , Kalbasi Alireza , Xie Ben , Mishal Moran , Cohan David Michael , Skolariki Aglaia , Middleton Mark R. 
Published: July 2024

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Background: Uveal melanoma is the most common primary intraocular tumor in adults and has a high risk of liver metastasis. Effective treatments for metastatic uveal melanoma (MUM) are limited, as MUM responds poorly to immune checkpoint inhibition. RP2 is an enhanced-potency oncolytic HSV-1–expressing human GM-CSF, a fusogenic glycoprotein (GALV-GP-R−), and an anti–CTLA-4 antibody-like molecule. We present safety, efficacy, and biomarker data for RP2 monotherapy and RP2 +nivolumab (nivo; anti–PD-1) in patients (pts) with MUM (NCT04336241). Methods: Pts ≥18 years old with advanced or metastatic non-neurologic solid tumors (including MUM) who progressed on, or could not tolerate, standard therapy were included in the clinical trial; pts had ≥1 measurable and injectable tumor (≥1 cm). After determination of the recommended phase 2 dose of intratumoral RP2 (1×106 PFU/mL once, then ≤7 doses at 1×107 PFU/mL; ≤10 mL total/treatment day), pts received RP2 Q2W as monotherapy or in addition to nivo (240 mg Q2W/480 mg Q4W). Responses were assessed per modified RECIST v1.1.Tumor biopsies and peripheral blood mononuclear cells were collected pre-treatment and at day 43 and were analyzed by immunohistochemistry (IHC) and/or sequencing of the CDR3β region of the T-cell receptor (TCR) by immunoSEQ. Results: A total of 17 pts with MUM were enrolled (RP2 monotherapy, n = 3; RP2 + nivo, n = 14). Most pts had received both anti–PD-1 and anti–CTLA-4 therapy (12/17 [70.6%]), and 3/17 (17.6%) had received ≥3 prior lines of therapy. The ORR was 29.4% (5/17; all PRs; RP2 monotherapy, 1/3; RP2 + nivo, 4/14). The DCR (CR + PR + SD) was 58.8% (10/17). The median (range) duration of response at the data cutoff was 11.5 (2.8–21.2) months, with some responses and disease stabilizations ongoing. The most common overall grade 1–2 treatment-related AEs (TRAEs; ≥20% overall) were pyrexia, chills, fatigue, hypotension, and pruritus. The only grade 3 TRAE in > 1 pt was hypotension (2 pts receiving RP2 + nivo); no grade 4/5 TRAEs occurred. Evaluable baseline and post-treatment biopsies were used for IHC (n = 8) and TCR sequencing analyses. Paired biopsies from pts with clinical benefit (n = 5; 2 PR, 3 SD) showed an increase in tumor PD-L1 expression by IHC analysis, and 4 of these pts (2 PR, 2 SD) exhibited an increase in CD8+ T-cell infiltration into tumors. TCR sequencing following treatment with RP2 + nivo revealed expansion of pre-existing TCRs and generation of new T-cell clones. Conclusions: RP2 alone or combined with nivo demonstrated a favorable safety profile and meaningful antitumor activity in pts with previously treated MUM. Biomarker data indicated immune cell infiltration and increased PD-L1 expression in tumors and changes in the peripheral T-cell repertoire following RP2 ± nivo therapy. Based on these results, a randomized, controlled clinical development plan is being planned. Clinical trial information: NCT04336241 .