Editor's Note: Uveal melanoma (UM) is a severe ocular malignant tumor that threatens patients' vision and survival. Despite some progress in treatment methods in recent years, the survival rate of patients has not significantly improved due to the lack of effective drugs, especially those that inhibit metastasis. At the ongoing 2024 American Society of Clinical Oncology (ASCO) Annual Meeting, several rapid oral reports focused on the challenges of UM treatment and presented the latest research findings. Oncology Frontier has compiled relevant studies for readers.Background: Uveal melanoma is the most common primary intraocular tumor in adults with a high risk of liver metastasis. Effective treatments for metastatic uveal melanoma (MUM) are limited due to poor response to immune checkpoint inhibitors. RP2 is an enhanced oncolytic HSV-1 expressing human GM-CSF, a fusion glycoprotein (GALV-GP-R−), and an anti-CTLA-4 antibody-like molecule. This study presented safety, efficacy, and biomarker data of RP2 monotherapy and RP2+nivolumab (nivo; anti-PD-1) in MUM patients (NCT04336241).
Methods: The trial included patients aged ≥18 years with advanced or metastatic non-neuroendocrine solid tumors (including MUM) who had progressed on standard therapy or were intolerant to it, with ≥1 measurable and injectable tumor (≥1 cm). After determining the recommended phase II dose of RP2 (1×10⁶ PFU/mL once, 1×10⁷ PFU/mL ≤7 doses; ≤10 mL per treatment day), patients received RP2 Q2W monotherapy or combined with nivo (240 mg Q2W/480 mg Q4W). Treatment response was assessed per RECIST v1.1. Tumor biopsies and peripheral blood mononuclear cells were collected pre-treatment and on day 43, with TCR CDR3β region sequencing and IHC.
Results: Seventeen MUM patients were enrolled (RP2 monotherapy, n=3; RP2+nivo, n=14). Most patients had prior anti-PD-1 and anti-CTLA-4 therapy (12/17, 70.6%); 3/17 patients (17.6%) had ≥3 lines of prior therapy. The objective response rate (ORR) was 29.4% (5/17; all partial responses [PR]; RP2 monotherapy: 1/3; RP2+nivo: 4/14). The disease control rate (DCR), defined as CR+PR+stable disease (SD), was 58.8% (10/17). The median duration of response was 11.5 months (range: 2.8-21.2), with some responses ongoing. Common grade 1-2 treatment-related adverse events (TRAEs; ≥20%) included fever, chills, fatigue, hypotension, and pruritus. The only grade 3 TRAE occurring in more than one patient was hypotension (2 patients in the RP2+nivo group); no grade 4/5 TRAEs were reported. IHC and TCR sequencing analyses were performed on evaluable pre- and post-treatment biopsy tissues (n=8). In patients with clinical benefit (n=5; 2 PR, 3 SD), paired biopsies showed increased tumor PD-L1 expression, and 4 patients (2 PR, 2 SD) had increased CD8+ T-cell infiltration in tumors. Post-RP2+nivo treatment, TCR sequencing revealed expansion of existing TCRs and new T-cell clones.
Conclusion: RP2 monotherapy or combined with nivo demonstrated meaningful antitumor activity and a favorable safety profile in previously treated MUM patients. Biomarker data indicated increased immune cell infiltration and PD-L1 expression in tumors and peripheral T-cells post-RP2±nivo treatment. A randomized controlled clinical development plan is being planned based on these results.
References:
- Joseph J Sacco, Kevin Joseph Harrington, Anna Olsson-Brown, et al. 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. ASCO 2024; Abstract 9511.
