Darovasertib plus crizotinib vs investigator’s choice as first-line treatment for patients with HLA-A2 negative metastatic uveal melanoma: Primary results from the OptimUM-02 trial.

Background: Uveal melanoma (UM) is the most common ocular cancer in adults with up to 50% of patients developing metastasis with high mortality. No FDA-approved systemic treatments exist for HLA-A*02:01 (HLA-A2) -negative metastatic UM (mUM), and therapies effective in other melanoma subtypes have limited efficacy. Darovasertib (darova) is a first-in-class, oral PKC inhibitor that showed encouraging clinical outcomes in a prior phase 1/2 study in combination with the MET inhibitor crizotinib (crizo). Here we present primary safety & efficacy results from the nested phase 2/3 OptimUM-02 trial of darova+crizo as first-line treatment for HLA-A2 negative-mUM. Methods: OptimUM-02 is an open-label study of HLA-A2 negative first-line mUM patients who were randomized 2:1 to receive darova 300 mg plus crizo 200 mg BID or investigator’s choice (IC) of treatment (pembrolizumab, ipilimumab + nivolumab, or dacarbazine). The primary endpoint for efficacy for phase 2 was progression-free survival (PFS) by RECIST (BICR). Other endpoints included investigator assessed PFS (PFSinv), objective response rate (ORR), duration of response (DOR), disease control rate (DCR: CR+ PR + SD ≥ 12 weeks), and safety. Overall survival, the phase 3 primary endpoint, will be presented as the data matures. Results: Overall 338 patients received at least one dose of study treatment (safety population), 313 comprised the efficacy population. The median PFS by BICR was 6.9 months for darova+crizo (5.6, 8.3) and 3.1 months for IC (1.8, 4.2); HR: 0.42, p<.0001. Median PFSinv was 6.7 months (5.6, 8.2) and 2.7 months (1.7, 4.1) resp; HR 0.36, p< 0.0001. BICR ORR {37.1% [CR 2.4%; PR 34.8%] vs. 5.8% [CR 0%, PR 5.8%], DCR (73.3% vs 31.1%), DOR (median 6.8 months vs. Non-Evaluable) as well as ORRinv [39.5% vs. 1.9%], DCRinv [74.3% vs. 27.2%] and DORinv (6.8 months vs. NE) all favored darova+crizo (p-value < 0.0001). Preliminary OS is also trending favorably. The most common treatment emergent adverse events (AEs) for darova+crizo were diarrhea (89.5%), nausea (78.2%), peripheral edema (70.7%), & vomiting (53.6%). In the IC arm, these were nausea (41.4%), diarrhea (36.3%), fatigue (33.3%), AST & ALT elevation (31.1%). AEs led to discontinuation & dose reduction of darova in 3.8% & 23.8% and crizo in 10.9% & 27.2% subjects. In the IC arm, 19.2% discontinued due to AEs. The most common Grade 3 or 4 AEs for darova + crizo were diarrhea (10.9%) & syncope (7.9%) and for IC, AST & ALT increase (8.1%), diarrhea (6.1%) & hepatitis (5.1%). Treatment related serious AEs occurred in 9.2% and 25.3% on darova + crizo and IC respectively. One treatment related fatal AE occurred in each arm. Conclusions: In patients with HLA-A2-negative-mUM treated in the first-line setting, darova+crizo demonstrated a clinically and significantly longer PFS, and improved ORR and DCR compared with the investigator’s choice treatment. AEs were consistent with the previously reported safety profiles in each arm. These results support a potential new therapeutic standard for a disease with limited treatment options and poor prognosis. Clinical trial information: NCT05987332.