IDEAYA’s darovasertib plus crizotinib achieved registrational success in the Phase 2/3 OptimUM‑02 trial, doubling PFS and boosting response rates in HLA‑A*02:01‑negative metastatic uveal melanoma, with a manageable safety profile and FDA submission planned under Real‑Time Oncology Review in H2 2026.
Written By: Chikkula Pavan Kumar, PharmD
Reviewed By: Pharmacally Editorial Team
IDEAYA Biosciences and Servier have reported complete primary analysis results from the registrational Phase 2/3 OptimUM‑02 trial (NCT05987332) evaluating darovasertib plus crizotinib in patients with first‑line HLA‑A*02:01‑negative metastatic uveal melanoma (mUM). Presented in a late‑breaking oral session at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting, the results demonstrated significant improvements in progression‑free survival (PFS) and objective response rates compared with investigator’s choice therapy (ICT).
Addressing a Critical Unmet Need
Metastatic uveal melanoma is a rare and aggressive cancer with poor outcomes and limited treatment options. Patients who are HLA‑A*02:01‑negative currently have no approved systemic therapies and are typically treated with immune checkpoint inhibitors despite modest benefit. Darovasertib, a first‑in‑class protein kinase C (PKC) inhibitor, combined with the MET inhibitor crizotinib, targets signaling pathways driven by GNAQ and GNA11 mutations that are common in uveal melanoma.
Registrational Trial Meets Primary Endpoint
The registrational OptimUM‑02 trial enrolled 313 patients randomized 2:1 to receive darovasertib plus crizotinib or ICT, primarily ipilimumab plus nivolumab (~77%) or pembrolizumab.
The study met its Phase 2 primary endpoint. Median PFS was 6.9 months with the combination versus 3.1 months with ICT (HR 0.42; 95% CI: 0.30–0.59; p<0.0001), representing a 58% reduction in the risk of disease progression or death. Investigator‑assessed PFS confirmed the benefit, with median PFS of 6.7 months versus 2.7 months (HR 0.36; p<0.0001).
Robust Secondary Outcomes
Objective response rate by blinded independent central review was 37.1% with darovasertib plus crizotinib compared with 5.8% for ICT (p<0.0001). Investigator‑assessed response rates were 39.5% and 1.9%, respectively.
Disease control rates reached 73.3% versus 31.1%, while median duration of response was 6.8 months. Median follow‑up was 9.2 months in the combination arm and 8.0 months in the control arm.
Early Survival Signal
Overall survival, the primary endpoint of the Phase 3 portion of the study, remains immature. However, an early trend favored darovasertib plus crizotinib, with a future pre‑specified interim analysis expected to provide a more definitive assessment of survival benefit.
Dr. Marlana Orloff, Professor of Medical Oncology at Thomas Jefferson University Hospital and lead investigator of the trial, said the results represent a significant advance for patients with HLA‑A*02:01‑negative metastatic uveal melanoma, demonstrating meaningful improvements in both progression‑free survival and response rates compared with commonly used immunotherapy regimens.
Manageable Safety Profile
The combination demonstrated a safety profile consistent with previous studies, with no new safety signals identified. Grade 3/4 treatment‑related adverse events occurred in 40.6% of patients receiving darovasertib plus crizotinib versus 37.0% with ICT.
Treatment‑related serious adverse events occurred in 9.2% and 25.0% of patients, respectively. Discontinuation rates due to treatment‑related adverse events were 2.5% for darovasertib, 10.0% for crizotinib, and 19.0% for ICT. The most common Grade 3/4 adverse events were diarrhea (10.0%), syncope (7.1%), and hypotension (3.8%).
Regulatory Path Forward
IDEAYA and Servier are advancing a New Drug Application for darovasertib plus crizotinib under the FDA’s Real‑Time Oncology Review program, with submission expected in the second half of 2026. If approved, the combination would become the first systemic therapy specifically indicated for patients with HLA‑A02:01‑negative metastatic uveal melanoma*, addressing a major unmet need in this rare cancer.
Reference
About the Writer
Chikkula Pavan Kumar (LinkedIn), PharmD is a Doctor of Pharmacy with a keen interest in clinical pharmacy, pharmacovigilance, and evidence-based practice. In his words, he is passionate about patient safety and translating complex medical information into clear, research-driven communication.