IDEAYA Biosciences has initiated a New Drug Application (NDA) submission to the US FDA for darovasertib in combination with crizotinib, seeking approval in patients with first-line HLA-A*02:01-negative metastatic uveal melanoma. The filing, which the company said will proceed under the FDA's Oncology Center of Excellence Real-Time Oncology Review (RTOR) program, follows positive topline data from the Phase 2/3 OptimUM-02 registrational trial. IDEAYA said it plans to submit the first pre-submission package in May 2026, with completion of the full NDA expected in the second half of 2026.
The RTOR program allows sponsors to submit components of an NDA on a rolling basis before the complete application is filed, enabling the FDA to begin reviewing clinical data earlier in the process. IDEAYA said the FDA agreed to review the darovasertib application under this pathway based on topline results from OptimUM-02. No priority review designation or PDUFA date has been disclosed at this stage, as the full filing remains pending.
The OptimUM-02 trial evaluated darovasertib in combination with crizotinib against investigator's choice of therapy — which could include pembrolizumab, ipilimumab plus nivolumab, or dacarbazine — in patients with first-line HLA-A*02:01-negative metastatic uveal melanoma. The trial met its primary endpoint, with the combination reducing the risk of disease progression by 58% compared with investigator's choice, yielding a hazard ratio of 0.42 (95% CI: 0.30, 0.59; p<0.0001). Median progression-free survival by blinded independent central review was 6.9 months in the darovasertib arm versus 3.1 months in the control arm. On secondary endpoints, an overall response rate of 37.1% was observed with the combination, including five complete responses, compared with 5.8% in the investigator's choice arm (p<0.0001), with a median duration of response of 6.8 months. Overall survival data were not yet mature at the time of the topline readout, though the company said an early trend in OS improvement was observed. Full results from OptimUM-02 are scheduled to be presented in a late-breaking oral session at the 2026 American Society of Clinical Oncology annual meeting in Chicago.
The HLA-A02:01-negative subgroup that OptimUM-02 enrolled represents approximately half to 60% of all patients with metastatic uveal melanoma, and currently has no FDA-approved systemic therapy. The only approved agent in the broader metastatic uveal melanoma setting is Kimmtrak (tebentafusp-tebn), which received FDA approval in January 2022 for patients who are HLA-A02:01-positive — the complementary biomarker subgroup. Tebentafusp is a bispecific fusion protein that redirects T cells to gp100-expressing tumor cells and was the first therapy to demonstrate an overall survival benefit in metastatic uveal melanoma, though its use is restricted by the HLA biomarker requirement. For HLA-A*02:01-negative patients, current management relies on off-label use of checkpoint inhibitors or cytotoxic chemotherapy, none of which has demonstrated a survival benefit in randomized trials.
Uveal melanoma arises from melanocytes in the uveal tract of the eye and is biologically distinct from cutaneous melanoma. Approximately 90% of uveal melanomas harbor mutations in GNAQ or GNA11, which encode G-protein alpha subunits that constitutively activate protein kinase C (PKC) and downstream signaling. Darovasertib is a small molecule inhibitor of PKC designed to suppress this oncogenic driver. Crizotinib, a MET/ALK/ROS1 inhibitor approved in other oncology settings, is combined with darovasertib to block MET-mediated bypass signaling that can allow tumor cells to escape PKC inhibition. The combination targets two nodes within the uveal melanoma signaling network and is administered orally, in contrast to tebentafusp's intravenous route.