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OptimUM-02 — Darovasertib + crizotinib, 1L HLA-A*02:01-negative metastatic uveal melanoma

Abstract: LBA9503 · Session: Melanoma/Skin Cancers — Oral Abstract Session, Mon Jun 1, 2026, 8:00–11:00 AM CT · Presenter: Marlana M. Orloff, MD (Thomas Jefferson University Hospital, Philadelphia) · Embargo: at presentation

At a glance

  • Sponsor: IDEAYA Biosciences (in collaboration with Servier)
  • PI / presenter: Marlana M. Orloff, MD — Thomas Jefferson University Hospital
  • NCT ID: NCT05987332
  • Phase: 2/3 (multiarm, multistage), randomized, open-label, registrational
  • Design: Darovasertib 300 mg BID + crizotinib 200 mg BID vs investigator's choice of therapy (ICT); randomized 2:1
  • N: 313 randomized (210 darovasertib + crizotinib; 103 ICT)
  • Primary endpoint(s): PFS by BICR
  • Comparator: ICT — ipilimumab + nivolumab (~76–77%) or pembrolizumab (~24%)
  • Indication: First-line HLA-A*02:01-negative metastatic uveal melanoma
  • Line: 1L

Headline result

The darovasertib + crizotinib combination met the primary endpoint with a statistically significant improvement in median PFS by BICR: 6.9 vs 3.1 months vs ICT (HR 0.42; 95% CI 0.30–0.59; p<0.0001), a 58% reduction in risk of progression (64% by investigator assessment). Secondary endpoint ORR by BICR was 37.1% vs 5.8% (p<0.0001), with 5 complete responses in the combination arm and none with ICT; DCR was 73.3% vs 31.1% and median DOR 6.8 months (95% CI 5.5–11.3). OS was immature at the January 23, 2026 cutoff with an early trend favoring the combination. Grade 3/4 TRAEs were 40.6% vs 37.0%; treatment-related SAEs 9.2% vs 25.0%.

Mechanism / class

Darovasertib is an oral, small-molecule protein kinase C (PKC) inhibitor targeting the Gq/11–PKC signaling axis activated by GNAQ/GNA11 mutations that drive nearly all uveal melanomas. Crizotinib is an oral c-MET/ALK/ROS1 inhibitor used to exploit synthetic-lethal MET dependence in combination. Neither agent is approved in uveal melanoma; the combination is under FDA RTOR review with an NDA filing planned 2H 2026 for accelerated approval. HLA-A*02:01-positive patients are eligible for tebentafusp (the only approved 1L systemic agent), so OptimUM-02 targets the HLA-A2-negative population that lacks an approved option.

Discussant takeaway

Not reported at time of writing; omit pending session coverage.

Practice-changing?

Pending → likely yes if approved. Metastatic uveal melanoma has no approved systemic therapy for HLA-A*02:01-negative patients (tebentafusp is restricted to HLA-A2-positive disease). A positive randomized phase 2/3 with a doubling of PFS, a 6-fold higher ORR, and a favorable Grade 3/4 safety profile versus checkpoint-based ICT would establish the first targeted standard of care in this orphan setting. Practice impact hinges on FDA action; OS maturation will be watched.

  • Other ASCO 2026 trials: none in this niche on this index yet
  • JPM 2026: IDEAYA/Servier darovasertib collaboration — ../../jpm-2026/index.md

Sources

  • ASCO Meeting Library (LBA9503): https://meetings.asco.org/abstracts-presentations/search?q=LBA9503
  • IDEAYA press release (complete ASCO data): https://www.prnewswire.com/news-releases/ideaya-biosciences-and-servier-provide-complete-data-from-phase-23-registrational-optimum-02-trial-of-the-darovasertib-combination-in-first-line-hlaa201-negative-metastatic-uveal-melanoma-in-a-late-breaking-oral-presentation-at-302786486.html
  • IDEAYA topline (Apr 13, 2026): https://ir.ideayabio.com/2026-04-13-IDEAYA-Biosciences-and-Servier-Announce-Positive-Topline-Results-from-Phase-2-3-Registrational-Trial-OptimUM-02-of-Darovasertib-in-Combination-with-Crizotinib-in-First-line-HLA-A-02-01-Negative-Metastatic-Uveal-Melanoma
  • OncLive: https://www.onclive.com/view/first-line-darovasertib-plus-crizotinib-yields-pfs-benefit-in-metastatic-uveal-melanoma
  • Targeted Oncology: https://www.targetedonc.com/view/darovasertib-crizotinib-improves-pfs-in-metastatic-uveal-melanoma
  • CancerNetwork: https://www.cancernetwork.com/view/darovasertib-crizotinib-meets-pfs-end-point-in-metastatic-uveal-melanoma