Dr Orloff on Key Findings From the Phase 2/3 OptimUM-02 Trial in Uveal Melanoma

“The diarrhea we manage mostly with antidiarrheals. Sometimes patients will go on to get a drug called octreotide [Sandostatin] for nausea. We found that taking the pills with a fatty or high protein meal is very helpful in minimizing nausea.”

Marlana M. Orloff, MD, the Alexander & Johnston Family Endowed Clinical Director in Uveal Melanoma Professor at Thomas Jefferson University, and an associate professor at Jefferson Health, discussed data presented at the 2026 ASCO Annual Meeting from the phase 2/3 OptimUM-02 trial (NCT05987332) in uveal melanoma.

The trial, which evaluated the combination of darovasertib and crizotinib (Xalkori), demonstrated a statistically significant improvement in progression-free survival (PFS) vs investigator’s choice of therapy in patients with HLA-A*02:01–negative metastatic uveal melanoma. The trial was conducted in 2 parts: a phase 2a dose-optimization portion that established the recommended dose, which was then carried forward into the randomized phase 2b portion. The primary end point of the 2b portion was PFS by blinded independent central review.

In the darovasertib plus crizotinib arm, the median PFS was 6.9 months (95% CI, 5.6-8.3) compared with 3.1 months (95% CI, 1.8-4.2) in the investigator’s choice arm, meeting the trial’s primary end point, Orloff said. Investigator’s choice therapy included single-agent pembrolizumab (Keytruda), the combination of nivolumab (Opdivo) and ipilimumab, or dacarbazine, Orloff added. Approximately 77% of patients in the comparator arm received combination immunotherapy, and 23.3% received single-agent pembrolizumab. Secondary end points including overall response rate and disease control rate also favored the darovasertib plus crizotinib arm.

From a tolerability standpoint, the most common adverse effects in the investigational arm were diarrhea, nausea, vomiting, peripheral edema, and rash, which is consistent with the known profile of this drug class, Orloff reported. Diarrhea was primarily managed with antidiarrheals or octreotide in refractory cases. Nausea was mitigated by administering the drug with a high-fat or high-protein meal, and antiemetics were also employed, Orloff explained. Edema was managed with diuretics. Investigators also noted hypotension and syncope risk attributable to the PKC inhibitor class; this was addressed by withholding antihypertensives, ensuring adequate hydration, and implementing a 7-day darovasertib run-in period prior to adding crizotinib, Orloff concluded.