Darovasertib-Crizotinib Shows Activity in Uveal Melanoma Regardless of HLA

The oral combination of the protein kinase C (PKC) inhibitor darovasertib (IDE196) and the MET inhibitor crizotinib (Xalkori) showed antitumor activity in previously untreated metastatic uveal melanoma, regardless of HLA-A*02:01 status, according to phase 2 results from the OptimUM-01 trial (NCT03947385) published in the Journal of Clinical Oncology.¹ Additional data from HLA-A*02:01–positive patients, including those previously treated with tebentafusp-tebn (Kimmtrak), were presented at the European Society for Medical Oncology (ESMO) Congress 2026.²

Among 44 treatment-naive patients, the confirmed objective response rate (ORR) was 34.1%, with partial responses in all responders and stable disease in 56.1%. The median duration of response (DOR) was 9.0 months. At a median follow-up of 25 months, median progression-free survival (PFS) was 7.0 months (95% CI, 3.8-7.7) and median overall survival (OS) was 21.1 months (95% CI, 12.5-27.1).¹

“…The OptimUM-01 findings reinforce its potential to become a new standard of care for the broader population of patients irrespective of HLA-A*02:01 status and line of therapy,” said Meredith McKean, MD, MPH, director of melanoma and skin cancer research at Sarah Cannon Research Institute, in a news release.³

Study Design

OptimUM-01 is a phase 1/2, multicenter, open-label dose-escalation and -expansion study in patients with solid tumors harboring GNAQ or GNA11 mutations, which activate PKC and are detected in about 95% of uveal melanomas. The published report focuses on first-line patients with metastatic uveal melanoma enrolled in a phase 2 expansion cohort who received darovasertib 300 mg twice daily plus crizotinib 200 mg twice daily. Eligible patients had measurable disease by RECIST v1.1 and an ECOG performance status of 0 or 1, and enrollment was not restricted by HLA status.¹

In the first-line cohort, the median age was 64.5 years (range, 21-80). The cohort was 68.2% HLA-A*02:01–negative and 27.3% HLA-A*02:01–positive. Elevated baseline lactate dehydrogenase (LDH) was present in 31.8%, and 40.9% had both hepatic and extrahepatic disease.¹

Activity by HLA Status

In the first-line cohort, ORRs were 30.0% in HLA-A*02:01–positive patients (n = 10) and 31.0% in HLA-A*02:01–negative patients (n = 29). Among 20 patients with tumor GNAQ/11 mutations, 95% had a greater than 50% reduction in circulating cell-free DNA from baseline.¹

The ESMO poster, presented by McKean with a March 23, 2026, data cutoff, reported on 101 HLA-A*02:01–positive patients, two-thirds of whom had received at least 2 prior lines of therapy. In 13 treatment-naive patients, the ORR was 36.4% (n = 4/11 evaluable), median PFS was 7.4 months (95% CI, 3.6-19.6), and median OS was 27.1 months (95% CI, 8.9-not evaluable). In 15 patients treated in the second line after tebentafusp, the ORR was 35.7%, median PFS was 5.7 months, and median OS was 12.1 months. Across all 101 patients, the ORR was 22.1%, median PFS 5.4 months, and median OS 13.4 months.²

Safety Findings

In the first-line cohort, the most common treatment-emergent adverse events (TEAEs) were diarrhea (95.5%), nausea (84.1%), peripheral edema (61.4%), and vomiting (52.3%). Grade 3 or higher TEAEs occurred in 52.3% of patients, most commonly pulmonary embolism (9.1%) and iron deficiency anemia (6.8%), and serious TEAEs occurred in 20.5%. TEAEs led to discontinuation in 6.8% of patients, and 68.2% had at least 1 dose hold. Two patients had grade 5 adverse events; 1 was considered unrelated to treatment, and the other was deemed possibly related.¹

In the 101 HLA-A*02:01–positive patients, grade 3 or higher treatment-related adverse events included hypotension (5.9%), syncope (5.9%), and pulmonary embolism (5.0%), and 9 patients (8.9%) discontinued treatment because of treatment-related events.²

Clinical Context and Limitations

Tebentafusp, the only FDA-approved systemic therapy for metastatic uveal melanoma, is restricted to HLA-A*02:01–positive patients, and no therapy is approved for the HLA-A*02:01–negative patients who make up 50% to 70% of this population, the authors noted.¹ Clinicians have also cited the weekly infusion schedule of tebentafusp as a barrier to access.

In the randomized phase 2/3 OptimUM-02 trial (NCT05987332) in HLA-A*02:01–negative patients, darovasertib plus crizotinib improved PFS vs investigator’s choice of therapy (median, 6.9 vs 3.1 months; HR, 0.42; 95% CI, 0.30-0.59; P < .0001).⁴ IDEAYA Biosciences, the sponsor, expects to complete a new drug application for the combination in first-line metastatic uveal melanoma in the second half of 2026.³

The authors cautioned that OptimUM-01 is a single-arm, open-label study whose results should be considered hypothesis-generating, and that PFS and OS remain preliminary.¹

“Together, these data represent a meaningful advancement toward addressing the diverse and significant needs of the metastatic uveal melanoma patient community,” McKean stated of the OptimUM-01 and OptimUM-02 trials in the news release.³

REFERENCES

1. McKean M, Chmielowski B, Butler MO, et al. Darovasertib and crizotinib first-line treatment for metastatic uveal melanoma: overall survival, efficacy, and safety from the OptimUM-01 study. J Clin Oncol. Published online October 28, 2026. doi:10.1200/JCO-26-00802

2. McKean M, Chmielowski B, Butler MO, et al. Darovasertib and crizotinib for HLA-A*02:01–positive metastatic uveal melanoma: results from the phase 2 OptimUM-01 study. Presented at: European Society for Medical Oncology Congress 2026; October 23-27, 2026; Madrid, Spain. Poster 2086P.

3. IDEAYA Biosciences and Servier announce data from three clinical trials at ESMO 2026 supporting the potential of darovasertib to become a foundational new therapy for patients across the treatment journey of uveal melanoma. News release. IDEAYA Biosciences. October 19, 2026. Accessed November 5, 2026. https://tinyurl.com/3537typw

4. Orloff MM, Ramelyte E, Butler MO, et al. 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. J Clin Oncol. 2026;44(suppl 17):LBA9503. doi:10.1200/JCO.2026.44.17_suppl.LBA9503