Darovasertib Combo Improves PFS in Metastatic Uveal Melanoma Trial

Clinically meaningful and statistically significant improvements in progression-free survival (PFS) were observed among patients with HLA-A*02:01–negative metastatic uveal melanoma who received darovasertib plus crizotinib (Xalkori), according to data from the phase 3 OptimUM-02 trial (NCT05987332) presented at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting.¹

Why investigate PKC inhibition in uveal melanoma?

Uveal melanoma is the most common ocular cancer in adults, but metastatic disease carries a poor prognosis with a median PFS of 2.8 months and median overall survival (OS) of 10 to 12 months.² Mutations in GNAQ or GNA11 that activate protein kinase C (PKC) are detected in more than 95% of uveal melanomas, making PKC a rational therapeutic target. No FDA-approved treatments currently exist for patients with HLA-A*02:01–negative metastatic uveal melanoma, further underscoring a target population with high unmet clinical need.
Darovasertib is a first-in-class, oral PKC inhibitor with demonstrated clinical activity across both HLA-A*02:01–positive and –negative metastatic uveal melanoma. The agent is being evaluated in combination with crizotinib, an oral MET inhibitor that has shown complementary antitumor activity with darovasertib both preclinically and clinically, with rationale driven by parallel pathway activation through hepatocyte growth factor and MET overexpression.

What was the design of the trial?

The phase 2/3, multi-center, multi-arm, multi-stage, open-label study enrolled patients with HLA-A*02:01–negative metastatic uveal melanoma. In phase 2a, patients were randomly assigned 2:2:1 to first-line therapy with darovasertib at 300 mg plus crizotinib at 200 mg twice daily, darovasertib at 200 mg plus crizotinib at 200 mg twice daily, or investigator’s choice of pembrolizumab (Keytruda), ipilimumab (Yervoy) plus nivolumab (Opdivo), or dacarbazine. In phase 2b and phase 3, patients were randomly assigned 2:1 to darovasertib at 300 mg plus crizotinib at 200 mg twice daily, or investigator’s choice of the aforementioned 3 therapies.

The primary end point of phase 2b was PFS by BICR. Secondary end points included PFS by investigator, objective response rate (ORR) by both BICR and investigator, duration of response (DOR), 12-week disease control rate (DCR), and safety. The primary end point of the phase 3 portion is OS, which will be shared once the data mature.

All patients in the intention-to-treat population or the phase 2b portion of the trial were evaluated for efficacy per BICR and investigator: 210 in the 300-mg darovasertib arm and 103 patients in the investigator’s choice arm. Safety was evaluated in all patients in phase 2a and 2b who received at least 1 dose of the 300-mg darovasertib regimen (n = 239) or the control (n = 100).

What statistical assumptions were baked into the trial’s design?
A total of 130 PFS events were required to detect a HR of 0.55 with 90% power. A stratified log-rank test was used with a 1-sided alpha of 2.5%. The median PFS in the control arm was approximated at 3 months. With a target HR of 0.55, representing a 45% reduction in the risk of disease progression or death, the median PFS was expected to be approximately 5.5 months in the investigational arm factoring in exponential distributions.

What were the baseline characteristics of the trial population?

In the combination arm the mean age was 61.1 years (range, 22-85) and the minority of patients were female (n = 101; 48.1%). Patients were White (n = 177; 84.3%), non-White (n = 4; 1.9%), or did not have reported data (n = 29; 13.8%). ECOG performance status was 0 (n = 162; 77.1%) or 1 (n = 48; 22.9%), and baseline lactate dehydrogenase (LDH) levels fell below the upper limit of normal (ULN), between the ULN and below twice the ULN, and above twice the ULN in 57.1% (n = 120), 31.0% (n = 65), and 11.9% (n = 25) of patients, respectively.

Within the investigational arm the median time since first metastatic diagnosis was 0.18 years (range, 0.0-8.1). The size of the largest metastatic lesion was no more than 3 cm (n = 119; 56.7%), between 3.1 and 8.0 cm (n = 73; 34.8%), and at least 8.1 cm (n = 18; 8.6%). Metastatic sites comprised hepatic (n = 127; 60.5%), extrahepatic (n = 11; 5.2%) or both (n = 72; 34.3%).

In the control arm the mean age was 61.5 years (range, 29-85) and most patients were female (n = 52; 50.5%). Patients were White (n = 83; 80.6%), non-White (n = 4; 3.9%), or did not have reported data (n = 16; 15.5%). ECOG performance status was 0 (n = 87; 84.5%) or 1 (n = 16; 15.5%), and baseline LDH levels fell below the ULN, between the ULN and below twice the ULN, and above twice the ULN in 60.2% (n = 62), 28.2% (n = 29), and 11.7% (n = 12) of patients, respectively. Additionally, patients received either ipilimumab plus nivolumab (n = 79; 76.7%) or pembrolizumab (n = 24; 23.3%); no patients received dacarbazine.

In the control arm the median time since first metastatic diagnosis was 0.19 years (range, 0.0-4.6). The size of the largest metastatic lesion was no more than 3 cm (n = 67; 65.0%), between 3.1 and 8.0 cm (n = 31; 30.1%), and at least 8.1 cm (n = 5; 4.9%). Metastatic sites comprised hepatic (n = 65; 63.1%), extrahepatic (n = 7; 6.8%) or both (n = 31; 30.1%).

How did the combination perform in terms of responses?

With respect to secondary end points, the ORR according to BICR was 37.1% (n = 78; 95% CI, 30.6%-44.1%) in the combination arm vs 5.8% (n = 6; 95% CI, 2.2%-12.3%) in the control arm (OR, 10.8; 95% CI, 4.4-26.4; P < .0001). The median DOR was 6.8 months (95% CI, 5.5-11.3) vs not evaluable (NE) in the investigational and control arms, respectively. The 12-week DCRs were 73.3% (n = 154; 95% CI, 66.8%-79.2%) and 31.1% (n = 32; 95% CI, 22.3%-40.9%) in the respective arms (OR, 7.7; 95% CI, 4.3-13.5; P < .0001).

Best overall responses per BICR in the combination and control arms, respectively, consisted of complete responses (CRs; 2.4%; 0%), partial responses (PRs; 34.8%; 5.8%), stable disease (SD; 51.0%; 41.7%), and progressive disease (PD; 6.2%; 28.2%); 1 patient was NE by RECIST criteria in the control arm, and a total of 12 (5.7%) and 24 (23.3%) cases were not reported because no post baseline assessments were available.

When investigator assessment was applied, the ORR was 39.5% (n = 83; 95% CI, 32.9%-46.5%) in the combination arm vs 1.9% (n = 2; 95% CI, 0.2%-6.8%) in the control arm (OR, 34.6; 95% CI, 8.1-146.9 ; P < .0001). The median DOR was 6.8 months (95% CI, 4.8-9.7) vs NE in the investigational and control arms, respectively. The 12-week DCRs were 74.3% (n = 156; 95% CI, 67.8%-80.1%) and 27.2% (n = 28; 95% CI, 18.9%-36.8%) in the respective arms (OR, 9.5; 95% CI, 5.3-17.0; P < .0001).

Best overall responses per investigator assessment in the combination and control arms, respectively, consisted of PRs (39.5%; 1.9%), SD (47.1%; 37.9%), and PD (7.1%; 33.0%); 1 (0.5%) and 4 (3.9%) patients were NE by RECIST criteria in the respective arms, and a total of 12 (5.7%) and 24 (23.3%) cases were not reported because no post baseline assessments were available.

Orloff noted that OS data, although not mature, demonstrated an early trend toward improvement with the combination.

What was the safety profile of the regimen?

The median relative dose intensity was 91.0% for darovasertib, 77.1% for crizotinib, and 100% for investigator’s choice of therapy. Treatment-related serious adverse effects (AEs) were less frequent with darovasertib plus crizotinib, at 9.2% (n = 22) compared with 25.0% (n = 25) for investigator's choice therapy; events leading to treatment withdrawal occurred in 0.8% (n = 2) and 5.0% (n = 5) of patients, respectively.

Treatment-related AEs (TRAEs) leading to darovasertib or crizotinib withdrawal occurred in 2.5% (n = 6) and 10.0% (n = 24) of patients, respectively. Nineteen (19.0%) patients discontinued investigator’s choice therapy because of a TRAE. TRAEs leading to dose reduction of either darovasertib or crizotinib occurred in 23.4% (n = 56) and 26.4% (n = 63) of patients, respectively. No dose reductions owing to TRAEs were required in the investigator’s choice arm.

Any-grade TRAEs that occurred in at least 20% of patients in the combination arm (n = 235; 98.3%) were diarrhea (n = 203; 84.9%), nausea (n = 179; 74.9%), peripheral edema (n = 160; 66.9%), vomiting (n = 119; 49.8%), dermatitis acneiform (n = 100; 41.8%), fatigue (n = 94; 39.3%), hypotension (n = 79; 33.1%) , hypoalbuminemia (n = 61; 25.5%), dysgeusia (n = 61; 25.5%), dizziness (n = 61; 25.5%), and decreased appetite (n = 57; 23.8%).

Any-grade TRAEs that were reported in the control arm (n = 88; 88.0%) were diarrhea (n = 29; 29.0%), increased alanine aminotransferase (ALT) levels (n = 25; 25.0%), increased aspartate aminotransferase (AST) levels (n = 25; 25.0%), fatigue (n = 25; 25.0%), nausea (n = 25; 25.0%), and pruritus (n = 24; 24.0%).

“The AEs were consistent with [the regimen’s] prior safety profile, with a low rate of treatment-related serious AEs and discontinuations due to TRAEs for darovasertib and crizotinib,” Orloff reported.

In the combination arm the most common grade 3/4 TRAEs that occurred in at least 2% of patients (n = 97; 40.6%) were diarrhea (n = 24; 10.0%), syncope (n = 17; 7.1%), hypotension (n = 9; 3.8%), nausea (n = 7; 2.9%), peripheral edema (n = 7; 2.9%), and anemia (n = 6; 2.5%).

In the control arm the most common grade 3/4 TRAEs that occurred in at least 2% of patients (n = 37; 37.0%) were increased ALT levels (n = 7; 7.0%), increased AST levels (n = 7; 7.0%), diarrhea (n = 6; 6.0%), hepatitis (n = 5; 5.0%), colitis (n = 4; 4.0%), increased lipase (n = 3; 3.0%), autoimmune hepatitis (n = 3; 3.0%), increased amylase (n = 3; 3.0%), tubulointerstitial nephritis (n = 2; 2.0%), hypophysitis (n = 2; 2.0%), and hyperthyroidism (n = 2; 2.0%).

Grade 5 TRAEs occurred in 0.4% (n = 1) and 1.0% (n = 1) of patients in the combination and control arms, respectively.

Disclosures: Orloff disclosed employment from Pfizer (I); honoraria from Immunocore; consulting or advisory roles with Delcath Systems, IDEAYA Biosciences, Immunocore, Replimune, and TriSalus Life Sciences; speakers' bureau participation with Immunocore; and research funding from Bristol-Myers Squibb (Inst), Delcath Systems (Inst), IDEAYA Biosciences (Inst), Immunocore (Inst), iOnctura (Inst), Iovance Biotherapeutics (Inst), Linnaeus Therapeutics (Inst), Novelwise (Inst), Regeneron (Inst), Replimune (Inst), and TriSalus Life Sciences (Inst).

References

1. Orloff M, 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. 10.1200/JCO.2026.44.17_suppl.LBA9503
2. Khoja L, Atenafu E, Leyvraz S, et al. Updated analyses from a global meta-analysis in metastatic uveal melanoma (mUM) to determine progression free and overall survival benchmarks by line of therapy: an international rare cancers initiative (IRCI) ocular melanoma study. J Clin Oncol. 2025;43(suppl 16):9539. doi:10.1200/JCO.2025.43.16_suppl.9539