Slide 1: Darovasertib Plus Crizotinib vs Investigator's Choice as First-Line Treatment for HLA-A2 Negative Metastatic Uveal Melanoma
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 Marlana Orloff,1 Egle Ramelyte,2 Marcus O. Butler,3 Piotr Rutkowski,4 Lorenza Di Guardo,5 Matteo S. Carlino,6 Bartosz C
Slide 2: Targeting PKC and MET in Metastatic Uveal Melanoma
HLA, human leukocyte antigen. mOS, median overall survival. mPFS, median progression free survival. PKC, protein kinase C. 1. Khoja L, et al. J Clin Oncol. 2025;43(suppl) [abstract 9539]. 2. Rantala ES, et al. Melanoma Res. 2019;29:561-568. 3. Park JJ, et al. Oncogenesis. 2024;13:9. 4. Sullivan RJ,
Slide 3: OptimUM-02 Study Design
OptimUM-02 Study Design Phase 2/3, multi-center, multi-arm, multi-stage, open-label study Marlana Orloff, MD. Alexander & Johnston Family Endowed Clinical Director in Uveal Melanoma; Professor Primary: PFS by BICR Secondary: PFS by Investigator ORR by BICR, Investigator Duration of response Disease
Slide 4: Analysis Populations
Analysis Populations Efficacy All patients in the ITT population setting (phase 2b portion of trial) Darovasertib 300 mg + crizotinib 200 mg (n=210) Investigator’s Choice (control, n=103) Analysis based on both BICR and Investigator assessments Safety Safety was evaluated in all patients (phase 2a a
Slide 5: Primary Endpoint Statistical Analysis
Primary Endpoint Statistical Analysis PFS per BICR 130 PFS events were required to detect a hazard ratio of 0.55 with 90% power Stratified log-rank test at a 1-sided α of 2.5% The median PFS in the control arm was assumed to be 3 months The target HR of 0.55 represents a 45% reduction in the risk of
Slide 6: Baseline Characteristics
Baseline Characteristics Efficacy Analysis Population Darovasertib + Crizotinib (N=210) Investigator’s Choice (N=103) Age, mean (range) 61.1 (22 - 85) 61.5 (29 - 85) Female, n (%) 101 (48.1) 52 (50.5) Race, n (%) White 177 (84.3) 83 (80.6) non-White 4 (1.9) 4 (3.9) Not reported 29 ( 13.8) 16 ( 15.5)
Slide 7: Baseline Tumor Characteristics
Baseline Tumor Characteristics Efficacy Analysis Population Darovasertib + Crizotinib (N=210) Investigator’s Choice (N=103) Time since First Metastatic Diagnosis (year) n 210 103 Median (range) 0.18 (0.0 – 8.1) 0.19 (0.0 – 4.6) Size of Largest Metastatic Lesion Category ≤ 3 cm 119 ( 56.7) 67 ( 65.0)
Slide 8: Primary Efficacy Endpoint Results
Primary Efficacy Endpoint Results BICR Assessment Investigator Assessment Clinically meaningful and statistically significant improvement in PFS with darova + criz vs control Reduction in the risk of progression or death: 58% by BICR (HR: 0.42); 64% by investigator assessment (HR: 0.36), p < 0.0001
Slide 9: Secondary Efficacy Endpoint Results
Secondary Efficacy Endpoint Results Darovasertib + Crizotinib (N=210) Investigator’s Choice (N=103) Darovasertib + Crizotinib (N=210) Investigator’s Choice (N=103) Objective Response Rate Patients with a complete or partial response, n (%) 78 (37.1) 6 (5.8) 83 (39.5) 2 (1.9) 95% CI 30.6, 44.1 2.2, 1
Slide 10: Best Overall Response
Best Overall Response Darovasertib + Crizotinib (N=210) Investigator’s Choice (N=103) Darovasertib + Crizotinib (N=210) Investigator’s Choice (N=103) Best Overall Response, n (%) Complete Response 5 (2.4) 0 0 0 Partial Response 73 (34.8) 6 (5.8) 83 (39.5) 2 (1.9) Stable Disease 107 (51.0) 43 (41.7)
Slide 11: Best Overall Response
Best Overall Response BICR Assessment Investigator Assessment BICR, blinded independent central reader. CR, complete response. NR, not reported. PD, progressive disease. PR, partial response. SD, stable disease. Marlana Orloff, MD. Alexander & Johnston Family Endowed Clinical Director in Uveal Melan
Slide 12: Primary Endpoint Results: PFS Subgroup Analysis
Hazard Ratio (95% CI) Darova+Criz − Control Results by BICR. Unstratified model. BICR, blinded independent central reader. Control, investigator’s choice of treatments. Daca, dacarbazine. Darova + Criz, darovasertib 300mg + crizotinib 200mg. ECOG, Eastern Cooperative Oncology Group. Ipi, ipilimumab.
Slide 13: Overall Treatment Related Adverse Event Summary
Marlana Orloff, MD. Alexander & Johnston Family Endowed Clinical Director in Uveal Melanoma; Professor Darovasertib + Crizotinib (N=239) Investigator’s Choice (N=100) Median Relative Dose Intensity 91.0% for Darovasertib 77.1% for Crizotinib 100% Any TRAE, n (%) 235 (98.3) 89 (89.0) Grade 3 or 4 97
Slide 14: Most Common Treatment Related Adverse Events All Grades
Most Common Treatment Related Adverse Events All Grades Marlana Orloff, MD. Alexander & Johnston Family Endowed Clinical Director in Uveal Melanoma; Professor Darovasertib + Crizotinib (N=239) Any TRAEs (≥20%), n (%) 235 ( 98.3) Diarrhea 203 ( 84.9) Nausea 179 ( 74.9) Peripheral edema 160 ( 66.9) Vo
Slide 15: Grade 3/4 Treatment Related Adverse Events
Grade 3/4 Treatment Related Adverse Events Marlana Orloff, MD. Alexander & Johnston Family Endowed Clinical Director in Uveal Melanoma; Professor Darovasertib + Crizotinib (N=239) Any Grade 3/4 Adverse Events (≥2%), n (%) 97 ( 40.6) Diarrhea 24 ( 10.0) Syncope 17 ( 7.1) Hypotension 9 ( 3.8) Nausea 7
Slide 16: Summary
Summary In patients with HLA-A2-negative-mUM treated in the first-line setting, darovasertib +crizotinib demonstrated: Clinically meaningful and significantly longer PFS vs investigator’s choice (mPFS of 6.9 months vs 3.1 months, HR 0.42, indicating a 58% reduction in disease progression or death) S
Slide 17: Acknowledgements
Acknowledgements Marlana Orloff, MD. Alexander & Johnston Family Endowed Clinical Director in Uveal Melanoma; Professor We gratefully acknowledge the Patients and their families for participating in this study, and all investigators and site staff whose contributions made the OptimUM-02 study possib