darovasertib (IDE196) / Novartis, Ideaya Biosci, Servier - LARVOL DELTA

Protein Kinase C fusions - Rare but Targetable Initiating Mutations in Melanoma? (AAD 2026) - "Small-molecule PKC inhibitors (e.g., LXS196) have demonstrated clinical activity in uveal melanoma, suggesting their potential utility against PKC fusion–driven tumors (4)...To further investigate their role in tumor initiation, we developed a transgenic mouse model in which expression of a PKC fusion gene (ATP2B4::PRKCA) is induced in melanocytes following tamoxifen administration...This model offers an effective system for understanding PKC fusion mediated signaling, evaluating targeted therapies, and studying cooperating genetic events. Collectively, our findings establish PKC fusions as initiating events in melanoma and underscore the importance of continued preclinical modeling to guide translational advances."

Eye Cancer • Melanoma • Nevi and Melanomas • Solid Tumor • Uveal Melanoma • BRAF • GNA11 • GNAQ • PRKCA

Targeting Hippo/YAP-TEAD increases the antitumor activity of darovasertib in uveal melanoma (AACR 2026) - "Darovasertib has demonstrated encouraging activity in UVM patients, and clinical trials using darovasertib as a single agent in primary UVM lesions and in combination with crizotinib in mUVM are currently ongoing. Ongoing studies are now exploring the preclinical benefit of combining darovasertib with small-molecule TEADi for the treatment of human UVM tumor xenografts in mice. Emerging evidence will be presented supporting that the Hippo YAP/TEAD pathway represents an adaptive mechanism of resistance to darovasertib treatment, and that the combination of TEADi with darovasertib may prevent the development of treatment resistance, thereby increasing the depth and duration of the anti-tumor response in UVM."

IO biomarker • Cutaneous Melanoma • Eye Cancer • Melanoma • Oncology • Solid Tumor • Uveal Melanoma • GNA11 • GNAQ • LATS1 • YAP1

IDEAYA Biosciences…provided updated guidance related to the timing of its upcoming topline data release from the Phase 2/3 OptimUM-02 trial in first-line HLA-A2-negative metastatic uveal melanoma (PRNewswire) - "The database lock is projected in the first half of April, followed by the topline data analysis thereafter."

P2/3 data • Trial status • Uveal Melanoma

DAR-UM-2: IDE196 (Darovasertib) in Combination With Crizotinib as First-line Therapy in Metastatic Uveal Melanoma (clinicaltrials.gov) - P2/3 | N=420 | Active, not recruiting | Sponsor: IDEAYA Biosciences | Recruiting ➔ Active, not recruiting

Enrollment closed • Eye Cancer • Melanoma • Oncology • Solid Tumor • Uveal Melanoma

IDE196-009: (Neo)Adjuvant IDE196 (Darovasertib) in Patients With Localized Ocular Melanoma (clinicaltrials.gov) - P2 | N=160 | Active, not recruiting | Sponsor: IDEAYA Biosciences | Recruiting ➔ Active, not recruiting

Enrollment closed • Eye Cancer • Melanoma • Ocular Melanoma • Oncology • Solid Tumor • Uveal Melanoma

Adverse Events and Toxicity of Systemic Treatments for Uveal Melanoma: A Systematic Review. (PubMed, Cancers (Basel)) - "Analysis of treatment-related adverse events (TRAEs) of grade ≥3 showed that patient cohorts receiving trametinib, selumetinib, and darovasertib experienced the lowest incidence of severe events (with the exception of creatine phosphokinase elevation observed with selumetinib), suggesting a comparatively more favorable safety profile for these agents. At present, the most robust efficacy data in the metastatic uveal melanoma setting are available for tebentafusp and darovasertib. This study provides the most comprehensive analysis of TRAEs in randomized trials of UM, delineating the toxicity and safety profiles of current therapies to guide personalized treatment decisions."

Adverse events • Journal • Review • Eye Cancer • Melanoma • Oncology • Solid Tumor • Uveal Melanoma

Uveal Melanoma: Changing Paradigms of Treatment. (PubMed, Ocul Oncol Pathol) - "In 2022, tebentafusp became the first approved systemic therapy to improve overall survival in metastatic UM...As half of the patients are HLA A02:01 negative, alternative strategies are under investigation, including the protein kinase C inhibitor darovasertib in the NADOM neoadjuvant/adjuvant trial and in combination with crizotinib in metastatic UM. DYP688, a first-in-class PMEL17-targeting antibody-drug conjugate that inhibits GNAQ/11 signaling, has shown promise in metastatic UM and other GNAQ/11-mutant melanomas. The landscape of UM treatment is rapidly evolving following the identification of new targets and pathways such as PKC or PRAME. Combination of liver-directed therapies with personalized systemic immunotherapies or targeted agents in the metastatic disease, as well as the early use of systemic therapies in the primary tumor setting will refine treatment strategies in UM and suggest improved outcomes in the near future."

IO biomarker • Journal • Review • Eye Cancer • Melanoma • Oncology • Solid Tumor • Uveal Melanoma • GNAQ • PMEL • PRAME

IDE196-010: Darovasertib before Surgery or Radiation Therapy to Treat Early-stage Eye Cancer (Uveal Melanoma) (clinicaltrialsregister.eu) - P2/3 | N=297 | Not yet recruiting | Sponsor: Ideaya Biosciences Inc.

New P2/3 trial • Eye Cancer • Melanoma • Ocular Melanoma • Oncology • Solid Tumor • Uveal Melanoma

Enrollment of approximately 100 HLA* A2-positive mUM patients in single-arm, Phase 2 OptimUM-01 trial of darovasertib in combination with crizotinib is expected to be complete by Q2 ’26. (PRNewswire) - "Data may support a potential future submission to the U.S. Food and Drug Administration (FDA) to expand the labeled use of darovasertib and/or a national comprehensive cancer network (NCCN)/compendia listing to enable use of the combination in these patients; Targeting to submit two manuscripts for publication with data from 1) treatment naïve mUM patients and 2) HLA*A2-positive mUM patients enrolled in the OptimUM-01 trial in H1 '26 and H2 '26, respectively."

Enrollment status • P2 data • Uveal Melanoma

Neoadjuvant Darovasertib in Primary Uveal Melanoma (clinicaltrials.gov) - P3 | N=520 | Recruiting | Sponsor: IDEAYA Biosciences | Initiation date: Oct 2025 ➔ Jan 2026

Trial initiation date • Eye Cancer • Melanoma • Oncology • Solid Tumor • Uveal Melanoma

A phase 2 safety and efficacy study of neoadjuvant/adjuvant darovasertib for localized ocular melanoma. (ASCO 2024) - P2 | "NADOM provides the first evidence that a globe-salvage neoadjuvant treatment strategy in UM is feasible, safe, and efficacious. The results suggest that PKC inhibition with darovasertib can induce clinically meaningful tumor shrinkage in patients with primary UM patients who otherwise require enucleation. Larger trials are in now progress (NCT05907954) to further quantify visual and oncological outcomes."

Clinical • P2 data • Eye Cancer • Fatigue • Hypotension • Melanoma • Ocular Melanoma • Oncology • Pruritus • Solid Tumor • Uveal Melanoma • GNA11 • GNAQ

Enucleation prevention and vision preservation in primary uveal melanoma (UM): Preliminary results from a phase II study of neoadjuvant darovasertib (ESMO 2025) - P2 | "Conclusions Darovasertib is well-tolerated & is the first Rx to show tumor shrinkage in primary UM resulting in EP, radiation dose reduction & potential for vision preservation. Based on these promising results, a registrational study is planned."

Clinical • P2 data • Eye Cancer • Melanoma • Oncology • Solid Tumor • Uveal Melanoma • GNA11 • GNAQ

Darovasertib: “OptimUM-09 primary phase 2 efficacy results in neoadjuvant uveal melanoma” ; Uveal melanoma (44th Annual J.P. Morgan Healthcare Conference, IDEAYA Biosciences)

P2 data • Oncology • Uveal Melanoma

Darovasertib: “OptimUM-09 primary phase 2 efficacy results in neoadjuvant uveal melanoma” ; Uveal melanoma (44th Annual J.P. Morgan Healthcare Conference, IDEAYA Biosciences)

P2 data • Oncology • Uveal Melanoma

2026 Corporate Objectives: Darovasertib in uveal melanoma (UM) (PRNewswire) - "(i) Topline results, including progression free survival (PFS) data, from ongoing registrational Phase 2/3 OptimUM-02 trial of the darovasertib and crizotinib combination in first line (1L) patients with HLA*A2-negative metastatic UM (mUM) are expected in Q1 '26....The topline PFS results, if positive, are anticipated to enable a potential accelerated approval filing in the United States...; (ii) Complete enrollment of approximately 80 HLA*A2-positive mUM patients in ongoing single-arm, Phase 2 OptimUM-01 trial of darovasertib in combination with crizotinib by Q2 '26; data to support a potential real world evidence (RWE) submission to the U.S. Food and Drug Administration (FDA) and/or NCCN/compendia listing in this patient subset."

Enrollment status • P2/3 data • Uveal Melanoma

Darovasertib is anticipated to be in three randomized, Phase 3 registrational trials across all stages of uveal melanoma by H1 '26 (PRNewswire) - "(i) OptimUM-02 (mUM): full enrollment of 437 patients complete; overall survival (OS) data expected to support a filing for full approval in 1L HLA*A2-negative mUM; (ii) OptimUM-10 (neoadjuvant): complete full enrollment of approximately 450 patients across enucleation and plaque brachytherapy cohorts by H1 '27; (iii) OptimUM-11 (adjuvant): initiate trial in collaboration with Servier in Q2 '26."

Enrollment status • New P3 trial • Uveal Melanoma

First reported overall survival results from a phase 1/2 study of darovasertib (OptimUM-01) plus crizotinib as first-line treatment for metastatic uveal melanoma (SMR 2025) - No abstract available

Clinical • Metastases • P1/2 data • Eye Cancer • Melanoma • Oncology • Solid Tumor • Uveal Melanoma

IDEAYA Biosciences Completes Targeted Full Enrollment in Randomized Pivotal Phase 2/3 Trial (OptimUM-02) of Darovasertib in Combination with Crizotinib in First-line HLA*A2-Negative Metastatic Uveal Melanoma (PRNewswire) - "IDEAYA Biosciences...has completed its targeted full enrollment of 435 patients....IDEAYA expects to report median progression-free survival (PFS) data from this trial in the first quarter 2026 to support a potential accelerated approval filing in the United States."

Enrollment closed • P2/3 data • Uveal Melanoma

Darovasertib (PRNewswire) - "Median progression-free survival (PFS) data from the Phase 2/3 trial (OptimUM-02) of darovasertib in combination with crizotinib in first line (1L) HLA*A2:01-negative mUM is on track to be reported by year-end 2025 to 1Q 2026; this data has the potential to enable an accelerated approval filing in the United States. The trial is nearing full enrollment, which remains on track to be completed by year-end."

Enrollment status • P2/3 data • Uveal Melanoma

Adjuvant therapy for primary UM (PRNewswire) - "In collaboration with Servier, IDEAYA plans to initiate a global Phase 3 combination trial of darovasertib and crizotinib as an adjuvant therapy for primary UM in the first half of 2026."

New P3 trial • Uveal Melanoma

IDEAYA Biosciences Reports Positive Median Overall Survival Data from Phase 2 Trial of the Darovasertib and Crizotinib Combination in First-line Metastatic Uveal Melanoma at the 2025 Society for Melanoma Research Congress (Nasdaq) - "Combination demonstrated median overall survival (OS) of 21.1 months, compared to reported historical mOS of approximately 12 months in published meta-analysis of metastatic uveal melanoma in the first-line setting; Median progression free survival (PFS) of 7.0 months; Confirmed overall response rate (ORR) by RECIST 1.1 of 34%, median duration of response (mDOR) of 9 months and disease control rate (DCR) of 90%"

P2 data • Uveal Melanoma

IDEAYA Biosciences Announces Positive Phase 2 Data for Darovasertib in the Neoadjuvant Setting of Primary Uveal Melanoma in a Proffered Paper Oral Presentation at ESMO 2025 (PRNewswire) - "83% (78/94) of patients demonstrated ocular tumor shrinkage, with 54% (51/94) achieving ≥20% tumor shrinkage. 57% (24/42) eye preservation rate in enucleation (EN) recommended patients, which increased to 95% (19/20) in patients achieving ≥20% ocular tumor shrinkage. 70% (26/37) of plaque brachytherapy (PB) eligible patients achieved a reduction in predicted radiation dose to the eye from baseline, resulting in 65% (24/37) of patients having lower predicted risk of vision loss 3-years post-PB treatment."

P2 data • Uveal Melanoma

IDE196-009: (Neo)Adjuvant IDE196 (Darovasertib) in Patients With Localized Ocular Melanoma (clinicaltrials.gov) - P2 | N=160 | Recruiting | Sponsor: IDEAYA Biosciences | N=82 ➔ 160 | Trial completion date: Jan 2029 ➔ Apr 2030 | Trial primary completion date: Jan 2026 ➔ Apr 2027

Enrollment change • Trial completion date • Trial primary completion date • Eye Cancer • Melanoma • Ocular Melanoma • Oncology • Solid Tumor • Uveal Melanoma

Inhibition of anti-apoptotic BCL2 overcomes adaptive resistance to co-targeting of the protein kinase FAK and MEK in GNAQ-driven uveal melanoma. (PubMed, J Biol Chem) - "Moreover, expression of a stable BCL2 mutant confers resistance to both FAKi+MEKi and FAKi+"RAF-MEK clamp" (avutometinib) treatment. Of direct translational relevance, we found that an approved BCL2 inhibitor (venetoclax) displays synergistic efficacy with FAK+MEK blockade and overcomes acquired resistance, including when combined with darovasertib, a dual PKC/PKN inhibitor limiting MEK and FAK signaling that is under clinical evaluation. Our findings suggest that resistance to FAKi+MEKi in UVM cells can be driven by an adaptive upregulation of the anti-apoptotic protein BCL2, and that, in turn, BCL2 inhibitors represent a promising precision-targeted strategy to overcome FAKi+MEKi treatment resistance and improve therapeutic outcomes."

IO biomarker • Journal • Eye Cancer • Melanoma • Ocular Melanoma • Oncology • Solid Tumor • Uveal Melanoma • BCL2 • GNA11 • GNAQ

IDEAYA Biosciences Announces Agenda for 10-Year Anniversary R&D Day on September 8, 2025 (PRNewswire) - "Members of IDEAYA's senior leadership team will provide an overview of the company's progress to date, including presentation of new clinical data on darovasertib in neoadjuvant uveal melanoma (UM), IDE849 (DLL3 TOP1 ADC) and IDE397 (MAT2A)..."

Clinical data • Uveal Melanoma