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

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

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

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

Neoadjuvant Darovasertib in Primary Uveal Melanoma (clinicaltrials.gov) - P3 | N=520 | Recruiting | Sponsor: IDEAYA Biosciences | Not yet recruiting ➔ Recruiting | Trial completion date: Dec 2027 ➔ Mar 2031 | Trial primary completion date: May 2027 ➔ Oct 2030

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

Darovasertib: “Darovasertib is well tolerated in the neoadjuvant setting; majority of TRAEs are grade 1 & 2”; Uveal melanoma (IDEAYA Biosciences) - IDEAYA Biosciences 10-Year Anniversary R&D Day: “76% ORR (% of subjects with >20% ocular tumor shrinkage)”

P2 data • Oncology • Uveal Melanoma

IDEAYA Biosciences to Present First Median Overall Survival Data from Phase 2 Trial of the Darovasertib / Crizotinib Combination in Metastatic Uveal Melanoma at the 2025 Society for Melanoma Research Congress (PRNewswire) - "The presentation will include data from over 40 patients in the trial, including the first reported median overall survival (OS) data for the combination of darovasertib and crizotinib in mUM."

P2 data • Uveal Melanoma

Discovery of darovasertib (NVP-LXS196), a novel PKC inhibitor for the treatment of Uveal Melanoma (ACS-Fall 2025) - "The lead series was optimized for kinase and off target selectivity to afford a compound that is rapidly absorbed and well tolerated in pre-clinical species. Darovasertib is currently in clinical trials to assess efficacy in 1L HLA-A2-negative metastatic uveal melanoma patients and neoadjuvant/adjuvant setting in primary UM."

Eye Cancer • Melanoma • Solid Tumor • Uveal Melanoma • GNA11 • GNAQ

Servier and IDEAYA Biosciences Partner to Bring Darovasertib, a Promising Uveal Melanoma Treatment, to Patients Worldwide (PRNewswire) - "Under the agreement, Servier obtains the regulatory and commercial rights for darovasertib in all territories outside the United States....IDEAYA and Servier will target to launch a global Phase 3 randomized clinical trial in 2026....Under the terms of the agreement, IDEAYA will receive an upfront payment of $210 million, and be eligible for up to $100 million in regulatory approval-based milestone payments and up to $220 million in commercial milestone payments..."

Licensing / partnership • New P3 trial • Uveal Melanoma

IDEAYA Biosciences, Inc. Reports Second Quarter 2025 Financial Results and Provides Business Update (PRNewswire) - "IDEAYA is also evaluating darovasertib as a monotherapy in the neoadjuvant setting for primary UM, where the goal of treatment is to prevent enucleation (surgical eye removal), preserve vision prior to and post-plaque brachytherapy, and slow disease progression and metastasis. Initial safety and visual benefit data will be reported from the Phase 2 clinical trial from over 20 patients in the plaque brachytherapy-eligible cohort at IDEAYA's R&D Day on September 8th, followed by additional data from over 90 patients in both the enucleation-eligible and plaque brachytherapy-eligible cohorts in a Proffered Paper Oral Presentation at ESMO, taking place from October 17-21, 2025 in Berlin, Germany. Following a successful Type D meeting with the FDA in April 2025, the company initiated a randomized Phase 3 registration-enabling trial of darovasertib in the neoadjuvant setting for primary UM in the third quarter of 2025."

P2 data • Trial status • Uveal Melanoma

IDEAYA Biosciences, Inc. Reports Second Quarter 2025 Financial Results and Provides Business Update (PRNewswire) - "Median progression-free survival (PFS) data from the Phase 2/3 trial of darovasertib in combination with crizotinib in first line (1L) HLA-A2-negative MUM is on track to be reported by year-end 2025; this data has the potential to enable an accelerated approval filing in the United States. Over 350 patients have been enrolled in the trial as of August 4, 2025, and the company expects to complete full enrollment of approximately 400 patients by year-end. Based on feedback from the U.S. Food and Drug Administration (FDA), IDEAYA plans to submit median overall survival (OS) data from this trial to support full U.S. approval in HLA-A2-negative MUM. Median OS data from a single-arm, Phase 2 trial of darovasertib in combination with crizotinib will be presented at a medical conference in the fourth quarter of 2025."

P2 data • P2/3 data • Trial status • Uveal Melanoma

IDEAYA Biosciences Announces Proffered Paper Oral Presentation at ESMO 2025 for Phase 2 Clinical Trial of Neoadjuvant Darovasertib in Primary Uveal Melanoma (PRNewswire) - "IDEAYA Biosciences...announced that results from a multi-site global Phase 2 study of neoadjuvant darovasertib in primary uveal melanoma was accepted for a Proffered Paper oral presentation at the 2025 European Society of Medical Oncology (ESMO) meeting....A summary of the data from the abstract will be shared at a future date....The presentation will include data from over 90 patients in both the plaque brachytherapy and enucleation-eligible cohorts....Initiated a multi-site, global randomized Phase 3 neoadjuvant registrational trial in primary uveal melanoma (OptimUM-10) in Q3 2025."

P2 data • Trial status • Uveal Melanoma

A uveal melanoma murine model which faithfully recapitulates organotropism and dormancy (EACR 2025) - "Additionally, this model enables in vivo studies of candidate targeted drug treatments such as the PKC inhibitor darovasertib, currently in clinical trial... This model faithfully represents a unique opportunity to dissect the pathways that lead to UM hepatotropism and an extrahepatic dormancy-like phenotype as well as the opportunity of developing more effective therapeutic options in order to improve patient outcomes."

Preclinical • Eye Cancer • Melanoma • Oncology • Solid Tumor • Uveal Melanoma

A Brief Overview of Uveal Melanoma Treatment Methods with a Focus on the Latest Advances. (PubMed, J Clin Med) - "This localized approach may provide significant benefit for patients with limited extrahepatic spread. Future research should focus on optimizing these novel strategies-tebentafusp, darovasertib, melphalan, and combination therapies-and on expanding our understanding of UM's molecular drivers to enable the development of more effective, personalized treatments."

Journal • Eye Cancer • Melanoma • Oncology • Solid Tumor • Uveal Melanoma • GNA11 • GNAQ

Neoadjuvant Darovasertib in Primary Uveal Melanoma (clinicaltrials.gov) - P3 | N=520 | Not yet recruiting | Sponsor: IDEAYA Biosciences

New P3 trial • Eye Cancer • Melanoma • Oncology • Solid Tumor • Uveal Melanoma

IDEAYA Biosciences, Inc. Reports First Quarter 2025 Financial Results and Provides Business Update (PRNewswire) - "Commencement of the Phase 3 registration-enabling trial for darovasertib in neoadjuvant UM is targeted for the first half of 2025....Two clinical updates from the Company-sponsored Phase 2 trial targeted at medical conferences in mid-2025 and the second half of 2025. The mid-2025 update will be focused on vision data and the plaque brachytherapy patients, and the update in second half of 2025 will include over 90 UM patients from both the enucleation and plaque brachytherapy eligible cohorts."

Clinical data • New P3 trial • Uveal Melanoma

IDEAYA Biosciences, Inc. Reports First Quarter 2025 Financial Results and Provides Business Update (PRNewswire) - "Median progression-free survival (PFS) readout for Phase 2/3 registration-enabling trial of the darovasertib and crizotinib combination in 1L HLA-A2-negative MUM targeted by year-end 2025. Rapid enrollment in the trial continues with over 300 patients as of May 5, 2025. Phase 2 median overall survival (OS) readout from study IDE196-001 in over 40 1L MUM patients targeted at a medical conference in the second half of 2025. The readout will include both 1L HLA-A2-negative and HLA-A2-positive MUM patients. We continue to enroll additional HLA-A2-positive MUM patients in the IDE196-001 trial."

P1/2 data • P2/3 data • Uveal Melanoma

Unveiling epigenetic mechanisms driving RasGRP3 upregulation via oncogenic Gαq signaling in uveal melanoma (AACR 2025) - "Treatment of UM cells with the Gαq inhibitor YM-254890 (YM) or the PKC inhibitor LXS-196 (LXS) for 24 hours significantly reduced all three histone modifications (H3K4me3, H3K27ac, H3K4me1) at the RasGRP3 locus. Ongoing investigations aim to delineate the precise mechanisms by which Gαq signaling drives these epigenetic changes. Our results highlight the potential of targeting specific histone modifiers as a novel therapeutic strategy for UM treatment."

Cutaneous Melanoma • Eye Cancer • Melanoma • Oncology • Solid Tumor • Uveal Melanoma • GNA11 • GNAQ

IDEAYA Biosciences Announces Successful FDA Type D Meeting on Phase 3 Registrational Trial Design for Darovasertib as Neoadjuvant Therapy for Primary Uveal Melanoma (PRNewswire) - "IDEAYA Biosciences...announced a successful FDA Type D meeting on the Phase 3 registrational trial design that will assess the safety and efficacy of darovasertib for potential regulatory approval as neoadjuvant therapy for primary uveal melanoma (UM)....'The successful FDA Type D meeting provides darovasertib a registrational path as neoadjuvant therapy for UM, using primary clinical endpoints of eye preservation and proportion of patients with vision loss, with no detriment to EFS as a secondary endpoint required for both cohorts'....Key highlights of the Phase 3 registrational trial design in neoadjuvant UM, based on FDA guidance: Proportion of patients with vision loss from the time of randomization and time of completion of PB is the primary endpoint for the plaque brachytherapy cohort. Vision detriment will be measured by the Early Treatment Diabetic Retinopathy Study (ETDRS) Best-Corrected Visual Acuity (BCVA) of >15-letters lost."

Clinical protocol • FDA event • Uveal Melanoma

IDEAYA Biosciences Receives US FDA Breakthrough Therapy Designation for Darovasertib Monotherapy in Neoadjuvant Uveal Melanoma (PRNewswire) - "IDEAYA Biosciences...today announced that the U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy designation (BTD) for darovasertib, a potential first-in-class protein kinase C (PKC) inhibitor, for the neoadjuvant treatment of adult patients with primary uveal melanoma (UM) for whom enucleation has been recommended....The BTD application was supported by updated interim clinical data from an ongoing Phase 2 open-label trial (NCT05907954) evaluating darovasertib monotherapy in the neoadjuvant setting for localized UM....The Company also intends to initiate a Phase 3 randomized registrational trial in neoadjuvant UM in the first half of 2025."

Breakthrough therapy • New P3 trial • Uveal Melanoma