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

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

IDEAYA Biosciences, Inc. Reports Fourth Quarter and Full Year 2024 Financial Results and Provides Business Update (PRNewswire) - "Initiation of the Phase 3 registration-enabling trial for darovasertib in neoadjuvant UM is targeted for the first half of 2025...Targeting Phase 1/2 expansion in the first quarter of 2025 and clinical data update for IDE397 in combination with Trodelvy in MTAP-deletion UC in 2025...IDEAYA and Amgen mutually agreed to wind down the IDE397 and AMG 193 clinical combination study in February 2025, and will not pursue dose expansion...IDEAYA plans to submit a U.S. IND for the evaluation of IDE849 as a monotherapy in SCLC in the first half of 2025. Targeting to initiate the evaluation in combination with IDE161 and in NETs in the second half of 2025. Clinical data update targeted in 2025."

Clinical data • IND • New trial • Trial completion • Neuroendocrine Tumor • Small Cell Lung Cancer • Urothelial Cancer • Uveal Melanoma

Orphan Drug Designations and Approvals (FDA) - Generic Name: darovasertib, Date Designated: 04/27/2022, Orphan Designation: Treatment of Uveal Melanoma, Orphan Designation Status: Designated

Orphan drug • Uveal Melanoma

IDEAYA Biosciences Announces Participation at the 43rd Annual J.P. Morgan Healthcare Conference and 2025 Corporate Guidance (PRNewswire) - "Median progression free survival readout for potential Phase 2/3 registration-enabling trial of the darovasertib and crizotinib combination in first-line (1L) patients with HLA-A2-negative MUM targeted by year-end 2025, pending enrollment status and data maturity. Enrollment has exceeded over 200 patients as of January 6, 2025; Phase 2 1L MUM median overall survival readout for the darovasertib and crizotinib combination in approximately 38 1L MUM patients targeted in 2025; Targeting Phase 2 neoadjuvant UM clinical data update for darovasertib in over 75 patients and a regulatory update in 2025..."

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

IDEAYA Announces IDMC Recommendation of Move-Forward Dose in Part 2a of Registration-Enabling Trial of Darovasertib and Crizotinib Combination in 1L HLA-A2-Negative Metastatic Uveal Melanoma (PRNewswire) - "IDEAYA Biosciences, Inc...announced the Independent Data Monitoring Committee (IDMC) recommendation of a move-forward dose and the completion of the Part 2a dose optimization consistent with the U.S. Food and Drug Administration's (FDA) Project Optimus guidelines for the potential registration-enabling Phase 2/3 trial evaluating the combination of darovasertib and crizotinib in the first-line (1L) setting in patients with HLA-A2-negative (HLA-A2(-)) metastatic uveal melanoma (MUM)....'This allows us to complete the Part 2a portion of the study and seamlessly continue to enroll in Part 2b towards a potential accelerated approval based on the primary endpoint of median progression free survival'...IDEAYA is also finalizing a clinical trial protocol and is targeting to initiate a potential Phase 3 registration-enabling study for neoadjuvant uveal melanoma patients in the first half of 2025."

DSMB • New P3 trial • Uveal Melanoma

IDE196 (darovasertib) in combination with crizotinib versus investigator's choice of treatment as first-line therapy in HLA-A2 negative metastatic uveal melanoma (ESMO 2024) - P2/3 | "The purpose of this study is to determine clinical and safety outcomes of IDE196 in combination with crizotinib in adult participants with HLA-A2 negative MUM.Trial design: Study IDE196-002 (NCT05987332) is a phase II/3, multi-arm, multi-stage, multicenter, global, open-label study for first-line therapy for HLA-A*02:01 negative patients with MUM who will be randomized to receive either IDE196 + crizotinib or investigator's choice of treatment (ipilimumab + nivolumab, pembrolizumab or dacarbazine). Secondary endpoints include ORR, disease control rate (DCR), safety and pharmacokinetics parameters. The primary endpoint of the phase III portion is to compare IDE196 + crizotinib to investigator's choice of treatment with respect to overall survival (OS)."

Clinical • Combination therapy • Metastases • Eye Cancer • Melanoma • Mucosal Melanoma • Oncology • Solid Tumor • Uveal Melanoma • GNA11 • GNAQ • HLA-A

MUM: Study of IDE196 in Patients with Solid Tumors Harboring GNAQ/11 Mutations or PRKC Fusions (clinicaltrials.gov) - P1/2 | N=341 | Recruiting | Sponsor: IDEAYA Biosciences | Trial completion date: May 2025 ➔ Mar 2027 | Trial primary completion date: Oct 2024 ➔ Dec 2026

Trial completion date • Trial primary completion date • Colorectal Cancer • Cutaneous Melanoma • Eye Cancer • Melanoma • Oncology • Solid Tumor • Uveal Melanoma

IDEAYA Biosciences, Inc. Reports Third Quarter 2024 Financial Results and Provides Business Update (PRNewswire) - "Darovasertib in 1L MUM and Neoadjuvant Uveal Melanoma (UM): Enrollment in darovasertib + crizotinib 1L HLA-A2+ MUM potential Ph2/3 registration-enabling trial is ahead of schedule and has exceeded 150 patients....Following a successful Type C meeting with the U.S. Food and Drug Administration (FDA), IDEAYA is finalizing the Phase 3 registrational trial protocol and is targeting to initiate its potential registration-enabling trial in the first half of 2025. IDE397 in MTAP-Deletion Solid Tumors: Enrollment is ongoing in the IDE397 and AMG 193 Phase 1 dose escalation, and targeting expansion in NSCLC in late 2024 to early 2025. Ongoing Phase 1 trial evaluating IDE397 in combination with Trodelvy in MTAP-deletion UC; targeting combination expansion in the fourth quarter of 2024."

Trial status • Non Small Cell Lung Cancer • Urothelial Cancer • Uveal Melanoma

Darovasertib: “Darovasertib neoadjuvant treatment in Ph2 trials demonstrates robust clinical efficacy and manageable AE profile, including ~82% of UM patients with ocular tumor shrinkage and ~61% eye preservation rate”; Uveal melanoma (IDEAYA Biosciences) - Darovasertib Neoadjuvant Uveal Melanoma Clinical Program Update: “Darovasertib neoadjuvant therapy: Ph2 company sponsored and Ph2 IST UM trials”

P2 data • Oncology • Uveal Melanoma

FDA Guidance in Type C Meeting supports Initiation of Potential Registrational Trial (PRNewswire) - "IDEAYA is targeting to initiate a potential registration-enabling Phase 3 randomized clinical trial in neoadjuvant UM patients following finalization of the clinical protocol with the FDA. The randomized Phase 3 clinical trial design incorporates guidance and feedback from the U.S. FDA following a recent Type C meeting. In the Phase 3 clinical trial, we currently project approximately 400 patients will be randomized for treatment with darovasertib in the treatment arm or the control arm, with potential modifications pending further FDA feedback....Based on FDA meeting, potential for consideration of broad indication label in neoadjuvant UM for subjects with low, intermediate and high risk for metastatic disease; 300mg BID darovasertib noted in FDA briefing book as the move-forward dose for registrational trial."

FDA event • Eye Cancer • Ocular Melanoma • Oncology • Solid Tumor • Uveal Melanoma

Phase 2 Clinical Data Update – Darovasertib in Neoadjuvant UM (PRNewswire) - P2 | N=82 | NCT05907954 | Sponsor: IDEAYA Biosciences | "The company observed further evidence of encouraging clinical activity from an ongoing company-sponsored Phase 2 trial (NCT05907954) evaluating darovasertib in neoadjuvant uveal melanoma....31 enucleation and 18 plaque brachytherapy evaluable UM patients treated with darovasertib neoadjuvant therapy in Phase 2 company-sponsored and IST trials; ~59% (29 of 49) of patients with >20% ocular tumor shrinkage by product of diameters; ~49% (24 of 49) of patients with >30% ocular tumor shrinkage by product of diameters; ~61% (19 of 31) eye preservation rate observed; Evidence of visual preservation observed by reducing the amount of radiation associated with plaque brachytherapy."

P2 data • Eye Cancer • Ocular Melanoma • Oncology • Solid Tumor • Uveal Melanoma

IDEAYA Announces Webcast to Report Interim Phase 2 Data for Darovasertib and Regulatory Update from FDA Type C Meeting in Neoadjuvant Uveal Melanoma on Monday, September 23, 2024 (PRNewswire) - "IDEAYA Biosciences...announced that the company plans to issue a pre-market press release and conduct an investor webcast on Monday, September 23, 2024, at 8:00 a.m. ET to report interim Phase 2 data for darovasertib and provide a regulatory update from FDA Type C meeting in neoadjuvant uveal melanoma (UM)....The investor webcast presentation agenda to review the interim Phase 2 clinical data and regulatory update for darovasertib in neoadjuvant UM will be the following: (i) Market introduction: annual incidence of UM; (ii) Registrational trial design based on FDA Type C meeting guidance; (iii) Phase 2 clinical data update - Baseline characteristics; AE profile; Clinical efficacy from Phase 2 company-sponsored and IST."

FDA event • P2 data • Uveal Melanoma

IDEAYA Biosciences, Inc. Reports Second Quarter 2024 Financial Results and Provides Business Update (PRNewswire) - "IDE196-009 (NCT05907954) is a company-sponsored Phase 2 trial evaluating darovasertib as neoadjuvant treatment of UM prior to primary interventional treatment of enucleation or radiation therapy, and as adjuvant therapy following the primary treatment....The trial has enrolled over 50 patients in 20 sites globally, as of July 31, 2024. An amendment to the study protocol was submitted to the FDA in July 2024 to enable dosing of darovasertib as neoadjuvant and adjuvant therapy up to 12 months each. As part of this amendment the number of patients in the study was increased from 82 to 122 patients...Additional clinical efficacy update from the company-sponsored Phase 2 of darovasertib neoadjuvant UM trial in over 30 patients is anticipated in the second half of 2024....IDEAYA has scheduled a Type C meeting with the FDA in the third quarter of 2024 to discuss a potential registrational trial for darovasertib in the neoadjuvant UM setting."

FDA event • P2 data • Trial status • Eye Cancer • Ocular Melanoma • Oncology • Solid Tumor • Uveal Melanoma

The Current State of Systemic Therapy of Metastatic Uveal Melanoma. (PubMed, Am J Clin Dermatol) - "Notably, tebentafusp, an entirely novel class of anti-cancer drugs, has received official authorization for the treatment of metastatic UM. Further, promising data from targeted therapies independent of MEK-inhibitors, such as the combination of darovasertib and crizotinib, raise hope for additional options in metastatic UM in the future. This narrative review provides a timely and comprehensive overview of the current treatment landscape for metastatic UM."

Journal • Metastases • Tumor mutational burden • Cutaneous Melanoma • Eye Cancer • Gastrointestinal Cancer • Hepatocellular Cancer • Melanoma • Oncology • Solid Tumor • Uveal Melanoma • HLA-A • TMB

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

Darovasertib: “NADOM provides the first prospective evidence that a neoadjuvant treatment strategy in UM is feasible, tolerable and safe”; Ocular melanoma (IDEAYA Biosciences) - ASCO 2024: “Protein Kinase C inhibition with darovasertib can induce tumor shrinkage and facilitate eye preservation in suitable patients”

P2 data • Ocular Melanoma • Oncology

IDEAYA Announces Results for Darovasertib Phase 2 IST in Neoadjuvant Uveal Melanoma at ASCO and Clinical Update for Phase 2 Company-Sponsored Neoadjuvant Study (PRNewswire) - P2 | N=15 | NADOM (NCT05187884) | "As of May 14, 2024, 75% (9 out of 12 enucleation patients) had confirmed Eye Saved (i.e., converted to plaque brachytherapy or EBRT) and approximately 67% (8 out of 12 enucleation patients) observed greater than 30% tumor shrinkage (maximum volume change) after 6 months. Median tumor shrinkage (maximum volume change) in 12 enucleation patients was approximately 47% after 6 months....The darovasertib monotherapy neoadjuvant treatment had a manageable adverse event (AE) profile with no drug-related serious adverse events observed....The Company is targeting a Type C meeting with the FDA to discuss a potential registrational trial for darovasertib in the neoadjuvant UM setting and a clinical efficacy update from its Phase 2 company-sponsored darovasertib neoadjuvant UM trial in H2 2024."

FDA event • P2 data • Uveal Melanoma

IDEAYA Biosciences Announces Abstract Summary Results of ASCO 2024 Oral Presentation for Phase 2 Investigator Sponsored Study of Darovasertib in Neoadjuvant Uveal Melanoma (PRNewswire) - P2 | N=15 | NADOM (NCT05187884) | "IDEAYA Biosciences...announced the publication of the abstract for an oral presentation of preliminary clinical results from its investigator-sponsored Phase 2 trial of darovasertib, a first-in-class oral, small molecular inhibitor of protein kinase C (PKC), as neoadjuvant/adjuvant treatment in uveal melanoma (UM) at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting...In summary, 15 patients planned for enucleation with localized UM were treated with darovasertib 300mg twice daily...As of the database lock, 11 patients had completed primary treatment, four remained on neoadjuvant treatment, and six patients received adjuvant darovasertib after primary treatment of their UM with three patients completing the planned six months. At that time, approximately 67% (6 of 9 patients) had confirmed Eye Saved (i.e., converted to plaque brachytherapy or EBRT). Median tumor shrinkage (maximum volume change) was approximately 45%..."

P2 data • Eye Cancer • Oncology • Solid Tumor • Uveal Melanoma

IDEAYA Biosciences, Inc. Reports First Quarter 2024 Financial Results and Provides Business Update (PRNewswire) - "Phase 2 trials of darovasertib as neoadjuvant / adjuvant therapy in primary UM: IDE196-009 (NCT05907954) is a company-sponsored Phase 2 trial evaluating darovasertib as neoadjuvant treatment of UM prior to primary interventional treatment of enucleation or radiation therapy, and as adjuvant therapy following the primary treatment. A clinical efficacy update on over 30 patients and an FDA regulatory guidance update are both targeted in the second half of 2024. NADOM (NCT05187884) is a Phase 2 neoadjuvant / adjuvant trial of darovasertib in ocular melanoma....The interim results from the trial have been accepted for an oral presentation at the upcoming 2024 ASCO annual meeting on June 3, 2024."

FDA event • P2 data • Eye Cancer • Ocular Melanoma • Oncology • Solid Tumor • Uveal Melanoma

IDEAYA Biosciences Announces ASCO 2024 Oral Presentation for Darovasertib in Neoadjuvant Uveal Melanoma Phase 2 Investigator Sponsored Study (PRNewswire) - "IDEAYA Biosciences, Inc...announced that interim results from the investigator-sponsored Phase 2 trial evaluating darovasertib safety and efficacy as neoadjuvant/adjuvant treatment in uveal melanoma (UM) have been selected for an oral presentation at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting taking place May 31-June 4, 2024 in Chicago, Illinois."

P2 data • Eye Cancer • Melanoma • Ocular Melanoma • Oncology • Skin Cancer • Solid Tumor • Uveal Melanoma

PKC-independent PI3K signalling diminishes PKC inhibitor sensitivity in uveal melanoma. (PubMed, Oncogenesis) - "We examined the transcriptome of UM biopsies collected pre- and post-PKC inhibitor therapy and confirmed that MAPK, but not PI3K/AKT signalling, was inhibited early during treatment with the second-generation PKC inhibitor IDE196...We also show that re-activation of MAPK signalling has a dominant role in regulating PKC inhibitor responses in UM and that PI3K/AKT signalling diminishes UM cell sensitivity to PKC inhibitor monotherapy. Thus, combination therapies targeting PKC and PKC-independent signalling nodes, including PI3K/AKT activity, are required to improve responses in patients with metastatic UM."

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

IDEAYA Biosciences, Inc. Reports Fourth Quarter and Full-Year 2023 Financial Results and Provides Business Update (PRNewswire) - "IDE196-002: Phase 2/3 Potential Registration-Enabling Clinical Trial of Darovasertib + Crizotinib combination in First-Line HLA-A2*02:01(-) MUM....The company has several clinical sites open and is targeting to open an aggregate of over 50 clinical sites across U.S., Canada, Europe and Australia to support this registrational study. Clinical program update(s) are anticipated in 2024....As of February 1, 2024, double digit patients have been dosed with several sites open and actively recruiting additional patients into the company-sponsored Phase 2 clinical trial. Two independent clinical efficacy updates for darovasertib in neoadjuvant UM are anticipated in mid-2024, including from the Phase 2 IST study and IDEAYA's Phase 2 company-sponsored study. A regulatory guidance update is planned in 2024."

P2 data • P2/3 data • Regulatory • Trial status • Eye Cancer • Ocular Melanoma • Oncology • Solid Tumor • Uveal Melanoma

Discovery of Darovasertib (NVP-LXS196), a Pan-PKC Inhibitor for the Treatment of Metastatic Uveal Melanoma. (PubMed, J Med Chem) - "The lead series was optimized for kinase and off target selectivity to afford a compound that is rapidly absorbed and well tolerated in preclinical species. LXS196 is being investigated in the clinic as a monotherapy and in combination with other agents for the treatment of uveal melanoma (UM), including primary UM and metastatic uveal melanoma (MUM)."

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