On September 23, 2024 IDEAYA Biosciences, Inc. (the "Company") reported interim clinical data for darovasertib in neoadjuvant uveal melanoma ("UM") from the Company’s ongoing company-sponsored Phase 2 trial and guidance from the U.S. Food and Drug Administration ("FDA") in a Type C meeting, which the Company believes supports the initiation of a potential registration-enabling Phase 3 randomized clinical trial in neoadjuvant UM patients (Press release, Ideaya Biosciences, SEP 23, 2024, View Source [SID1234646819]).
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Darovasertib is a potent and selective protein kinase C ("PKC") inhibitor being developed to broadly address primary and metastatic UM. Darovasertib is currently being evaluated in four ongoing clinical trials, two of which are in collaboration with Pfizer. The darovasertib and crizotinib combination in metastatic uveal melanoma ("MUM") has FDA Fast Track designation. IDE196-009 (NCT05907954) is a company-sponsored Phase 2 trial evaluating darovasertib as neoadjuvant treatment for UM prior to primary interventional treatment of enucleation or radiation therapy, and as adjuvant therapy following the primary treatment. In addition, there is an investigator-sponsored trial ("IST"), NCT05187884, evaluating darovasertib as a neoadjuvant UM treatment.
The Phase 2 darovasertib data in neoadjuvant UM demonstrated encouraging clinical activity. Collectively with the IST trial, the clinical efficacy data from the Phase 2 company-sponsored trial substantiate clinical proof of concept for the use of darovasertib in the neoadjuvant uveal melanoma setting. For the Phase 2 company-sponsored trial, the data cutoff date is August 15, 2024, with an enrollment cut-off of May 13, 2024.
The Company evaluated 31 enucleation and 18 plaque brachytherapy UM patients who were treated with darovasertib neoadjuvant therapy in the Phase 2 company-sponsored and IST trials. The Company observed approximately 59%, or 29 of the 49 total evaluable patients, with greater than or equal to 20% ocular tumor shrinkage by product of diameters and approximately 49%, or 24 of the 49 total evaluable patients, with greater than or equal to 30% ocular tumor shrinkage by product of diameters. The Company also observed an approximately 61% eye preservation rate in enucleation patients. The Company found evidence of visual preservation by reducing the amount of radiation associated with plaque brachytherapy.
The Company observed manageable adverse event ("AE") profile from the Phase 2 company-sponsored trial. In 38 patients, 11% of patients experienced a Grade 3 or higher AE and 5% of patients experienced a serious AE rate. The Company observed a discontinuation rate of 3%. The most common AEs observed included diarrhea, nausea, vomiting and fatigue.
The Company’s ocular oncology advisory board recommended product of diameters for tumor measurement to determine overall response rate ("ORR") criteria in ocular melanoma. In the Phase 2 trial with darovasertib, a greater than or equal to 20% ocular tumor shrinkage by product of diameters correlates to clinical benefit, including eye sparing for enucleation UM patients and visual preservation for plaque brachytherapy UM patients.
In the Phase 3 clinical trial, the Company currently projects approximately 400 patients will be randomized for treatment with darovasertib in the treatment arm or the control arm, with potential modifications pending further feedback from the FDA. Based on the currently targeted clinical trial design, there will be two cohorts enrolled, including enucleation eligible UM patients and plaque brachytherapy eligible UM patients. For the enucleation cohort, the randomization will be with or without darovasertib as neoadjuvant therapy. For the plaque brachytherapy cohort, the randomization will be darovasertib followed by plaque brachytherapy versus plaque brachytherapy alone.
Based on FDA guidance and information provided in the Company’s FDA briefing book, the Company expects that eye preservation rate will be the primary endpoint for enucleation UM patients for the target registrational trial design in neoadjuvant UM. The FDA briefing book noted an objective to exceed lower bound of 10% eye preservation rate with a 95% confidence interval for this primary endpoint. Time to vision loss will be the primary endpoint for plaque brachytherapy UM patients. No detriment to Event-Free-Survival ("EFS") in the treatment arms will be a secondary endpoint.
Pending ongoing discussions with the FDA, the Company currently expects that ORR will be included as a potential surrogate and composite endpoint to support earlier approval scenarios. The FDA briefing book noted that a greater than or equal to 20% ocular tumor shrinkage by product of diameters correlates to clinical benefit in the ongoing Phase 2 clinical study, including eye sparing for enucleation UM patients and visual preservation for plaque brachytherapy UM patients. The registrational study will enroll UM patients with a high risk for metastatic disease. Based on the FDA meeting, there is a potential for consideration of a broad indication label in neoadjuvant UM for subjects with low, intermediate and high risk for metastatic disease. The Company anticipates approximately two years of data maturity to initial readout for no detriment to EFS in the treatment arms for this high-risk patient population based on preliminary projections. 300mg BID darovasertib was noted in the FDA briefing book as the move-forward dose for the registrational trial.
Neoadjuvant UM represents a significant expansion opportunity for darovasertib, with a potential annual incidence of approximately 12,000 patients aggregate in North America, Europe, and Australia. The Company owns or controls all commercial rights in darovasertib, including in MUM and in UM, subject to certain economic obligations pursuant to its exclusive, worldwide license with Novartis.