Neoadjuvant Darovasertib Receives FDA Breakthrough Therapy Designation for Uveal Melanoma

Uveal Melanoma | Image Credit:
© Sebastian Kaulitzki – stock.adobe.com

The FDA has granted breakthrough therapy designation to neoadjuvant darovasertib (IDE196) monotherapy for the treatment of adult patients with uveal melanoma.1

The breakthrough therapy designation application was supported by updated interim findings from an ongoing, open-label, company-sponsored phase 2 IDE196-009 trial (NCT05907954) investigating the agent as monotherapy in the neoadjuvant setting in patients with localized uveal melanoma. Investigators plan to present updated data from this trial at medical meetings in mid-2025 and the second half of 2025, Yujiro S. Hata, president and chief executive officer of IDEAYA Biosciences—the developer of darovasertib—stated in a news release. Updated data that were submitted as part of the breakthrough therapy designation and are pending presentation include efficacy, safety, eye preservation, vision preservation/improvement during treatment, and radiation reduction.

Darovasertib is a potential first-in-class PKC inhibitor. The IDE196-009 trial, which had an enrollment cutoff date of May 13, 2024, included patients with primary localized uveal melanoma who required either enucleation (cohort 1) or plaque brachytherapy (cohort 2), had an ECOG performance status of 0 or 1, had adequate organ function, and did not have any other significant underlying ocular disease.2,3 Patients in this trial receive neoadjuvant treatment with darovasertib for up to 6 months or maximum benefit, followed by subsequent primary local therapy.2 Thereafter, patients receive an additional 6 months of adjuvant treatment followed by long-term follow-up for a maximum of 3 years.

Primary end points of the IDE196-009 trial include the incidence of adverse effects (AEs) and significant laboratory abnormalities in all patients, as well as the number of patients who convert from requiring enucleation to radiation (cohort 1) and the estimated change in modeled radiation dose (cohort 2). Secondary end points include tumor response to neoadjuvant darovasertib, assessment of visual acuity loss, rate of local disease recurrence, and rate of metastatic disease. Overall survival is an additional end point.

Interim data from the IDE196-009 trial had a data cutoff date of August 15, 2024. Combined findings from the IDE196-009 trial and the investigator-sponsored phase 2 NADOM trial (NCT05187884) showed that among 49 evaluable patients who received neoadjuvant darovasertib (enucleation population, n = 31; plaque brachytherapy population, n = 18), approximately 49% achieved 30% or greater tumor shrinkage, and approximately 59% achieved 20% or greater tumor shrinkage.3 Additionally, the eye preservation rate for patients in cohort 1 was approximately 61%. Evidence of visual preservation was also noted through the reduction of the amount of radiation associated with plaque brachytherapy.

Additionally, the IDE196-009 trial showed that darovasertib had a manageable AE profile among 38 evaluable patients. The respective rates of grade 3 or higher AEs, serious AEs, and treatment discontinuation were 11%, 5%, and 3%, respectively. The most frequently observed AEs were nausea, diarrhea, fatigue, and vomiting.

"We are pleased to receive FDA breakthrough therapy designation as we prepare to advance neoadjuvant darovasertib into a potential phase 3 registrational trial in patients with primary uveal melanoma,” Darrin Beaupre, MD, PhD, chief medical officer of IDEAYA Biosciences, added in the news release.1 “This designation highlights the potential of [darovasertib monotherapy] in a patient population with significant unmet medical need where there are currently no FDA-approved systemic therapies."

The phase 3 trial is planned to launch in the first half of 2025, according to the news release, and would examine neoadjuvant darovasertib in patients with primary uveal melanoma who are not eligible for enucleation (cohort 1) or plaque brachytherapy (cohort 2).

Notably, this breakthrough therapy designation follows the December 2022 FDA fast track designation that was granted to darovasertib plus crizotinib (Xalkori) for adult patients with metastatic uveal melanoma.4

Earlier, in May 2022, the FDA granted orphan drug designation to darovasertib for the treatment of patients with uveal melanoma, including metastatic uveal melanoma.5

References

1. IDEAYA Biosciences receives US FDA breakthrough therapy designation for darovasertib monotherapy in neoadjuvant uveal melanoma. News release. IDEAYA Biosciences, Inc. March 31, 2025. Accessed April 3, 2025. https://ir.ideayabio.com/2025-03-31-IDEAYA-Biosciences-Receives-US-FDA-Breakthrough-Therapy-Designation-for-Darovasertib-Monotherapy-in-Neoadjuvant-Uveal-Melanoma
2. (Neo)adjuvant IDE196 (darovasertib) in patients with localized ocular melanoma. ClinicalTrials.gov. Updated October 28, 2024. Accessed April 3, 2025. https://www.clinicaltrials.gov/study/NCT05907954
3. IDEAYA Biosciences announces positive interim phase 2 data for darovasertib and successful FDA Type C meeting on registrational trial design for regulatory approval in neoadjuvant uveal melanoma. News release. IDEAYA Biosciences, Inc. September 23, 2024. Accessed April 3, 2025. https://ir.ideayabio.com/2024-09-23-IDEAYA-Biosciences-Announces-Positive-Interim-Phase-2-Data-for-Darovasertib-and-Successful-FDA-Type-C-Meeting-on-Registrational-Trial-Design-for-Regulatory-Approval-in-Neoadjuvant-Uveal-Melanoma
4. IDEAYA Biosciences receives fast track designation for darovasertib combination therapy with crizotinib for the treatment of metastatic uveal melanoma. News release. IDEAYA Biosciences, Inc. December 5, 2022. Accessed April 3, 2025. https://ir.ideayabio.com/2022-12-05-IDEAYA-Biosciences-Receives-Fast-Track-Designation-for-Darovasertib-Combination-Therapy-with-Crizotinib-for-the-Treatment-of-Metastatic-Uveal-Melanoma
5. IDEAYA Biosciences receives orphan drug designation for darovasertib, a PKC inhibitor, for the treatment of uveal melanoma. News release. IDEAYA Biosciences, Inc. May 2, 2022. Accessed April 3, 2025. https://ir.ideayabio.com/2022-05-02-IDEAYA-Biosciences-Receives-Orphan-Drug-Designation-for-Darovasertib,-a-PKC-Inhibitor,-for-the-Treatment-of-Uveal-Melanoma