FDA Type C Meeting Shows Clinical Activity of Darovasertib/Crizotinib in MUM


Promising results from a type C meeting with the FDA has led to a phase 2/3 trial of darovasertib and crizotinib being initiated in 2023 for patients with first-line HLA-A2 negative metastatic uveal melanoma.

During a successful type C meeting with the FDA, interim phase 2 study (NCT03947385) results showed promising safety and efficacy in patients with metastatic uveal melanoma (MUM) when treated with the combination of darovasertib (IDE196) and crizotinib (Xalkori).1

Findings showed that among the 20 evaluable patients with first-line MUM, there was a confirmed overall response rate (ORR) of 45%, disease control rate (DCR) of 90%, and median progression-free survival (PFS) of 7 months. Among the 63 evaluable any-line patients, the confirmed ORR was 30%, DCR was 87%, and the median PFS was 7 months. The 20 patients with hepatic-only MUM had an ORR of 35%, DCR of 100%, and median PFS of 11 months.

Based on the conclusions of the FDA meeting, a phase 2/3 registrational trial will be initiated in 2023 in first-line HLA-A2 negative MUM.

"The observed efficacy in first-line metastatic uveal melanoma patients – including confirmed ORR of 45% and median PFS of 7 months – is clinically significant and represents a potential paradigm shift for treating MUM patients.The interim data for the darovasertib and crizotinib combination treatment in MUM suggests a compelling clinical efficacy and tolerability profile," said Meredith McKean, MD, MPH, director, Melanoma and Skin Cancer Research at Sarah Cannon Research Institute, in the press release.

Historically, patients with MUM have had low ORR and median PFS rates, typically ranging from 0%-5% for the confirmed ORR and 2-3 months for the median PFS. There are also no FDA approved treatments currently available for patients with MUM with an HLA-A2-negative serotype.

Darovasertib is a small molecule, potential first-in-class protein kinase C (PKC) inhibitor that is being evaluated in synthetic lethal combination with crizotinib, a small molecule cMET inhibitor, among patients with MUM.

The phase 2 clinical trial included 20 evaluable first-line patients with MUM and 63 evaluable any-line patients in the darovasertib and crizotinib combination study at the expansion dose of darovasertib 300 mg 2 times a day, and crizotinib 200 mg, also 2 times a day.2

Primary end points of the study included dose-limiting toxicities, maximum-tolerated dose, recommended phase 2 dose, ORR, DOR, and pharmacokinetics. Secondary end points were ORR, DOR, safety, DCR, and pharmacodynamics, with other end points of PFS, overall survival, reduction in tumor burden by total volumetric measurement, treatment-related gene signatures and/or molecular profiling, and treatment-related changes in tumor tissue or cell-free DNA from blood.

Reported data are preliminary and based on investigator review from an unlocked database as of the data analyzed cutoff date of March 8, 2023. Enrollment in the darovasertib and crizotinib combination expansion dose cohort of the Phase 2 clinical trial is ongoing.1

In the study, darovasertib with crizotinib showed robust clinical efficacy in first-line and any-line patients with MUM. The combination of darovasertib and crizotinib also led to a manageable adverse event profile among 68 patients with MUM, with a low rate of drug-related serious adverse events (AEs).

Drug-related AEs were predominantly grade 1 or 2, and 31% of patients reported at least 1 grade 3 AE. While no patients had a grade 4 AE, there was 1 patient who had a grade 5 AE. Further, treatment was discontinued in 4 (6%) patients due to a drug-related AE.

"These clinical data, considered with the FDA's guidance from our recent Type C meeting, provides IDEAYA with a registrational trial design in first-line HLA-A2 negative [patients with] MUM which includes a path to potential accelerated approval based on median PFS as the primary end point," said Darrin Beaupre, MD, PhD, chief medical officer, IDEAYA Biosciences, in the press release.

Following the Type C meeting with the FDA, the company plans to begin an open-label phase 2/3 clinical trial of the combination in first-line HLA-A2-negative patients with MUM patients.In the phase 2 portion of the trial, the primary end point will be median PFS. Those enrolled in this phase will also continue on treatment within the same clinical trial and will be considered together with additional enrolled patients to assess OS in support of a potential phase 3 registrational trial.

This phase 2 portion plans to randomize approximately 230 patients in a 2:1 ratio to receive treatment with darovasertib plus crizotinib in the treatment arm or investigators choice in the control arm. The investigator's choice will be selected from a combination of ipilimumab (Yervoy) and nivolumab (Opdivo).

In the treatment arm, investigators aim to confirm the move forward combination dose for the integrated phase 2/3 clinical trial. This will include cohorts at the phase 2 expansion doses of darovasertib 300 mg twice daily plus crizotinib 200 mg twice daily, and darovasertib 200 mg twice daily with crizotinib 200 mg twice daily. This nested study design will include the enrolled patients at the move forward dose within the phase 2/3 registrational trial.

Further, the phase 2 portion will observe an efficacy and safety data set consisting of approximately 200 patients who are randomized 2:1 with the treatment arm at the move forward dose to support a potential accelerated approval based on median PFS. Those enrolled in phase 2 of the study at the selected dose would continue on treatment and be included in the phase 3 study analysis.

Approximately 120 additional patients will be enrolled into the phase 3 part of the clinical trial with 2:1 randomization on the same basis as the phase 2 portion. Utilizing the efficacy data from this phase 3 could help support the potential approval of the combination, using the median PFS as a primary end point.

Further evidence of encouraging clinical activity for treatment with darovasertib as neoadjuvant therapy was seen in patients with primary uveal melanoma (UM), including responses in primary ocular tumor lesions. Data come from an ongoing investigator sponsored trial which is assessing darovasertib in (neo)adjuvant uveal melanoma.

Ocular tumor shrinkage by investigator review was observed in 100% of patients, including 6 with UM and 3 with MUM who were treated with darovasertib monotherapy or darovasertib in combination with crizotinib. This also included a patient with neoadjuvant UM who was treated with darovasertib and had a partial response at 1 month, as well as a second patient treated with the darovasertib and crizotinib combination who had 80% ocular tumor shrinkage at 4 months.

A company-sponsored clinical trial will soon evaluate darovasertib as monotherapy in (neo)adjuvant UM. Investigators are evaluating potential near-term clinical neoadjuvant end points, including organ preservation for large ocular tumors and reduction in radiation dose and/or vision preservation for small or medium ocular tumors.

"These additional clinical data underscore the potential for darovasertib as a (neo)adjuvant approach for the treatment of uveal melanoma patients.If clinically validated, this approach could significantly improve current primary treatment paradigms, which typically include radiotherapies and/or enucleation of the eye," said Anthony Joshua, MBBS, PhD, FRACP, head of the department of Medical Oncology, Kinghorn Cancer Centre, St Vincent's Hospital/Garvan Medical Research Institute, Sydney, Australia, in the press release.

  1. IDEAYA announces positive interim phase 2 data for darovasertib and crizotinib combination and successful FDA type C meeting on registrational trial design for accelerated approval in first-line metastatic uveal melanoma. News release. IDEAYA Biosciences, Inc. April 23, 2023. Accessed April 25, 2023. https://prn.to/41y2mK2
  2. Study of IDE196 in patients with solid tumors harboring GNAQ/11 mutations or PRKC fusions. ClinicalTrials.gov. Updated March 28, 2023. Accessed April 25, 2023. https://clinicaltrials.gov/ct2/show/NCT03947385
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