Darovasertib/Crizotinib Demonstrates Efficacy in Metastatic Uveal Melanoma

With an overall response rate of 50% and greater than 5 months median progression-free survival in patients with first-line metastatic uveal melanoma, darovasertib and crizotinib shows a compelling clinical efficacy profile.

Interim results of a phase 2 clinical trial (NCT03947385) evaluating darovasertib (IDE196) and crizotinib (Xalkori) synthetic lethal combination showed clinical efficacy in patients with metastatic uveal melanoma (mUM), according to IDEAYA Biosciences, Inc.1

Findings revealed that 4 of the 8 evaluable patients with first-line mUM had confirmed partial responses (PRs) and an overall response rate (ORR) of 50%. Eleven of the 35 evaluable patients with any-line mUM also had confirmed PRs and an ORR of 31%.

Further, tumor shrinkage was observed in 31 of the 35 patients (89%) with any-line mUM and the median progression-free survival (PFS) had not yet been reached and was greater than 5 months in the evaluable patients with first-line mUM. For patients with any-line mUM, the observed median PFS was 5 months.

"The confirmed partial responses and high percentage of patients with tumor shrinkage shown in these interim phase 2 data are extremely encouraging for patients with metastatic uveal melanoma. The 50% overall response rate and greater than 5 months median progression-free survival observed in first-line mUM patients reflects the potential for a compelling clinical efficacy profile irrespective of haplotype status. The partial responses shown in first-line and any-line mUM patients are clinically significant and build on previously-reported results for any-line mUM patients, now with a larger patient data set," said Marlana Orloff, MD, associate professor, Sidney Kimmel Cancer Center, Jefferson Health, in the press release.

These findings come from the expansion portion of the phase 1/2, multi-center, open-label basket study evaluating the safety and anti-tumor activity of darovasertib in patients with solid tumors harboring GNAQ or GNA11 mutations or PRKC fusions, including mUM, cutaneous melanoma, colorectal cancer, and other solid tumors.2

The study aims to enroll 254 patients across 7 cohorts. Here, patients will receive either darovasertib alone, darovasertib plus binimetinib (Mektovi), or darovasertib plus crizotinib. During the dose-escalation and dose-expansion phases of the study, darovasertib will be administered orally, twice a day for each 28-day cycle.

The end points of the study are to determine the dose-limiting toxicity, maximum-tolerated doses, recommended phase 2 dose, the plasma concentration of darovasertib monotherapy, ORR by blinded independent review committee, and duration of response (DOR). The secondary end points are ORR, DOR, and disease control rate (DCR) by investigator assessment. The secondary safety end points include safety and tolerability determined by the number of patients with adverse events, and the study is also exploring treatment-related pharmacodynamic effects in all patients.

Other outcomes being investigated in the study of darovasertib include 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.

Inclusion in the study is open to patients at least 18 years of age or older with measurable disease, an ECOG performance status of at least 3 months, adequate organ function, and contraceptive measures for non-sterilized male and female patients of childbearing potential at the time of screening.

To be eligible to receive the binimetinib combination, patients must also have adequate cardiac function represented by a left ventricular ejection fraction ≥ 50%. For the crizotinib combination arms, patients must have received prior chemotherapy, or other therapies and major surgeries 4 weeks prior to the start of crizotinib in the study, and any preexisting peripheral neuropathy must grade 1 or lower for patients to be eligible for inclusion.

A total of 37 patients were enrolled to receive the combination of darovasertib and crizotinib at the expansion dose of 300mg twice-a-day darovasertib and 200mg twice-a-day crizotinib, as of the data analysis cutoff date of June 26, 2022. Among the 37 patients, 35 were evaluable. The 2 non-evaluable patients were pretreated and withdrew from the trial prior to the first scan. Neither of the two non-evaluable patients progressed due to disease, but 1 patient withdrew consent and 1 patient discontinued due to fatigue.

In the phase 2 expansion dose cohort, encouraging clinical activity of darovasertib and crizotinib synthetic lethal combination was observed in patients with mUM.

The DCR was 83% for 29 of the 35 evaluable patients with any-line mUM. These 29 patients had stable disease or better as determined by target lesion size reduction. Then, 15 patients had PRs with a greater than 30% tumor reduction, including 11 confirmed and 4 unconfirmed PRs.

The median study follow-up was 6.5 months for patients with first-line mUM vs 7.8 months for patients with any-line mUM. Median duration of response (DOR) in the evaluable patients with first-line mUM has not yet been reached. Further, 4 of 4 patients with confirmed PRs in first-line mUM remain in response. For patients with any-line mUM, the median DOR has not yet been reached and 7 of 11 patients with confirmed PRs remain in response.

Regarding safety, the combination of darovasertib and crizotinib had a manageable adverse events (AEs)profile in the 37 patients with mUM. Patients reported primarily grade 1 or 2 drug-related AE and all patients experienced a drug-related AE, of which 76% were reported as grade 1 or 2 and 24% were reported as grade 3. Additionally, no patients had grade 4 or 5 AEs. One patient discontinued treatment due to a drug-related AE.

Findings from the trial provide robust clinical proof-of-concept for the efficacy of the combination of darovasertib and crizotinib. The orally-administered small molecule precision medicine therapeutic demonstrated antitumor activity and a manageable safety profile, leading the combination therapy to have the potential to be impactful in this patient population.

Enrollment in the darovasertib and crizotinib combination expansion dose cohort of the clinical trial is ongoing.

"The clinical efficacy observed in first-line patients in these interim phase 2 data presents an opportunity to pursue a front-line strategy and provides a rationale for a potential registration-enabling clinical trial in mUM," said Matt Maurer, MD, vice president, head of clinical oncology and medical affairs at IDEAYA Biosciences, in the press release.

References
1. IDEAYA reports positive interim phase 2 clinical results for darovasertib and crizotinib synthetic lethal combination in metastatic uveal melanoma. News release. Ideaya Biosciences, Inc. Published September 11, 2022. Accessed September 13, 2022. https://prn.to/3QFZzbq
2. Study of IDE196 in patients with solid tumors harboring GNAQ/11 mutations or PRKC fusions. ClinicalTrials.gov. Updated May 12, 2022. Accessed September 13, 2022.