Darovasertib Plus Crizotinib Shows Early Promise in Metastatic Uveal Melanoma

The combination of darovasertib (IDE196) and crizotinib (Xalkori) demonstrated clinical activity and an acceptable safety profile when utilized in first- and any-line patients with metastatic uveal melanoma, according to interim results from a phase 2 trial (NCT03947385).¹

Preliminary data were based on investigator review from an unlocked database and had a data cutoff date of March 8, 2023. Among evaluable patients who received darovasertib at a twice-daily dose of 300 mg plus crizotinib at a twice-daily dose of 200 mg as first-line treatment (n = 20), the confirmed overall response rate (ORR) by RECIST v1.1 criteria was 45%. Specifically, 9 patients experienced a partial response (PR) to treatment.

Moreover, the disease control rate (DCR) in this group was 90%. Eighteen patients achieved disease control, including 9 confirmed PRs, 1 unconfirmed PR, and 8 cases of stable disease (SD). The median progression-free survival (PFS) was approximately 7 months.

In evaluable patients who received the regimen in any line (n = 63), the confirmed ORR with the doublet was 30%, with 19 patients achieving a PR. Notably, these patients were heavily pretreated, with more than half (63%) having received at least 1 previous line of therapy and 43% having received 2 or more prior lines of therapy in the metastatic setting.

In this group, the DCR was 87%, with 55 patients experiencing disease control; this included 19 confirmed PRs, 4 unconfirmed PRs, and 32 patients with SD. Again, the median PFS was approximately 7 months.

Lastly, in the group of first- and any-line patients with hepatic-only disease (n = 20), the confirmed ORR with darovasertib plus crizotinib was 35%, with 7 patients experiencing a confirmed PR. Here, the DCR was 100%, with all 20 patients achieving disease control, including 7 confirmed PRs, 1 unconfirmed PR, and 12 cases of SD. In this group, the median PFS was approximately 11 months.

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

For the multicenter, open-label basket trial, investigators sought to assess the safety and antitumor activity of darovasertib in patients with solid tumors that harbor GNAQ or GNA11 mutations or PRKC fusions, including metastatic uveal melanoma, cutaneous melanoma, colorectal cancer, and other solid tumors.²

Patients were required to be at least 18 years of age and have measurable disease, an ECOG performance status of 0 to 1, a life expectancy of more than 3 months, and acceptable organ function at screening.

Additional inclusion criteria for the darovasertib/crizotinib combination were that previous chemotherapy, other therapies, or major surgeries must have been completed at least 4 weeks before crizotinib was initiated. Moreover, those with pre-existing peripheral neuropathy were permitted if it was grade 1 or lower in severity before crizotinib was started.

Darovasertib plus crizotinib was found to have a manageable toxicity profile in patients with metastatic uveal melanoma (n = 68). Most of the treatment-related toxicities that were reported were noted to be mostly grade 1 or 2 in severity. Thirty-one percent of patients experienced at least one grade 3 adverse effect (AE), but no patients had a grade 4 AE. One patient had a grade 5 toxicity, and 6% of patients discontinued treatment with either drug because of a treatment-related toxicity.

Previous data from the basket trial showed that when darovasertib was explored as a monotherapy and in combination with binimetinib (Mektovi), it also showcased early activity.³

The 1-year overall survival (OS) rate with single-agent darovasertib was 57% (95% CI, 44%-69%) in heavily pretreated patients with metastatic uveal melanoma who received the drug in the second- or third-line setting. The median OS was 13.2 months (95% CI, 10.7-not reached) with the monotherapy. Sixty-one percent of the 75 evaluable patients experienced tumor reduction per RECIST v1.1 criteria, with 20% experiencing a reduction in target lesion of 30% or more.

When paired with binimetinib, the agent induced 2 PRs in the 9 patients with metastatic uveal melanoma who had at least 2 post-baseline scans; 1 PR was confirmed and 1 was unconfirmed awaiting confirmation. In this group, 79% who had at least 1 post-baseline scan were noted to have experienced tumor reduction, although follow-up for overall response was immature at the time of the report.

The precision medicine oncology company, Ideaya Biosciences, Inc., shared plans to launch a potential registrational-enabling phase 2/3 clinical trial in the second quarter of 2023 to further evaluate darovasertib plus crizotinib in the frontline treatment of patients with metastatic uveal melanoma who have an HLA-A*02:01 negative serotype.¹

The trial design will incorporate guidance and feedback from the FDA from a recent Type C meeting. It uses a phase 2 portion where median PFS will serve as the primary end point to support a potential accelerated approval. This portion will enroll about 230 participants who will be randomly assigned 2:1 to the doublet or investigator’s choice of ipilimumab (Yervoy) plus nivolumab (Opdivo), a PD-1–targeted monotherapy, or DTIC.

According to the press release, this treatment arm of this portion of the research will comprise a nested study to confirm the dose of the regimen for the integrated phase 2/3 trial, including cohorts at the following expansion doses: darovasertib at 300 mg twice daily plus crizotinib at 200 mg twice daily, and darovasertib at 200 mg twice daily plus crizotinib at 200 mg twice daily.

Those included in the phase 2 portion of the trial will continue treatment within the same trial and will be considered together with more patients who will be enrolled to examine overall survival in support of a possible phase 3 registrational trial of the regimen.

“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 [metastatic uveal melanoma] patients, which includes a path to potential accelerated approval based on median PFS as the primary end point,” Darrin Beaupre, MD, PhD, chief medical officer of Ideaya Biosciences, added in the press release.

References

• 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 24, 2023. https://media.ideayabio.com/
• Study of IDE196 in patients with solid tumors harboring GNAQ/11 mutations or PRKC fusions. ClinicalTrials.gov. Updated February 17, 2021. Accessed April 24, 2023. https://clinicaltrials.gov/ct2/show/NCT03947385
• Ideaya reports darovasertib (IDE196) monotherapy overall survival data and observes early partial responses in binimetinib combination in metastatic uveal melanoma. News release. Ideaya Biosciences, Inc. April 16, 2021. Accessed April 24, 2023. https://ir.ideayabio.com/