Darovasertib/Crizotinib Combo Achieves Promising Responses in Pretreated Metastatic Uveal Melanoma


Patients with heavily pretreated metastatic uveal melanoma appeared to benefit from treatment with a synthetic lethal combination of darovasertib and crizotinib.

Treatment with the synthetic lethal combination of darovasertib (IDE-196) and crizotinib (Xalkori) resulted in promising responses in a population of patients with heavily pre-treated metastatic uveal melanoma, according to a press release of a clinical update on a phase 1/2 trial.

All of the 16 evaluable patients on the trial experienced demonstratable tumor shrinkage, translating to a disease control rate of 100%. Additionally, investigators reported an overall response rate of 31%, with 4 patients achieving a confirmed partial response (PR). Thus far, no patients have withdrawn from treatment prior to the second scan. Among those with more than 2 baseline scans, 46% experienced tumor shrinkage of more than 30%; this included an unconfirmed PR that requires next tumor assessment.

“The partial responses, percentage of patients with tumor shrinkage and disease control rate observed from the darovasertib and crizotinib synthetic lethal combination in heavily pre-treated [metastatic uveal melanoma] patients represents a new clinical efficacy benchmark and provides an opportunity to deliver meaningful patient impact in this high unmet medical need patient population,” Meredith McKean, MD, an associate director of melanoma and skin cancer research at Sarah Cannon Research Institute at Tennessee Oncology, said in the press release.

Patients with metastatic uveal melanoma or GNAQ/GNA11 solid tumors do not currently have any FDA approved therapies. Darovasertib, a small molecular and potential first-in-class PKC inhibitor, with crizotinib may work to meet this clinical unmet need.

The trial enrolled 22 patients as of the data cut off of November 25, 2021, 91% of whom had received prior treatment and 59% who underwent 2 prior treatments or more. Sixteen evaluable patients received 1 or more tumor scans and 6 patients are currently awaiting their first scan. Additionally, 13 patients received 2 or more scans to identify potential responses. Enrollment for the trial is ongoing.

“These data provide clinical proof-of-concept for the PKC and cMET synthetic lethal combination, and further validate IDEAYA's synthetic lethality platform. We look forward to exploratory evaluation of this novel PKC and cMET synthetic lethal combination in other potential tumor settings, including GNAQ/11 skin melanoma and MET-amplified and MET high expression tumors,” Yujiro S. Hata, president and chief executive officer at IDEAYA Biosciences, stated.

The combination yielded a manageable safety profile, with a low rate of serious adverse effects (AEs). Most treatment-related AEs (TRAEs) were grade 1/2. A total of 18 patients experienced TRAEs, 6 of whom had grade 3 toxicities. There were no reports of grade 4/5 TRAEs.

Investigators stated that the clinical findings from the trial provide proof-of-concept and validate phase 1 data that highlighted responses to single agent darovasertib. Regulatory feedback for the combination’s registrational path is expected during the first half of 2022.


IDEAYA reports clinical data from phase 2 expansion dose of darovasertib and crizotinib synthetic lethal combination in heavily pre-treated metastatic uveal melanoma. News release. December 7, 2021. Accessed December 7, 2021. https://bit.ly/3y0KppH

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