Darovasertib/Crizotinib Shows Early Efficacy in Metastatic Uveal Melanoma

Preliminary results from a trial of darovasertib (IDE196) and crizotinib (Xalkori) demonstrated promising efficacy and tolerable safety in patients with metastatic uveal melanoma (MUM), according to a press release from IDEAYA Biosciences.¹

The multi-arm phase 1/2 trial (NCT03947385) of darovasertib in solid tumors is exploring the use of darovasertib as a monotherapy, as a combination with crizotinib, and as a combination with binimetinib (Mektovi). Previous results of the binimetinib combination arm demonstrated a favorable overall survival (OS) and overall response rate (ORR) compared with historically low ORRs for other MUM treatments.

Darovasertib is a small molecule protein kinase C (PKC) inhibitor, and in combination with crizotinib, it may have a synthetic lethality effect in solid tumors. Crizotinib is a cMET inhibitor that is approved for treating ALK and ROS1-positive non–small cell lung cancer and anaplastic large-cell lymphoma.^2,3

Based on preliminary data, darovasertib/crizotinib showed a 100% disease control rate (DCR) based on scans showing tumor shrinkage in all 16 evaluable patients.¹ The ORR of the patients who received more than 2 scans was 31%, or 4 out of 13 patients with partial response. All partial responses were based on RECIST 1.1. Investigators observed tumor reduction of greater than 30% in 46% of patients with multiple scans (n = 6). No patients came off treatment prior to their second tumor scan.

“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 [patients with] MUM 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, associate director of Melanoma and Skin Cancer Research at Sarah Cannon Research Institute at Tennessee Oncology, said in a statement.

The combination showed a manageable safety profile; while drug-related adverse events (AEs) occurred in 18 of the 22 patients, these were primarily grade 1 and 2 AEs. Only 6 of the 18 patients experienced grade 3 AEs, and there were no grade 4 or 5 AEs.

Following a phase 1 trial of an escalation dose to determine the recommended phase 2 dose, 22 patients in the phase 2 trial received the expansion dose of darovasertib and crizotinib orally twice a day for each 28-day cycle. The participants were heavily pretreated; 91% of patients had received prior therapies and 59% had received 2 or more prior therapies. These patients received the phase 2 expansion dose. Investigators performed tumor scans on 16 of the treated patients, while 6 were awaiting their first scan. Out of the 16 evaluated patients, 13 received 2 or more tumor scans.

"These data provide clinical proof-of-concept for the PKC and cMET synthetic lethal combination, and further validate IDEAYA's synthetic lethality platform,” Yujiro S. Hata, president and CEO of IDEAYA Biosciences, said in a press release.

Investigators intend to collect more clinical data on the combination including median progression-free survival in patients with MUM treated with darovasertib/crizotinib. Moving forward, the expansion dose of the darovasertib/crizotinib combination identified in the phase 1 trial will be utilized in future trials.

Other arms of this trial are evaluating darovasertib’s efficacy in other settings including solid tumors with GNAQ or GNA11 (GNAQ/11) mutations and PRKC fusions, which could be MUM, cutaneous melanoma, colorectal cancer, or other disease types. There are currently no FDA approved therapies for MUM or GNAQ/GNA11 solid tumors.

“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," Hata stated.

_REFERENCES:

_{1. IDEAYA reports clinical data from phase 2 expansion dose of darovasertib and crizotinib synthetic lethal combination in heavily pre-treated metastatic uveal melanoma. IDEAYA Biosciences. Published December 7, 2021. Accessed December 9, 2021. https://bit.ly/3GKmGNJ}

_{2. FDA approves crizotinib capsules. FDA. Published March 11, 2016. Accessed December 9, 2021. https://bit.ly/3EFV0ZD}

_{3. FDA approves crizotinib for children and young adults with relapsed or refractory, systemic anaplastic large cell lymphoma. FDA. Published January 14, 2021. Accessed December 9, 2021. https://bit.ly/3GqIu0s}