Phase 2 clinical trial results of the combination of Darovasertib and Crizotinib, and an update on the clinical efficacy of neoadjuvant MUM and GNAQ/11 in cutaneous melanoma

A Phase 2 evaluation of the combination of Darovasertib and Crizotinib in first-line and pretreated patients with metastatic uveal melanoma (MUM) showed a manageable safety profile (n=68) and demonstrated clinical efficacy in patients with any-line (n=63) and first-line (n=20) MUM that appeared to be superior to the current standard of care. The reported Phase 2 clinical data are based on evaluable first-line and any-line patients through 2022 who were enrolled in the Darovasertib and Crizotinib combination study at extended doses of Darovasertib 300 mg twice daily and Crizotinib 200 mg twice daily.

Circulating tumorDNA (ctDNA) Molecular response was determined based on changes in mean allele frequency (MAF) measured on treatment compared with baseline MAF levels in a subgroup of MUM patients (n=32) from any cell line. Patients whose ctDNA showed a greater than 50% reduction in MAF after treatment were characterized as having a ctDNA molecular response. Reported ctDNA data showed reduced MAF in all but one patient. Of note, molecular responses were observed in 30 of 32 evaluable patients, reflecting a 94% molecular response rate. The ctDNA molecular response identified was profound and sustained, with approximately 80% of patients tested experiencing a reduction in MAF of more than 80%. ctDNA molecular responses correlated with observed efficacy, including confirmed partial responses (PRs) as determined by RECIST 1.1.

Clinical efficacy was observed in both human leukocyte antigen (HLA)-A2-positive (HLA-A2(+)) andHLA-A2-negative (HLA-A2(-)) patients. Of the 63 patients evaluable for efficacy, 50 full-line MUM patients had known HLA-A2 status, of which 31 had HLA-A2(-) status and 19 had HLA-A2(+) status. Efficacy data reported by HLA-A2 serotype are based on a preliminary analysis of an unlocked database through investigator review and RECIST 1.1 through August 2023. For HLA-A2(-)μm patients, confirmed PRs were observed in 9 of 31 first-line patients (29% overall response rate (ORR)) and 5 of 12 first-line patients (42% ORR). For HLA-A2(+)μm patients, confirmed PRs were also observed in 6 of 19 first-line patients (32% ORR) and in 3 of 5 first-line patients (60% ORR).

Since the previous data analysis, approximatelyWith 5.5 months of additional follow-up, approximately 30% of patients with MUM of any cell line have now been treated for more than one year, and multiple patients with RECIST 1.1 confirmed PRs have been treated for more than 24 months. With approximately 20% of patients with MUM of any cell line (13 of 63 evaluable patients) continuing treatment, the duration of treatment (DOT) analysis has the potential for further enhancement. Based on the two-year progression-free survival (PFS) and Kaplan-Meier (KM) curves of the daroversertib and crizotinib combination in any cell line MUM, the combination provided promising PFS trends compared with other therapies including tebentafusp. Interestingly, the observed tail of the PFS curve suggested durable benefit in the large proportion of patients who remained progression-free at 2 years.

In the subgroup of patients participating in clinical trials evaluating darovasertib HLA-A*02:01 (HLA-A2) status was known. The prevalence of HLA-A2(+) and HLA-A2(-) in patients with MUM was determined based on data from the first cohort of 149 patients with MUM who were treated with darovasertib as monotherapy or in the combination arm of the clinical trial, and in the second cohort of 118 patients with MUM who were treated with the combination of darovasertib and crizotinib, respectively. Collectively, these data indicate that approximately 70% of MUM patients with known HLA-A2 status are HLA-A2(-). These data included 102 of 149 patients (68%) in the full treatment subgroup and 81 of 118 patients (69%) in the daroversertib + crizotinib combination subgroup.

In MUM patients (n=68), the daroversertib and crizotinib combination continued to demonstrate an overall manageable adverse event profile, with a low incidence of drug-related serious adverse events (SAEs) (10%) and limited grade 4 and 5 SAEs and discontinuations. Drug-related adverse events (AEs) were mainly grade 1 or 2. At least one Grade 3 AE was reported in 31% of patients; Grade 4 AEs were observed in no patients; a Grade 5 AE was observed in one patient. Five patients (7%) discontinued darovatinib and crizotinib combination therapy due to drug-related adverse events.