Darovasertib/crizotinib combination: a potential first-line therapy in metastatic uveal melanoma

The initial evaluation of darovasertib/crizotinib in both first-line and pretreated participants with metastatic uveal melanoma (MUM) showed a manageable safety profile and clinical efficacy. The levels of circulating tumour DNA (ctDNA) were reduced in almost all participants.

Approximately 50% of patients with uveal melanoma will eventually develop metastatic disease which has a poor prognosis and a median overall survival of approximately 1 year. Currently, MUM has limited effective (and approved) therapies. In over 95% of MUM cases, the driver mutations in GNAQ/GNA11 occur, which activate protein kinase C (PKC) signalling. In a first-in-human study, the selective PKC inhibitor darovasertib demonstrated clinical responses in MUM [1]. Moreover, the oncogene cMET is overexpressed in MUM and can additionally drive cell growth and survival pathways. The current phase 1/2 study (NCT03947385) consequently evaluated the efficacy and safety of the darovasertib combined with the potent cMET inhibitor crizotinib. Dr Meridith McKean (Tennessee Oncology, TN, USA) presented results from the expansion cohort [2].

The participants had a large tumour burden, where 66% of them presented with the largest metastatic lesions over 3 cm, 65% had hepatic and extrahepatic disease, and 60% had elevated lactate dehydrogenase (LDH) levels. Participants were treated with the darovasertib/crizotinib combination until progression of disease or signs of toxicity occurred.

A clinical partial response was observed in 30% of the participants, stable disease in 59%, and tumour shrinkage in 92% (see Figure). These responses were noted regardless of prior lines of treatment (62% of participants had ≥2 prior treatment lines in the metastatic setting), LDH status, and HLA-A*02.01 status. A deep and sustained decrease in plasma ctDNA levels was observed in 94% of the participants. The depth of this molecular response correlated with the best overall response (RECIST 1.1). The interim median progression-free survival was 7.1 months in the first-line setting (n=20), 6.8 months in the any-line setting (n=63), and 11.0 months in participants with hepatic-only (i.e. early phase) metastatic disease (n=19).

Figure: Overall response and disease control rates in participants with any-line MUM [2]



DCR, disease control rate (pCR+SD); MUM, metastatic uveal melanoma; ORR, objective response rate; pCR, pathological complete response; PD, progressive disease; SD, stable disease.

The combination of darovasertib/crizotinib had a manageable safety profile. Serious treatment-related adverse events were seen in 10.3% of the participants and adverse events led to discontinuation in 7.4% of the participants.

Based on these results, Dr McKean concluded that “the efficacy and safety of darovasertib/crizotinib in first-line and hepatic-only participants support the ongoing registration study (NCT05987332) of darovasertib/crizotinib in first-line MUM.”

1. 
   
   1. Piperno-Neumann S, et al. Br J Cancer. 2023;128:1040–1051.
   2. McKean M, et al. ctDNA reduction and clinical efficacy of the darovasertib + crizotinib (Daro + Crizo) combination in metastatic uveal melanoma (MUM). Abstract 1081O, ESMO 2023, 20–24 October, Madrid, Spain.

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Posted on 19 December, 202319 December, 2023