RVU120, a first-in-class CDK8/19 inhibitor, has shown early signs of clinical activity and a favorable toxicity profile in patients with relapsed/refractory metastatic or advanced solid tumors. These findings were presented from part 2 of the phase 1/2 RVU120-SOL-021 (AMNYS-51) trial (NCT05052255) at the 36th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics. The study suggests that CDK8/19 inhibition is a viable approach for cancer therapies, particularly in heavily pretreated populations with limited treatment options.
RVU120 Trial: Design and Patient Population
The open-label, multicenter, multinational AMNYS-51 trial employed a 3+3 design to evaluate RVU120 in patients with advanced or metastatic solid tumors who had exhausted standard therapeutic options. Part 2 of the trial involved administering RVU120 at doses of 100 mg (n = 6) or 150 mg (n = 5) once daily. Of the 11 patients, 9 were evaluable for food-effect, and 7 were evaluable for dose-limiting toxicities (DLTs). Key inclusion criteria included being at least 18 years of age, having measurable or evaluable disease per RECIST 1.1 criteria, an ECOG performance status of 0-2, and a life expectancy of at least 12 weeks.
At the data cutoff of September 16, 2024, the patient cohort included individuals with various cancer types: adenoid cystic carcinoma (n = 4), pancreatic adenocarcinoma (n = 2), hormone receptor-positive/HER2-negative breast cancer (n = 2), non-small cell lung cancer adenocarcinoma (n = 1), melanoma (n = 1), and colon cancer (n = 1). The median patient age was 58 years, and the median number of prior lines of therapy was 5, indicating a heavily pretreated population.
Clinical Activity in Adenoid Cystic Carcinoma
The most notable clinical benefit was observed in patients with adenoid cystic carcinomas (n = 8 across parts 1 and 2 of the trial). Five of these patients experienced a longer duration of treatment on RVU120 compared to their most recent prior line of therapy. Furthermore, a reduction of more than 10% in target lesion size was observed in 3 patients. For example, one patient with parotid adenoid cystic carcinoma achieved an 11% reduction in target lesion size and remained on treatment for over 8 months. Another patient with nasopharyngeal adenoid cystic carcinoma experienced a 20% reduction and discontinued treatment after more than 12 months. A third patient with adenoid cystic carcinoma of the tongue had a 14% reduction in lesion size and discontinued treatment after more than 5 months.
Safety and Tolerability
According to Magdalena Błaszkowska, PhD, the lead study author, RVU120 demonstrated a favorable safety profile in this heavily pretreated population. No DLTs or other significant safety signals were observed. Gastrointestinal-related adverse events (AEs), such as nausea and vomiting, were the most common, but were predominantly low-grade and manageable with supportive care. Specific AEs reported included nausea (55%), increased aspartate aminotransferase and alanine aminotransferase levels (45% each), vomiting (36%), and dyspepsia (36%).
The study authors noted that continuous daily dosing of RVU120 at 100 mg and 150 mg is considered safe and may improve tolerability compared to a 250 mg every-other-day regimen.
Pharmacokinetic Profile
Pharmacokinetic (PK) data showed that plasma exposure of RVU120 increased with dose. The median time to maximum concentration was approximately 6 hours post-dose, with a half-life of about 40 hours. Daily dosing at 100 mg and 150 mg resulted in similar plasma exposure to the equivalent every-other-day dose after repeated dosing. Pharmacodynamic analyses supported these PK findings, demonstrating that 100 mg and 150 mg QD dosing led to the expected target engagement levels.
Ongoing and Future Research
Currently, there are four ongoing phase 2 trials evaluating RVU120 as a monotherapy and in combination therapies for patients with hematological malignancies, including acute myeloid leukemia, high-risk myelodysplastic syndrome (MDS), low-risk MDS, and myelofibrosis. These trials aim to further define the role of RVU120 in cancer treatment and explore its potential in different disease settings.
