Selumetinib Misses Endpoint in Phase III Uveal Melanoma Study

Antoine Yver

Treatment with the combination of selumetinib and dacarbazine failed to improve progression-free survival (PFS) compared with dacarbazine alone in patients with metastatic uveal melanoma, according to top-line findings from the phase III SUMIT trial released by AstraZeneca.

Selumetinib was developed by Array BioPharma and licensed to AstraZeneca in 2003. The agent continues to be assessed across a variety of settings, including separate phase III trials for KRAS-mutant advanced non—small cell lung cancer (NSCLC) and differentiated thyroid cancer. Additionally, a phase II study is assessing the drug for patients with neurofibromatosis Type 1.

"Selumetinib is supported by a strong development program with different scientific rationale in multiple tumor types as both monotherapy and in alternative combinations," Antoine Yver, Head of Oncology, Global Medicines Development at AstraZeneca, said in a statement. "The findings from SUMIT have no impact on the other studies and we look forward to presenting the data in due course."

The MEK inhibitor initially generated excitement for patients with uveal melanoma when findings from a phase II study comparing selumetinib with chemotherapy were presented at the 2013 ASCO Annual Meeting. This study demonstrated marked improvements in PFS with selumetinib monotherapy compared with chemotherapy.

In the study, 101 patients with metastatic uveal melanoma were randomized to receive continuous selumetinib at 75 mg (n = 50) or investigator's choice of chemotherapy (n = 51). PFS was the primary endpoint, with OS, objective response rate (ORR), and toxicity as secondary outcome measures. In the chemotherapy arm, patients received temozolomide or dacarbazine.

According to findings published in JAMA,¹ the median PFS with single-agent selumetinib was 15.9 weeks compared with 7 weeks with chemotherapy (HR = 0.46; 95% CI, 0.30-0.71; P <&thinsp;.001). The median OS with selumetinib was 11.8 versus 9.1 months with chemotherapy (HR = 0.66; 95% CI, 0.41-1.06); however, this was not deemed statistically significant (P&thinsp;=&thinsp;.09).

None of the patients in the chemotherapy arm experienced a response to therapy compared with a 14% ORR with selumetinib. Additionally, 49% of patients in the selumetinib arm experienced tumor regression.

Improvements in clinical outcomes were accompanied by a high incidence of adverse events (AEs). Treatment-related AEs were observed in 97% of patients treated with selumetinib, with 37% requiring at least 1 dose reduction. In a statement, AstraZeneca noted that AEs were similar in the phase III SUMIT study to prior experiences.

The most common all-grade AEs with selumetinib were acneiform rash (75%), creatine kinase elevation (60%), fatigue (57%), aspartate aminotransferase (AST) elevation (48%), and alanine aminotransferase (ALT) elevation (42%). Grade 3/4 AEs were seen in 37% of patients, including creatine kinase elevation (13%), AST elevation (7%), and ALT elevation (6%).

Based on this early experience, selumetinib was given an FDA orphan drug designation for patients with uveal melanoma in April 2015. This designation is meant to address a high unmet medical need. In a similar scenario, selumetinib is also being explored in patients with NSCLC who harbor a KRAS mutation, which generally denotes a poor prognosis and for which there are limited treatment options.

The combination of selumetinib and docetaxel is being explored in the phase III SELECT-1 study, which plans to enroll 634 patients with KRAS-mutant NSCLC. Patient in the study will be randomized to selumetinib at 75mg in combination with docetaxel at 75mg/m² or placebo with docetaxel (NCT01933932).

“This is an area of pressing clinical need, and our decision to progress selumetinib was based on phase II results, which showed promising clinical activity in this group of patients,” Yver said when the trial was launched.

In the prior phase II study, patients with advanced KRAS-mutant NSCLC who progressed on frontline therapy received selumetinib plus docetaxel (n = 44) or docetaxel and placebo (n = 43). Findings from this analysis were published in Lancet Oncology in 2013.²

In the phase II study, the median OS was 9.4 months with selumetinib versus 5.2 months with docetaxel alone (HR = 0.80; 80% CI, 0.42-0.79; P = .014). The median PFS was 2.1 months with docetaxel versus 5.3 months in the combination arm (HR = 0.58, 80% CI, 0.42-0.79; P = .014). An ORR was not seen with docetaxel alone versus 37% with the combination (P <.0001).

The most frequently reported grade 3/4 AEs with selumetinib versus without were neutropenia (67% vs 55%), febrile neutropenia (18% vs none), dyspnea (2% vs 12%), and asthenia (9% vs none).

References

1. Carvajal RD, Sosman JA, Quevedo JF, et al. Effect of selumetinib vs chemotherapy on progression-free survival in uveal melanoma: A randomized clinical trial. JAMA. 2014;311(23):2397-2405.
2. Janne PA, Shaw AT, Pereira JR, et al. Selumetinib plus docetaxel for KRAS-mutant advanced non-small cell lung cancer: a randomized, multicenter, placebo-controlled, phase 2 study. Lancet Oncology. 2013;14(1):38—47.