Selumetinib Fails to Improve PFS in Phase III Lung Cancer Study

Sean Bohen, MD, PhD

The combination of selumetinib and docetaxel failed to improve survival compared with docetaxel alone as a second-line treatment for patients with KRAS-mutant locally advanced or metastatic non—small cell lung cancer (NSCLC), according to top-line findings from the phase III SELECT-1 trial released by AstraZeneca.

In the phase III study, 510 patients with KRAS-mutant NSCLC were randomized to receive docetaxel plus placebo or selumetinib. A meaningful difference was not observed between the two groups for progression-free survival (PFS) and overall survival (OS). Adverse events (AEs) associated with the combination were inline with expectations. Full results from the trial will be presented at an upcoming medical meeting, according to the company.

“A randomized phase II trial showed promising activity of selumetinib in combination with docetaxel in patients with KRAS mutation-positive lung cancer. It is disappointing for patients that these results have not been confirmed in phase III," Sean Bohen, MD, PhD, executive vice president, Global Medicines Development and chief medical officer at AstraZeneca, said in a statement. "We expect to present data at a forthcoming medical meeting. We remain committed to further developing treatments in the lung cancer setting, such as our immunotherapy combinations and targeted EGFR treatments.”

In the study, which was initiated in August 2013, the oral MEK1/2 inhibitor was administered at 75 mg twice daily and docetaxel was given at 75 mg/m² on the first day of each 21-day cycle. The primary endpoint of the study was PFS, with secondary outcome measures focused on OS, objective response rate (ORR), duration of response, and safety.

The combination of selumetinib and docetaxel had shown promising results in a prior phase II study, which raised expectations for the phase III study. In this 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 2013.¹

The median OS was 9.4 months with selumetinib versus 5.2 months with docetaxel alone, which was not statistically significant (HR, 0.80; 80% CI, 0.56-1.14; P = .21). The median PFS was 5.3 months with selumetinib versus 2.1 months for docetaxel alone (HR, 0.58, 80% CI, 0.42-0.79; P = .014). The 6-month PFS rate was 37.1% with selumetinib versus 15.85 with docetaxel (HR, 0.54; 80% CI, 0.37-0.78; P = .016).

Docetaxel did not elicit a response when administered alone compared with an ORR of 37% with the combination, which were all partial responses (P <.0001). Stable disease for >6 weeks was experienced by 44% of patients in the combination arm versus 50% of those with docetaxel and placebo.

Selumetinib was initially developed by Array BioPharma and licensed to AstraZeneca in 2003. The agent continues to be assessed across a variety of settings. In May 2016, the MEK1/2 inhibitor received an orphan drug designation from the FDA for its potential for differentiated thyroid cancer (DTC). This designation is meant to address a high unmet medical need.

Phase II findings for DTC were published in The New England Journal of Medicine. In this trial, which did not enroll patients specifically with NRAS mutations, treatment with selumetinib enhanced radioactive iodine (RAI) uptake for 12 of 20 patients with previously treated DTC. Overall, 5 of 5 patients with NRAS alterations responded.²

“Uptake of RAI is crucial for patients with thyroid cancer where no other therapies have proven beneficial," said Bohen, when the designation was announced. "Selumetinib could significantly enhance currently available treatment options for these patients. The orphan drug designation is an important achievement as we advance our development plans for this potential treatment in differentiated thyroid cancer.”

In July 2015, selumetinib also failed to improve PFS when added to dacarbazine for patients with metastatic uveal melanoma in the phase III SUMIT trial. Prior to this development, the agent had similarly shown promising phase II results, including a 54% reduction in the risk of progression or death.

In addition to DTC, selumetinib continues to be explored for patients with neurofibromatosis Type 1 and in various combination strategies. A phase I study is looking at the agent in combination with PD-L1 inhibitor durvalumab for patients with solid tumors (NCT02586987).

References

1. 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.
2. Ho AL, Grewal RK, Leboeuf R, et al. Selumetinib-Enhanced Radioiodine Uptake in Advanced Thyroid Cancer. N Engl J Med. 2013;368:623-632.

Grade 3/4 AEs were experienced by 82% of patients in the selumetinib arm compared with 67% of those receiving docetaxel alone. 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).