Selumetinib plus docetaxel provides clinical benefit to patients with KRAS-mutant NSCLC.
Major finding: Selumetinib plus docetaxel provides clinical benefit to patients with KRAS-mutant NSCLC.
Clinical relevance: Dual treatment improved PFS and patient responses but was associated with more adverse events.
Impact: Further clinical trials of this drug combination in advanced KRAS-mutant NSCLC are warranted.
KRAS mutations are prevalent in many cancers, including non–small cell lung cancer (NSCLC), in which they are associated with decreased response to chemotherapy and reduced survival. Because no effective therapies exist for KRAS-mutant cancer and attempts to directly target KRAS activity have been unsuccessful, recent studies have instead focused on blocking downstream effectors, including MAP/ERK kinase (MEK) 1 and MEK2. Selumetinib is an orally available, selective inhibitor of MEK1/2 that impaired tumor growth and synergized with the chemotherapeutic agent docetaxel to induce apoptosis in preclinical studies. Based on these data, Jänne and colleagues performed a double-blind phase II trial to investigate the efficacy and safety of the selumetinib and docetaxel combination as a second-line therapy in patients with KRAS-mutant advanced NSCLC. These patients had failed first-line chemotherapy but had not been previously treated with docetaxel or MEK inhibitors, and 83 patients with confirmed mutant KRAS-positive tumors and similar baseline parameters were randomly assigned to receive docetaxel plus either selumetinib or placebo. Addition of selumetinib resulted in enhanced median progression-free survival (PFS) compared with the placebo group (5.3 months vs 2.1 months) and a greater incidence in objective partial responses (37% vs 0%). Furthermore, combined treatment with selumetinib and docetaxel was associated with improvements in patient-reported disease symptoms and a trend toward increased overall survival (9.4 months vs 5.2 months), although this did not reach statistical significance. However, patients who received selumetinib experienced a higher frequency of adverse events, particularly grade 3 and 4 events, including neutropenia and pneumonia. These results support additional trials to confirm this clinical activity and to ensure proper management of toxic effects and suggest that the combination of MEK inhibitors and chemotherapy may also be an effective therapeutic strategy for patients with other KRAS-mutant cancers.