KRAS TARGETED TREATMENT OF NSCLC 

Selumetinib Plus Docetaxel for KRAS-Mutant Advanced Non-Small-Cell Lung Cancer: A Randomised, Multicentre, Placebo-Controlled, Phase 2 Study

Jänne PA, Shaw AT, Pereira JR, et al

Lancet Oncol. 2013;14:38-47

Background

The management of advanced non-small cell lung cancer (NSCLC) has been transformed with the transition to molecular oncology. Our treatment algorithms are now defined largely by the presence or absence of identifiable, clinically relevant "driver mutations" for which we may have a specific, effective, inhibitory therapy that leads to impressive and often prolonged responses. Unfortunately, we have not had such a therapy to target KRAS, which is the most frequently mutated oncogene in this setting, accounting for 20% of NSCLC patients in North America. This is a NSCLC population in which efficacy has been reported to be lower with epidermal growth factor receptor tyrosine kinase inhibitors^[1,2] as well as conventional chemotherapy.^[3]

Study Summary

In this context, the randomized phase 2 study from Jänne and colleagues, just published in Lancet Oncology, provides great hope and a potentially significant breakthrough in the treatment impasse for KRAS mutation-positive patients. The international trial screened over 400 patients with previously treated advanced NSCLC; 87 patients were randomly assigned to receive second-line docetaxel (75 mg/m² IV every 21 days) and either placebo or the novel agent selumetinib, an inhibitor of MEK, which is an effector molecule downstream in the RAS-RAF-MEK-ERK (MAPK) signaling pathway. This agent had been noted to have an inhibitory effect in xenograft models,^[4] although it failed to demonstrate efficacy as a single agent in a single-arm phase 2 trial for unselected advanced NSCLC.^[5] In contrast, the combination selumetinib/docetaxel appeared active, and even synergistic,^[4,6] with a tolerable safety profile in a phase 1 trial.^[7]

Efficacy was markedly superior across every endpoint in the group receiving the combination therapy: The response rate was 37% vs 0% (2-sided P < .0001), median progression-free survival (PFS) 5.3 vs 2.1 months (HR, 0.58; 1-sided P = .014), and median overall survival (OS) 9.4 vs 5.2 months (HR, 0.80; 1-sided P = .21). Given the markedly superior PFS provided by selumetinib/docetaxel, the duration of second-line therapy was nearly double in the investigational arm (117 vs 68 days).

Selumetinib/docetaxel was associated with a significantly higher rate of serious adverse events, including neutropenia and febrile neutropenia (despite increased use of growth factor support), diarrhea, nausea, vomiting, peripheral edema, rash, and stomatitis. Of note, the hospitalization rate was 48% with selumetinib/docetaxel vs 19% with docetaxel/placebo.

Viewpoint

Although the OS was markedly improved by selumetinib, this trial of only a few dozen patients should be viewed more as a promising step toward effective therapy for KRAS mutation-positive patients than as a definitive answer. Moreover, the increased toxicity is a critical obstacle to overcome, especially in a palliative setting. The opportunity to hone the therapeutic index of this regimen will present itself in subsequent studies of selumetinib and other MEK inhibitors currently in clinical development. Certainly this trial can be seen as a profoundly encouraging starting point for subsequent studies in a population of KRAS mutation-positive patients -- a population that will only increase as molecular testing becomes more widespread. As more potentially effective therapies are offered in clinical trials, we can have a realistic hope of adding a specific, targeted therapy for the large subgroup of advanced NSCLC patients with a KRAS mutation.