In a commentary accompanying reporting of the phase II study of the MEK inhibitor selumetinib by Dr. Pasi A. Jänne, MD, PhD, and colleagues, Sarah B. Goldberg, MD, MPH, Assistant Professor of Medicine, and colleagues at Yale Cancer Center, New Haven, Connecticut, noted that KRAS, a member of the RAS family of oncogenes, has remained an elusive target in cancer therapy.1 Some of the genetically defined subsets of NSCLC, including those characterized by EGFR and ALK activating mutations, are sensitive to tyrosine kinase inhibitors, which can produce sustained clinical responses in patients with these disease subtypes. Activating KRAS mutations are implicated in the largest genetically defined subset, being found in approximately 25% of all patients with lung cancer, but until recently, there had been no reports of successful targeted therapy in such disease.

Interpreting the Results

Dr. Goldberg and colleagues make several points about the phase II study that need to be taken into account in interpreting its findings. First, they note that the efficacy of the selumetinib-plus-docetaxel combination may be considered more remarkable given the poor outcome and absence of objective response in the patients receiving docetaxel alone. Outcomes in this group of patients with KRAS-mutant disease were worse than has been observed in populations of unselected patients receiving docetaxel alone for refractory disease.

Second, they note that existing data suggest that KRAS mutation subtype may be an important predictor of treatment outcome and that the presence of certain comutations (ie, p53 and Lkb1 mutations) has been found to affect the activity of the selumetinib-plus-docetaxel combination in mice. Jänne and colleagues did not analyze outcomes by KRAS mutation subtype due to the small number of patients in the trial, and did not report on the status of comutated genes. The commentators note that future trials assessing outcome in KRAS-mutant tumors should include information about both mutation subtype and the presence of comutations, given their potential importance.

Mechanism Unclear

Finally, as stated by the commentators, “[A]lthough Jänne and colleagues showed a benefit with the addition of an MEK inhibitor to a chemotherapeutic agent in the population of patients studied, the mechanism of why these two drugs together are synergistic remains unclear in view of the modest activity with either alone. Moreover, in the absence of information about the effect of selumetinib plus docetaxel in patients with NSCLC that do not harbor an oncogenic KRAS mutation, one cannot definitively conclude that the clinical benefit of selumetinib plus docetaxel has anything to do with the status of RAS in these tumors.”

They note that although effective KRAS inhibitors are currently not available, genetic studies have identified drug targets that are essential for RAS cellular localization and function, raising the hope that novel inhibitors of KRAS and other RAS members will be discovered.

The authors conclude, “In the meantime, [this study] lays the groundwork for a regimen that could bring us one step further in the treatment of NSCLC; however, additional work is needed to confirm these findings and to determine the optimum subset of patients who will benefit from this therapy.” ■

Disclosure: Commentary authors Drs. Sarah B. Goldberg, Joseph Schlessinger, Julie L. Boyer, and Roy S. Herbst reported no potential conflicts of interest.

Reference

1. Goldberg SB, Schlessinger J, Boyer JL, et al: A step towards treating KRAS-mutant NSCLC (comment). Lancet Oncol 14:3-5, 2013.