A small, phase II clinical study has found a promising targeted therapy for the most common subtype of non-small cell lung cancer (NSCLC). A combination of chemotherapy and the MEK inhibitor drug selumetinib was more effective than chemotherapy alone in NSCLC patients with a mutation in the KRAS gene.
The KRAS mutation is found in about 20% of NSCLC cases. There are no targeted therapies available for this particular mutation and patients with KRAS-mutant NSCLC do not respond to kinase inhibitors that are effective in other oncogenic mutations. This study, led by scientists from Dana-Farber Cancer Institute and conducted across 12 countries, is the first to assess the new targeted therapy in conjunction with chemotherapy in patients with the KRAS mutation and advanced NSCLC.
Eighty-seven patients whose cancer had progressed after initial chemotherapy were randomized to receive either selumetinib plus the chemotherapeutic agent docetaxel, or docetaxel alone (placebo). The patients were, on average, just under age 60 years, white, and past or current smokers and the majority of their cancers were stage IIIB or IV adenocarcinomas. In the combination treatment group, 37% of the patients showed some tumor shrinkage, while none in the placebo group did. The two groups also differed in their progression-free survival, with the patients receiving selumetinib living a median of 5.3 months before their cancer got worse versus 2.1 months for the placebo group. Overall survival was also longer for patients in the combination treatment group (9.4 months) compared to the placebo group (5.2 months), but this difference was not statistically significant.
Because selumetinib monotherapy has shown only modest clinical efficacy, the researchers suggest that selumetinib and docetaxel work synergistically to inhibit tumor growth and induce cell death. Selumetinib functions by inhibiting the activity of a protein called MEK that contributes to uncontrolled cell proliferation when KRAS is mutated. Most patients in this study had a mutation in codon 12 of the KRAS gene. Such mutation subtypes may be an important predictor of treatment outcome, especially as KRAS mutations are also prevalent in pancreatic and colon cancers. Past studies have shown that KRAS-mutant NSCLC patients benefit less from conventional chemotherapy than other patients with NSCLC.
While the combination of selumetinib and docetaxel was effective, the treatment was associated with more side effects including neutropenia (deficiency of white blood cells), neutropenia with fever, weakness, and difficulty breathing. Nonetheless, the investigators noted a “clinically meaningful improvement in disease-related symptoms.” Management of adverse symptoms, for example, with the administration of growth factors for neutropenia, should mitigate the problems associated with the combination treatment, according to the researchers.
Further work into the mutation subtypes and co-mutations in KRAS-mutant patients could lead to more effective targeted therapies. In addition, testing of the combination therapy in NSCLC patients without the KRAS mutation could reveal more about the mechanism and help identify the subset of patients who could benefit the most.
Selumetinib is developed by AstraZeneca, which sponsored the study. This study was published in the January 2013 issue of The Lancet Oncology.