Selumetinib in combination with docetaxel for KRAS-mutant advanced NSCLC
A step forward in the treatment of KRAS-mutant NSCLC
A new study by an international team of investigators led by Dana-Farber Cancer Institute scientists is the first to demonstrate that chemotherapy and a new, targeted drug - selumetinib, work better in combination than chemotherapy alone in a clinical trial involving patients with a form of non-small cell lung cancer (NSCLC) that carries a mutation in the gene KRAS. Previously, no targeted agent, either alone or in combination with another drug, had proven beneficial in a study involving patients with this type of NSCLC. The study results were published online on 28 November 2012 in The Lancet Oncology.
During the past few years, NSCLC has been reclassified into several molecularly defined subsets of the disease. The largest subset harbours an activating KRAS mutation and includes about 25% of all patients with lung cancer, mainly adenocarcinoma. NSCLC tumours with KRAS mutations are more common in current and former smokers than in those who have never smoked, and occur at a higher rate in Caucasians than in others.
Selumetinib is an inhibitor of MEK1/MEK2, downstream of KRAS, with preclinical evidence of synergistic activity with docetaxel in KRAS-mutant cancers.
The study details and results
The investigators performed a prospective, randomized, phase II trial to assess selumetinib in combination with docetaxel in patients with histologically or cytologically confirmed stage IIIB and IV KRAS-mutant NSCLC, who had failed first-line therapy. The 87 patients who participated in the study, conducted at 67 sites around the world, were randomly assigned (1:1) to receive either selumetinib and docetaxel or docetaxel alone. The primary endpoint was overall survival, analysed for all patients with confirmed KRAS mutations.
The investigators found that while 37% of the patients in the selumetinib group experienced objective response rate, none of the patients in the docetaxel-only group did. Of particular significance, patients receiving selumetinib lived a median of 5.3 months before their cancer began to worsen, compared to 2.1 months for those receiving chemotherapy alone (p = 0.014). Patients in the selumetinib group also survived longer, on average, than those in the docetaxel group (9.4 months compared to 5.2 months) but the improvement was not considered statistically significant.
Adverse events of grade 3 or higher occurred in 82% patients in the selumetinib group and 67% patients in the placebo group. The most common grade 3/4 adverse events were neutropenia, febrile neutropenia, dyspnoea, and asthenia.
The authors interpreted the study results by concluding that the combination of selumetinib and docetaxel has promising efficacy, albeit with a higher number of adverse events than with docetaxel alone. The findings warrant further clinical investigation in previously treated advanced KRAS-mutant NSCLC. According to the study's lead author, Dr Pasi Janne of Dana-Farber, the findings suggest that selumetinib and docetaxel work synergistically.
The study findings are especially noteworthy because mutated KRAS – regardless of the type of tumour it appears in – has been one of the most difficult genes to block with targeted therapies. Selumetinib circumvents that problem by targeting not KRAS itself, but a protein called MEK that is indirectly activated by KRAS.
The opportunity for researchers is now to validate this approach in further clinical trials. Given that KRAS mutations are common in other cancers (90% of pancreatic cancers and 40% of colon cancers), these findings may be useful in developing therapies for patients with these cancers as well, according to Dr Janne.
The study was sponsored by AstraZeneca, which holds the rights to the development of selumetinib.
Image caption: A new study by researchers including Dr Pasi Janne reports first success of targeted therapy in most common genetic subtype of non-small cell lung cancer
Credit: Dana-Farber Cancer Institute
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