First success of targeted therapy in common genetic subtype of NSCLC

A new study is the first to demonstrate that the combination of chemotherapy and selumetinib, a new targeted therapy, works better than chemotherapy alone in treating patients with the most common genetic subtype of lung cancer.

Non-small cell lung cancer (NSCLC) with a mutation in the KRAS gene represents about 20% of all NSCLC cases. Previously, no targeted agent, either alone or in combination with another drug, had proven beneficial in a trial involving patients with this type of NSCLC.

This phase II trial, which was conducted at 67 sites around the world, involved 87 patients who had advanced, KRAS-mutant NSCLC that failed initial chemotherapy. The participants were randomly assigned to receive either selumetinib and docetaxel or docetaxel alone.

The investigators found that while 37% of the patients in the selumetinib group experienced some shrinkage of their tumor, 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. Also, patients in the selumetinib group survived longer, on average, than those in the docetaxel group—9.4 months compared with 5.2 months—but the improvement was not considered statistically significant.

“Our findings suggest that selumetinib and docetaxel work synergistically—each enhancing the effect of the other,” says the study's lead author, Pasi A. Janne, MD, PhD, of Dana-Farber Cancer Institute in Boston. “This opens the possibility that there may finally be a therapeutic strategy using a targeted therapy which could be clinically effective in this population of KRAS-mutant lung cancer patients.”

Some side effects, including neutropenia, febrile neutropenia, shortness of breath, and loss of strength, were more common in the selumetinib group than the other. Researchers and physicians will need to work on ways of managing these problems with patients, Jänne said.

NSCLC tumors 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 whites than in others. The study findings are especially noteworthy because mutated KRAS—regardless of the type of tumor 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 one of the gene's coconspirators, a protein called MEK that is indirectly activated by KRAS.

“The opportunity now is to validate this approach in further clinical trials so it can be developed into a real therapy for patients,” Jänne remarks. “Given that KRAS mutations are common in other cancers (found in 90% of pancreatic cancers and 40% of colon cancers), our findings may be useful in developing therapies for patients with these cancers as well.”

This study was published in The Lancet Oncology (2012; doi:10.1016/S1470-2045(12)70489-8).
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