Nick Mulcahy

June 14, 2012

June 14, 2012 (Chicago, Illinois) — KRAS mutations are the most common oncogenic alteration in nonsmall-cell lung cancer (NSCLC), with about 20% of cases affected. However, unlike for the less common EGFR and ALK mutations, there are no targeted therapies for KRAS-mutant NSCLC.

The experimental targeted therapy selumetinib (AstraZeneca) might change this situation, according to a presentation here at the 2012 Annual Meeting of the American Society of Clinical Oncology (ASCO).

The drug showed activity in a phase 2 trial in which patients receiving selumetinib fared better than those receiving placebo on a number of measures, according to Pasi A. Jänne, MD, PhD, from the Dana-Farber Cancer Institute in Boston, Massachusetts.

"For the first time, we may have an effective treatment for KRAS-mutant lung cancer, which is the largest single subtype of the disease," said Dr. Jänne in a press statement. He is scientific codirector of Dana-Farber's Belfer Institute for Applied Cancer Science.

All study participants had stage IIIB to IV disease and had received no previous chemotherapy. All received either selumetinib or placebo in addition to docetaxel, the standard chemotherapy.

Selumetinib demonstrated a superior response rate, compared with placebo (37% vs 0%; P < .0001), and prolonged progression-free survival (5.3 vs 2.1 months; hazard ratio, 0.58; 80% confidence interval, 0.42 to 0.79; 1-sided P = .0138).

The patients in the selumetinib group also survived longer, on average, than those in the placebo group (9.4 vs. 5.2 months), but the difference was not statistically significant.

This is the first prospective study to demonstrate the clinical benefit of a targeted therapy for patients with KRAS-mutant lung cancer, the study authors note.

More work is needed, but this is certainly encouraging.

At the ASCO meeting, a cancer expert endorsed the findings to date. "More work is needed, but this is certainly encouraging," said Thomas Lynch, MD, from the Yale Cancer Center and Smilow Cancer Hospital in New Haven, Connecticut. He was referring to the progression-free and overall survival findings in particular, and mentioned the study during a Highlights of the Day session.

Selumetinib is not the only targeted therapy currently being evaluated in KRAS-mutant NSCLC, according to Dr. Jänne. GlaxoSmithKline is undertaking a randomized phase 2 trial comparing their MEK inhibitor (GSK1120212) with docetaxel chemotherapy, he told Medscape Medical News.

More Details

From April 2009 to June 2010, 422 lung cancer patients were screened at 67 centers in 12 countries; 113 had KRAS-mutant NSCLC and 87 were randomized into the trial.

The baseline characteristics "were balanced," the authors report. About 50% of patients in each treatment group had a WHO performance score of 0, and about 50% were female. The median number of treatment cycles was 4 in the placebo group and 5 in the selumetinib group.

Discontinuation because of adverse events was a bit worse with selumetinib than with placebo (18.2% vs 11.9%). Neutropenia was the most common hematologic adverse event.

Adverse Events in the Selenium and Placebo Groups

Adverse Event Selumetinib Placebo
Neutropenia 67.4% 54.8%
Febrile neutropenia 15.9% 0.0%
Dyspnea 2.3% 11.9%
Respiratory failure 6.8% 4.8%
Asthenia 9.1% 0.0%

These clinical findings have implications not only for the treatment of lung cancer, but for all cancers that harbor KRAS mutations, including pancreatic and colorectal cancer, said Dr. Jänne.

The study was sponsored by AstraZeneca.

2012 Annual Meeting of the American Society of Clinical Oncology: Abstract 7503. Presented June 2, 2012.