MGH-led studies shed new light on targeted lung cancer therapy

Research teams led by Massachusetts General Hospital (MGH) Cancer Center investigators are publishing two important studies regarding use of the targeted cancer drug crizotinib for treatment of advanced lung cancer driven by specific genetic mutations. The first reports the final results of a global, phase 3 trial showing that crizotinib is superior to standard chemotherapy for treatment of advanced ALK-positive non-small cell lung cancer (NSCLC). The second paper describes the first report of resistance to crizotinib treatment in a patient with ROS1-positive NSCLC and reveals the mechanism underlying that resistance. Both papers are being published online in the New England Journal of Medicine to coincide with the American Society of Clinical Oncology annual meeting.

One of a group of drugs that directly targets genetic mutations spurring the uncontrolled growth of cancer, crizotinib has regulatory approval for the treatment of advanced NSCLC driven by rearrangements of the ALK gene and is being investigated for treatment of tumors driven by the MET and ROS1 genes. While previous studies showed that crizotinib was effective in treating ALK-positive lung cancer, the activity of standard chemotherapy against that type of tumor - which had only recently been described - was not known.

"This is the first randomized study to compare crizotinib with standard chemotherapy in advanced ALK-positive lung cancer," says Alice Shaw, MD, PhD, of the MGH Cancer Center, the first author and lead investigator for the study. "This study supports the full FDA approval of crizotinib in the U.S. and has also led to approval of crizotinib in many countries around the world." Preliminary results from this trial were first reported at the European Society for Medical Oncology meeting in September 2012.

The trial enrolled 347 patients with advanced ALK-positive NSCLC that had progressed after first-line treatment. Participants were randomly assigned to receive either oral crizotinib twice a day or standard chemotherapy with the intravenous drugs pemetrexed or docetaxel, given once every three weeks. Patients in the chemotherapy group whose tumors progressed were allowed to cross over to receive crizotinib.

Compared to chemotherapy, crizotinib more than doubled the average progression-free survival, from 3 months with chemotherapy to 7.7 months. The response rate with crizotinib was 65 percent, more than triple that of chemotherapy. Crizotinib more powerfully suppressed and prevented the recurrence of symptoms and resulted in significantly greater quality-of-life improvements. While overall survival rates for both groups were quite similar, more than 60 percent of those in the chemotherapy group eventually began receiving crizotinib which, the authors note, probably confounded the survival analysis.

"This study shows that patients with advanced ALK-positive lung cancer respond better to crizotinib and for longer periods of time," Shaw says. "Equally important, patients treated with crizotinib report better symptom control and quality of life than those treated with chemotherapy." Another ongoing phase 3 trial is comparing crizotinib to chemotherapy as first-line treatment for newly diagnosed patients.