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

(Press-News.org) 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.

The second paper describes an NSCLC patient who was treated with chemotherapy after initial genetic studies found none of the tumor-associated mutations known at the time. When her cancer continued to progress, additional molecular testing identified a rearrangement in ROS1 that Shaw and her colleagues had only recently described and shown could be treated with crizotinib. At first, the patient's tumor responded quickly, with symptomatic improvement after less than a week of crizotinib therapy. But after three months symptoms returned and her tumor resumed growing, eventually leading to the patient's death.

While the development of resistance to targeted cancer therapies is common, this is the first report of crizotinib resistance in ROS1-positive NSCLC. Detailed molecular analysis revealed a secondary mutation in the initial ROS1 rearrangement. The researchers then determined exactly how crizotinib binds to the ROS1 protein and showed that the new mutation, which is similar to one that confers resistance in ALK-positive tumors, interferes with binding and prevents the drug from inhibiting ROS1-driven tumor growth. Postmortem samples found this resistance mutation in every site to which the tumor had spread.

"Finding that mutation at all sites of disease suggests that it was an early and critical event in the development of resistance," says Jeffrey Engelman, MD, PhD, of the MGH Cancer Center, one of the senior authors of the study. "A similar and highly resistant mutation also occurs in ALK-positive tumors treated with crizotinib, so finding therapies that can overcome this particular type of mutation will be very important."

### Dong-Wan Kim, MD, PhD, of Seoul National University Hospital is co-lead author of the crizotinib/chemotherapy study, and Pasi Jänne, MD, PhD, Dana-Farber Cancer Institute is co-senior author. Additional co-authors include Benjamin Solomon, MB, BS, PhD, Peter MacCallum Cancer Centre, Melbourne, Australia; Fiona Blackhall, Ph.D., Christie National Health Service Foundation Trust, Manchester, U.K.; Ross Camidge, MD, PhD, University of Colorado at Aurora; Tony Mok, MD, Chinese University of Hong Kong; Vera Hirsh, MD, McGill University Health Centre; Keith Wilner, PhD, Pfizer Oncology. Mark M. Awad, MD, PhD, of the MGH Department of Medicine is lead author of the ROS1 resistance mutation study. Additional co-authors include Ryohei Katayama, PhD, Luc Friboulet, PhD, Elizabeth Lockerman and Justin F. Gainor, MD, MGH Medicine; Subba Digumarthy, MD, MGH Radiology; and James Stone, MD, PhD, Mari Mino-Kenudson, MD, and John Iafrate, MD, PhD, MGH Pathology.

Both studies were supported by grants from Pfizer, which markets crizotinib under the brand name Xalkori, and the second was also supported by the National Cancer Institute and the V Foundation.

Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $775 million and major research centers in AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, reproductive biology, systems biology, transplantation biology and photomedicine. In July 2012, MGH moved into the number one spot on the 2012-13 U.S. News & World Report list of "America's Best Hospitals."