Crizotinib in ALK-NSCLC; Response Rate "Unprecedented"

Zosia Chustecka

June 07, 2010

June 7, 2010 (Chicago, Illinois) — A new targeted agent has shown benefit in a subgroup of patients with nonsmall-cell lung cancer (NSCLC).

In a phase 2 clinical trial reported in a plenary session here at the American Society of Clinical Oncology 2010 Annual Meeting, the investigational drug crizotinib (under development by Pfizer), which is a specific ALK inhibitor, showed an objective response rate of 57% and a disease control rate of 87% in NSCLC patients whose tumors had a rearrangement of the ALK gene.

"This is stellar, compared with what we see in nonselected NSCLC patients treated with chemotherapy," said principal investigator Alice Shaw, MD, PhD, a thoracic oncologist at the Massachusetts General Hospital Cancer Center in Boston.

"This response rate is unprecedented in lung cancer," said Anil Potti, MD, associated professor of medicine at Duke University in Durham, North Carolina, who was approached for comment. The patients taking part in this clinical trial had already failed on at least 2 previous chemotherapies, and their chances of responding to a third chemotherapy would be "at best 10%," he explained. So the response rate that was reported here "is indeed stellar," he told Medscape Oncology in an interview.

"This is a huge success for biomarker-driven clinical trials," Dr. Potti said, adding that he hopes it will lead to a fundamental paradigm change in clinical trials and a move away from testing drugs in unselected patient populations.

This work adds another biomarker to the field of lung cancer, he pointed out. Already, there is a body of evidence showing that lung cancer with tumors that harbor a mutation of the epidermal growth-factor receptor (EGFR) benefit from the EGFR inhibitor erlotinib (with about a 70% response rate). This drug has become a first-line therapy and is used alone in this patient subgroup, he explained. Now there is another subgroup and another targeted agent.

EGRF mutations are found in about 10% of patients with NSCLC, and ALK gene rearrangements in about 3% to 5% of these patients. "But these 2 biomarkers are mutually exclusive," Dr. Potti pointed out, so together it means that there is now around 15% of patients who can be treated with targeted therapies.

Considering how common lung cancer is (200,000 cases of NSCLC are diagnosed each year in the United States), even these percentages translate into large numbers of patients, said Martin Edleman, MD, from the University of Maryland Greenebaum Cancer Center in Baltimore, who discussed the abstract. The 3% to 5% of NSCLC patients with the ALK gene represents 6,000 to 10,000 patients in the United States, which is as many as there are with Hodgkin's lymphoma, he said.

The proportion of lung cancer patients harboring these genetic changes is much greater when only nonsmokers are considered, he added.

Dr. Potti also pointed out that the targeted therapies are oral and have milder adverse effects than chemotherapy. These drugs offer better a quality of life, better responses, and with erlotinib — at least so far — better overall survival, so they are "winners all round," he added.

Crizotinib is now in expanded clinical trials, including a randomized phase 3 trial (PROFILE 1007) funded by Pfizer. The trials have started recruiting, and a central laboratory is currently carrying out the lung cancer tissue genotyping.

Genotyping of tumor tissue for all lung cancer patients is becoming more commonplace, said Dr. Shaw. At her clinic at the Massachusetts General Hospital, all patients have been tested for more than a year now, and many other large academic centers are genotyping all lung cancer patients, including Memorial Sloan-Kettering, Vanderbilt University, the University of Colorado, she added.

However, Dr. Edelman explained that there has also been some opposition to the collecting and testing of tissue and its storage, noting "the cynical refusal from some medical insurance companies to cover tissue testing," a comment that drew a round of applause from the audience.

Results of the Study

Dr. Yung-Jue Bang

The phase 2 study of crizotinib was presented by Yung-Jue Bang, MD, PhD, from Seoul National University College of Medicine in Korea. It was conducted in 82 patients with NSCLC who were found to have the ALK fusion gene and who had progressed on previous chemotherapy regimens (a median of 3); all received the new drug (250 mg twice daily).

More than 90% of patients showed tumor shrinkage, Dr. Bang reported. The responses have been durable (up to 15 months), and patients had a 72% probability of being progression-free at 6 months.

The drug is well tolerated, Dr. Bang said, adding that the most commonly reported adverse effects were nausea, diarrhea, and vomiting, but they were mild (grade 1) and subsided with time.

Dr. Bang and coauthors report receiving research funding and honoraria and serving as consultants or advisors to Pfizer.

American Society of Clinical Oncology (ASCO) 2010 Annual Meeting: Abstract 3. Presented June 6, 2010.