Crizotinib Continues to Show Promise for Some Lung Tumors, Faces Challenge of Drug Resistance

Adapted from the NCI Cancer Bulletin.

New data from a phase I trial of crizotinib, a small-molecule drug that targets cancer-causing chromosomal rearrangements involving the gene ALK, in patients with non-small cell lung cancer (NSCLC) add to positive results presented earlier at the 2010 American Society of Clinical Oncology annual meeting. Researchers led by Eunice Kwak, M.D. Ph.D., of Harvard Medical School reported that more than half of patients who have an ALK rearrangement and who received crizotinib had partial or complete shrinkage of their tumors. The updated results were published October 28, 2010, in the New England Journal of Medicine (NEJM).

In comparison, only about 10 percent of lung cancer patients who receive second-line chemotherapy respond to treatment. “It is gratifying to learn of responses like those seen in our study…especially when you consider that most patients had already received two or more therapies by the time they entered the trial,” stated Dr. Kwak in a press release.

The trial, which was sponsored by the drug’s developer, Pfizer, Inc., began as a dose-escalation study in patients with many different solid tumors to determine the maximum safe dose of crizotinib. Later, only patients with solid tumors that had proven molecular abnormalities thought to be targeted by crizotinib, including ALK gene rearrangements in lung cancer, were eligible to enroll.

The NEJM paper reported that 46 of the 82 NSCLC patients had a partial response (their tumors shrank by at least 30 percent in diameter) and one had a complete response. An additional 27 patients had stable disease (i.e., their tumors stopped growing during treatment). The researchers estimated the probability of being alive without progression of disease after 6 months of treatment to be 72 percent. Crizotinib led to few major side effects, and the most common low-grade effects included nausea, diarrhea, and mild visual disturbances.

Additional data from an expanded cohort of 113 patients were presented October 10 at the 2010 European Society for Medical Oncology (ESMO) Congress. Those data showed that response rates remained high, at 56 percent (including partial and complete responses), and that median progression-free survival was 9.2 months.

“As we added more patients to the study, the results remained entirely consistent, and the benefit is consistent across the line of therapy, sex, age, and general fitness,” said Ross Camidge, M.D., Ph.D., from the University of Colorado Cancer Center, an investigator on the trial who presented the data at the ESMO meeting. “That’s consistent with an agent that’s actually addressing the root cause of the cancer.”

Although only 2 to 7 percent of all NSCLC patients have tumors with the ALK genetic change, the sheer number of lung cancer cases diagnosed each year means that “the number of potential patients for crizotinib therapy is substantial, approaching 10,000 annually in the United States alone,” wrote Bengt Hallberg, Ph.D., and Ruth Palmer, Ph.D., from Umeå University in Sweden, in an accompanying editorial in NEJM. A phase III trial comparing crizotinib with standard chemotherapy in patients with advanced NSCLC that harbors an ALK gene rearrangement is ongoing.

Two additional articles in the October 28 NEJM about specific patients in the phase I trial shed some light on the potential future of crizotinib—both the good and the bad. In a case report published by researchers from Dana-Farber Cancer Institute and their colleagues, crizotinib caused disease regression in a patient with inflammatory myofibroblastic tumor (IMT), a rare type of sarcoma in which ALK gene rearrangements are common. In a second case report, researchers at Jichi Medical University in Japan analyzed how new mutations in the ALK gene of another patient led to emerging resistance of his lung tumor to crizotinib.

The case report from Dana-Farber took a closer look at two patients with IMT who had been enrolled in the original dose-escalation portion of the trial. Although both patients had IMT, only one patient turned out to have an ALK-positive cancer. That patient remained alive and in remission and was still receiving the drug at the time of publication, whereas the ALK-negative patient’s disease progressed almost immediately despite crizotinib treatment.

“Given these positive and negative examples and the rarity of the diagnosis, one can extrapolate that ALK inhibitors are appropriate therapy for people with ALK translocation-positive inflammatory myofibroblastic tumor,” said Robert Maki, M.D., Ph.D., a medical oncologist at Memorial Sloan-Kettering Cancer Center and an author on the paper. Recurrent IMTs are often resistant to traditional chemotherapy drugs.

“There’s increasing interest in targeted drugs for rarer cancers—researchers are branching out more and more,” explained Dr. Maki. “This is one of several recent examples of the personalization of medicine based on the targets that are known to be important in a given person’s tumors.”

Unfortunately, a persistent frustration found in the development of targeted drugs is that most tumors eventually develop mutations that confer resistance to the treatment. In the case report from Japan, researchers studied a patient from the phase I trial who developed resistance to crizotinib after 5 months of treatment.

The researchers identified and sequenced two independent mutations in the patient’s rearranged ALK gene that could block the response to crizotinib. These mutations likely alter the structure of the ALK protein, thereby preventing the drug from binding to the protein and diminishing its activity, explained the authors.

It is unknown how common these specific mutations will be in a larger group of patients, said Dr. Camidge, although it is likely that, through a variety of mechanisms, every patient will eventually develop resistance to the drug, he explained. “Every patient that progresses either has primary resistance—that’s the 10 percent or so of patients who don’t respond at all—or initially responds but then acquires resistance.”

One solution to this problem, said Dr. Maki, will be the development of drugs that can bind to mutated ALK proteins, much as dasatinib binds the BCR-ABL protein in patients with chronic myelogenous leukemia (CML). Dasatinib is used to treat imatinib-resistant CML by more broadly blocking the kinase that drives CML, he explained.

Widespread use of drugs tailored to the mutations that drive individual tumors will require the genotyping of tumors, and methods like those currently being employed at Dana-Farber Cancer Institute, the University of Colorado, and other centers are the first step toward making tumor genotyping a standard part of cancer diagnosis. “That’s going to become part of the routine work-up of cancer [patients],” Dr. Maki said. “The genetic changes found in a tumor are eventually going to be more important than whether the cancer began in the colon or the pancreas or the breast.”