New data from a phase I trial of Crizotinib ( Xalkori ), 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 ( ASCO ) annual meeting. Researchers led by Eunice Kwak, 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 in the New England Journal of Medicine ( NEJM ).

The trial 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% 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%.
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 at the 2010 European Society for Medical Oncology ( ESMO ) Congress. Those data showed that response rates remained high, at 56% ( including partial and complete responses ), and that median progression-free survival was 9.2 months.

Two additional articles in the NEJM about specific patients in the phase I trial shed some light on the potential future of Crizotinib. 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 inflammatory myofibroblastic tumor 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.
Recurrent inflammatory myofibroblastic tumors are often resistant to traditional chemotherapy drugs.

There’s increasing interest in targeted drugs for rarer cancers. 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.

Source: National Cancer Institute, 2010

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