Crizotinib for ALK-Positive Tumors -- A New Champion in the Cancer Wars?

Zosia Chustecka

October 27, 2010

October 27, 2010 — Striking activity reported for the oral investigational drug crizotinib (Pfizer) in tumors that harbor a specific mutant protein has prompted a New England Journal of Medicine editorial to suggest that it and similar drugs could be "the latest champions in the cancer wars."

The editorial and 3 papers about the new drug appear in the October 28 issue of the journal. One of the papers reports results from a phase 2 clinical trial in nonsmall-cell lung cancer (NSCLC) patients, which generated considerable excitement when they were reported earlier this year at the American Society of Clinical Oncology (ASCO) annual meeting.

Crizotinib acts specifically on tumors that are driven by an abnormally activated protein, ALK (anaplastic lymphoma kinase, named after the first disease in which it was found). It is not beneficial in other cancers.

Works in Only 5.5% of NSCLC Patients

This abnormality was found in only 5.5% of the cohort of 1500 patients with NSCLC who were studied. But in that small group of 82 patients who were ALK-positive, treatment with crizotinib showed striking activity, eliciting a 57% response rate and an 87% disease control rate at 8 weeks.

This response rate is unprecedented in lung cancer.

"This response rate is unprecedented in lung cancer," said Anil Potti, MD, associate professor of medicine at Duke University in Durham, North Carolina, speaking earlier this year at the ASCO meeting. The patients taking part in this clinical trial had already failed on 2 previous chemotherapies, and their chances of responding to a third chemotherapy would be "at best 10%," he told Medscape Medical News at the time.

This same point is made in the editorial accompanying this study, although it notes that there was no control group.

"These results raise the question of whether crizotinib will yield equally strong responses as the first therapeutic intervention or whether a combined approach will be more beneficial," write the editorialists, Bengt Hallberg, PhD, and Ruth Palmer, PhD, from the Department of Molecular Biology at Umeå University in Sweden.

They note that although only 5% of NSCLC patients had tumors that responded to crizotinib, this represents a "substantial" number of potential patients, approaching 10,000 annually in the United States alone.

But to find these patients and others with mutations that have responded to other drugs (EGRF, KRAS), there will need to be an acceptance of "genotyping as a standard practice," they write.

In an interview with Medscape Medical News, the lead author of this study, Eunice Kwak, MD, PhD, from the Massachusetts General Hospital Cancer Center in Boston, said that more recent data from this trial have shown that patients receiving crizotinib had a progression-free survival of 9.2 months, which compares very favorably with what would be expected with chemotherapy.

There is now a phase 3 trial in progress, she explained, in which patients with ALK-rearranged NSCLC who have failed on first-line (cisplatin-based) chemotherapy are being randomized to treatment with second-line chemotherapy (docetaxel or pemetrexed) or crizotinib.

The expectation is that these ALK NSCLC patients will do better on crizotinib, but it is important to test it against chemotherapy in case these patients also respond well to that approach, explained John Iafrate, MD, PhD, senior author of this study from the Massachusetts General Hospital Cancer Center.

The high response rate of ALK NSCLC patients to crizotinib is "very exciting," he said, but he added that it is in line with what has been seen before with targeted agents, such as erlotinib and gefitinib in EGRF NSCLC. Together, these 2 genotypes account for about 20% of all lung cancer (5% ALK and 15% EGRF), so there are still many patients who do not have the benefit of this targeted approach. Several more genotypes are under study, but many of these are rare (found in only 2% to 3% of patients). "But the elephant in the room is KRAS mutations, found in about 35% of lung cancer patients. So far, there is no agent that targets this," he said. Several have been tried but have failed. "What we need is a crizotinib-type drug for every patient," he added.

Response in Myofibroblastic Tumor

Another of the papers reports on how crizotinib was beneficial in a patient with an ALK-positive inflammatory myofibroblastic tumor (IMF), a rare and aggressive form of soft-tissue cancer.

James Butrynski, MD, and colleagues from the Dana-Farber Cancer Institute in Boston, report that the patient had previously been treated with chemotherapy and with imatinib (Gleevec), but the cancer returned as multiple lesions. Treatment with crizotinib produced a sustained partial response (with tumor shrinkage of >50%), but despite the continued partial response of multiple mesenteric and peritoneal lesions, the patient had other lesions (hepatic, peripancreatic, and perirectal) that continued to grow. The patient underwent surgery for maximal debulking of these growing lesions, and then restarted treatment with crizotinib 250 mg twice daily, which had been defined as the maximum tolerated dose. The result was complete radiographic remission and, as of September 2010, the patient remains clear of evidence of disease.

In contrast, a second patient with IMF that was not ALK-positive failed to respond to crizotinib, the researchers report.

Already, the Spectre of Resistance

The third paper discusses the problem of resistance to crizotinib, and describes a case study of 1 patient with NSCLC who had an initial strong clinical response to the drug, but then developed mutations in the ALK protein that conferred a resistance to the drug.

Although further study of the mechanisms involved is needed, "the appearance of crizotinib-resistance mutations in this patient indicates that additional ALK inhibitors will be required to target EML4-ALK mutants that are insensitive to crizotinib in a clinical setting," the editorialists note.

They also speculate that in the case of the IMF ALK-positive patients described at Dana-Farber, the lesions that continued to grow and that were then surgically removed might have harbored mutations that were resistant to crizotinib, although other lesions in that same patient responded to the drug.

The possibility that a series of ALK inhibitors will be needed to overcome emerging resistance will require close collaboration between basic scientists and clinicians, the editorialists write. "It is encouraging that some progress in this area has already been made," they add.

A number of new ALK inhibitors are already in the pipeline, they note, including AP26113 (Ariad Pharmaceuticals). Earlier this year at the American Association for Cancer Research annual meeting, it was reported that AP26113 overcomes mutations in EML4-ALK that confer resistance to crizotinib (abstract LB-298).

The clinical studies of NSCLC and IMF were supported by Pfizer. The study of mutations in tumor cells isolated from an NSCLC patient who became resistant to crizotinib was funded by the Japan Ministry of Health, Labor and Welfare.

N Engl J Med. 2010;363:1693-1703, 1727-1733, 1734-1739, 1760-1762. Abstract, Abstract, Abstract, Abstract

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