In a phase I study in advanced non-small cell lung cancer (NSCLC) presented at the Plenary Session of the 2010 ASCO Annual Meeting, a multinational group of researchers reported impressive clinical activity with an investigational agent unfamiliar to many oncologists.¹

The oral drug crizotinib (PF-02341066), an inhibitor of anaplastic lymphoma kinase, or ALK, produced tumor shrinkage in 57%, and prolonged remission in 72%, of heavily pretreated advanced NSCLC patients selected for ALK protein expression, reported Yung-Jue Bang, MD, PhD, Professor of Internal Medicine at Seoul National University in South Korea.

"Our results were very impressive. The majority of patients responded, often within the first 2 weeks of treatment, and the responses were often durable," Dr. Bang commented.

Crizotinib targets a fusion protein called EML4/ALK, which drives tumor growth in 3% to 5% of all NSCLC patients. In preclinical studies, crizotinib induces apoptosis in ALK-positive NSCLC cells.

The data come from an ongoing phase I trial of patients with ALK-positive NSCLC treated with oral crizotinib, 250 mg twice daily. This is the first study of the drug in patients. Dr. Bang presented the results from the first 82 patients for whom data were available as of April 7, 2010.

The patients' mean age was 51 years, 96% had adenocarcinoma histology, 76% were "never-smokers," and 41% had undergone at least three prior regimens.

Striking Tumor Shrinkage Observed

"Almost all patients had some degree of tumor shrinkage (Fig. 1), although more than half the patients (59%) had had at least two previous treatments," Dr. Bang reported.

Objective responses were observed in 57% of the cohort (63% when five unconfirmed partial responses are included), including more than half the patients with performance status 2 or 3. In terms of prior regimens, 80% of treatment-naive patients responded, as did 52% receiving the drug as second-line therapy, 67% as third line, and 56% as fourth line or greater. Response duration ranged from 1 to 14 months, and the disease control rate (response or stable disease at 8 weeks) was 87%.

At a median follow-up of 6.4 months, median progression-free survival (PFS) was not yet reached. However, the probability of being progression-free at 6 months is 72%. Approximately 77% of patients remain on treatment, including seven patients for more than 1 year, he said.

Treatment-related adverse events included nausea (52%), diarrhea (46%), vomiting (43%), and visual disturbance, ie, "shadows" (42%), but virtually all of these events were grade 1 and they tended to resolve over the course of treatment.

Based on these preliminary findings, Dr. Bang maintained that "for patients with ALK-positive NSCLC, crizotinib may offer a potential new standard of care."

Rapid Translational Research

Mark Kris, MD, Chief of the Thoracic Oncology Service at Memorial Sloan-Kettering Cancer Center in New York, who moderated a press briefing, commented that the findings are very important, not only for their clinical significance but as an example of rapid translational research. The fusion gene was first reported in 2007, he noted, and relevant clinical results are already being presented. "In just 3 short years we have gone from a description of an oncogene to a therapy" with which selected patients with the ALK mutation "can expect a dramatic benefit," he said.

"This speaks to the power of understanding the workings of the cancer cell, the mutations driving cancer growth, and how this can be parlayed into improvements in care," he said, adding that the "apparatus" is already in place to begin testing a variety of emerging mutations. ■

References

Bang Y, Kwak EL, Shaw AT, et al: Clinical activity of the oral ALK inhibitor PF-02341066 in ALK-positive patients with non-small cell lung cancer. 2010 ASCO Annual Meeting. Abstract 3. Presented June 6, 2010.