Crizotinib Continues to Produce High Response in ALK+ NSCLC



CHICAGO – Nearly two-thirds of patients with non–small cell lung cancer who were positive for the anaplastic lymphoma kinase responded to the experimental agent crizotinib. The responses were "rapid, dramatic, and durable," investigators reported at the annual meeting of the American Society of Clinical Oncology.

In an ongoing phase I trial, the overall response to crizotinub was 61%, and the median duration of response was 48 weeks. Median progression-free survival was 10 months, reported Dr. D. Ross Camidge, associate clinical director of the thoracic oncology program, University of Colorado, Aurora.

The study and its results are "truly brilliant," commented Dr. Nasser H. Hanna, associate professor of medicine at Indiana University in Indianapolis. Dr. Hanna was the invited discussant.

He added, however, that "most lung cancer is not driven by one or two gene mutations, so ultimately our future success depends upon combining targeted agents in these more complex tumors."

Activation of the anaplastic lymphoma kinase (ALK), primarily through gene rearrangements, is thought to be a primary oncogenic trigger in several different human cancers, including about 3-5% of non-small cell lung cancers (NSCLC).

Crizotinib is a potent and selective oral inhibitor of ALK. Interim results of the agent in ALK-positive NSCLC in a study of 82 patients treated for an average of 6.4 months were reported at the 2010 ASCO annual meeting and in the New England Journal of Medicine (N. Engl. J. Med. 2010; 363:1693-1703). Those data showed an overall response rate of 57% (47 of 82 patients, with 46 confirmed partial responses and 1 confirmed complete response). Additionally, 27 patients (33%) had stable disease.

In the current report, a continuation of the same study with 119 patients, Dr. Camidge reported data on 116 evaluable patients with a median duration of follow-up of 11 months. The median age was 51 years (range 21-79), and the sample was split evenly between men and women. In all, 72% of patients had never smoked. Nearly all of the cancers (97%) were adenocarcinomas.

The median time to response was 8 weeks, although some patients displayed measurable responses in as little as 2 weeks. The disease control rate was 79% at 8 weeks, and 67% at 16 weeks.

Patients 65 and older did slightly better, with a 69% objective response rate (ORR), compared with 60% for those under 65. Patients with no prior systemic therapies fared best, with an 80% ORR, compared with 60% for patients with metastatic disease who had received one prior systemic therapy, and 58% for those who had received at least two lines of therapy. Patients of Asian origin had an 82% ORR, compared with 52% of non-Asians; the difference could be due to pharmacogenomic differences in drug exposure, but the numbers are small and this effect needs to be explored further, Dr. Camidge said.

Median overall survival has not yet been reached. There have been 23 deaths (19%) and 2 patients lost to follow-up, leaving 94 patients (79%) for the overall survival analysis. No treatment-related study deaths have been reported.

Patients with documented disease progression could continue to receive crizotinib if, in the opinion of the investigators, they would derive a clinical benefit. A total of 40 patients (34%) experienced disease progression according to Response Evaluation Criteria in Solid Tumors (RECIST) at the time of the data cutoff (Oct. 29, 2010). Sixteen of these patients continued to receive crizotinib for more than 2 weeks.

Nearly all patients (96%) reported a treatment-related adverse event. Most of the events were grade 1 or 2, although 19 patients (16%) had grade 3 or 4 events. The most common adverse events were visual effects, nausea, diarrhea, vomiting, edema (both localized and peripheral), and constipation.

The results of the trial and another study (PROFILE 1005) have prompted investigators to seek accelerated approval for the drug in patients with ALK-positive NSCLC.

"Preclinical evidence suggests that ALK inhibitors are more effective than chemotherapy in ALK-positive disease, and retrospective clinical data supports this hypothesis. But ultimately, we have to wait for a definitive answer in a phase III trial which has just been completed comparing an ALK inhibitor vs. chemotherapy in this group of patients," Dr. Hanna noted.

The study was funded by Pfizer. Dr. Camidge and several of his coauthors have served in an advisory role and received research funding and honoraria from the company. Dr. Hanna had no relevant disclosures.

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