PROFILE 1007 Was a Headliner at ESMO
In a phase 3 head-to-head comparison trial, the anaplastic lymphoma kinase (ALK) inhibitor crizotinib proved more effective than standard chemotherapy with pemetrexed or docetaxel as a second-line treatment for non–small cell lung cancer (NSCLC) patients with the ALK genetic abnormality.
The results of the global PROFILE 1007 trial were reported by Alice Shaw, MD, of Massachusetts General Hospital in Boston, at the European Society for Medical Oncology (ESMO) 2012 Congress, held in Vienna, Austria.1
Rearrangements of the ALK gene are found in about 5% of all NSCLC. In previous studies, crizotinib was shown to induce significant clinical responses in patients with advanced ALK-positive NSCLC, but this is the first phase 3 study to directly compare the novel agent with standard chemotherapy. The study compared crizotinib with pemetrexed or docetaxel (by physician choice) in 347 patients with ALK-positive, stage IIIB/IV NSCLC who had already been treated with chemotherapy.
Crizotinib was superior to standard single-agent chemotherapy in terms of response, progression-free survival (PFS), and quality of life in ALK-positive patients who progressed after first-line, platinum-based chemotherapy, Shaw reported.
“These results establish crizotinib as the standard of care for patients with advanced, previously treated, ALK-positive NSCLC,” she maintained.
Doubling in PFS At 12 months’ median follow-up, crizotinib prolonged median PFS to 7.7 months, compared with 3.0 months with chemotherapy, a highly significant 51% reduction in the risk of progression (P <.0001). By type of chemotherapy, median PFS was 4.2 months with pemetrexed (P = .0004) and 2.6 months with docetaxel (P <.0001). The overall response rate was also significantly higher with crizotinib (65% vs 20%; P <.0001).
All subgroups experienced a PFS benefit with crizotinib, with the greatest advantages seen in patients with nonadenoma histology (hazard ratio [HR], 0.12).
Survival, Tolerability At this point, overall survival (OS) differences have not been observed, but the survival analysis is immature, with only 40% of events occurring. Also, 87% of chemotherapy-treated patients have crossed over to receive crizotinib upon progression, and this would dilute any OS differences, Shaw said.
Median OS at this point is approximately 22 months in each arm. When adjusted for confounding by crossovers, there was still a 17% reduced risk of dying from the disease for patients who received ALK inhibitor, she pointed out.
Side effects were more frequent with crizotinib, but Shaw pointed out that crizotinib-treated patients received an average of 11 cycles, compared with 4 with pemetrexed or docetaxel, which partly explains these differences. Toxicities with crizotinib are, however, distinct from those observed with chemotherapy, but are “generally tolerable and manageable,” she noted.
The most common treatment-related adverse events with crizotinib were diarrhea (60%), vision disturbance (60%), nausea (55%), and vomiting (47%), but few grade 3 or 4 toxicities were reported, except for elevated transaminases, which occurred in 16% of this arm. Patients receiving chemotherapy had more fatigue, alopecia, dyspnea, and rash.
Six percent of crizotinib patients, compared with 10% of pemetrexed/ docetaxel patients, discontinued the trial due to treatment-related adverse events.
Better Quality of Life With Crizotinib Patients on crizotinib also reported improved quality of life, compared with chemotherapy. “They reported greater improvement from baseline in cough, dyspnea, fatigue, alopecia, insomnia, and pain with crizotinib,” Shaw said, “and all of these were statistically significant (P <.0001).”
They also showed greater improvement from baseline in global quality of life (P <.0001). Furthermore, “time to deterioration in lung cancer symptoms” was significantly extended with crizotinib treatment, to 5.6 months, compared with 1.4 months with chemotherapy (HR, 0.54; P <.0001).
Crizotinib “Changes the Natural History” of Lung Cancer Discussing the paper at the meeting, Jean-Charles Soria, MD, of the Institut Gustave Roussy in Villejuif, France, noted that 2 months’ extended survival in advanced NSCLC is essentially “unheard of” in the general population of NSCLC patients.
“Comparison with historical data suggests that crizotinib has changed the natural history of the disease, with a median OS now of 22 months, versus 9 months in the past,” he said, “and this is accomplished with very mild toxicity.”
Even patients in the trial who initially received chemotherapy had a median OS of nearly 23 months “because they received crizotinib,” he added.
Soria suggested that clinicians become familiar with the toxicity profile, which is quite distinct from chemotherapy, but is generally manageable with the exception of “some rare side effects you need to be aware of,” he told attendees.
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