VIENNA – Long-awaited data from the phase III PROFILE 1007 confirm that crizotinib provides superior progression-free survival and responses, compared with second-line chemotherapy in advanced anaplastic lymphoma kinase–positive non–small cell lung cancer.
Median progression-free survival more than doubled from 3.0 months with single-agent chemotherapy to 7.7 months with crizotinib, according to an independent radiologic review (P value less than .0001; hazard ratio, 0.49).
Crizotinib (Xalkori) remained superior regardless of whether chemotherapy contained docetaxel (Taxotere) (7.7 vs. 2.6 months; P less than .0001) or pemetrexed (Alimta) (7.7 vs. 4.2; P = .0004), an agent previously shown to be effective against ALK-positive NSCLC.
The overall response rate was 65.3% for crizotinib and 19.5% for chemotherapy in the intent to treat population of 347 patients (overall response rate ratio 3.4; P less than .0001).
Patrice Wendling/IMNG Medical Media
Dr. Alice Shaw
Crizotinib was also associated with significantly greater improvement in lung cancer symptoms and quality of life, Dr. Alice Shaw reported during a presidential symposium at the joint congress of the European Cancer Organization, the European Society for Medical Oncology, and the European Society for Radiotherapy and Oncology.
"Taken together, these results establish crizotinib as the standard of care for patients with advanced, previously treated ALK-positive non–small cell lung cancer," she said.
ALK rearrangements are present in about 5% of lung cancers, typically in younger, never smokers.
Overall survival in the study was 22.8 months for chemotherapy and 20.3 months for crizotinib (P = .5394; HR, 1.02).
The interim survival analysis was immature with just 40% of expected deaths reported and likely confounded by the high number (87%) of chemotherapy patients who crossed over to crizotinib after progression, she noted. After adjusting for crossover, the hazard ratio suggests a survival advantage with crizotinib (HR, 0.83).
Discussant Jean-Charles Soria of Institut Gustave Roussy, Villejuif, France, agreed and said the survival times in either arm were impressive, observing that just two years ago survival in second-line ALK-positive NSCLC was just nine months.
"This is really changing the natural history of the disease," he said.
Crizotinib, an oral, first in class ALK inhibitor, was given accelerated approval in 2011 in the United States to treat advanced ALK-positive NSCLC but is not approved in Europe, where regulatory agencies have required data from the randomized trial.
"While the U.S. treats, Europe randomizes," Dr. Soria lamented to a loud round of laughter.
He observed that worldwide use of crizotinib will require that several financial and practical issues surrounding implementation of molecular testing in daily practice be addressed including the optimal technique, type of sample, and tissue availability.
Testing for epidermal growth factor receptor, another molecular alteration that directs targeted therapy in lung cancer, "should not compete with ALK," he said, adding that multiplexing test strategies "are key."
Investigators at 105 sites across 21 countries in Europe, the Americas, and Asia-Pacific, randomized 173 patients to crizotinib 250 mg twice-daily in a 21-day cycle and 174 patients to chemotherapy containing pemetrexed 500 mg/m2 or docetaxel 75 mg/m2 given intravenously on day 1 of a 21-day cycle.
Treatment duration varied significantly, with patients receiving a median of 11 cycles of crizotinib vs. 4 cycles of chemotherapy. This may have influenced the higher number of all-cause deaths among crizotinib patients (25 deaths vs. 7 deaths), said Dr. Shaw, a thoracic oncologist at Massachusetts General Hospital Cancer Center in Boston.
Crizotinib patients were more likely than were chemotherapy patients to experience the now well-known side effect of visual disturbances (any grade 60% vs. 9%), as well as diarrhea, nausea, elevated transaminases (16% grade 3/4 ), edema, upper respiratory infection, dysgeusia, and dizziness.
In contrast, fatigue, alopecia, dyspnea, and rash were more common in those receiving chemotherapy.
Despite the fact that patients on crizotinib experienced more nausea and vomiting, antiemetic use was significantly higher in the chemotherapy arm (67% vs. 20%), observed Dr. Shaw, who said the majority of adverse events were grades 1/2, generally manageable, and tolerable.