麻豆果冻传媒影音

VIENNA -- Patients with advanced non-small cell lung cancer (NSCLC) had a twofold improvement in progression-free survival when treated with a drug that targets a mutation found in 3% to 4% of cases, according to a study reported here.

Patients who received crizotinib (Xalkori) had a median progression-free survival (PFS) of 7.7 months versus 3 months for patients who received docetaxel or pemetrexed (Alimta). All of the patients had tumors with a mutant form of anaplastic leukemia kinase (ALK), reported Alice Shaw, MD, at the European Society for Medical Oncology (ESMO).

The results suggest crizotinib is a new standard of care for patients with ALK-positive NSCLC, added Shaw who is from Massachusetts General Hospital in Boston.

"Crizotinib significantly prolongs PFS and improves overall response rate compared with single-agent chemotherapy in advanced, previously treated ALK-positive non-small cell lung cancer," Shaw said at an ESMO press conference. "No statistically significant difference in overall survival (OS) was observed between crizotinib and chemotherapy, but the interim analysis was immature and may have been confounded by crossover."

"Compared with chemotherapy, crizotinib is associated with significantly greater improvement from baseline in both lung cancer symptoms and quality of life," she added. "These results establish crizotinib as the standard of care for patients with advanced, previously treated ALK-positive lung cancer."

ALK has emerged as a therapeutic target for several types of cancer. In NSCLC, chromosomal rearrangement (inversion or translocation) leads to activation of ALK and oncogene addiction, meaning that the cancer cell cannot survive without ALK activation.

Crizotinib is an oral, small-molecule tyrosine kinase inhibitor that targets ROS1 and MET in addition to ALK. The drug has demonstrated marked activity in advanced ALK-positive NSCLC, reflected in an overall response rate of about 60% and median PFS of 8 to 10 months, Shaw said.

In contrast to crizotinib,the activity of conventional chemotherapy in ALK-positive NSCLC remains unclear. However, in unselected patients with NSCLC, second-line chemotherapy has limited efficacy.

"We hypothesized that in a prospective, randomized trial, crizotinib would have superior efficacy compared with standard second-line chemotherapy in advanced ALK-positive NSCLC," Shaw said.

To test the hypothesis, investigators at 105 sites in 21 countries enrolled patients in a randomized, active-control trial to compare crizotinib with docetaxel and pemetrexed as second-line therapy for ALK-positive NSCLC. Key entry criteria included stage IIIB/IV NSCLC, ALK-positive status confirmed by fluorescence in-situ hybridization, and one prior platinum-containing chemotherapy regimen.

The trial involved 347 patients: 173 in the crizotinib arm and 174 in the chemotherapy arm. Treating physicians chose docetaxel for 72 patients and pemetrexed for the rest. Treatment continued until disease progression, and could continue beyond progression if a patient had ongoing clinical benefit. The primary endpoint was PFS, as determined by independent radiologic review.

Secondary endpoints included overall response rate, disease control rate, safety, OS, and patient-reported outcomes.

Both groups had a median follow-up of about 12 months. Median cycles of therapy initiated in the crizotinib arm were 11 versus four in the chemotherapy arm.

The primary analysis showed a 51% reduction in the hazard for progression in the crizotinib arm (HR 0.49, P<0.0001). The 3-month PFS in the chemotherapy arm included a median PFS of 4.2 months with pemetrexed (HR 0.59, P=0.o004 versus crizotinib) and 2.6 months with docetaxel (HR 0.30, P<0.0001).

An extensive subgroup analysis showed a consistent benefit in favor of treatment with crizotinib.

Overall response rate was significantly higher in the crizotinib arm (65.3% versus 19.5%, OR 3.4, P<0.0001). The overall rate included 29.3% with pemetrexed and 6.9% with docetaxel.

An interim analysis of OS showed a median survival of 20.3 months with crizotinib and 22.8 months with chemotherapy. Shaw pointed out that 111 patients in the chemotherapy arm crossed over to receive crizotinib.

Crizotinib was associated with more adverse events compared with the chemotherapy arm. The most common treatment-emergent adverse events with crizotinib were vision disorder, diarrhea, and nausea in 55% to 60% of patients. Vomiting, constipation, elevated liver enzymes, edema, upper respiratory infection, dysgeusia, and dizziness occurred in 22% to 47% of patients taking crizotinib.

Adverse events that occurred more often with chemotherapy were fatigue, alopecia, dyspnea, and rash.

Patient-reported outcomes all favored crizotinib, including global quality of life and physical, emotional, cognitive, and social functioning. The crizotinib had a median time to deterioration of symptoms of 5.6 months versus 1.4 months with chemotherapy (HR 0.54, P<0.0001).

Press conference moderator Fortunato Ciardiello, MD, PhD, of the Second University of Naples in Italy, said the results will have a major impact on treatment of NSCLC in Europe.

"This is really practice changing, because this is an important randomized study that shows that the best available treatment for these patients is an ALK inhibitor and it is giving a tremendously effective advantage," Ciardiello said. "This is an important step in the personalization of medicine."

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