Crizotinib better than standard chemotherapy in some patients, study says

In a phase 3 study of previously treated patients with anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC), crizotinib (Xalkori, Pfizer) more than doubled median progression free survival (PFS) than when treated with standard chemotherapy, according to a study published June 1, 2013 online in New England Journal of Medicine.

In the PROFILE 1007 study, crizotinib more than doubled median progression free survival (PFS) to 7.7 months (n=173) (95% CI, 6.0 to 8.8) compared to 3.0 months when treated with standard chemotherapy (pemetrexed or docetaxel) (n=174) (hazard ratio 0.49; 95% CI, 0.37 to 0.64; P˂0.001).

 At the time of data cutoff, the objective response rate (ORR), a key secondary end point, was higher in the crizotinib arm (65%; 95% CI, 58-72) compared with the chemotherapy arm (20%; 95% CI, 14-26) in the intent-to-treat population (P˂.001).

The phase 3 PROFILE 1007 trial was a randomized open-label, 2-arm study of 347 patients with ALK-positive advanced NSCLC of Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2, previously treated with 1 platinum based chemotherapy regimen. Patients with treated brain metastases were allowed in the study. Patients were randomly assigned 1:1 to crizotinib, administered at a starting dose of 250 mg twice daily, or chemotherapy (pemetrexed or docetaxel). The primary end point of the study was PFS as assessed by independent central review. Secondary end points included overall survival (OS), objective response rate (ORR), patient-reported outcomes, quality of life, and safety.

“These results demonstrate [crizotinib’s] superiority to standard chemotherapy in prolonging PFS in a patient population with limited treatment options,” said Dr. Robin Wiltshire, global medical affairs lead at Pfizer.  “[Crizotinib] is changing the treatment paradigm for patients with ALK-positive advanced NSCLC, and these findings reinforce the importance of routine molecular testing in the treatment of lung cancer.”

The OS analysis was preliminary with only 40% of the total number of deaths required for the final OS analysis and likely confounded by the high crossover rate of patients in the chemotherapy group; 112 of 174 patients (64%) randomly assigned to receive chemotherapy subsequently received crizotinib outside the study.

Interim analysis of OS showed no significant difference between the 2 study arms, according to Wiltshire.  Median OS was 20.3 months (95% CI, 18.1 to not reached) in patients treated with crizotinib and 22.8 months (95% CI, 18.6 to not reached) in those treated with chemotherapy (hazard ratio, 1.02; 95% CI, 0.68-1.54; P=0.54).

A total of 343 patients in the as-treated population were included in the safety analysis. This analysis was not adjusted for the longer study duration of crizotinib versus chemotherapy treated patients (median 31 weeks vs. 12 weeks respectively).

The adverse events observed on crizotinib and chemotherapy in PROFILE 1007 was generally consistent with their respective known adverse event (AE) profiles. The most common AEs observed with crizotinib with at least 5% greater incidence than chemotherapy were vision disorder (60% vs. 9%), diarrhea (60% vs 19%), nausea (55% vs. 37%), vomiting (47% vs. 18%), constipation (42% vs. 23%), elevated liver transaminases (38% vs. 15%), edema (31% vs. 16%), upper respiratory infection (26% vs. 13%), dysgeusia (26% vs. 9%) and dizziness (22% vs. 8%). The most common Grade 3/4 AEs associated with crizotinib include elevated transaminases (16% vs. 2%) and neutropenia (13% vs. 19%).

“A significantly greater overall improvement from baseline in global quality of life [QOL] was observed in patients treated with [crizotinib] compared with chemotherapy,” Wiltshire said. “Patients treated with [crizotinib] also demonstrated a significantly greater delay in worsening of symptoms.”

The role of ALK in NSCLC was identified 5 years ago in 2007 by Dr. Hiroyuki Mano, a Japanese researcher. At that time Pfizer was already studying crizotinib in a phase 1 clinical trial, enrolling patients with several different types of cancer. When Mano’s finding where published in Nature, Pfizer modified the phase 1 trial to include an expanded cohort of patients with ALK-positive advanced NSCLC.