Crizotinib proved superior to standard pemetrexed plus platinum chemotherapy as first-line treatment for adults with advanced ALK-positive non–small cell lung cancer in an international phase III clinical trial reported online Dec. 4 in the New England Journal of Medicine.
Crizotinib, an oral tyrosine kinase inhibitor of anaplastic lymphoma kinase (ALK), significantly prolonged progression-free survival; yielded a significantly higher response rate; and produced significantly greater improvements in patient-reported physical functioning, lung-cancer symptoms, and quality of life than the current standard of care chemotherapy in the industry-sponsored open-label study, said Dr. Benjamin J. Solomon of Peter MacCallum Cancer Centre, Melbourne, and his associates.
Rearrangements of the ALK gene are present in up to 5% of non–small cell lung cancers (NSCLCs) and characterize a distinct subgroup of tumors that typically occurs in younger patients who have never smoked. Crizotinib produced promising results in this subset of patients in phase I and II studies, but until now has not been tested as first-line therapy for the malignancy.
Dr. Solomon and his associates assessed the drug in adults with locally advanced, recurrent, or metastatic NSCLC that was positive for ALK rearrangements. During the 2.5-year study, they randomly assigned 172 patients to twice-daily oral crizotinb and 171 to IV chemotherapy (pemetrexed plus either cisplatin or carboplatin) every 3 weeks for a maximum of six cycles. Patients who showed disease progression while on chemotherapy were allowed to cross over to crizotinib treatment.
The median duration of follow-up was approximately 17 months. The primary endpoint of the study, progression-free survival, was 10.9 months with crizotinb and 7.0 months with chemotherapy, a significant difference (hazard ratio, 0.45). This beneficial effect was independent of patients’ performance status at baseline, race, and the presence or absence of brain metastases, the investigators said (N. Engl. J. Med. 2014 Dec. 4 [ doi:10.1056/NEJMoa1408440 ]).
In addition, the objective treatment response rate was significantly higher with crizotinib (74%) than with chemotherapy (45%), and the median duration of response was significantly longer (11.3 month vs 5.3 months).
At the time of initial data analysis in this ongoing trial, overall survival did not differ between the two study groups. This is probably due to the low rate of death from any cause at that time (only 26% overall mortality) and to the fact that 70% of the chemotherapy group crossed over to crizotinib, confounding the results of the overall survival analysis, Dr. Solomon and his associates said.
In previous research, the most serious adverse events linked to crizotinib were hepatotoxicity and pulmonary toxicity. In this trial, 14% of patients taking crizotinib developed grade 3 or 4 elevations in aminotransferase levels, which was managed with dose interruptions or dose reductions. Two patients discontinued crizotinib because of interstitial lung disease, and one patient died from pneumonitis believed to be associated with the drug.
Other adverse events possibly related to crizotinib included vision disorder (71% of patients), diarrhea (61%), and edema (49%). Adverse events that were significantly more common in the chemotherapy group included fatigue (38%), anemia (32%), and neutropenia (30%). Patients given crizotinib reported significantly greater improvement than those given chemotherapy in global quality of life, as well as in the individual physical, social, emotional, and role-functioning domains of quality of life. They also reported significantly greater reduction in pain, dyspnea, and insomnia, and a significantly greater improvement in general health status. The study participants who received crizotinib also reported greater improvement in symptoms specifically related to lung cancer, such as cough, chest pain, and arm or shoulder pain, as well as a significantly longer delay in the worsening of lung cancer symptoms.