Phase III trial shows crizotinib superior to single-agent chemotherapy for ALK-positive advanced NSCLC

The results of a new phase III trial show that crizotinib is more effective treatment than standard chemotherapy for patients with advanced, ALK-positive non-small cell lung cancer (NSCLC), who have been previously treated with first-line, platinum-based chemotherapy. The study results are reported at the ESMO 2012 Congress of the European Society for Medical Oncology in Vienna.

Rearrangements of the anaplastic lymphoma kinase (ALK) gene are found in about 5% of all NSCLC. In previous studies, crizotinib has been shown to induce significant clinical responses in patients with advanced ALK-positive NSCLC, but this is the first phase III study in this setting.
   
This study is also the first head-to-head comparison of crizotinib with standard chemotherapy and according to the lead study author, Dr Alice Shaw from Massachusetts General Hospital Cancer Center, Boston, USA, crizotinib is superior to standard single-agent chemotherapy in terms of response, progression-free survival and quality of life in ALK-positive patients who have been previously treated with first-line, platinum-based chemotherapy. These results establish crizotinib as the standard of care for patients with advanced, previously treated, ALK-positive NSCLC.
The current global randomised phase III study compared the efficacy and safety of crizotinib with standard chemotherapy with pemetrexed or docetaxel, in 347 patients with ALK-positive, stage IIIB/IV NSCLC who had already been treated with chemotherapy.

The study showed that crizotinib prolonged progression-free survival to a median of 7.7 months compared to 3.0 months among those patients who received the chemotherapy (HR 0.49; 95% CI 0.37–0.64; p < 0.0001). The overall response rate was also significantly higher in those treated with crizotinib (65% vs 20%; p < 0.0001). So far, the analysis of the overall survival rate with the two drugs is still immature, and there are no enough events to draw meaningful conclusions.

There was significant crossover in the study, patients who were randomized to receive chemotherapy and had disease progression were allowed to crossover to receive crizotinib. Hence, the majority of patients on the chemotherapy arm actually did receive crizotinib and this makes determination of overall survival benefit very challenging. Duration of treatment was longer for crizotinib where a median of 11 cycles compared to 4 with pemetrexed or docetaxel were started by patients.

The most common treatment-related adverse events with crizotinib were reported by 59% of patients, 53% diarrhoea, 52% had nausea, 44% vomiting and 36% of patients reported elevated transaminases. Adverse events including nausea, fatigue, neutropenia, decreased appetite, and alopecia were reported by 35%, 29% 22% 21% and 20% of patients receiving pemetrexed or docetaxel. All treatment groups had the same incidence of grade 3/4 treatment related adverse events of 31%. Six percent of crizotinib patients compared to 10% of pemetrexed/docetaxel patients discontinued the trial due to treatment related adverse events. However, despite side effects, patients still reported improved quality of life on crizotinib compared with chemotherapy.

Commenting on clinical relevance of these data, Dr Enriqueta Felip, Head of the Lung Cancer Unit in Oncology Department at Vall d'Hebron University Hospital in Barcelona, Spain, and chair of the ESMO 2012 Metastatic NSCLC programme track (who was not involved in the study) said that crizotinib, an oral drug, is more effective than standard chemotherapy in previously treated patients with advanced NSCLC with a specific molecular alteration, ALK. This is the first randomised study in this group of patients selected precisely because they have ALK-positive tumours.

After the worldwide implementation of targeted therapy in lung cancer patients defined by EGFR mutation, this is the second group of patients with non-small cell lung cancer to clearly benefit from a therapy directly targeting a molecular alteration. The results of this study represent a significant step towards more individualised therapy in lung cancer patients.