Type, incidence, severity, seriousness, and relationship to study medications of AEs and laboratory abnormalities were assessed.

At the data cutoff on January 2, 2012, a total of 901 patients had received treatment with crizotinib across 141 sites in 22 countries. The mature population included the first 261 patients enrolled and treated in the study as of February 1, 2011. In the overall population, 3 patients (<1%) had received no prior therapies; 248 (27.5%) had received 1 prior therapy; 299 (33.2%), 2 prior therapies; and 351 (39.0%), 3 or more prior therapies; 3 patients were ineligible due to prior adjuvant treatment only. In the mature population, all patients were previously treated: 32 patients (12.3%) had received 1 prior therapy; 91 (34.9%), 2 prior therapies, and 138 (52.8%), 3 or more prior therapies.

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At the time of analysis, 167 events (64%) had occurred; 140 events were PD and 27 deaths without PD. A total of 73 patients (28%) were still in follow-up for progression.

Median treatment duration was 48 weeks compared with 19.9 weeks in the overall population. In the mature population, ORR was 59.8% (95% CI, 53.6–65.9), 4 complete responses and 151 partial responses; median duration of response was 45.6 weeks (96% CI, 35.3–53.6). Of those patients with a response, 110 of 155 (71%) had a response within the first 8 weeks of treatment and median time to response was 6.1 weeks (range, 4.9–49.1). Median PFS was 8.1 months (95% CI, 6.9–9.7).

In the overall population, 348 patients (38.6%) discontinued study treatment for PD (18.0%), death (7.9%), treatment-related AEs (5.0%), withdrawal of consent not related to AE (2.8%), global deterioration of health status (1.6%), or were lost to follow-up (<1.0%).

The most frequent treatment-related adverse events (AEs) in the mature population were primarily grade 1 or 2 gastrointestinal effects such as nausea (56.7%), vomiting (44.4%), and diarrhea (40.6%) or vision disorder (59%), the latter of which included visual impairment, photopsia, vision blurred, vitreous floaters, photophobia, and diplopia.

Most frequently reported treatment-related AEs grade ≥3 in the overall population were neutropenia (5.5%), increased alanine aminotransferase (3.9%), and fatigue (1.9%). Five patients (<1%) discontinued treatment due to increased alanine aminotransferase and eight (<1%) due to pneumonitis, with rare instances of fatal pneumonitis reported. Four of 198 deaths during the study were considered treatment-related by the investigators.

A statistically significant (P<0.05) and clinically meaningful improvement from baseline was observed for patient-reported overall pain, chest pain, arm and shoulder pain and in key symptoms of lung cancer, including cough, dyspnea, fatigue, and global QOL.

Data from this global study, which served as the basis for the simultaneous approval of crizotinib and the FISH assay, are consistent with the efficacy and safety findings reported from the phase 1 expanded cohort of crizotinib in patients with ALK-positive advanced NSCLC, which reported an ORR of 61% and a similar AE profile.7 Dr. Kim and colleagues concluded these results show crizotinib continues to have a good safety profile in patients with previously treated ALK-positive advanced NSCLC, with clinically meaningful anti-tumor activity, and provide strong evidence for crizotinib as a standard of care for patients with advanced ALK-positive NSCLC.

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