METHODS: In this open-label phase III study (PROFILE 1029), patients were randomized 1:1 to receive orally administered crizotinib 250 mg twice daily continuously (3-week cycles) or intravenously administered chemotherapy (pemetrexed 500 mg/m2, plus cisplatin 75 mg/m2, or carboplatin [at a dose to produce area under the concentration-time curve of 5-6 mg·min/mL]) every 3 weeks for a maximum of six cycles. PFS confirmed by independent radiology review was the primary end point.
RESULTS: Crizotinib significantly prolonged PFS (hazard ratio, 0.402; 95% confidence interval [CI]: 0.286-0.565; p < 0.001). The median PFS was 11.1 months with crizotinib and 6.8 months with chemotherapy. The objective response rate was 87.5% (95% CI: 79.6-93.2%) with crizotinib versus 45.6% (95% CI: 35.8-55.7%) with chemotherapy (p < 0.001). The most common adverse events were increased transaminase levels, diarrhea, and vision disorders with crizotinib and leukopenia, neutropenia, and anemia with chemotherapy. Significantly greater improvements from baseline in patient-reported outcomes were seen in crizotinib-treated versus chemotherapy-treated patients.
CONCLUSIONS: First-line crizotinib significantly improved PFS, objective response rate, and patient-reported outcomes compared with standard platinum-based chemotherapy in East Asian patients with ALK-positive advanced NSCLC, which is similar to the results from PROFILE 1014. The safety profiles of crizotinib and chemotherapy were consistent with those previously published.
METHODS: Patients had progressed after initial benefit with erlotinib or gefitinib, and/or had an EGFR or HER2 mutation, had no other treatment options, and were ineligible for afatinib trials. The recommended starting dose of afatinib was 50 mg/day. Dose modifications were allowed, and afatinib was continued as long as deemed beneficial. Response and survival information was provided voluntarily. Safety reporting was mandatory.
RESULTS: 2242 patients (26% aged ≥ 70 years, 96% with adenocarcinoma) received afatinib at centers in 10 Asian countries. Most were heavily pre-treated, including prior treatment with erlotinib or gefitinib. Of 1281 patients tested, 1240 had EGFR mutations (common: 1034/1101; uncommon: 117/1101). There were no new safety signals, the most common adverse events being rash and diarrhea. Objective response rate (ORR) was 24% overall (n = 431 with data available), 27% for patients with common EGFR mutations (n = 230) and 28% for those with uncommon mutations (n = 32); median time to treatment failure (TTF) in these groups was 7.6 months (n = 1550), 6.4 months (n = 692) and 8.4 months (n = 83), respectively. In patients with EGFR exon 20 insertions (n = 23) and HER2 mutations (n = 12), median TTF exceeded 12 months.
CONCLUSIONS: Patient outcomes in this study were similar to those reported in the analysis of the global NPU. Afatinib achieved clinical benefits in patients with refractory NSCLC. ORR and TTF were similar between patients with tumors harboring uncommon and common EGFR mutations.