Ceritinib is superior to chemotherapy in pretreated patients with ALK-rearranged non-small-cell lung cancer
In the phase III ASCEND-5 study, the second generation ALK inhibitor ceritinib was shown to significantly delay the disease progression compared to chemotherapy in patients with ALK-rearranged non-small-cell lung cancer (NSCLC), who were previously treated with crizotinib and chemotherapy. These findings underline that there is greater benefit in using a second ALK inhibitor over standard chemotherapy in ALK-positive NSCLC patients who progress on crizotinib. This will likely establish sequential crizotinib followed by a second generation ALK inhibitor (i.e. ceritinib, or alectinib) as the standard treatment for patients with metastatic ALK-positive NSCLC.
The current standard of care for advanced NSCLC patients harboring rearrangements in the ALK gene consists of crizotinib. However, after a certain period of time, most patients develop resistance to crizotinib after which they are usually treated with chemotherapy. In the phase 1 ASCEND-1 study, ceritinib showed robust antitumor activity in ALK-positive NSCLC patients. This trial included both ALK-inhibitor-naïve patients and patients who previously received crizotinib. This finding was confirmed in the ASCEND-2 study, where ceritinib induced durable responses in ALK-positive NSCLC patients who progressed on chemotherapy and crizotinib. During ESMO 2016, results of the confirmatory phase III ASCEND-5 study were presented in which ceritinib was compared with second-line chemotherapy in crizotinib-pretreated patients.
ASCEND-5 included a total of 231 patients with metastatic, ALK-positive NSCLC who had progressive disease at enrolment. In order to be eligible for the study, patients should have been treated with prior crizotinib and 1 or 2 previous lines of chemotherapy (including at least one platinum-based regimen). Patients were randomized to receive either ceritinib (750mg once daily), or chemotherapy (pemetrexed 500mg/m2 [N=40] or docetaxel 75mg/m2 [N=73] every 21 days). In case of disease progression on chemotherapy, patients were allowed to crossover to ceritinib. The primary endpoint of the trial was progression-free survival (PFS) by independent review.
The median treatment exposure to ceritinib was 30.3 weeks as compared to 6.3 weeks for chemotherapy. After a median follow-up of 16.5 months, ceritinib was shown to be associated with a significantly longer PFS than chemotherapy: median PFS 5.4 vs. 1.6 months (HR[95%CI]: 0.49[0.36-0.67]; p<0.001). This PFS benefit with ceritinib was observed across all investigated subgroups, including age, sex, race, the presence of brain metastases at baseline, the WHO performance status, the smoking history, and the previous response to crizotinib. Also the objective response rate (ORR) was significantly higher with ceritinib than with chemotherapy (39.1% vs. 6.9%; p<0.001). No difference in OS was seen in this trial. The latter is impacted by the 75 patients who crossed over to ceritinib following discontinuation on chemotherapy.
Patients on ceritinib had similar toxicities than what was observed in phase I and II studies. The most frequent grade 3/4 adverse events on ceritinib were nausea (7.8%), vomiting (7.8%) and diarrhea (4.3%). With chemotherapy, neutropenia (15.5%), fatigue (4.4%), and nausea (1.8%) were the most common high-grade adverse events. Compared to chemotherapy, ceritinib also significantly improved the patient-reported outcomes, including cancer-specific symptoms and overall health status (p<0.05).
In summary, this is the first randomized study comparing a second generation ALK inhibitor to standard second-line chemotherapy in ALK-positive patients who fail the standard first line treatment (crizotinib). This study shows that ceritinib leads to a significantly longer PFS than what is seen with chemotherapy. As such, these data will likely establish sequential crizotinib followed by a second generation ALK inhibitor (i.e. ceritinib, or alectinib) as the standard treatment for patients with metastatic ALK-positive NSCLC.
Scagliotti G, Kim T, Crinò L et al. Ceritinib vs chemotherapy (CT) in patients (pts) with advanced anaplastoc lymphoma kinase (ALK)-rearranged (ALK+) non-small cell lung cancer (NSCLC) previously treated with CT and crizotinib (CRZ): results from the confirmatory phase 3 ASCEND-5 study. Presented at ESMO 2016; Abstract LBA42_PR.