Table 1.

Benefit–risk analysis for ceritinib in the treatment of patients with metastatic ALK-positive NSCLC who have progressed on or are intolerant to crizotinib

DiseasePatients with ALK-positive metastatic NSCLC who have progressed on or are intolerant to crizotinib have a serious and life-threatening condition for which treatment is not addressed adequately by available therapies.
Unmet medical needALK-positive metastatic NSCLC patients with acquired resistance to crizotinib are often treated with standard cytotoxic chemotherapy, which is generally associated with marginal clinical benefit and significant toxicity.
Clinical benefitCeritinib was associated with ORR of 44% (DOR, 7.1 months) and 55% (DOR, 7.4 months) according to BIRC and investigator assessments, respectively. The activity of ceritinib was generally consistent across all clinically relevant subgroups.
RiskThe majority of patients (74%) required at least one dose reduction or interruption, primarily for gastrointestinal adverse reactions or hepatotoxicity. However, discontinuation due to adverse reactions was acceptable (10%), indicating that ceritinib-related toxicities can be reasonably managed with dose modification/interruptions and supportive care.
UncertaintiesAlthough ORR is considered an endpoint that can reasonably predict clinical benefit in metastatic NSCLC, no correlation with overall survival or how a patient feels or functions has yet been established. Therefore, traditional approval for ceritinib requires confirmation of clinical benefit.
Additional data are needed to assess the safety and efficacy of ceritinib:
  • when the drug is taken with a meal, which has been shown to increase systemic exposure;

  • in patients with CNS metastasis;

  • and in the context of the optimal sequencing of ALK-inhibitor therapies.

ConclusionsCeritinib meets the criteria for accelerated approval under the provisions of subpart H of 21CFR314. Ceritinib has a favorable benefit–risk profile for the treatment of patients with ALK-positive metastatic NSCLC who have progressed on or are intolerant to crizotinib and is associated with a large magnitude of durable responses in a population of patients for whom available treatment options generally offer marginal clinical benefit. The risks associated with ceritinib are acceptable in the context of the disease being treated.