Ceritinib in patients with advanced anaplastic lymphoma kinase-rearranged anaplastic large-cell lymphoma.

The anaplastic lymphoma kinase (ALK) gene is expressed in.50% of anaplastic large-cell lymphomas (ALCLs). Although most patients withALK-positiveALCL respondwell to anthracycline-based chemotherapy, relapses do occur (5-year failure-free survival 60%) and require salvage therapy, generally with poor outcomes. Autologous stem cell transplant is an option in the salvage setting, but not all patients can tolerate this or achieve a sufficiently good response to high-dose chemotherapy to be candidates. Recently, brentuximab vedotin has shown encouraging activity in patients with relapsed or refractory ALCL. Ceritinib is a novel, selective ALK inhibitor which has been shown to induce complete tumor regression of crizotinib-resistant xenograft models of ALK1ALCL. A phase 1 dose-escalation study of ceritinib (ASCEND-1; this trial was registered at www.clinicaltrials.gov as #NCT01283516)was conducted inpatientswith advancedormetastatic ALK-positive tumors.Amonga totalof304patients, 3had relapsedwith ALK1ALCL. All patients were enrolled during the expansion phase of the study, with 1 included in the analysis reported previously. Here, we report in detail on the safety and efficacy of ceritinib in these 3 patients. In the ASCEND-1 study, all anatomical responses were assessed as per Response Evaluation Criteria in Solid Tumors 1.0 criteria, as patients with a variety of ALK1 cancers were enrolled. Responses were confirmed by computerized tomography or positron emission tomography/computerized tomography using fludeoxyglucose tracer. Full details of the trial design have been reported previously. All 3 patients with ALK-positive ALCL initiated ceritinib treatment at a dose of 750mg/d. Two patients achieved a complete response (CR) and 1 had a partial response (PR) (Table 1). The patient with a PR achieved a maximal tumor reduction of 94.8% from baseline. As of January 2015, responses were ongoing for all 3 patients, with durations ranging from$20 months to$26 months (Table 1). Two patients experienced adverse events that required ceritinib dose reductions (Table 1) but continue to receive ceritinib at the reduced dose level. The other patient continues to receive ceritinib at 750 mg/d. Toxicities observed in this subgroup analysis were mainly grade 1 or 2. Overall, the common adverse events observed in ALK-positive ALCL were similar to those observed with ALK-positive non–small cell lung cancer. Treatment of patients with chemotherapy-relapsed advanced ALK-rearranged ALCL can be challenging and generally has a poor outcome. Here, we have shown that the ALK inhibitor ceritinib is active in patients with ALCLwho have relapsed after anthracyclinebased chemotherapy. Although the number of patients with ALCL treated in our study is small, it is noteworthy that all 3 patients maintained responses to ceritinib salvage therapy for at least 20months