Ceritinib, a Newer ALK Inhibitor, Improves Progression-Free Survival After Crizotinib Failure in NSCLC

Charles Bankhead

November 2016, Vol 7, No 10 - Lung Cancer

Copenhagen, Denmark—Patients with heavily pretreated ALK mutation and non–small-cell lung cancer (NSCLC) had significant improvement in progression-free survival (PFS) after receiving the next-generation ALK inhibitor ce­ritinib, according to results from the ASCEND-5 study reported at the 2016 European Society for Medical Oncology Congress by Giorgio Scagliotti, MD, Professor of Respiratory Medicine, University of Torino, Italy.

The median PFS increased from 1.6 months with chemotherapy to 5.4 months with ceritinib (Zykadia). A subgroup analysis showed a consistent benefit from treatment with the newer ALK inhibitor, regardless of age, sex, brain metastasis status, and previous response to crizotinib therapy.

“Ceritinib demonstrated a significant and clinically meaningful improvement in progression-free survival compared with chemotherapy,” said Dr Scagliotti. “Ceritinib demonstrated superior efficacy compared with standard second-line chemotherapy in crizotinib-resistant, ALK-positive patients, establishing ceri­tinib as a preferred treatment option in this patient population.”

Chemotherapy is the standard of care for the majority of patients with advanced NSCLC. The ALK inhibitor crizotinib (Xalkori) has demonstrated efficacy in the subgroup of patients with ALK-positive NSCLC, but most patients eventually develop resistance to crizotinib.

Ceritinib has a 20-fold greater potency against ALK mutations compared with crizotinib, said Dr Scagliotti. In a phase 1 clinical trial involving patients with previously treated NSCLC with or without exposure to anti-ALK therapy, ceritinib demonstrated “robust” antitumor activity (Shaw AT, et al. N Engl J Med. 2014;370:1189-1197). In a subsequent phase 2 clinical trial, ceritinib led to durable responses in patients whose disease progressed during treatment with chemotherapy and crizotinib (Crino L, et al. J Clin Oncol. 2016;34:2866-2873).

The ASCEND-5 Clinical Trial

The positive results from previous studies led to the phase 3 ASCEND-5 clinical trial, which involved 231 patients with locally advanced or metastatic ALK-positive NSCLC. At enrollment, eligible patients had progressive disease, received crizotinib, and received 1 or 2 chemotherapy regimens.

Patients were randomized to receive crizotinib or standard chemotherapy with pemetrexed or docetaxel. The primary end point was PFS.

There was nearly a 4-month difference in the median PFS favoring crizotinib, which translated into a 51% reduction in the hazard for disease progression or death (P <.001). Patients who received ceritinib had an overall response rate of 39.1% versus 6.9% in patients who received chemotherapy. The duration of response was also extended with ceritinib, said Dr Scagliotti.

A subgroup analysis failed to identify any patients who did not benefit more from treatment with ceritinib than with chemotherapy. Before the clinical trial ended, 75 patients in the chemotherapy arm had crossed over to ceritinib.

Adverse events were more common with ceritinib than with chemotherapy, including all-grade and grade 3 or 4 adverse events. The most common grade 3 or 4 adverse events with ceritinib included nausea (7.8%), vomiting (7.8%), and diarrhea (4.3%).

The safety profile of ceritinib was consistent with previous studies—adverse events were manageable, and no new ceritinib-related serious adverse events were reported.

The ASCEND-5 clinical trial was the first randomized comparison of an ALK inhibitor with conventional second-line chemotherapy in the setting of crizotinib failure, said Alice T. Shaw, MD, Director of Thoracic Oncology, Massachusetts General Hospital Cancer Center, Boston.

“Single-arm studies suggested that ce­ritinib and alectinib [Alecensa; also a next-generation ALK inhibitor] could be standard options in the second-line setting after crizotinib has failed,” said Dr Shaw. “The positive effect on progression-free survival in this phase 3 study confirmed that there is greater benefit using a second ALK inhibitor over standard chemotherapy. This will establish sequential crizotinib, followed by a second-generation ALK inhibitor as the standard treatment for patients with metastatic ALK-positive lung cancer.”

Dr Scagliotti agreed, saying, “This study opens up a new treatment paradigm after crizotinib failure. It would be logical now to give a sequence of active drugs, starting with crizotinib in the first-line setting and moving to ceritinib in the second-line setting.”