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Ceritinib Benefit After Crizotinib for Advanced ALK-Positive Lung Cancer

Goodwin, Peter M.

doi: 10.1097/01.COT.0000512071.59032.56
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COPENHAGEN, DENMARK—A “clinically meaningful” improvement in progression-free survival (PFS) was achieved in the phase III ASCEND 5 study comparing the second generation anaplastic lymphoma kinase (ALK) inhibitor ceritinib with chemotherapy in patients with advanced ALK-rearranged non-small cell lung cancer (NSCLC) previously treated with crizotinib and chemotherapy.

Results were reported at the European Society for Medical Oncology (ESMO) 2016 Congress (Abstract LBA42_PR).

“We have another active agent that should be implemented in the clinical armamentarium for those patients with lung cancer that is ALK-positive—a preferred option over chemotherapy,” said Giorgio Scagliotti, MD, PhD, Professor of Medical Oncology at the University of Turin, Italy, in an interview with Oncology Times.

“Ceritinib is a second generation ALK inhibitor that is much more potent than crizotinib and the study was [with] patients who were already exposed to crizotinib and cytotoxic chemotherapy and was looking at ceritinib versus the standard treatment in second and third-line—pemetrexed or taxotere (docetaxel),” Scagliotti explained.

The open-label ASCEND-5 study included 231 patients with NSCLC who had received crizotinib. The median PFS in patients then treated with ceritinib was 5.4 months as compared with 1.6 months for those receiving chemotherapy—a hazard ratio of 0.49 for PFS. Compared to chemotherapy, ceritinib increased overall response rate (39.1% compared with 6.9%), but there was no improvement in overall survival with ceritinib.

“In this selected patient population, where the target is present, this drug can give very interesting PFS in second, third, or fourth line—as long as the tumor is not resistant to [it],” said ESMO officer Solange Peters, MD, PhD, Médecin Cheffe in the Department of Thoracic Malignancies at Centre Hospitalier Universitaire Vaudois, University of Lausanne, Switzerland.

Stefan Zimmermann, MD, from the Hôpital Fribourgeois, HFR Hôpital Cantonal, Fribourg, Switzerland, noted that ceritinib had demonstrated an advantage over standard chemotherapy in second and further lines of therapy. “But the real question is: what do we have to use in first line?” he asked.

Scagliotti welcomed the addition of ceritinib to the family of tyrosine kinases for the small subgroup of patients who have the ALK translocation genomic alteration. “The first in class was crizotinib—a highly effective agent inducing 70 percent response rate, improving survival over cytotoxic chemotherapy as shown in the PROFILE studies,” he noted. “But the issue with targeted therapies is that sooner or later you get relapse or progression of the disease and patients develop resistance.”

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Toxicities

The most frequent grade 3 to 4 adverse events with ceritinib were nausea (7.8%), vomiting (7.8%), and diarrhea (4.3%), and with chemotherapy were neutropenia (15.5%), fatigue (4.4%), and nausea (1.8%). Ceritinib significantly improved patient-reported outcomes including lung cancer-specific symptoms and overall health status, compared to placebo.

“The toxicity profile was exactly what we were expecting from previous studies with ceritinib—with ALK treatment-naïve and ALK-pretreated patients having more gastrointestinal toxicities with ceritinib and some liver function test elevations that were not clinically relevant,” Scagliotti said. “In patients who received docetaxel hematological toxicities were much more commonly reported.”

But he said it was too early to give clear clinical guidelines about using ceritinib since there had not yet been head-to-head comparisons with crizotinib, and other ALK inhibitors were under investigation. “We need to wait a few months to identify the right sequence among these different treatment options,' he noted.

But Scagliotti was optimistic. “Having many treatment options is much better than to have only one treatment option,” he emphasized, adding that ceritinib was now the preferred option for patients who had already been exposed to crizotinib.

While ceritinib was the only second generation ALK inhibitor so far licensed in Switzerland, giving it an advantage there for treating patients who had failed crizotinib, there were some outstanding issues, said Zimmerman—including gastrointestinal toxicity—which distinguished ceritinib from other second generation ALK inhibitors such as alectinib.

“This data has to be put in the context of the ALEX trial, which is going to change what we've seen from the data at ASCO [about] the way we treat these ALK-rearranged patients—meaning that we'll most certainly be starting with second generation inhibitors up front in the hope that at least we can overcome this extremely high rate of cerebral progression, which is a major issue with crizotinib and one of the major reasons why we do not like to use it and we—absolutely—are desperate for better agents,” Zimmerman stated.

Peters said the ASCEND 5 study had successfully answered an important question. “Once you have given crizotinib and platinum-based chemotherapy what should you do? Should you go to the usual docetaxel or second-line chemotherapy or should you switch to a targeted therapy? And the answer is very clear. Targeted therapies are better than chemotherapy,” she noted.

Peter M. Goodwin is a contributing writer.

Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.
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