Expert Point of View: Alice T. Shaw, MD, PhD


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[ASCEND-5] will establish sequential crizotinib followed by a second-generation ALK inhibitor as the standard treatment for patients with metastatic ALK-positive lung cancer.
— Alice T. Shaw, MD, PhD

Commenting on ASCEND-5, Alice T. Shaw, MD, PhD, Director of Thoracic Oncology at the Massachusetts General Hospital Cancer Center, Boston, noted that it is the first randomized study to examine how a second-generation anaplastic lymphoma kinase (ALK) inhibitor compares to standard second-line chemotherapy in ALK-positive patients for whom the standard first-line therapy, crizotinib (Xalkori), has failed.

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

The optimal first-line ALK inhibitor is still a matter of debate. Studies comparing ceritinib to chemotherapy, and alectinib to crizotinib, in the first-line setting will help answer this question, she said.

Confirmatory Findings


CNS relapses represent pharmacokinetic failure rather than biologic resistance…. Activity in the brain will be an important readout for these two studies.
— Egbert F. Smit, MD, PhD

Egbert F. Smit, MD, PhD, of The Netherlands Cancer Institute in Amsterdam, discussed both studies, first noting that ceritinib is known to be 20 times more potent than crizotinib and 36 times more potent against cells harboring the L1196 mutation that is implicated in crizotinib resistance. Clinically, he added, “We have a real body of evidence that ceritinib has activity against ALK-positive NSCLC [non–small cell lung cancer], even in patients previously treated with crizotinib…. The studies presented today are confirmatory,” showing “clinically meaningful differences,” he said, but he agreed with Dr. Shaw that the best placement for ceritinib remains unclear.

Of importance, this drug is better able than crizotinib to target metastases in the brain, which is the first site of progression for 70% of patients on crizotinib. In ASCEND-3, the response rate in the brain was almost 60%—“more or less the same as the extracranial response”—compared [historically] to 18% with crizotinib, he said.

“CNS [central nervous system] relapses represent pharmacokinetic failure rather than biologic resistance,” he pointed out. “Activity in the brain will be an important readout for these two studies.”

Other Side of the Coin

“Toxicities are the other side of the coin,” Dr. Smit said. “ASCEND-5 is the first trial in which a toxicity associated with a targeted agent in NSCLC is actually worse than was seen with chemotherapy. Gastrointestinal toxicity is the most prevalent and most troublesome side effect. While the frequency of grade 3/4 diarrhea and nausea was low, grade 2 diarrhea in association with grade 2 nausea, every day for 16 months [the median progression-free survival in the phase II study], is something that is simply not bearable.”

“More importantly,” he continued, “while we have seen that in every trial of targeted agents the quality of life improves with the use of targeted agents, in this study we found a deterioration in two scales for gastrointestinal symptoms in patients on ceritinib.”

Dr. Smit maintained that the dose of ceritinib (750 mg/d) may simply be too high. “This is definitely not the optimal biologic dose of this agent…. We need to define the lowest dose with a favorable trade-off between response and acceptable toxicity,” he said, pointing out that responses have been observed with ceritinib at 400 mg/d.


Ceritinib’s dose was close to the maximum tolerated dose, and we probably don’t need to give that much…. I think that, eventually, we will be using ceritinib in a different way.
— David Gandara, MD

Commenting for The ASCO Post, David Gandara, MD, Director of the Thoracic Oncology Program at the University of California, Davis, agreed. “Different drug companies use different ways to select the dose we will use in the clinic. Ceritinib’s dose was close to the maximum tolerated dose, and we probably don’t need to give that much. The company is now doing studies in which the drug is given with food. This increases its absorption so we can lower the dose and have less toxicity,” he said. “I think that, eventually, we will be using ceritinib in a different way.” ■

Disclosure: Dr. Shaw reported no potential conflicts of interest. Dr. Smit is a consultant for Eli Lilly; is on the advisory boards of AstraZeneca, Boehringer Ingelheim, Bayer, Celgene, Novartis, Roche-Genentech, Pfizer, BMS, and MSD; and receives research funding from Boehringer Ingelheim, Roche-Genentech, MSD, and BMS. Dr. Gandara has received grants from Pfizer and Novartis and is a consultant for Novartis.


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