Expert Point of View: Fiona Blackhall, PhD, FRCP

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ASCEND-4 challenges the current treatment algorithm of using a next-generation ALK inhibitor for treatment after progression on crizotinib.
— Fiona Blackhall, PhD, FRCP

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“There has undoubtedly been extremely rapid progress made in establishing effective therapies for anaplastic lymphoma kinase (ALK)-positive non–small cell lung cancer (NSCLC) patients in less than a decade,” said Fiona Blackhall, PhD, FRCP, Chair of Thoracic Oncology and medical oncologist at the University of Manchester and The Christie Hospital, United Kingdom. She compared the results of the ASCEND-4 trial to those of the PROFILE 1014 study,1 in which the superiority of crizotinib (Xalkori) over chemotherapy for the first-line treatment of advanced ALK-positive NSCLC patients was established.

Study Comparisons

“Chemotherapy in ASCEND-4 behaved comparably to PROFILE 1014,” she pointed out. “But in contrast, for ceritinib (Zykadia), median progression-free survival is 16.6 months—6 months longer than what was achieved for crizotinib in PROFILE 1014.”

She commented, “ASCEND-4 challenges the current treatment algorithm of using a next-generation ALK inhibitor for treatment after progression on crizotinib. But there are no prospective data for a sequential approach using a first-generation, then a next-generation, vs a next-generation inhibitor in the first line.”

Regarding intracranial efficacy, Dr. Blackhall called the results “very interesting,” pointing out that about 40% of patients in ASCEND-4 had had prior brain radiotherapy, whereas in PROFILE 1014, it is not known. “In both trials, the ALK inhibitor was superior to chemotherapy in patients with brain metastases, but the magnitude of benefit was much less for ceritinib vs chemotherapy in patients with brain metastases compared to those without,” she noted, “with a very impressive more than doubling of progression-free survival for ceritinib relative to ­crizotinib in the subgroup with no brain ­metastases.”

Possible Implications

Dr. Blackhall underscored the importance of precisely determining the molecular characteristics of progression on an ALK tyrosine kinase inhibitor and said she believes “there may be an opportunity to combine pragmatism with precision.”

Crizotinib may be a better-tolerated first-line option in patients where the gastrointestinal toxicities of ceritinib may be detrimental, she commented. Serial tumor tissue biopsy and concomitant evaluation of serial liquid biopsy look set to become routine for precise matching of ALK-resistance mechanisms to select optimal therapy after failure of first-line ALK inhibitor treatment, she added. ■

Disclosure: Dr. Blackhall has received research funding and honoraria from Novartis and Pfizer.


1. Solomon BJ, Mok T, Kim DW, et al: First-line critzotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med 371:2167-2177, 2014.

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