Abstract
Findings from the global phase III ALEX trial unequivocally show that alectinib is superior to crizotinib as first-line therapy for ALK+ non-small cell lung cancer. Alectinib more than doubled progression-free survival, significantly reduced the incidence of brain and CNS metastases, and should be considered the new standard of care.
Findings from the global phase III ALEX trial unequivocally show that alectinib (Alecensa; Roche) is superior to crizotinib (Xalkori; Pfizer) as first-line therapy for ALK+ non–small cell lung cancer (NSCLC), which accounts for approximately 5% of NSCLC cases. The results were presented by Alice Shaw, MD, PhD, during the 2017 American Society of Clinical Oncology Annual Meeting in Chicago, IL, and concurrently published in The New England Journal of Medicine.
“In earlier studies, we already saw that alectinib demonstrated robust clinical activity in patients who had not been treated with crizotinib, as well as those who were crizotinib-resistant,” said Shaw, a thoracic oncologist at Massachusetts General Hospital in Boston. Based on those data, alectinib received the FDA's go-ahead in 2015 as a second-line option for patients whose disease had progressed on crizotinib, the current standard of care.
Now, however, ALEX—which enrolled 303 patients across 98 sites in 29 countries— “is a game-changer that will, without question, lead to alectinib being approved in the first-line setting,” said Corey Langer, MD, director of thoracic oncology at the University of Pennsylvania's Abramson Cancer Center in Philadelphia. It's remarkable, he added, that the last decade “has seen us identify a subset [of NSCLC] that wasn't apparent before, a drug that works, at least initially, and now we have all these next-generation ALK inhibitors—five and counting so far. The therapeutic trajectory for this patient population is entirely different.”
Shaw reported that among patients randomly assigned to receive alectinib, the investigator-assessed median progression-free survival (PFS) was not reached, compared with 11.1 months for those given crizotinib. An independent review arrived at similar findings: a median PFS of 25.7 months versus 10.4 months. Alectinib was better tolerated, with fewer patients requiring dose reductions or a halt in treatment. Due to its excellent brain penetration, the incidence of brain or central nervous system (CNS) metastases at 12 months was much lower with alectinib than with crizotinib—9% versus 41%—and alectinib also reduced the risk of disease progression in the CNS by 84%.
“To be blunt, this magnitude of benefit is unprecedented in thoracic oncology,” Langer remarked, “especially with alectinib being so much better at preventing a process [CNS metastases] that often spells doom for these patients.”
“Going forward, I think it's pretty clear that if you have a newly diagnosed patient [with ALK+ NSCLC], alectinib should be the standard of care,” Shaw said. “For patients already on crizotinib, what happens next will require a case-by-case evaluation.”
John Heymach, MD, PhD, chair of thoracic/head and neck medical oncology at The University of Texas MD Anderson Cancer Center in Houston, agreed. “I view this as a watershed moment for the treatment of ALK+ lung cancer,” he said. “Studies comparing agents in the same class usually show incremental, not dramatic, improvement. As well, advances often come at the cost of increased toxicity, but that's not the case with alectinib.”
Whether a different ALK inhibitor could eventually replace alectinib as the favored first-line therapy will depend on studies such as ALTA-1L, a phase III trial pitting brigatinib (Alunbrig; Takeda Oncology) against crizotinib. Data from that study are expected sometime in 2018; however, “unless it hits a similar PFS benchmark, brigatinib will be found wanting,” Langer said.
For clinicians treating this disease, the biggest issue will be what to do when alectinib stops working. “With acquired resistance to ALK inhibition, there's tremendous heterogeneity and no consistent theme,” Langer noted. “Besides at least 14 types of ALK alterations that can occur, some individuals also develop resistance mutations that have nothing to do with this pathway.”
There could be a role for crizotinib here, especially if MET is involved in mediating resistance, Shaw observed. Although touted as the first ALK-targeted therapy, crizotinib is really more of a MET inhibitor. She also pointed out a case study in which acquired resistance to lorlatinib, Pfizer's investigational ALK inhibitor, paradoxically restored responsiveness to crizotinib.
Optimal sequencing of these drugs remains murky, but Shaw hopes the ALK Master Protocol she's working on with the NCI—evaluating next-generation agents with a single shared control arm, crizotinib—will eventually resolve this outstanding question. –Alissa Poh