The investigational ALK inhibitor lorlatinib, whose early clinical activity was first reported last year, continues to look promising in advanced ALK-positive or ROS1-positive non–small cell lung cancer. In a phase II study, robust responses were seen in previously untreated patients, as well as those who had received as many as three prior ALK inhibitors.

Findings from a phase II study show that the investigational ALK inhibitor lorlatinib (Pfizer), whose early clinical activity was first reported last year and recently published, continues to look promising in a wide range of patients with advanced ALK-positive or ROS1-positive non–small cell lung cancer (NSCLC; Lancet Oncol 2017 Oct 23 [Epub ahead of print]). The trial's results were presented by Benjamin Solomon, MD, of Peter MacCallum Cancer Centre in Melbourne, Australia, during the International Association for the Study of Lung Cancer's 2017 World Conference on Lung Cancer in Yokohama, Japan.

Three second-generation ALK inhibitors are now FDA-approved as second-line treatment options for patients who have become resistant to crizotinib (Xalkori; Pfizer). Lorlatinib, a third-generation agent, is specifically designed to overcome most known ALK resistance mutations, and to penetrate the brain and central nervous system, where the disease frequently metastasizes.


Structural model of crizotinib binding to ALK. Many patients with ALK-positive non–small cell lung cancer who develop resistance to crizotinib may benefit from lorlatinib.

Solomon reported data on five groups of patients: The first had never received an ALK inhibitor; the next three cohorts had previously received crizotinib, a second-generation ALK inhibitor, or two to three prior ALK inhibitors; and the final group had previously treated ROS1-positive lung cancer. The objective response rates (ORR) to lorlatinib were 90%, 69%, 33%, 39%, and 36%, respectively. In terms of intracranial activity, assessed through MRI, the ORRs were 75%, 68%, 42%, 48%, and 56%. Lorlatinib was well tolerated, and patients reported improvements in their overall quality of life and in common symptoms such as coughing, chest pain, and dyspnea.

“It's very reassuring to see such a high ORR among previously untreated patients,” says trial investigator Alice Shaw, MD, PhD, of Massachusetts General Hospital in Boston. The cohort that received as many as three prior ALK inhibitors is particularly noteworthy, she adds. “These patients' disease may be refractory to all the approved agents out there, but a significant fraction still respond to lorlatinib.”

Christine Lovly, MD, PhD, of Vanderbilt Ingram Cancer Center in Nashville, TN, notes that the standard of care is about to change for ALK-positive NSCLC, with the phase III ALEX study having unequivocally demonstrated alectinib's (Alecensa; Roche) superiority to crizotinib earlier this year. Alectinib has since been recommended for approval as initial therapy in the European Union; in the United States, clinicians anticipate a favorable decision from the FDA later this fall. Meanwhile, lorlatinib's first-line potential is being assessed in the phase III CROWN trial, and “the hope is that it will prove even better than alectinib, when compared with crizotinib,” Shaw says.

As next-generation ALK inhibitors replace first-line crizotinib, “the spectrum of ALK resistance mutations may well change,” Lovly notes. “We think G1202R, for instance, may occur more frequently than it does now, in which case lorlatinib has the best efficacy data against this alteration.” She hopes the ALK Master Protocol, which Shaw is working on with the NCI, will help stratify patients to the appropriate drugs, based on individual mutation status.

“What's more pressing,” Lovly continues, “is figuring out how to treat the subset of patients, about half in all, whose relapse is driven by ALK-independent mechanisms. Right now, they'd be offered chemotherapy as their best option.”

“These are the tough cases, and they represent a huge unmet need,” Shaw says. “We've been going after low-hanging fruit, in a way, with ALK resistance mutations.” Combination therapies are warranted, she adds, to address the off-target resistance mechanisms these tumors are likely to evolve.

“We need rational, potent combinations up front,” Lovly agrees. “The idea is to constrain tumor clonality from the start, which could prevent resistance from ever coming up.” –Alissa Poh

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