Abstract
The FDA has approved a third ALK inhibitor, alectinib, for advanced ALK-positive non–small cell lung cancer. Two phase II studies show that patients who have become resistant to crizotinib respond well to alectinib; the drug is also effective against brain metastases, which are common in this disease subtype.
Patients with advanced ALK-positive non–small cell lung cancer (NSCLC) who have developed resistance to crizotinib (Xalkori; Pfizer) have a new option: alectinib (Alecensa; Roche), the third drug for this molecular subset of NSCLC to garner FDA approval since the discovery of ALK as a therapeutic target in 2007.
“Even before crizotinib was approved [in 2011], drug resistance in this patient population was recognized as a major issue—almost every patient relapses at some point,” says Alice Shaw, MD, PhD, a thoracic oncologist at Massachusetts General Hospital in Boston. There are multiple routes to resistance, Shaw adds, chief among them secondary mutations within ALK's kinase domain, amplification of the ALK fusion gene, or activation of other signaling pathways.
To overcome this problem, pharmaceutical companies began developing more potent ALK inhibitors, with ceritinib (Zykadia; Novartis) being the first approved next-generation drug in 2014, and now alectinib.
Alectinib's approval was based on data from two multicenter phase II clinical trials, one led by Shaw and colleagues. In their study, which enrolled patients in the United States and Canada, the objective response rate (ORR) to alectinib was 48% among 69 crizotinib-resistant patients, and the median duration of response (DOR) was 13.5 months (Lancet Oncol 2015 Dec 18 [Epub ahead of print]).
A global study yielded “remarkably similar results,” Shaw observes: The ORR was 49% among 122 patients, and the median DOR was 11.2 months (J Clin Oncol 2015 Nov 23 [Epub ahead of print]).
“Notably, we saw that alectinib also works extremely well in the brain,” a common site of metastasis among patients with ALK-positive NSCLC, she says. More than half of the participants in both clinical trials had brain metastases; in Shaw's study, 75% of these patients experienced a complete or partial reduction of their brain tumors, with a median DOR of 11.1 months. The response rate in the international study was 57%, and the median DOR was 10.3 months.
“Alectinib can penetrate into the brain at high levels, probably close to what's achieved in the blood, partly because it's not a substrate of the drug efflux pump MDR1,” Shaw explains. The drug has also shown clinical activity in leptomeningeal disease—metastatic involvement of the lining of the brain—which historically has had no effective treatment options.
Of equal importance, Shaw says, alectinib's side effects—mainly fatigue, edema, constipation, and muscle pain—are mild; overall, it's “a very easy pill that lacks the GI toxicities seen with other ALK inhibitors.”
With still more ALK inhibitors in pharmaceutical pipelines, including brigatinib (ARIAD) and lorlatinib (Pfizer), Shaw is working with the NCI on a master protocol “that we hope will address the fundamental question of how to properly sequence these drugs,” she says. “For instance, after a patient relapses on crizotinib, which next-generation drug should be used next? It's likely that patients' specific ALK alterations—along with acquired resistance mutations—will inform us as to the most appropriate choice.”
Ultimately, Shaw favors finding ways to prevent resistance from developing at all in these patients. “It will be more effective than trying to overcome each round of resistance that emerges,” she says, “especially given the heterogeneity of the mechanisms involved.” –Alissa Poh
For more news on cancer research, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/content/early/by/section.
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