Lyudmila A. Bazhenova, MD
Alectinib (Alecensa) is the frontline de-facto standard of care for patients with ALK
-positive non–small cell lung cancer (NSCLC), said Lyudmila A. Bazhenova, MD. Exploration into mechanisms of resistance will help physicians unveil how to best sequence available therapies.
The ALK inhibitor armamentarium has expanded in recent years beyond crizotinib (Xalkori), with the addition of ceritinib (Zykadia), alectinib, brigatinib (Alunbrig), and, potentially, lorlatinib, which currently has a priority review designation with the FDA as a second- or later-line agent.
However, acquired resistance continues to remain an area of focus. Although alectinib outperformed crizotinib in the phase III ALEX trial, crizotinib may still play a role in the management of the disease for patients who fail second-line lorlatinib following crizotinib, as they may have sensitivity to the original drug. The response was reported in a study published in the New England Journal of Medicine.
“The response was not long lasting, but it’s still a proof of concept that constant re-evaluation of the tumor using liquid biopsy or tissue biopsy to understand what the emerging mechanism of resistance is can [enable the] possibility of sequencing ALK inhibitors back-to-back,” said Bazhenova, a professor of clinical medicine at the University of California, San Diego.
Research is emerging in other areas of lung cancer, too, Bazhenova explains, including tumors with lesser-common abnormalities.
In an interview during the 2018 OncLive®
State of the Science Summit™ on Non–Small Cell Lung Cancer, Bazhenova discussed treatments for patients with ALK
-positive NSCLC, as well as the progress in less common oncogenic drivers, such as NTRK
OncLive: Please discuss the recent questions in ALK-positive NSCLC.
My lecture about ALK
-positive lung cancer concentrates on sequencing strategies. We now have more than 1 ALK inhibitor approved in lung cancer. The common questions that come up are, “How do we sequence them? What is the right first-line and second-line ALK inhibitor?” And [we need to know] whether you need to do a postprogression biopsy to understand the mechanism of resistance to ALK inhibition.
In addition, the ALEX trial compared crizotinib versus alectinib in the first-line setting. Now the question becomes, “What do we do after patients fail first-line alectinib?” Are there any data to suggest using other ALK inhibitors after second-generation ALK inhibitors?
What are your thoughts on alectinib as the frontline standard of care for patients with ALK-positive NSCLC?
It is the de-facto standard of care in lung cancer. The data are very strong, and the trial is a well-designed, randomized phase III [study] showing clinically meaningful improvement in progression-free survival (PFS). More importantly, there is better central nervous system control in the alectinib arm compared with the crizotinib arm.
Are there identified mechanisms of resistance for alectinib?
Not yet. We know the mechanism of resistance after crizotinib. We also know the mechanism of resistance following alectinib when it’s given after crizotinib. We know that those mechanisms of resistance are completely different from patients who have only been exposed to crizotinib.
We do not yet know if the mechanism of resistance after alectinib as a sole ALK inhibitor is going to be any different than crizotinib followed by alectinib. My prediction is that they are going to be different because it is a different pressure on the tumor. However, at this point, there have not been any data as to what to expect post–alectinib failure.
How will the potential approval of lorlatinib change the landscape?
Right now, the data on lorlatinib are only for patients who have failed prior ALK inhibitors. The study of lorlatinib had a treatmentnaïve cohort, so we have some idea of how lorlatinib works in patients who haven’t been exposed to alectinib or crizotinib. However, we don’t have the randomized trial results yet.