Bazhenova Highlights Treatments for ALK+ NSCLC, Less Common Drivers

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.

OncLive: Please discuss the recent questions in ALK-positive NSCLC.

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 fusions.Bazhenova: 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.

What are your thoughts on alectinib as the frontline standard of care for patients with ALK-positive NSCLC?

Are there identified mechanisms of resistance for alectinib?

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?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.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.

How will the potential approval of lorlatinib change the landscape?

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.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.

Is there still a role for crizotinib in this landscape?

What do you believe to be the role of chemotherapy in ALK-positive NSCLC?

What research is emerging with the less common oncogenic drivers?

Lorlatinib is running a head-to-head study against crizotinib. It is very possible that, in the future, we might have another option for newly diagnosed patients. What is important about the lorlatinib study is the way the trial was designed. It had several cohorts, and some of those cohorts allowed 2 or more prior ALK inhibitors. We will have some sense that lorlatinib could work after brigatinib, alectinib, or ceritinib.It is not yet defined. Alice Shaw, MD, PhD, published a paper looking at the clonal evolution of a patient who had received multiple ALK inhibitors. Following lorlatinib, the patient developed the mutation [that] was sensitive to crizotinib but resistant to lorlatinib. The patient was switched back to crizotinib and showed a response. [We may be able to] return back to crizotinib should the mutation show that the tumor is now resensitized to crizotinib.In my practice, I use chemotherapy after patients have failed ALK inhibitors. I doubt that we will ever have data compelling enough to look at the combination of ALK inhibitors and chemotherapy, because ALK inhibitors by themselves are fairly effective. It would be hard to improve upon that without taking a hit on quality of life.There is more to lung cancer than ALK, EGFR, ROS1, and BRAF. Those are the 4 mutations for which we have FDA-approved drugs. Lung cancer is much more diverse than that. We have seen lung cancer mutations such as RET, HER2, EGFR exon 20, MET, and NTRK. These mutations, although very rare, can still be found in lung cancer.

What are some of these therapies that are being explored in clinical trials?

There are other options for patients with those mutations who don’t have access to an FDA-approved agent. There are always clinical trials that offer patients the target therapy of interest or other FDA-approved drugs for different indications that have activity against that mutation.I’m very excited about NTRK fusions because the data published by Dr Alexander Drilon in the New England Journal of Medicine [are] fairly striking and showed response rates in the order of 70% to 80%. Responses are very durable with larotrectinib. We also have some data with entrectinib; that is another NTRK inhibitor.

Will basket trials become a focus of research with these lesser-common drivers?

The entrectinib data is in fewer patients, but still [have] a very similar efficacy ballpark, with high response rates and very durable responses. Unless you look for that mutation, you’re not going to find it. These drugs are very effective, and the toxicity is very reasonable.Basket trials and mutation-specific trials are the way to go because when you look at NTRK, for example, it is very rare. In order for you to do a lung cancer—specific NTRK trial, it’s going to take decades because there are not enough patients like that. I would have to screen 100 patients to find 1 in about 2 years. When you have those mutation-specific trials, it is easy for you to attract cancers that are not necessarily lung cancer, but other diseases in which NTRK can be found.

NTRK can be found in some pediatric tumors and some other malignancies. You can then accelerate the approval of the drug through the regulatory agencies, and offer the drug to patients sooner rather than if you had done individual NTRK-mutant colorectal cancer, lung cancer, or pediatric cancer trials. It’s faster and less expensive to run a trial for specific mutations that allow different histologies.

Shaw AT, Friboulet L, Leshchiner I, et al. Resensitization to crizotinib by the lorlatinib ALK resistance mutation L1198F. N Eng J Med. 2016;374(1):54-61. doi: 10.1056/NEJMoa1508887.