Expert Calls for Clinical Trial Referrals in Molecularly Targetable NSCLC

Victoria M. Villaflor, MD

Molecular abnormalities in non—small cell lung cancer (NSCLC) need to be recognized and tested for, explained Victoria M. Villaflor, MD, which means evaluating and referring more patients to clinical trials.

In particular, there has been success in the ALK-positive lung cancer landscape with regard to clinical trials. This past year, data were reported from the phase III ALEX study, which showed that alectinib (Alecensa) significantly reduced the risk of disease progression or death compared with standard-of-care crizotinib (Xalkori) as a frontline treatment in patients with ALK-positive NSCLC.

OncLive: Can you please provide an overview of your lecture?

In an interview during the 2017 OncLive^® State of the Science Summit^TM on Advanced Non—Small Cell Lung Cancer, Villaflor, an associate professor of medicine at Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, discussed driver mutations in NSCLC and remaining challenges in treating patients with targetable disease.Villaflor: Essentially, I spoke about many different molecular driver mutations and translocations that can occur in lung cancer. We covered ALK, ROS1, BRAF V600E, and we talked a little bit about HER2/neu, RET, and NTRK mutations.

Can you share some insight on the promise of alectinib in ALK-positive disease?

ALK is one of the more common molecular abnormalities, it is a fusion or a translocation. HER2/neu is actually very rare; it is about 1% to 2% of all patients with NSCLC and in predominately younger patients. They generally tend to have adenocarcinoma and were never-smokers. There really are very limited data within HER2/neu; it is mostly afatinib (Gilotrif) or trastuzumab (Herceptin) in small series. Responses do occur, but the data are very limited. The standard of care, up until recently, was crizotinib. The PROFILE 1014 trial showed that there was a definite benefit in patients when they were given crizotinib over a conventional platinum-chemotherapy doublet. As far as the PROFILE 1014 trial, it showed a very large improvement in progression-free survival (PFS) when giving crizotinib, hence its use as the standard of care for many years.

More recently, the ALEX trial showed that compared with crizotinib, [the] second-generation [ALK inhibitor] alectinib showed a huge benefit in survival. In patients who received crizotinib, the PFS was about 11 months, and, even at 24 months, the PFS had not been reached in the patients who had received alectinib.

What are the big challenges that still exist in treating patients with driver mutations?

Something else of important note is that patients who received alectinib had a very large benefit with CNS metastases. This was both in response to alectinib, plus it also took longer until they progressed in the CNS because of the inability to pass the blood-brain barrier.Even with the ALK-positive patients, they can develop the G1202R mutation. This is a point mutation that can render them resistant to any of the therapies that are out there, including crizotinib, ceritinib (Zykadia), brigatinib (Alunbrig), and alectinib. There are some newer drugs that are out there such as lorlatinib, which is in a clinical trial right now and may be beneficial to these patients.

I fully believe that a patient who has an ALK fusion should be placed on ALK inhibitors as long as the tumor is ALK-[driven]. By developing, testing, and looking at mechanisms of resistance, we might be able to make this more of a chronic disease. It is very important that after patients start frontline therapy, they are sent for evaluation for clinical trials so that we can have more effective treatments for our patients in years to come.

ROS1 is a similar type of abnormality. These patients can be given crizotinib; it is an FDA-approved drug for patients who are ROS1-mutant. However, there are newer drugs that may be better, such as entrectinib, which is currently in clinical development. Again, I urge people to send patients for clinical trials.

What do you hope community oncologists took away from your talk?

Regarding many of the other mutations and translocations that I spoke about, including HER2/neu, BRAF V600E, NTRK mutations—all of these need a lot of work to determine what would be a very good and, hopefully, less toxic therapy for many of these patients. First and foremost, I would like for people to be aware that there are different molecular targets that do occur in NSCLC. I hope that it prompts them to test for those molecular abnormalities. Up to approximately 25% of patients with NSCLC can harbor a targetable mutation. I also hope that they realize that many of these molecular targets have not been fully worked out; there are a lot of resistance mechanisms that can develop. Also, I hope that they send patients for clinical trials.