Clinical Trials Are Crucial in Mutation-Driven Lung Cancer

More patients with non-small cell lung cancer (NSCLC) should be evaluated and referred to clinical trials, especially those who may have molecular abnormalities, says Victoria M. Villaflor, M.D.
BY Angelica Welch
PUBLISHED October 30, 2017
More patients with non-small cell lung cancer (NSCLC) should be evaluated and referred to clinical trials, especially those who may have molecular abnormalities, says Victoria M. Villaflor, M.D.

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 3 ALEX study, which showed that Alecensa (alectinib) significantly reduced the risk of disease progression or death compared with standard-of-care Xalkori (crizotinib) as a frontline treatment in patients with ALK-positive NSCLC.

In an interview with CURE during the 2017 OncLive® State of the Science SummitTM 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.

Can you please provide an overview of your lecture?

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.

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 percent to 2 percent 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 Gilotrif (afatinib) or Herceptin (trastuzumab) in small series. Responses do occur, but the data are very limited. 

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

The standard of care, up until recently, was Xalkori. The PROFILE 1014 trial showed that there was a definite benefit in patients when they were given Xalkori 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 Xalkori, hence its use as the standard of care for many years. 

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

Something else of important note is that patients who received Alecensa had a very large benefit with CNS metastases. This was both in response to Alecensa, plus it also took longer until they progressed in the CNS because of the inability to pass the blood-brain barrier.

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

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 Xalkori, Zykadia (ceritinib), Alunbrig (brigatinib) and Alecensa. 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 Xalkori; 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.

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. 
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