Immunotherapy, Molecular Testing Propel Dramatic Changes in Lung Cancer Care

Gina Columbus @ginacolumbusonc
Published Online: Thursday, Feb 16, 2017

Dr. Joel Neal

Joel Neal, MD

2017 is poised to be another pivotal year in non–small cell lung cancer (NSCLC), given the exciting advances in field at the end of last year.

In October 2016, the FDA approved pembrolizumab (Keytruda) for the frontline treatment of patients with metastatic NSCLC whose tumors have more than 50% PD-L1 expression. The agent was previously approved for second-line NSCLC.

Also in October 2016, the FDA approved atezolizumab (Tecentriq) for the treatment of patients with metastatic NSCLC who have progressed after a platinum-containing regimen and an FDA-approved targeted therapy for those patients harboring EGFR or ALK abnormalities. 

Nivolumab (Opdivo), which is approved by the FDA in second-line NSCLC, had negative first-line NSCLC results from the CheckMate-026 trial reported in October 2016 at the annual ESMO Congress. However, researchers have noted issues that contributed to the negative findings, including the PD-L1 expression inclusion criteria used in the study.

In a recent interview with OncLive, Joel Neal, MD, PhD, assistant professor of Medicine (Oncology), Stanford University Medical Center, discussed how recent immunotherapy advances are transitioning the field of NSCLC and how the impact of molecular testing continues to shape treatment decisions.

OncLive: What are some exciting advancements in lung cancer we have witnessed over the last year?

Neal: The biggest thing that comes first to mind is immunotherapy. After a couple of years, we are getting a better understanding of how immunotherapy works, who it works for, and who we should use it in. However, we haven’t quite figured out who we shouldn’t use it in yet. 

We are refining what our probability is that a given patient will respond to immunotherapy. There are 3 drugs that all have approval and a couple more waiting in the wings. The biggest questions are, who should we give it to in first line, who should we maybe wait for second line, and who should we wait for third line and beyond?

There are also some developments for targeted therapies. One of the big exciting stories for EGFR-mutant lung cancer was the T790M-active drug osimertinib (Tagrisso). Testing for T790M has become a very hot topic as that drug has become FDA approved, as well.

What are your thoughts on frontline PD-1 inhibitors in NSCLC? We saw in CheckMate-026 that nivolumab did not meet the PFS endpoint, but pembrolizumab does have approval in the frontline setting.

Both agents use different assays for PD-L1 testing, and we saw data that not all of the PD-L1 tests are exactly the same. The IHC 28-8 PharmDx test, which is the diagnostic test for nivolumab, looks like it captures a wider group of positive people. The IHC 22C3 PharmDx test, which is the test for pembrolizumab, may be a little bit more selective. Then, the Ventana PD-L1 (SP142) test for atezolizumab…looked like it had the fewest positives out of anyone. All of these tests are accepting in different positive groups, plus there are different cutoffs for each of the drugs. 

I’m not convinced that the differences between pembrolizumab and nivolumab led to the differences in the trial, so much that the differences are in testing and selecting different groups of patients. The patients with the tumors that express the highest level of PD-L1, are going to be the ones most likely to respond—and the frontline setting makes sense. When we see response rates of 30%, 40%, and 50%, those rival what we see from platinum chemotherapy doublets. But, when we see response rates of 10%, 20%, or less than 10% for EGFR-mutant patients, then we think, “Wait until second- or third-line.” It’s mainly a PD-L1 testing issue that has to be figured out. 

Beyond frontline, what do you recommend for second-line treatment?

Nivolumab is approved for all second-line patients without any testing diagnostics, so that is the more commonly used drug, I suspect. I am increasingly doing the IHC 22C3 PharmDx pembrolizumab test for patients. If I have a few weeks to decide and determine my level of enthusiasm of whether I should go with the anti–PD-1 agent or more standard cytotoxic chemotherapy, then I’ll do the test in advance and figure out the probability of response. 

For the 0% PD-L1–positive patients, you could make an argument that second-line chemotherapy or third-line single-agent chemotherapy is as good—not worse. 

Do you envision there being more combinations with immunotherapy or immunotherapy with chemotherapy?

Immunotherapy can be combined with almost everything: chemotherapy, radiation therapy, targeted therapy, and, most excitedly, are other immunotherapies. We are trying to figure out how to make immunotherapy work for more patients and work for a longer time. We have a number of trials open in the combination immunotherapy realm.


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Online CME Activities
TitleExpiration DateCME Credits
Medical Crossfire®: Leveraging Liquid Biopsies in Tumor Characterization for NSCLC TherapyJan 31, 20181.5
Oncology Best Practice™: Choosing Therapies for Patients with EGFR-Mutant Lung Cancers: More Options... More Decisions... Better OutcomesFeb 28, 20182.0
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