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Dr. David Ettinger Discusses the Road Ahead for Immunotherapy in NSCLC

Gina Columbus @ginacolumbusonc
Published: Tuesday, Oct 06, 2015

David S. Ettinger, MD

David S. Ettinger, MD

Immunotherapy options are expanding in the field of non–small cell lung cancer (NSCLC), with the recent FDA approval of pembrolizumab (Keytruda) for patients with pretreated advanced NSCLC across all histologies whose tumors express PD-L1.

Pembrolizumab is the second PD-1 inhibitor approved for treatment of this disease. The approval was based on findings from the phase I KEYNOTE-001 trial. In this study, a subgroup of patients treated with pembrolizumab had an overall response rate (ORR) of 41%. In the entire study population, the ORR was nearly 20%.

The anti–PD-1 agent nivolumab (Opdivo) was previously approved by the FDA in March 2015 for patients with squamous NSCLC who have progressed on or after platinum-based chemotherapy. Nivolumab also recently received an FDA priority review designation in the nonsquamous NSCLC setting, with a decision deadline of January 2, 2016.

However, with these approvals more challenges exist, such as determining how to optimally integrate these therapies to elicit more than 20% response rates in patients, managing immune-related toxicities, and affording the costs associated with both the anti–PD-1/PD-L1 agents and the associated adverse events.

In an interview with OncLive, David S. Ettinger, MD, professor of Oncology, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, discusses recent advancements in NSCLC, specifically with immunotherapy, and explains challenges that have stemmed from these developments.

OncLive: Can you discuss some of the recent advancements in NSCLC?

Dr Ettinger: That is a good question. I have been here for 40 years, and things have changed dramatically in lung cancer. Not only in the therapy of lung cancer, but also in diagnosis and treatment, such as radiation therapy. Surgery has gotten better. The other big part of what has changed is palliative care in lung cancer, specifically how we face and deal with patients and their families. I think that is critical in getting a patient well.

Focusing on immunotherapy, what is the optimal integration of nivolumab and other anti–PD-1/PD-L1 therapies into the treatment paradigm for metastatic NSCLC?

Right now, nivolumab, which is an immunotherapy, is approved for squamous cell carcinoma of the lung. It will be approved for nonsquamous histology very shortly. Already, it is in the NCCN Guidelines for adenocarcinoma of the lung, which is more common than squamous cell carcinoma of the lung. The real problem is that it only has a 20% response rate. However, if you have a response to nivolumab, the duration of response is longer. In the original studies that were done, the 3-year survival is 18%. We never talked about 3-year survivals of 18% in lung cancer before. If you look at stage IV lung cancer, the median survival is 8 to 10 months, the 1-year survival is 30% to 35%, and the 2-year survival is 20% to 25%.

Yet, our physicians should be telling the patients, “Those are the statistics. You are not a statistic; you are an individual.” You can get better in spite of what the doctor says, or you can do worse in spite of what the doctor says. The real problem is how a patient looks at that data. If a patient looks at that data and says, “Well, I’m going to take it seriously. I am going to die in less than 2 years.” Then, you have to worry about depression and other symptoms that may be related to that particular diagnosis.

What is exciting about nivolumab is we are talking about longer survival. However, what is not so exciting is the cost of the drug. At the 2015 ASCO Annual Meeting, there were two things discussed in NSCLC. One was immunotherapy, and the other was financial toxicity. If you look at bankruptcies in this country, 62% are due to healthcare. It is a real problem.

What effect do you envision pembrolizumab having in the treatment of NSCLC?

The big issue with all of these drugs is that each company has a different biomarker. In other words, we need a uniform biomarker.

Also, in the pembrolizumab studies, for example, researchers looked at the cutoff for the biomarker. If 50% of the tumor cells had the biomarker, there was about a 37% response rate. If 1% or less had it, there was perhaps a 10% response rate. That is why, if you look at all of these drugs for lung cancer, there are about a 20% response rates. There will be a number of these anti–PD-1/PD-L1 therapies approved. One would hope that if they all get approved, then the companies would challenge each other and maybe lower the price. However, I don’t think that is going to happen.

As far as biomarkers go, what do you think is the best use of PD-1/PD-L1 expression levels, given everything we know that was presented at ASCO?

Currently, we are not using the biomarker, unless it relates to a study. Several of the studies require patients having the biomarker for that particular trial done by that particular pharmaceutical company.




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