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

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.

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

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?

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

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

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?

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.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.

What contributions have Johns Hopkins researchers made to the field of immunotherapy?

PD-1/PD-L1 expression is not routinely used in the clinic. Obviously, if you test a patient for PD-1/PD-L1 expression and the result is negative, the question is: would you still treat that patient with nivolumab? There is a response rate in patients with no biomarker expression, so I probably would treat them with nivolumab.We have been dealing with immunotherapy here for years. For example, Drew M. Pardoll, MD, PhD, and his colleagues, initially started with vaccines. They are still looking at vaccines, but now the studies have really focused on the anti—PD-1/PD-L1 therapies. We have a lot of our colleagues taking the lead on clinical trials, such as Julie R. Brahmer, MD, who is taking the lead in lung cancer.

However, what they are also learning in the laboratory, which is more important, is how to enhance immunotherapy. One of the studies we are doing here, Stand Up To Cancer for lung cancer, involves administering an epigenetic therapy prior to giving nivolumab with the hope that it will increase the response rate. Remember, a 20% response rate is not high. Eighty percent of the patients are not going to respond.

When we talk about the cost of immunotherapy, the costs associated with managing these toxicities are not included, correct?

There are also toxicities associated with the immunotherapy, and they are all related to all of the “itis’” you can think of, such as pneumonitis, colitis, and arthritis. It is all of the immune phenomena you can think of. One of the problems is that you cannot give the therapy to patients with an autoimmune disease, or else you are putting them at risk for the toxicities.Yes, that is another topic. For example, if you look at western Maryland, their hospitals are not even offering anti—PD-1/PD-L1 therapies on their formula because of the cost. It is very expensive.

How do we measure cost versus efficacy versus safety? Both the NCCN and ASCO are also trying to develop ways to conquer this issue. What you want to do with any therapy is make sure it is appropriate for an individual patient. In other words, patients with a performance status of 3 and 4 are patients who are in bed more than 50% of the time. They do not do well with any therapy we give them, unless they have a target such as EGFR or ALK rearrangement. Then, even poor performance status patients could have a response.

What research questions still need to be answered?

There are a number of companies that are helping insurers judge what therapies they should give. We do that as well here, and we are trying to develop techniques to make it easier to judge what therapies to give, irrespective of any of the guidelines. If you follow a guideline, you are going to save cost. However, the cost is not related so much to the therapy. It is related to hospitalization, treating end-of-life patients who are dying and should be on hospice, and they should not be getting chemotherapy. All of the other things that relate to hospitalization, there is savings. I think that becomes important for the patient, as well as for the healthcare system.We are talking about stage IV disease, which is metastatic. Obviously, we want to cure patients. We are making some headway now, as we are prolonging a better life for patients. We want the response rates to immunotherapy to be higher. Can we put these therapies up earlier, perhaps in the adjuvant setting, or in earlier-stage disease? Can they be combined with radiation therapy to enhance the effectiveness of our therapies?