It has been an "embarrassment of riches" in the treatment paradigm for patients with non–small cell lung cancer (NSCLC) with two approved two PD-1 agents.
It has been an "embarrassment of riches" in the treatment paradigm for patients with non—small cell lung cancer (NSCLC) with two approved two PD-1 agents, says Benjamin Levy.
Keytruda (pembrolizumab) was granted an accelerated approval by the FDA as a treatment for patients with pretreated advanced NSCLC across all histologies whose tumors express PD-L1 in October 2015. Keytruda was approved along with a companion diagnostic, the PD-L1 IHC 22C3 pharmDx test, and is indicated for patients who progressed on or after platinum-containing chemotherapy or EGFR- or ALK-targeted agents in patients harboring those mutations.
Most recently, the FDA accepted a supplemental new drug application for Keytruda as a treatment for patients with advanced NSCLC with PD-L1 expression on less than 1 percent of tumor cells.
Also in October 2015, the FDA expanded the approval of Opdivo (nivolumab) to include patients with nonsquamous NSCLC who progress on or following platinum-based chemotherapy, or EGFR- or ALK-targeted agents in patients who have those mutations.
How have the approvals of Opdivo and Keytruda in the second-line setting changed the treatment paradigm of NSCLC?
In an interview with CURE, Levy, assistant professor of Medicine, Hematology, and Medical Oncology at Mount Sinai Hospital, discusses how Opdivo and Keytruda have impacted the treatment landscape of NSCLC, how to choose between the two for patients, and what biomarkers are in development for PD-1/PD-L1 agents.Opdivo and Keytruda have completely created a completely new therapy paradigm for patients with both squamous and nonsquamous cell NSCLC.
Opdivo was compared with docetaxel as a second-line drug in both the squamous and nonsquamous population in two competing CheckMate studies. In both of those studies, Opdivo provided a meaningful improvement in overall survival. Because of that improvement, Opdivo is now approved as a second-line drug for patients who are platinum-refractory.
We need to remember that, most often, lung cancer trials fail to show survival advantages. If you look at the data, probably 90 to 95 percent of all phase 3 lung cancer trials fail to show this. There are two that we have, and they have been published in The New England Journal of Medicine. It has completely changed how we treat patients in the second-line setting.
Keytruda is the other checkpoint inhibitor that was recently approved from the KEYNOTE-010 study. It showed very competitive response rates — close to 40 to 45 percent in patients with PD-L1—expressing lung cancers that were squamous or adenocarcinoma. The difference between Opdivo and Keytruda is that Keytruda requires patients to be PD-L1–positive, and Opdivo does not have that in its approval.
How else would you choose between the two agents when deciding on treatment for a patient?
What are your thoughts on the value of PD-L1 as a biomarker?
Overall, these drugs are great. It’s an embarrassment of riches for patients. They are checkpoint inhibitors, have very similar activity, and very similar adverse events. It just so happens that Keytruda does require PD-L1 testing and Opdivo does not.It really comes down to whether your institution is doing PD-L1 testing, or whether the testing can be done at a third-party laboratory. At our institution, we have a lot of problems with having enough tissue available. This is not only for molecular interrogation, but also for samples to be provided for clinical trials. I have not been routinely testing for PD-L1 in my patient population because I can give Opdivo regardless of PD-L1 status.What we know is it may not be the best biomarker that predicts efficacy to these drugs. I have had many patients that had been screened for trials, who have been PD-L1—negative, end up getting Opdivo, and they do great. For me, I have been more commonly using Opdivo.
What is the status of the development of other biomarkers for PD-1/PD-L1 agents?
That being said, I think Keytruda is a great drug. It works just as well in patients as Opdivo. I have been using Keytruda in a clinical trial that I am leading, and I have seen wonderful things. It’s very similar to what I see with Opdivo. However, in routine use outside of a clinical trial, I’m more often using Opdivo. This is just based on that PD-L1 testing that has to be done.Right now, the search is on to find the optimal biomarker that predicts efficacy to these drugs. We started out with PD-L1 in the tissue. However, the problem with the immunohistochemistry test is that there are different platforms that test for PD-L1; there are different cutoff values.
We are just beginning to understand what the appropriate biomarker may be. Some argue that we should be measuring PD-L1 not only in tumor cells, but also in immune cells.
With President Obama’s impending trip to Cuba, the potential lung cancer vaccine Cimavax is in the news again. What are your thoughts on the vaccine, which is now being examined at Roswell Park Cancer Institute?
Overall, everyone has their own ideas about it, but not a real understanding of what they’re looking for. We are at the ground floor for biomarker development for checkpoint inhibitors; it is truly in its infancy.Cimavax is a vaccine that targets the epidermal growth factor protein. It is one that I wasn’t too familiar with until recently. This is a vaccine that was developed in Cuba and, in many small studies, has shown meaningful survival advantages in patients who had advanced stage lung cancer.
Because of the survival advantages it has shown, and because of the renewed relationships between the United States and Cuba, Roswell Park has been very fortunate to try to work out how to get this drug to their institution, start to develop it, and put it into a clinical trial.
My research would suggest it has been used in about 5,000 patients since its development, 1,000 of those in Cuba. I think we need to learn more. There is a lot of excitement around this vaccine, and it did show robust survival advantages.
However, the studies were very small, and we need to formerly test this in the United States. We need a large study; we need to define the patient population that it is most likely to work in. With all of the excitement over the checkpoint inhibitors, such as Opdivo and Keytruda, this would be a nice story to tell. This vaccine works a little differently than the checkpoint inhibitors, but clearly there has been a lot of interest about this vaccine.
It is going to be rolled out very soon in a clinical trial at Roswell Park. There is some debate over whether it should be a phase 1 study, or a more advanced phase study. Regardless, it is going to require a lot of patients to really test what we know in a small set of patients. I look forward to seeing if this vaccine really comes and bears fruit and provides meaningful survival advantage in patients.