PD-1 Agents Top Choice for Second-Line NSCLC

Roman Perez-Soler, MD

The PD-1 inhibitors pembrolizumab (Keytruda) and nivolumab (Opdivo) should be considered for all patients with advanced non—small cell lung cancer (NSCLC), especially in the second-line setting, said Roman Perez-Soler, MD, in an interview at the 10th Annual New York Lung Cancer Symposium.

“These drugs have been a gift for thoracic oncologists,” said Perez-Soler, chairman of the Department of Oncology and chief of the Division of Medical Oncology at Montefiore Medical Center, Albert Einstein College of Medicine of Yeshiva University. “Because of these drugs our patients are going to live significantly longer. Our tool bag is now much more interesting. We used to have just a hammer and a screwdriver, now we have all sorts of tools.”

Nivolumab is FDA-approved as a second-line therapy for all patients with NSCLC regardless of PD-1 expression level. The approval for nonsquamous histology was based on data from the phase III CheckMate-057 trial, in which second-line nivolumab reduced the risk of death by 27% versus docetaxel. For patients with squamous NSCLC, at an 18-month analysis, the overall survival rate with nivolumab was 28% versus 13% with docetaxel.

Pembrolizumab received an accelerated approval from the FDA for pretreated patients with advanced PD-L1-positive NSCLC along with a companion diagnostic, the PD-L1 IHC 22C3 pharmDx test. A ≥50% PD-1 expression level is needed as a prerequisite for administering the drug; however, the recent KEYNOTE-10 study may change that requirement, says Perez-Soler.

In this study, pembrolizumab was investigated versus docetaxel in all patients who expressed PD-L1 on >1% of their tumor cells. Researchers also assessed a subgroup of “strongly PD-L1—positive” patients, defined as those expressing PD-L1 on ≥50% of their tumor cells.

The study found improved overall survival in both the overall study population and in the strongly PD-L1—positive subgroup. Progression-free survival (PFS) was also improved with both doses of pembrolizumab versus chemotherapy in the high PD-L1 expressers. Among patients with PD-L1 expression <50%, PFS was improved with pembrolizumab, but the difference was not statistically significant.

This data suggests that all patients, even those who low PD-1 expression should be considered for PD-1 inhibitors, says Perez-Soler.

OncLive: What questions remain regarding the use of PD-L1/PD-1 therapies?

Is PD-1/PD-L therapy the first choice now in the second line?

In an interview with OncLive, Perez-Soler expanded on the importance of PD-1 inhibitors for all patients and the role of biomarker testing.Perez-Soler: One question that comes up is “can we exclude any patients from treatment with these drugs?” The answer is no. The reason is because patients with no expression of PD-L1 in the tumors, still respond, not as often, but there is an 8% to 10% response rate and some of these responders are really strong. We don’t understand why that is but it is the reality.Yes, based on efficacy across the board and lower toxicity. Patients typically progress in two or three months. The initial drugs, typically chemotherapy, shrink the tumor but then it comes back and the same drug cannot kill it.

With two PD-1 agents approved and possibly two PD-L1 agents being approved down the line, how should an oncologist decide which agents are best for which patient?

If patients without PD-1 expression respond to PD-1 inhibitors is biomarker testing still necessary?

The most important thing now is to try and move these therapies to the frontline because they are non-toxic and might be more effective. These therapies could also be used in combination with chemotherapy. That has been studied and so far the results look fairly promising.At this point, I would suggest that oncologist could use either of them. We should wait for the superiority trials to tell us one is better than the other because it has been proven with an experiment. We need evidence. It may be that all are equally good and then we will not need to choose one over the other. One drug is given every 3 weeks [pembrolizumab] and one is given every 2 weeks [nivolumab], so perhaps if they are proven to be equal that may prove to be the most important factor in the end.If an oncologist does not have access to biomarker testing, just give the drug because it may have a benefit for those who don’t have PD-1 expression. If you are in an environment where you can utilize the biomarker, use it. The more we can know without costing too much money or hardship on the patient, the better.

The cost of these immunohistochemistry tests is a few dollars; it is not a big deal. Damage to the patient is none, because you already have the tissue. So if you can do a PD-1 test, do it. You will learn something. Maybe the patient has a 99% PD-1 expression.

I like to recognize who may have the potential to be cured. I would use it as an informational tool, but not as a therapeutic decision tool. I will give nivolumab or pembrolizumab because I have to because it is the best I have.

What challenges remain in the treatment of NSCLC?

At this point pembrolizumab is tied to a biomarker test, but the new KEYNOTE-10 trial shows that the benefit is for all patients with above 1% PD-1 expression, so I think they are going to change that. The FDA is going to say that pembrolizumab is approved for patients with more than 1%. This will greatly increase the amount of patients that can receive this drug.We are not curing patients. In melanoma we know that these drugs can cure a percentage of patients. The immune system, if you know how to use it, is tremendously effective. That is why the dream is that some of these treatments will produce cures in a percentage of patients.

Cure in advanced lung cancer is a revelation. It doesn’t happen. We are getting there. I think we are going to start to see similar things that we saw in melanoma. That is the excitement.

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