Chemotherapy and Immunotherapy in Non–Small Cell Lung Cancer

Suresh Ramalingam, MD: For us, having heard this, who would use the chemotherapy plus IPI/NIVO [ipilimumab/nivolumab] approach, and if you choose that approach, is 2 cycles of chemotherapy, in your impression, sufficient?

Firas Badin, MD: Suresh, before I go to the chemotherapy/nivolumab/ ipilimumab, the nivolumab/ ipilimumab combination has proven itself in multiple other tumor types prior to the non–small cell lung indication. We’ve seen that in melanoma, we’ve seen that in GI [gastrointestinal] and renal cell carcinoma, and here it is the same story in non–small cell lung cancer. If you believe the science behind this combination improving the function, as well as the quantity of the T cells, then you would expect to see better results with this combination. What is interesting about this combination, it tends to overcome histology, it tends to overcome PD-L1 suppression, since we’re seeing the same results regardless of histology as well as regardless of PD-L1 status.

Now back to your question on the combination of I/O [immunotherapy]-I/O plus a platinum doublet, the CheckMate 9LA protocol, I was one of the primary investigators on this study. It’s a very nice, well-designed, phase 3 clinical trial looking at the standard of care chemotherapy platinum doublet vs just 2 cycles. This is a novel approach. We’ve never done just 2 rounds of chemotherapy, we tend to do 4 to 6 cycles, that’s the standard in our clinic. But it’s a novel approach with only 2 doses of chemotherapy, trying to get some of the synergy from chemotherapy, plus Opdivo [nivolumab] and Yervoy [ipilimumab], and then patients will go into Opdivo/Yervoy maintenance.

The dosing is different. Yes, we’re used to giving Opdivo/Yervoy in our clinic, but we’re not used to giving Yervoy at the lower dose, but I don’t think any of my colleagues here will argue against a lower dose of Yervoy. I think we’re just going to give enough of the drug with limited toxicities or adverse effects. It was only 1 mg/kg every 6 weeks. Then the primary end point is to look at progression-free survival as well as overall survival, and the study did meet its primary end point, and about two-thirds of patients are still alive at 1 year with this quadruplet regimen.

Now, is this an appropriate regimen for everybody? I don’t think so, but definitely it’s a good option. If you don’t want to miss the opportunity of using chemotherapy in the first-line setting, but at the same time you don’t want to give the full force of 4 to 6 cycles, then here is another option for our patients.

Suresh Ramalingam, MD: Great. As we talk about these new regimens, we don’t want to forget the ones that we’ve already had in the clinic. In fact, we heard about long-term outcomes with pembro [pembrolizumab] in the high PD-L1 expression population. For us, this was the update at ESMO [the European Society for Medical Oncology annual meeting] about the KEYNOTE-024 study. Can you talk to us about those results?

Firas Badin, MD: This is a dear study to my heart because it was the first time that we were able to use a checkpoint inhibitor as a single agent for patients with metastatic non–small cell lung cancer across different histologies, but in patients who have strongly positive or a high expression of PD-L1, more than 50%. We all are aware of the initial data with the trial having an overall survival advantage compared to platinum doublets, but here we have the 5-year data. We’re always talking about flattening the curve with COVID-19 [coronavirus disease 2019] and we’re doing the same thing with lung cancer. We are trying to flatten the tail of the curve with lung cancer, we want to see long-term survival. We start to wonder if we are curing some of our metastatic patients with immune checkpoint inhibitors or with immune therapy, and with this study, more than one-third of patients who received pembrolizumab in the first-line setting are still alive. These are wonderful data.

You mentioned, Suresh, the 3-year data also of Opdivo/Yervoy. We’re seeing more long-term survival. You look at numbers, 5-year survival with chemotherapy for those patients, 5 years ago you were seeing about 0%, or definitely less than 5%, and here today we’re talking about one-third of patients are still alive at 5 years. That’s wonderful.

What’s also nice to see with the trial, there were no added toxicities, nothing out of the ordinary. We’ve learned from different trials that immune-mediated reactions, if they are going to happen, they tend to happen early, usually in the first 6 months. They could happen at any time, but are more likely to happen in the first 6 months rather than later, which allows us to continue treatment beyond that period.

Suresh Ramalingam, MD: Absolutely. It is amazing that we have a third of the patients make it beyond 5 years. There was a discussion whether that represents a cure, and Roy Herbst, MD, PhD, the discussant for that abstract, certainly said those patients are cured. The important message there is you give 2 years of therapy and you stop. If the patient progresses, reintroducing the drug was associated with activity there, so that’s what I have done in my clinic for those patients. Steve and Christine, how do you approach that situation, when they progress on immunotherapy?

Christine Bestvina, MD: In similar fashion to you, I first rechallenge with immunotherapy, single agent, and do a short interval CT scan. I’ll take a peek at 6 weeks to make sure we’re headed in the right direction. But seeing another set of data about rates of efficacy at reintroduction, I’m comfortable. The majority of patients had either a response or at least disease stability, so this also helps me feel more comfortable in coaching patients in that decision at 2 years of whether to stop therapy, because I think that’s a huge point of patient anxiety in their treatment course. They’ve been told they have metastatic lung cancer, then they’re told they have this miraculous immunotherapy option. They get disease control for 2 years, and stopping the drug is such an anxiety-provoking episode for them. Now it’s nice to have some additional data to give them about, “OK, well if the cancer does come back, here’s what we would do, and here’s the likelihood of success in that case.”

Stephen Liu, MD: I agree with that. Fortunately for me, it hasn’t happened yet. All of my patients who have gotten to 2 years where I’ve stopped, it simply hasn’t recurred. I like having that assurance, but so far, so good. Ultimately it’s not going to be a one-size-fits-all. I think there probably are predeterminants of who can stop early and who can’t, of who needs specific strategies. All of my patients who have made it to 2 years and we’ve stopped electively, their disease remains in control now off therapy.

Transcript Edited for Clarity