Treatment Selection in mNSCLC without Actionable Genetic Alterations

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EP: 1.Treatment Selection in mNSCLC without Actionable Genetic Alterations

Hossein Borghaei, DO, MS: Hello everyone. Thank you for joining this OncLive webinar titled “Immune Checkpoint Inhibitors in First-Line Treatment of Metastatic Non–Small Cell Lung Cancer.” I am Hossein Borghaei. I'm a thoracic medical oncologist at Fox Chase Cancer Center in Philadelphia.

Today I am joined by Dr Martin Reck from the Lung Clinic Grosshansdorf in Schlewsig-Holstein, Germany, who is going to be helping us go through some of the recent data regarding management of patients with non–small cell lung cancer. It's been very exciting. We've seen many advances in the treatment of this disease in the last few years, and we know that new treatment options are continually added to the management of this particular group of patients, which is good.

Today, we will discuss all of these advances in the area of immunotherapy, primarily. Our objectives are going to be to gain insights into factors guiding treatment selection in non–small cell lung cancer in patients who do not have actionable genetic alterations. We're going to review safety and efficacy data of immune checkpoint inhibitors in first-line treatment of metastatic non–small lung cancer. We also hope to discuss treatment decision-making based on PD-L1 expression levels in this disease. Again, welcome, and thank you for joining us.

Let's begin. Martin, again, it's been really exciting to see all these new options becoming available for our patients with this disease. Can you guide us a little bit through how you would manage a patient that you see in your clinic in terms of factors that might guide you in the treatment selection for this disease, like biomarkers, what kind of molecular testing you get, and issues like that?

Martin Reck, MD, PhD: Thank you, Hoss. Nice to see you, and thank you for the invitation to participate in this webcast. This is really a huge new story, a new perspective that we can offer our patients. As you mentioned, we are talking about patients without oncogenic alterations. I think this is the first step that we need; the molecular testing first before we can go into these new treatment decisions.

It's critical at least to offer patients with nonsquamous non–small cell lung cancer this opportunity of molecular testing. If we do not see any actionable genetic alterations, then indeed we have a couple of characteristics which can guide us through the treatment selection when we talk about our different opportunities for immunotherapy.

I think 1 of the first important factors is indeed the marker of the PD-L1 expression. This is the oldest marker which has been developed for a designation of immunotherapies, but it's still a good point to look at the PD-L1 expression.

We have a couple of treatment decisions that are based on this PD-L1 expression. It's a very easy test that can be made on immune histochemistry. It's a fast test. We can get the results within 2 days. This is a very important point, but besides that, there are other important features related to patient characteristics.

Age is a factor in correlation with comorbidities. In particular, when we talk about the decision to offer the patient immunotherapies, we have to think about some contraindications, like underlying autoimmune diseases, which may be a factor not to go for immunotherapy or an immunotherapy-based combination. Besides that, I think we can expand on this later on a little bit.

There are some genetic alterations which are correlated to potential resistance: checkpoint inhibitors, like certain mutations that you can find in the tumor, but these are the critical points that I'm looking for in the PD-L1 expression.

I'm looking at potential immune resistance mediating mutations. I'm looking at the patient with the comorbidities. Then I'm also looking at the histology and the smoking status of the patient because this is also a very important factor when we take our treatment decisions.

Hossein Borghaei, DO, MS: That's great. Definitely, a lot of points to consider, but I would highlight that some of the stuff that we now go through. For instance, when we see a patient in the clinic [and are] looking at comorbidities, performance status, histology—these are the kinds of factors that we've had to look at in terms of treatment decision in the world of lung cancer for a while.

I think what you bring out are several important points. First of all, we do need the molecular testing done. I think we all agree that that's 1 of the most important aspects of taking care of a patient with non–small cell lung cancer. Even though we're going to concentrate on immunotherapies today, I think we have to emphasize the fact that neither 1 of us would want to treat somebody with immunotherapy, unless we know the full molecular profile of a patient.

Also, as you pointed out, an easy test to add now is the PD-L1, because that really does guide you in terms of what kind of options you have. At the end of the day, you might look at the PD-L1 and decide that you are going to treat the patient in 1 particular way anyway, but I think having the PD-L1 actually allows you to introduce those nuances that, hopefully, we get to discuss today in the management of these patients.

I guess because we have an audience from both continents, maybe we should discuss some of the basic differences between Europe and the US in terms of guideline recommendations. What is it that you see that's different in Europe versus the US?

Martin Reck, MD, PhD: I think this has been the reason where I had some focus on the PD-L1 expression testing because indeed in Europe we have a number of labels that are related to the PD-L1 expression testing.

In particular, when we look at the opportunity to offer the patient a monotherapy alone with the checkpoint inhibitors, we have now 3 labels that are really addicted to the PD-L1 test because we need the confirmation of a high PD-L1 expression. There we have the opportunity when we can confirm a PD-L1 expression—a high PD-L1 expression—in the tumor cell. We can offer the patient a monotherapy with pembrolizumab as a checkpoint inhibitor.

We have a new opportunity, which is the cemiplimab, also in patients with the high PD-L1 expression in the tumor cells, and we have the opportunity to offer the patient a monotherapy with an anti–PD-L1 antibody, which is atezolizumab. There we have an interesting additional marker, which is important for a number of our patients because there we do also have the label for the PD-L1 high expression in the immune cells. This is different to other checkpoint inhibitors, where we only look at the PD-L1 expression in the tumor cells.

Besides that, we have the big opportunity to go for combinations which can be a combination of chemotherapy, with a checkpoint inhibitor that is independent from the PD-L1 expression, but we also can go for this Nova opportunity of double immunotherapy with a short chemotherapy treatment, which is also independent from the PD-L1 expression. In summary, we need the high PD-L1 expression for patients where we would like to use the monotherapy with the checkpoint inhibitor, but perhaps you can tell us the situation in the United States.

Hossein Borghaei, DO, MS: Well, to some extent, it's really similar when it comes to PD-L1 testing. Definitely, if you have high PD-L1, and we define that as PD-L1 expression with a TPS [tumor proportion score] of greater than 50%—50 or greater, I would say—then you have the option of using single-agent checkpoint inhibitors, very similar to what you just said.

If somebody has negative PD-L1, that tumor expression is low or intermediate. We have the option of using chemo in combination with immunotherapy, and for patients regardless of the level of PD-L1, we have the same regimen of [CheckMate]9LA [NCT03215706], which you spearheaded with 2 short courses of chemotherapy plus I-O [immuno-oncology] regardless of the level of PD-L1.

In the US we also have access to a regimen of IPI-NIVO [ipilimumab plus nivolumab] based on CheckMate 227, but that is right now restricted to patients with PD-L1 expression of 1% or higher. Again, there are multiple options as long as we have sort of proven that patients don't have any actionable alteration.

In a way, when we look at slide 3, you see a whole host of options that we very briefly discussed based on PD-L1 expression. In the beginning, you started by telling us that you look at a number of other factors when the patient is in front of you in the office, trying to figure out which 1 of these treatments you really want to take, but it is kind of hard to come up with an exact algorithm.

I wonder if you can sort of tell us how you would decide which 1 of these regimens that you have access to would be your favorite, and based on what. Is it more on toxicity, based on efficacy, [or] a combination?

Again, PD-L1 expression obviously is important as we establish it, but how can we guide our colleagues who maybe don't do lung cancer day in and day out in terms of choosing the best regimen for their patients?

Martin Reck, MD, PhD: Well, this is good, and it's a very difficult question because it kept us busy for the previous 2 years, and I think it will keep us busy also for the next couple of years. In principle, what we can say is we have this great achievement of the monotherapies for the patients with the high PD-L1 expression. When we look at terms of tolerability or quality of life measurements, they have been quite beneficial compared just with chemotherapy, and we have seen this in several phase 3 trials.

The problem is that not every patient with a high PD-L1 expression really responds to a monotherapy. There are some situations where we have the feeling that we cannot really control the disease just by the monotherapy. These are the patients where we would go for a combination approach despite their high PD-L1 expression in the tumor cells.

Currently, it's a bit difficult to figure out a good predictive marker because we do not have prospective data on the definition of these markers, but there are some features where I think we have the feeling that a combination might be superior to the monotherapy. These are patients where we really have a dominant tumor, where we have a high tumor burden, where we have a high number of metastases, where we have active tumors with a lot of paraneoplastic syndromes, where we have high inflammatory clinical sites, like ICRP [International Commission on Radiological Protection] levels.

There is 1 group, and I think this is really special: These are the really confirmed never smokers with a high PD-L1 expression, where I also would be a bit in doubt of using a monotherapy, because when we look at all the trial results that have been generated for this monotherapy, there was a missing impact on efficacy in this particular group—in this group of never smokers.

These would be some of the factors that would contribute to my treatment decision. What would be your idea when you have the patient in the office?

Hossein Borghaei, DO, MS: It would be pretty much the same. I think that [there is] 1 thing that I do absolutely want to highlight—actually 2 points. One is that having PD-L1 expression data—knowing the data in the clinical trials is really important.

However, when a patient is in front of you, and they have significant symptoms, and it looks like the disease burden is to the extent that the opportunity to necessarily give 1 drug regimen to work, and all that might not be there. I think that's when to put aside some of the stuff that we just discussed, some of the points that we just discussed, and just say chemoimmunotherapy would be the way to go because you do get a higher response rate.

I think we've seen that, for instance, in KEYNOTE-189, when you add chemo to a combination with pembrolizumab you do get higher response rates. If getting that response rate is important in terms of reducing the disease burden and symptoms, then I think regardless of the level of PD-L1, it kind of makes sense to go with the combination.

On the other hand, if a patient is relatively asymptomatic, even in the presence of metastatic disease, and there is high PD-L1 expression, then I think single-agent checkpoint inhibitors can be very, very effective and spare the potential toxicities of chemotherapy. I think that's a really important factor to highlight.

The other 1 is the specific patient population that you highlighted, and that's the never-smoker patients. These are by and large patients with very little or no history of smoking who do not seem to have an actionable mutation based on the currently available molecular testing. I agree with you that I am a little bit hesitant about using single-agent checkpoint inhibitors in that case, and I think that's where I would pull the trigger on combination therapy. I think those are really good points to sort of keep in mind.

Transcript edited for clarity.