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Choosing Second-Line Therapy for Squamous NSCLC

Panelists: Mark A. Socinski, MD, Florida Hospital Cancer Institute; Tracey L. Evans, MD, University of Pennsylvania; David M. Jackman, MD, Dana-Farber Cancer Institute; Edward S. Kim, MD, Levine Cancer Institute; Jared Weiss, MD, UNC Lineberger Comprehensive Cancer Center
Published: Wednesday, Mar 22, 2017



Transcript:

Mark Socinski, MD:
Let’s talk a little bit about traditional second-line therapy. Ed, what are your factors? We have made the argument that there’s not a good maintenance strategy—4 months later the patient is progressing. When do you jump in with second-line therapy? What are the factors that you’re thinking about, or influence your decision-making?

Edward S. Kim, MD: It’s interesting, because as in history, we’ve divided non–small cell and small cell. They’re different buckets, and we consider them a little bit differently. We’ve considered nonsquamous and squamous—squamous being almost like small cell where there hasn’t been much information. And if a patient has squamous, you’re like, “Oh no, darn,” or, “You’re a heavy smoker.” Immunotherapy has clearly changed that. I have so much optimism, now, when I see a person who has had a 60-pack-year smoking history, right? I expect they’re going to be PD-L1-positive. These are the things that you’re hoping for. And so, that happens now in squamous, whereas in nonsquamous, we don’t look at lines of therapy as much anymore, because it has meshed together with the integration of maintenance and biomarkers. Is giving an EGFR drug in the first line the same as giving a second line then, afterwards? No, it’s really first line revisited. I think squamous is trying to move in that direction right now, but we’re still a little ways out. We have 1 marker—it’s a PD-L1 marker. If you have the high expressor, which, again, I think we hold out hope—especially in patients who have squamous histology because they do usually have smoking histories—that those can be categorized. If not, we’ve discussed using cytotoxics upfront.

And then, in second-line, we have a couple to choose from—3 actually, right now—in immunotherapies. There were some interesting docetaxel/ramucirumab data before. We’ve had EGFR TKIs in there as well. And then, we’ve also had the whole potpourri of chemotherapies that never really proved themselves so much, but existed in that setting.

Mark Socinski, MD: And they were used.

Edward S. Kim, MD: They were used quite commonly. Options such as gemcitabine, Navelbine, mitomycin, and others. So, I think that the paradigm is beginning to shift. I think PD-L1 has started to bring that together, as well as the immunotherapies. Now we’re not thinking, “Pemetrexed is a great drug for a nonsquamous disease. I wish we could have the equivalent for patients who have squamous cell disease.” It’s nice to see that happening, that now lung cancer is starting to become a little more universal—all of the breast cancer patients and not the just the triple-negative population, per se.

I do think these patients are beat up more, but if there is more immunotherapy given and monitored, I think that’s going to change our approach to patients who have squamous histology. And it will allow them to take some subsequent lines of therapy and get more therapies in. So, I don’t think we look at them anymore as the pessimistic, “Oh man, there are going to be a lot of comorbidities and a lot of problems with breathing.” I think we actually look at them in a different manner now.

Mark Socinski, MD: Yes, I know. I think I’ll never forget the first time I saw the CheckMate-017 overall survival curve, with a hazard ratio of 0.59, and curves that went like this. That was the reaction there. And then, there are the pembrolizumab data. A couple of months ago, we had the OAK data presented in, yet, another choice. The OAK data obviously included squamous patients. It was a positive trial. Your thoughts on the OAK trial?

Jared Weiss, MD: Once again, we saw, in this case, a PD-L1 agent beating docetaxel in both groups of patients.

Mark Socinski, MD: Docetaxel has had a rough couple of years.

Jared Weiss, MD: Docetaxel was never my most beloved drug. After cisplatin, it might be my least favorite cytotoxic that we use in the thoracic oncology space. I was thrilled to see docetaxel get beaten up yet again. The story was a lot like we’ve seen previously—better outcome results and better tolerability. I think what was unique here, that influences our clinical practice, is there might be 2 things to take away from this. One was the subgroups. Every subgroup looked better. We got some subgroups we hadn’t seen before. But for the practical clinical purpose, this is an every-3-week drug, which has the advantages of pembrolizumab without requiring biomarker testing, which has the advantage of nivolumab. If you don’t have a result, or if that result is negative, this does de-medicalize the life of the patient a little bit by giving an every-3-week instead of an every-2-week treatment. And I think that matters to patients to a much greater extent than we sometimes recognize as practitioners.

Mark Socinski, MD: I thought one of the impressive things on the OAK trial was with SP142 as a biomarker. The hazard ratio for OS in the biomarker, in positive versus negative, was identical. Hence, there was no need for using that particular biomarker.

Jared Weiss, MD: There was no clinical or biologic way to say that docetaxel won in this trial. Every way they cut it, atezolizumab came out on top.

Mark Socinski, MD: Yes, exactly. That’s important. So, now we have 3. In the second-line setting, where we have 3 that are agnostic to histology, does histology make a difference in any of your thinking about which one to use?

Tracey L. Evans, MD: No.

Mark Socinski, MD: Does PD-L1 testing in the second-line setting make any difference? Obviously, the backdrop, today, is that everyone is going to be tested first-line. So, you’re going to know it’s second line. Is that going to make a difference?

Tracey L. Evans, MD: Yes. I’m going to probably give pembrolizumab if I know they have some PD-L1 positivity—just for some ability to keep things the same. I already talked this up when I was testing for PD-L1 in the first place.

Mark Socinski, MD: You’ve got to be consistent.

Tracey L. Evans, MD: But don’t worry if it’s negative because then you’re going to get the other 3-week drug, atezolizumab.

Edward S. Kim, MD: Regarding what happened to melanoma, and again, this is to the convenience standpoint, that’s the only reason why I really liked docetaxel before—because of the Q3 week. And that’s mostly in first-line combinations. But there was a tendency to give the one that was less frequent. Pembrolizumab was the drug of choice in melanoma because of the Q2 week versus Q3 week—nivolumab being Q2 week—and then, what changed was, again, the doublet. So, then you got ipilimumab/nivolumab, and that became more popular. Even all things being considered, and again, PD-L1 positivity has to occur with pembrolizumab, if the 3 of them were equal without any testing, I would probably lean toward pembrolizumab just because of the schedule.

Mark Socinski, MD: Do things like flat dosing, single-vial, make a difference to you guys?

David M. Jackman, MD: I don’t think they make a clinical difference. I think they make a difference from a pharmacy standpoint. There’s less wastage. It’s easier to order.

Mark Socinski, MD: Was it a step forward in the movement to flat-dose nivolumab?

Tracey L. Evans, MD: Not for us. We did try to figure out what would be the effect of the cost. Are more going to move up or move down? It seems like it’s mostly a wash on that. That was actually true when we costed out the 3 drugs compared to each other. They all roughly came out to the same price, so there’s no clear winner from that standpoint.

Mark Socinski, MD: Yes, and then at the World Conference on Lung Cancer, we saw that there’s now the fourth and fifth in line for the second- and third-line space—durvalumab—with activity that looks very similar to the other ones and others coming. How many do we need?

Tracey L. Evans, MD: I don’t see any clear distinctions between them.

Mark Socinski, MD: And does anyone? Is anyone out there making a biosimilar?

Tracey L. Evans, MD: I don’t know the answer to that.

Edward S. Kim, MD: I haven’t heard of biosimilars yet for immunotherapy drugs.

Jared Weiss, MD: Too early, right?

Tracey L. Evans, MD: Yes, I think there has to be some time.

Mark Socinski, MD: Yes, I guess. I actually don’t know though.

Jared Weiss, MD: It will take some number of years. I couldn’t tell you the number, but we’re not close to it.

Transcript Edited for Clarity

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Transcript:

Mark Socinski, MD:
Let’s talk a little bit about traditional second-line therapy. Ed, what are your factors? We have made the argument that there’s not a good maintenance strategy—4 months later the patient is progressing. When do you jump in with second-line therapy? What are the factors that you’re thinking about, or influence your decision-making?

Edward S. Kim, MD: It’s interesting, because as in history, we’ve divided non–small cell and small cell. They’re different buckets, and we consider them a little bit differently. We’ve considered nonsquamous and squamous—squamous being almost like small cell where there hasn’t been much information. And if a patient has squamous, you’re like, “Oh no, darn,” or, “You’re a heavy smoker.” Immunotherapy has clearly changed that. I have so much optimism, now, when I see a person who has had a 60-pack-year smoking history, right? I expect they’re going to be PD-L1-positive. These are the things that you’re hoping for. And so, that happens now in squamous, whereas in nonsquamous, we don’t look at lines of therapy as much anymore, because it has meshed together with the integration of maintenance and biomarkers. Is giving an EGFR drug in the first line the same as giving a second line then, afterwards? No, it’s really first line revisited. I think squamous is trying to move in that direction right now, but we’re still a little ways out. We have 1 marker—it’s a PD-L1 marker. If you have the high expressor, which, again, I think we hold out hope—especially in patients who have squamous histology because they do usually have smoking histories—that those can be categorized. If not, we’ve discussed using cytotoxics upfront.

And then, in second-line, we have a couple to choose from—3 actually, right now—in immunotherapies. There were some interesting docetaxel/ramucirumab data before. We’ve had EGFR TKIs in there as well. And then, we’ve also had the whole potpourri of chemotherapies that never really proved themselves so much, but existed in that setting.

Mark Socinski, MD: And they were used.

Edward S. Kim, MD: They were used quite commonly. Options such as gemcitabine, Navelbine, mitomycin, and others. So, I think that the paradigm is beginning to shift. I think PD-L1 has started to bring that together, as well as the immunotherapies. Now we’re not thinking, “Pemetrexed is a great drug for a nonsquamous disease. I wish we could have the equivalent for patients who have squamous cell disease.” It’s nice to see that happening, that now lung cancer is starting to become a little more universal—all of the breast cancer patients and not the just the triple-negative population, per se.

I do think these patients are beat up more, but if there is more immunotherapy given and monitored, I think that’s going to change our approach to patients who have squamous histology. And it will allow them to take some subsequent lines of therapy and get more therapies in. So, I don’t think we look at them anymore as the pessimistic, “Oh man, there are going to be a lot of comorbidities and a lot of problems with breathing.” I think we actually look at them in a different manner now.

Mark Socinski, MD: Yes, I know. I think I’ll never forget the first time I saw the CheckMate-017 overall survival curve, with a hazard ratio of 0.59, and curves that went like this. That was the reaction there. And then, there are the pembrolizumab data. A couple of months ago, we had the OAK data presented in, yet, another choice. The OAK data obviously included squamous patients. It was a positive trial. Your thoughts on the OAK trial?

Jared Weiss, MD: Once again, we saw, in this case, a PD-L1 agent beating docetaxel in both groups of patients.

Mark Socinski, MD: Docetaxel has had a rough couple of years.

Jared Weiss, MD: Docetaxel was never my most beloved drug. After cisplatin, it might be my least favorite cytotoxic that we use in the thoracic oncology space. I was thrilled to see docetaxel get beaten up yet again. The story was a lot like we’ve seen previously—better outcome results and better tolerability. I think what was unique here, that influences our clinical practice, is there might be 2 things to take away from this. One was the subgroups. Every subgroup looked better. We got some subgroups we hadn’t seen before. But for the practical clinical purpose, this is an every-3-week drug, which has the advantages of pembrolizumab without requiring biomarker testing, which has the advantage of nivolumab. If you don’t have a result, or if that result is negative, this does de-medicalize the life of the patient a little bit by giving an every-3-week instead of an every-2-week treatment. And I think that matters to patients to a much greater extent than we sometimes recognize as practitioners.

Mark Socinski, MD: I thought one of the impressive things on the OAK trial was with SP142 as a biomarker. The hazard ratio for OS in the biomarker, in positive versus negative, was identical. Hence, there was no need for using that particular biomarker.

Jared Weiss, MD: There was no clinical or biologic way to say that docetaxel won in this trial. Every way they cut it, atezolizumab came out on top.

Mark Socinski, MD: Yes, exactly. That’s important. So, now we have 3. In the second-line setting, where we have 3 that are agnostic to histology, does histology make a difference in any of your thinking about which one to use?

Tracey L. Evans, MD: No.

Mark Socinski, MD: Does PD-L1 testing in the second-line setting make any difference? Obviously, the backdrop, today, is that everyone is going to be tested first-line. So, you’re going to know it’s second line. Is that going to make a difference?

Tracey L. Evans, MD: Yes. I’m going to probably give pembrolizumab if I know they have some PD-L1 positivity—just for some ability to keep things the same. I already talked this up when I was testing for PD-L1 in the first place.

Mark Socinski, MD: You’ve got to be consistent.

Tracey L. Evans, MD: But don’t worry if it’s negative because then you’re going to get the other 3-week drug, atezolizumab.

Edward S. Kim, MD: Regarding what happened to melanoma, and again, this is to the convenience standpoint, that’s the only reason why I really liked docetaxel before—because of the Q3 week. And that’s mostly in first-line combinations. But there was a tendency to give the one that was less frequent. Pembrolizumab was the drug of choice in melanoma because of the Q2 week versus Q3 week—nivolumab being Q2 week—and then, what changed was, again, the doublet. So, then you got ipilimumab/nivolumab, and that became more popular. Even all things being considered, and again, PD-L1 positivity has to occur with pembrolizumab, if the 3 of them were equal without any testing, I would probably lean toward pembrolizumab just because of the schedule.

Mark Socinski, MD: Do things like flat dosing, single-vial, make a difference to you guys?

David M. Jackman, MD: I don’t think they make a clinical difference. I think they make a difference from a pharmacy standpoint. There’s less wastage. It’s easier to order.

Mark Socinski, MD: Was it a step forward in the movement to flat-dose nivolumab?

Tracey L. Evans, MD: Not for us. We did try to figure out what would be the effect of the cost. Are more going to move up or move down? It seems like it’s mostly a wash on that. That was actually true when we costed out the 3 drugs compared to each other. They all roughly came out to the same price, so there’s no clear winner from that standpoint.

Mark Socinski, MD: Yes, and then at the World Conference on Lung Cancer, we saw that there’s now the fourth and fifth in line for the second- and third-line space—durvalumab—with activity that looks very similar to the other ones and others coming. How many do we need?

Tracey L. Evans, MD: I don’t see any clear distinctions between them.

Mark Socinski, MD: And does anyone? Is anyone out there making a biosimilar?

Tracey L. Evans, MD: I don’t know the answer to that.

Edward S. Kim, MD: I haven’t heard of biosimilars yet for immunotherapy drugs.

Jared Weiss, MD: Too early, right?

Tracey L. Evans, MD: Yes, I think there has to be some time.

Mark Socinski, MD: Yes, I guess. I actually don’t know though.

Jared Weiss, MD: It will take some number of years. I couldn’t tell you the number, but we’re not close to it.

Transcript Edited for Clarity
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