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RELAY: Erlotinib with Ramucirumab for EGFR+ NSCLC

Panelists: Joshua Bauml, MD, University of Pennsylvania; D. Ross Camidge, MD, University of Colorado School of Medicine; Robert Doebele, MD, PhD, University of Colorado School of Medicine; Benjamin Levy, MD, Johns Hopkins Sidney Kimmel Cancer Center; Zofia Piotrowska, MD, Harvard Medical School
Published: Friday, Aug 09, 2019



Transcript:

Benjamin Levy, MD: Another study we had was looking at the role of antiangiogenesis in combination with a first-generation TKI [tyrosine kinase inhibitor] in EGFR-mutated lung cancer, the RELAY study. Bob, you want to talk, and walk us through that a little bit and tell us what that showed?

Robert Doebele, MD, PhD: Yes, this was another randomized phase III trial of erlotinib plus erlotinib and ramucirumab in EGFR-mutation-positive patients. And these were very exciting results in terms of dramatically improved progression-free survival [PFS], going from 11 months to 19 months. And, on the surface, that looks fantastic because now we’re talking about numbers that are similar to osimertinib—19 months, 19 months. I think there are a couple of cautions here. First, patients with brain metastasis were excluded, and so that’s roughly a third of our patients who would not be applicable for this therapy. We know that osimertinib has good CNS [central nervous system] penetration, and that those patients also tend to do worse, so the numbers might look worse in this study had we put them in.

What I think is most interesting about this study is that it’s telling us something about antiangiogenic therapies. Like the prior chemotherapy setting, we have two prior phase II and a phase III study out of Japan demonstrating similar results adding bevacizumab to a first-generation TKI. I really think that there’s something to this combination in terms of synergy. And what we really need to wait for is an osimertinib plus an antiangiogenic trial.

Benjamin Levy, MD: We’ll talk about the osimertinib with bevacizumab poster. How do we interpret this data? I think Eli Lilly is going to move forward with approval of this. Does this have traction or is this a big nothing burger?

Joshua Bauml, MD: I think the issue is that in the United States we have access to osimertinib, which showed clear improvement over first-generation TKIs. If I have my choice, I would give osimertinib. If I don’t have access to osimertinib, if somebody blindfolds me and I can’t find the pharmacy where it is—I don’t know why that would happen—but if I were unable to give, or I was in a country, right, another option….

Zofia Piotrowska, MD: More likely.

Joshua Bauml, MD: Slightly.

D. Ross Camidge, MD: Although do you get blindfolded a lot?

Joshua Bauml, MD: Very frequently. It’s a whole problem we have to deal with.

Joshua Bauml, MD: Anyway, if I did not have access to osimertinib, then your 2 options to add to a first-generation TKI, based upon the data that we saw today and the data we’ve seen in the past would be adding chemotherapy or adding VEGF. And to me, you’ve got one in chemotherapy that is associated with an overall and progression-free survival advantage that is remarkable. And then you have another where you have a PFS advantage that is impressive, but you have no OS [overall survival] advantage. And we saw in the bevacizumab studies with first-generation TKIs that despite an even more impressive PFS improvement, the OS failed to improve. And we’ve seen this over and over with VEGF inhibition. So, to me, if I was going to add something to a TKI, I would add chemotherapy way before I would add VEGF inhibition.

D. Ross Camidge, MD: Just on that point though, the chemotherapy did double the rate of grade 3 toxicities.

Joshua Bauml, MD: Yes.

D. Ross Camidge, MD: From something like 25% to 50%. And then bear in mind that that overall survival may be a factor of the setting in which the study was conducted in the country, where access to subsequent treatments might be an issue.

Joshua Bauml, MD: That’s true. I believe that in the study presented today, only 11% of patients got osimertinib. So that’s a big difference. But in the Japanese study, NEJ009, I believe they did have access to osimertinib in that study. We still saw benefit there. If I were adding something to a first-generation TKI, I would add chemotherapy. I personally don’t see a major drive to add VEGF.

Robert Doebele, MD, PhD: The temptation is that with erlotinib plus ramucirumab, you still have osimertinib as a backup therapy, right? And I actually looked at the T790M rate, and it was very similar in the 2 arms.

Joshua Bauml, MD: Sure.

Robert Doebele, MD, PhD: However, again, I think we don’t have those brain metastases patients, and I think that’s the biggest limitation of the study.

Benjamin Levy, MD: Zofia, do you want to comment briefly on moving the bar forward and adding bevacizumab to next-generation TKI with osimertinib? We had a poster from Helena Yu, MD, mostly looking at safety from a phase I experience, but having some efficacy results as well.

Zofia Piotrowska, MD: I think we all agree. With both the VEGF story and with the chemotherapy story, it’s hard to know what to do with these data in the era of osimertinib. And I think all of these data really will be worth repeating with osimertinib. Dr Yu and Dr Mark Kris ,MD, did present data from an ongoing single-arm phase II study that they have combining osimertinib with bevacizumab at Memorial Sloan Kettering Cancer Center in New York. Relatively small number still, about 49 patients have been treated. But overall, I think promising results. Response rate is about 69%, but 70% of the patients were progression free at a year, they don’t have longer term follow-up yet. And importantly the toxicities seem to be pretty similar to what we expected. Some rate of diarrhea, some thrombocytopenia, things we’re used to seeing with osimertinib, some VEGF toxicities like hypertension. But overall manageable, and I think that speaks to the fact that this feasible. Perhaps even more feasible than doing it with erlotinib or gefitinib. And importantly there will be an ECOG study, an [Eastern Cooperative Oncology Group] study, looking at this exact question, randomizing patients to osimertinib versus osimertinib and bevacizumab.

D. Ross Camidge, MD: How frequently is the bevacizumab given? Where’s the ramucirumab? Was every 2 weeks, a really short leash?

Benjamin Levy, MD: Yes, it is. That was one of the comments.

Robert Doebele, MD, PhD: It was an important question perhaps for the future whether we could deescalate that to free up patients from our infusions.

Zofia Piotrowska, MD: And is that the continuous or is there, I think with some of the chemotherapies, the question is, do you give maintenance chemotherapy or just the upfront? I think there’s a lot of questions that could be teased out. But my sense is that if the benefit is big enough, patients will be willing to come in every 2 or 3 weeks, whatever it may be, if it really is helping them to live longer.

Transcript Edited for Clarity
 

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Transcript:

Benjamin Levy, MD: Another study we had was looking at the role of antiangiogenesis in combination with a first-generation TKI [tyrosine kinase inhibitor] in EGFR-mutated lung cancer, the RELAY study. Bob, you want to talk, and walk us through that a little bit and tell us what that showed?

Robert Doebele, MD, PhD: Yes, this was another randomized phase III trial of erlotinib plus erlotinib and ramucirumab in EGFR-mutation-positive patients. And these were very exciting results in terms of dramatically improved progression-free survival [PFS], going from 11 months to 19 months. And, on the surface, that looks fantastic because now we’re talking about numbers that are similar to osimertinib—19 months, 19 months. I think there are a couple of cautions here. First, patients with brain metastasis were excluded, and so that’s roughly a third of our patients who would not be applicable for this therapy. We know that osimertinib has good CNS [central nervous system] penetration, and that those patients also tend to do worse, so the numbers might look worse in this study had we put them in.

What I think is most interesting about this study is that it’s telling us something about antiangiogenic therapies. Like the prior chemotherapy setting, we have two prior phase II and a phase III study out of Japan demonstrating similar results adding bevacizumab to a first-generation TKI. I really think that there’s something to this combination in terms of synergy. And what we really need to wait for is an osimertinib plus an antiangiogenic trial.

Benjamin Levy, MD: We’ll talk about the osimertinib with bevacizumab poster. How do we interpret this data? I think Eli Lilly is going to move forward with approval of this. Does this have traction or is this a big nothing burger?

Joshua Bauml, MD: I think the issue is that in the United States we have access to osimertinib, which showed clear improvement over first-generation TKIs. If I have my choice, I would give osimertinib. If I don’t have access to osimertinib, if somebody blindfolds me and I can’t find the pharmacy where it is—I don’t know why that would happen—but if I were unable to give, or I was in a country, right, another option….

Zofia Piotrowska, MD: More likely.

Joshua Bauml, MD: Slightly.

D. Ross Camidge, MD: Although do you get blindfolded a lot?

Joshua Bauml, MD: Very frequently. It’s a whole problem we have to deal with.

Joshua Bauml, MD: Anyway, if I did not have access to osimertinib, then your 2 options to add to a first-generation TKI, based upon the data that we saw today and the data we’ve seen in the past would be adding chemotherapy or adding VEGF. And to me, you’ve got one in chemotherapy that is associated with an overall and progression-free survival advantage that is remarkable. And then you have another where you have a PFS advantage that is impressive, but you have no OS [overall survival] advantage. And we saw in the bevacizumab studies with first-generation TKIs that despite an even more impressive PFS improvement, the OS failed to improve. And we’ve seen this over and over with VEGF inhibition. So, to me, if I was going to add something to a TKI, I would add chemotherapy way before I would add VEGF inhibition.

D. Ross Camidge, MD: Just on that point though, the chemotherapy did double the rate of grade 3 toxicities.

Joshua Bauml, MD: Yes.

D. Ross Camidge, MD: From something like 25% to 50%. And then bear in mind that that overall survival may be a factor of the setting in which the study was conducted in the country, where access to subsequent treatments might be an issue.

Joshua Bauml, MD: That’s true. I believe that in the study presented today, only 11% of patients got osimertinib. So that’s a big difference. But in the Japanese study, NEJ009, I believe they did have access to osimertinib in that study. We still saw benefit there. If I were adding something to a first-generation TKI, I would add chemotherapy. I personally don’t see a major drive to add VEGF.

Robert Doebele, MD, PhD: The temptation is that with erlotinib plus ramucirumab, you still have osimertinib as a backup therapy, right? And I actually looked at the T790M rate, and it was very similar in the 2 arms.

Joshua Bauml, MD: Sure.

Robert Doebele, MD, PhD: However, again, I think we don’t have those brain metastases patients, and I think that’s the biggest limitation of the study.

Benjamin Levy, MD: Zofia, do you want to comment briefly on moving the bar forward and adding bevacizumab to next-generation TKI with osimertinib? We had a poster from Helena Yu, MD, mostly looking at safety from a phase I experience, but having some efficacy results as well.

Zofia Piotrowska, MD: I think we all agree. With both the VEGF story and with the chemotherapy story, it’s hard to know what to do with these data in the era of osimertinib. And I think all of these data really will be worth repeating with osimertinib. Dr Yu and Dr Mark Kris ,MD, did present data from an ongoing single-arm phase II study that they have combining osimertinib with bevacizumab at Memorial Sloan Kettering Cancer Center in New York. Relatively small number still, about 49 patients have been treated. But overall, I think promising results. Response rate is about 69%, but 70% of the patients were progression free at a year, they don’t have longer term follow-up yet. And importantly the toxicities seem to be pretty similar to what we expected. Some rate of diarrhea, some thrombocytopenia, things we’re used to seeing with osimertinib, some VEGF toxicities like hypertension. But overall manageable, and I think that speaks to the fact that this feasible. Perhaps even more feasible than doing it with erlotinib or gefitinib. And importantly there will be an ECOG study, an [Eastern Cooperative Oncology Group] study, looking at this exact question, randomizing patients to osimertinib versus osimertinib and bevacizumab.

D. Ross Camidge, MD: How frequently is the bevacizumab given? Where’s the ramucirumab? Was every 2 weeks, a really short leash?

Benjamin Levy, MD: Yes, it is. That was one of the comments.

Robert Doebele, MD, PhD: It was an important question perhaps for the future whether we could deescalate that to free up patients from our infusions.

Zofia Piotrowska, MD: And is that the continuous or is there, I think with some of the chemotherapies, the question is, do you give maintenance chemotherapy or just the upfront? I think there’s a lot of questions that could be teased out. But my sense is that if the benefit is big enough, patients will be willing to come in every 2 or 3 weeks, whatever it may be, if it really is helping them to live longer.

Transcript Edited for Clarity
 
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