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First-Line Treatment Recommendations Based on TMB

Panelists: David R. Gandara, MD, UC Davis Comprehensive Cancer Center; Everett E. Vokes, MD, University of Chicago Medicine
Published: Sunday, Dec 02, 2018



Transcript: 

Everett E. Vokes, MD: How do you view these 4 trials?

David R. Gandara, MD: Well, the other trials that come into play—and we’re really talking primarily about non-squamous cell lung cancer now—have had both histologic subtypes, and the one I’m thinking about is the CheckMate-227, which was a complicated study, also published in the New England Journal of Medicine, which included an immunotherapy combination, nivolumab and ipilimumab [Opdivo and Yervoy] versus platinum chemotherapy and then also a nivolumab/chemotherapy arm. So in that trial, the addition is, it had a coprimary endpoint—tumor mutational burden. As you know and for our audience, this is an emerging biomarker for immunotherapy.

The study was positive for the group of patients that had high TMB, which was defined in this study as greater than or equal to 10, using the FoundationOne assay. The reason I bring it up now is that in that trial, if patients had high TMB but absent PD-L1 in their cancer, they still had an equivalent benefit for progression-free survival. And, in fact, the patients that had low TMB and low PD-L1 had no benefit whatsoever. In other words, they did just as well with platinum chemotherapy.

So, when we talk about the other trials that have not incorporated TMB, you have to wonder, what if you had TMB and PD-L1. So, at UC Davis [University of California Davis], we use both. Now, some people would say that’s premature, but we have a research and clinical collaboration with Foundation Medicine. We get the Foundation Medicine test. We have our PD-L1 test and, if we have it in a timely fashion, we use both of them to make the determination. So, for me, regardless of the TMB and PD-L1, just based on the PD-L1, monotherapy with pembrolizumab would be my choice of therapy for patients with a PD-L1 greater than or equal to 50%. Based on the KEYNOTE-024 and more recently, KEYNOTE-042, I think that’s very solid data. I’m sure that some of our colleagues, our practicing oncologists who are in favor of the combination of chemotherapy plus pembrolizumab in this setting might favor it. But it’s hard for me to justify the additional [adverse] effects of chemotherapy and just the additional burden of receiving treatment for patients in that category. Maybe we could just sort this out by PD-L1 levels. In the group of patients with—and this is for both histologies—high PD-L1, would you think monotherapy or are you in favor or the combination?

Everett E. Vokes, MD: Yes, I think it may be a good idea to look at KEYNOTE-042 a little bit more. So, it was presented, and it is a trial that looked at all patients with PD-L1–positive tumors, 1% or higher, and clearly was overall positive. But, when you analyzed a little bit more—and they did that to their credit—the patients that had a PD-L1 level of 1 to 49 really had very marginal benefit compared to chemotherapy. And I think that is really where the algorithm that I think you’re trying to propose comes from. All of us I think are very comfortable to offer monotherapy to both squamous and non-squamous for PD-L1 over 50, and then would probably consider and simply spare patients the toxicity, just as you mentioned, of chemotherapy. And then for those that have lower levels, consider the addition of chemotherapy with pembrolizumab or atezolizumab and expose them to the triplet.

David R. Gandara, MD: Yes, I agree with that completely.

Everett E. Vokes, MD: So then the question comes, where do you then in your practice, because you have a lot of experience with this, in addition use TMB?

David R. Gandara, MD:  Right. So, I think it would be for the category of patients who are PD-L1–negative because if you just look at the trials which didn’t include TMB and you look at the data, then you’d say, “What should I do in that group of patients? Should I give them pembrolizumab plus chemotherapy? Based on all these IMpower trials, should I give them atezolizumab plus chemotherapy?” We heard additional data presented today in the nonsquamous subset that suggested that there was benefit across PD-L1 levels, including 0. But when they showed the curves for how patients did with very high levels, or 1% to 49%, or absent, there was a shrinking benefit. So that’s where I think I would, if I had it, would employ the TMB data to help guide me.

Now, I guess the other thing is the nivolumab/ipilimumab combination is not FDA-approved yet. I’m not sure whether it will be, but it is being reimbursed in the United States. I know some of our audience may be international. And the reason I mention that is we’re at an ESMO [European Society for Medical Oncology] meeting, and the ESMO guidelines last week added nivolumab plus ipilimumab combination as a recommended combination based on TMB. They even included that; so that was pretty forward-thinking. What do you think there?

Everett E. Vokes, MD: So I think this is important to sort out. This is a subset of patients that are PD-L1–negative but TMB-high, and for that subset you don’t consider the addition of chemotherapy necessarily, but the addition of ipilimumab. I think that the Hellmann [Matthew Hellmann, MD) data really from CheckMate-227 do support that. I have very limited personal experience with that but some experience with it, and I do find it actually tolerable, somewhat less predictable in terms of toxicity development and particularly late toxicity development. But I think you’re right, it is that group of patients to consider that in.

Transcript Edited for Clarity 

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Transcript: 

Everett E. Vokes, MD: How do you view these 4 trials?

David R. Gandara, MD: Well, the other trials that come into play—and we’re really talking primarily about non-squamous cell lung cancer now—have had both histologic subtypes, and the one I’m thinking about is the CheckMate-227, which was a complicated study, also published in the New England Journal of Medicine, which included an immunotherapy combination, nivolumab and ipilimumab [Opdivo and Yervoy] versus platinum chemotherapy and then also a nivolumab/chemotherapy arm. So in that trial, the addition is, it had a coprimary endpoint—tumor mutational burden. As you know and for our audience, this is an emerging biomarker for immunotherapy.

The study was positive for the group of patients that had high TMB, which was defined in this study as greater than or equal to 10, using the FoundationOne assay. The reason I bring it up now is that in that trial, if patients had high TMB but absent PD-L1 in their cancer, they still had an equivalent benefit for progression-free survival. And, in fact, the patients that had low TMB and low PD-L1 had no benefit whatsoever. In other words, they did just as well with platinum chemotherapy.

So, when we talk about the other trials that have not incorporated TMB, you have to wonder, what if you had TMB and PD-L1. So, at UC Davis [University of California Davis], we use both. Now, some people would say that’s premature, but we have a research and clinical collaboration with Foundation Medicine. We get the Foundation Medicine test. We have our PD-L1 test and, if we have it in a timely fashion, we use both of them to make the determination. So, for me, regardless of the TMB and PD-L1, just based on the PD-L1, monotherapy with pembrolizumab would be my choice of therapy for patients with a PD-L1 greater than or equal to 50%. Based on the KEYNOTE-024 and more recently, KEYNOTE-042, I think that’s very solid data. I’m sure that some of our colleagues, our practicing oncologists who are in favor of the combination of chemotherapy plus pembrolizumab in this setting might favor it. But it’s hard for me to justify the additional [adverse] effects of chemotherapy and just the additional burden of receiving treatment for patients in that category. Maybe we could just sort this out by PD-L1 levels. In the group of patients with—and this is for both histologies—high PD-L1, would you think monotherapy or are you in favor or the combination?

Everett E. Vokes, MD: Yes, I think it may be a good idea to look at KEYNOTE-042 a little bit more. So, it was presented, and it is a trial that looked at all patients with PD-L1–positive tumors, 1% or higher, and clearly was overall positive. But, when you analyzed a little bit more—and they did that to their credit—the patients that had a PD-L1 level of 1 to 49 really had very marginal benefit compared to chemotherapy. And I think that is really where the algorithm that I think you’re trying to propose comes from. All of us I think are very comfortable to offer monotherapy to both squamous and non-squamous for PD-L1 over 50, and then would probably consider and simply spare patients the toxicity, just as you mentioned, of chemotherapy. And then for those that have lower levels, consider the addition of chemotherapy with pembrolizumab or atezolizumab and expose them to the triplet.

David R. Gandara, MD: Yes, I agree with that completely.

Everett E. Vokes, MD: So then the question comes, where do you then in your practice, because you have a lot of experience with this, in addition use TMB?

David R. Gandara, MD:  Right. So, I think it would be for the category of patients who are PD-L1–negative because if you just look at the trials which didn’t include TMB and you look at the data, then you’d say, “What should I do in that group of patients? Should I give them pembrolizumab plus chemotherapy? Based on all these IMpower trials, should I give them atezolizumab plus chemotherapy?” We heard additional data presented today in the nonsquamous subset that suggested that there was benefit across PD-L1 levels, including 0. But when they showed the curves for how patients did with very high levels, or 1% to 49%, or absent, there was a shrinking benefit. So that’s where I think I would, if I had it, would employ the TMB data to help guide me.

Now, I guess the other thing is the nivolumab/ipilimumab combination is not FDA-approved yet. I’m not sure whether it will be, but it is being reimbursed in the United States. I know some of our audience may be international. And the reason I mention that is we’re at an ESMO [European Society for Medical Oncology] meeting, and the ESMO guidelines last week added nivolumab plus ipilimumab combination as a recommended combination based on TMB. They even included that; so that was pretty forward-thinking. What do you think there?

Everett E. Vokes, MD: So I think this is important to sort out. This is a subset of patients that are PD-L1–negative but TMB-high, and for that subset you don’t consider the addition of chemotherapy necessarily, but the addition of ipilimumab. I think that the Hellmann [Matthew Hellmann, MD) data really from CheckMate-227 do support that. I have very limited personal experience with that but some experience with it, and I do find it actually tolerable, somewhat less predictable in terms of toxicity development and particularly late toxicity development. But I think you’re right, it is that group of patients to consider that in.

Transcript Edited for Clarity 
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