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Neoadjuvant Therapy in the Treatment of Melanoma

Panelists: Sanjiv S. Agarwala, MD, Temple University School of Medicine; Alexander Eggermont, MD, PhD, Institut Gustave Roussy; Caroline Robert, MD, PhD, Institut Gustave Roussy; Dirk Schadendorf, MD, PhD, West German Cancer Center at University Hospital Essen
Published: Thursday, Jul 18, 2019



Transcript: 

Sanjiv S. Agarwala, MD: Dirk Schadendorf, I’d like to ask you specifically about 1 very interesting aspect with the combination of neoadjuvant T-VEC [talimogene laherparevec] and the immunotherapy. Very quickly if you could comment. It was a randomized trial.

Dirk Schadendorf, MD, PhD: It was a large randomized trial. One of the largest in neoadjuvant trials so far, with 150 patients randomized in 2 arms. T-VEC [talimogene laherparevec] in front, and then surgery in the first arm, and the control arm was surgery right away. And I think what was seen at the presentation at ASCO [American Society of Clinical Oncology Annual Meeting] is that there are several benefits in favor of the combination of up-front T-VEC [talimogene laherparevec] therapy, with improved rates of 0 resections…. The combination of 1 resection was also better; for the third 1, a it was 51% of the patients. So the resectability of the disease was much better.

And that also translated into a relapse-free survival rate at 1 year, which was 22% to 29%. So already after 1 year a clear benefit. The only small caveat I would see in that setting is that roughly 25% of the patients with a T-VEC [talimogene laherparevec] in front of patients have not made it to the planned surgery. And in the control arm, 7% of the patients did not undergo planned surgery. I think that’s a concern with all new adjuvant approaches: are you reaching the standard of care at the end?

Sanjiv S. Agarwala, MD: And I know, just before I go to Dr Robert, I think that goes back to the point of what are the correct endpoints for such a challenge. If you’d like to make a comment maybe on it.

Caroline Robert, MD, PhD: We have to realize that we are away from the usual objective of neoadjuvant treatment with chemotherapy or even BRAF/MEK, which really had the goal to decrease the size and to make the tumor accessible to surgery. Now we know that the main goal is to induce a distant immune response. And maybe finally not being able to do the surgery. Maybe it’s not going to be that bad in the end.

Dirk Schadendorf, MD, PhD: I completely agree with you, Caroline, because I think the concept of neoadjuvant therapy—which was borne in the field of breast cancer, for example—had a completely different objective from what we are doing now with neoadjuvant approaches in melanoma. And I think, not to confuse the community, I think it’s important to clarify the different endpoints and aims of such a treatment, and that possibly even missing a surgery might not be a disadvantage for the patient. I think that needs to be tested in further clinical trials.

Caroline Robert, MD, PhD: And we’ll do the complete pathological response, which is not correlated to overall survival in breast or in pancreas; it might be with immunotherapy. We have the hope that it will be.

Dirk Schadendorf, MD, PhD: Looking at this meta-analysis presented by Alex Menzies, on more than 180 patients collected globally, two-thirds of these patients had neoadjuvant checkpoint blockades and one-third had targeted therapy. The rate of complete responses, pathological responses, was quite comparable. But if you look at the relapse-free survival after 1 year, pathology therapy was just 65%. For checkpoint blockade it was 20% better. I think that clearly emphasizes what was said.

Alexander Eggermont, MD, PhD: Let’s not forget that the very best data sets of all those data sets in there, in the metanalysis, the Amsterdam study, which shows 2 things. That neoadjuvant with just anti–PD-1 [programmed cell death protein 1] is inferior to neoadjuvant with anti–PD-1 plus anti-CTLA4. And you actually have a biomarker there, because it’s the magnitude and the variety of T-cell clones that are being induced by the combination of anti–PD-1 and anti-CTLA4. It gives the highest biomarker output and gives the highest pathologic complete responses, and there’s not a single patient who has relapsed after surgery, and all patients made it through surgery.

This is now the golden standard to look up to and to compare all other data with, and all other data are inferior to this. We should not do as if there is not a superior data set. There is a superior data set out there that will define what is going to happen in the future. Because on top of that, they have a locally advanced rectal cancer program for MSI [microsatellite instable] rectal cancers. The first 8 patients, 7 of 8 have a pathological complete response. And what do you do? You don’t even operate them anymore, you just follow them by rectoscopy and by MRI. And no more rectal amputations for MSI colorectal cancers. I mean, this is a true revolution.

Let’s not underestimate what the data are right now telling us. This is the superior approach that we need to work with and that we need to use as a comparator to any other development.

Sanjiv S. Agarwala, MD: Very interesting, but let’s emphasize it’s still experimental. We don’t have any approved neoadjuvant approaches but...

Alexander Eggermont, MD, PhD: It will be approved. Believe me, it will be approved.

Sanjiv S. Agarwala, MD: Yes, I hope so.

Transcript Edited for Clarity

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Transcript: 

Sanjiv S. Agarwala, MD: Dirk Schadendorf, I’d like to ask you specifically about 1 very interesting aspect with the combination of neoadjuvant T-VEC [talimogene laherparevec] and the immunotherapy. Very quickly if you could comment. It was a randomized trial.

Dirk Schadendorf, MD, PhD: It was a large randomized trial. One of the largest in neoadjuvant trials so far, with 150 patients randomized in 2 arms. T-VEC [talimogene laherparevec] in front, and then surgery in the first arm, and the control arm was surgery right away. And I think what was seen at the presentation at ASCO [American Society of Clinical Oncology Annual Meeting] is that there are several benefits in favor of the combination of up-front T-VEC [talimogene laherparevec] therapy, with improved rates of 0 resections…. The combination of 1 resection was also better; for the third 1, a it was 51% of the patients. So the resectability of the disease was much better.

And that also translated into a relapse-free survival rate at 1 year, which was 22% to 29%. So already after 1 year a clear benefit. The only small caveat I would see in that setting is that roughly 25% of the patients with a T-VEC [talimogene laherparevec] in front of patients have not made it to the planned surgery. And in the control arm, 7% of the patients did not undergo planned surgery. I think that’s a concern with all new adjuvant approaches: are you reaching the standard of care at the end?

Sanjiv S. Agarwala, MD: And I know, just before I go to Dr Robert, I think that goes back to the point of what are the correct endpoints for such a challenge. If you’d like to make a comment maybe on it.

Caroline Robert, MD, PhD: We have to realize that we are away from the usual objective of neoadjuvant treatment with chemotherapy or even BRAF/MEK, which really had the goal to decrease the size and to make the tumor accessible to surgery. Now we know that the main goal is to induce a distant immune response. And maybe finally not being able to do the surgery. Maybe it’s not going to be that bad in the end.

Dirk Schadendorf, MD, PhD: I completely agree with you, Caroline, because I think the concept of neoadjuvant therapy—which was borne in the field of breast cancer, for example—had a completely different objective from what we are doing now with neoadjuvant approaches in melanoma. And I think, not to confuse the community, I think it’s important to clarify the different endpoints and aims of such a treatment, and that possibly even missing a surgery might not be a disadvantage for the patient. I think that needs to be tested in further clinical trials.

Caroline Robert, MD, PhD: And we’ll do the complete pathological response, which is not correlated to overall survival in breast or in pancreas; it might be with immunotherapy. We have the hope that it will be.

Dirk Schadendorf, MD, PhD: Looking at this meta-analysis presented by Alex Menzies, on more than 180 patients collected globally, two-thirds of these patients had neoadjuvant checkpoint blockades and one-third had targeted therapy. The rate of complete responses, pathological responses, was quite comparable. But if you look at the relapse-free survival after 1 year, pathology therapy was just 65%. For checkpoint blockade it was 20% better. I think that clearly emphasizes what was said.

Alexander Eggermont, MD, PhD: Let’s not forget that the very best data sets of all those data sets in there, in the metanalysis, the Amsterdam study, which shows 2 things. That neoadjuvant with just anti–PD-1 [programmed cell death protein 1] is inferior to neoadjuvant with anti–PD-1 plus anti-CTLA4. And you actually have a biomarker there, because it’s the magnitude and the variety of T-cell clones that are being induced by the combination of anti–PD-1 and anti-CTLA4. It gives the highest biomarker output and gives the highest pathologic complete responses, and there’s not a single patient who has relapsed after surgery, and all patients made it through surgery.

This is now the golden standard to look up to and to compare all other data with, and all other data are inferior to this. We should not do as if there is not a superior data set. There is a superior data set out there that will define what is going to happen in the future. Because on top of that, they have a locally advanced rectal cancer program for MSI [microsatellite instable] rectal cancers. The first 8 patients, 7 of 8 have a pathological complete response. And what do you do? You don’t even operate them anymore, you just follow them by rectoscopy and by MRI. And no more rectal amputations for MSI colorectal cancers. I mean, this is a true revolution.

Let’s not underestimate what the data are right now telling us. This is the superior approach that we need to work with and that we need to use as a comparator to any other development.

Sanjiv S. Agarwala, MD: Very interesting, but let’s emphasize it’s still experimental. We don’t have any approved neoadjuvant approaches but...

Alexander Eggermont, MD, PhD: It will be approved. Believe me, it will be approved.

Sanjiv S. Agarwala, MD: Yes, I hope so.

Transcript Edited for Clarity
View Conference Coverage
Online CME Activities
TitleExpiration DateCME Credits
Advances in™ Melanoma: Exploring BRAF/MEK in Adjuvant and Neoadjuvant SettingsSep 28, 20191.5
Medical Crossfire®: What Does Data Tell Us About How to Optimize Checkpoint Inhibitor Strategies Across Lines of Care for Patients with Melanoma?Nov 30, 20191.5
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