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Novel Treatment Strategies in Recurrent Ovarian Cancer

Panelists: Bradley J. Monk, MD, FACS, FACOG, Arizona Oncology Practice of US Oncology; Oliver Dorigo, MD, PhD, Stanford University Medical Center; Thomas Herzog, MD, University of Cincinnati Cancer Institute; Kathleen Moore, MD, Stephenson Cancer Center; Leslie M. Randall, MD, MAS, University of California, Irvine
Published: Friday, Sep 21, 2018



Transcript:

Bradley J. Monk, MD, FACS, FACOG:
We’ve got earlier lines of therapy. We’ve got novel combinations. We’re not going to talk about it, but we have other tumor types. As you know, we have olaparib for breast cancer, and talazoparib has shown activity. So, it’s an exciting time. After angiogenics, PARP inhibitors, and immuno-oncology, the fourth category is antibody-drug conjugates. I can’t believe that we are now talking about the fourth area of targeted therapy, antibody-drug conjugates. The leading candidate would be mirvetuximab soravtansine. Tell us about that.

Kathleen Moore, MD: Mirvetuximab soravtansine is an antibody-drug conjugate. It’s an antibody that targets folate receptor alpha, which is highly overexpressed in epithelial ovarian cancer. We don’t really know why or what it’s doing there, but it’s there and there is relatively little to no expression on normal tissue. Conjugated to the antibody are molecules of a very potent cytotoxin called DM4, which is a microtubular toxin. These cytotoxins that are on these ADCs are active at the picomolar level. They’re really potent, but you are only getting a few molecules on each one. It’s intravenous. It’s given every 21 days. Patients have to be screened with archival tissue to make sure that they have moderate to high expression of folate receptor alpha.

Bradley J. Monk, MD, FACS, FACOG: The target, yes.

Kathleen Moore, MD: The phase I expansion was published in the Journal of Clinical Oncology. Patients with recurrent platinum-resistant ovarian cancer, who were relatively heavily pretreated, had an overall response rate of about 25%. That was good. But when we looked at that group of patients who had 1 to 3 prior lines of therapy, excluding the low expressors, the response rate was over 40%. And so, that drove the development of FORWARD I, which is the randomized phase III trial in that same population.

Bradley J. Monk, MD, FACS, FACOG: This will be, again, the fourth category of active agents. When may we have this available in clinic?

Kathleen Moore, MD: The readout of FORWARD I should happen in the first half of 2019. That’s pretty exciting. Then, the submission would go from there. There are other antibody-drug conjugates that are FDA-approved in other disease types—breast cancer and hematologic malignancies. There are a number of these in the pipeline for ovarian cancer, which has a lot of novel antigens. We don’t have a lot of mutations to target, but we have a lot of weird stuff on the surface. This may be a really fruitful line of research for our patients.

Bradley J. Monk, MD, FACS, FACOG: Great. Oliver, we haven’t really talked about what the single-agent activity is of checkpoint inhibitors. There’s a study of single-agent pembrolizumab. What could we expect from single-agent checkpoint inhibitors? Every patient that walks in the door wants a checkpoint inhibitor.

Oliver Dorigo, MD, PhD: Yes. We are very excited about the availability of checkpoint inhibitors. In gynecologic malignancy, they really haven’t shown the efficacy that we have seen in lung cancer, melanoma, and renal cell carcinoma. The first checkpoint inhibitor that was presented in 2014 demonstrated 2 complete responses in clear cell carcinoma. The patients were heavily pretreated. That generated excitement.

Pembrolizumab was studied in KEYNOTE-028. One of the many solid tumors was treated with single-agent pembrolizumab and there was some signal. It was particularly interesting to see signals in those patients whose ovarian cancers had PD-L1 expression. KEYNOTE-100 takes it a step further. It looks at 2 different cohorts of patients with more or less prior lines of chemotherapy. Those patients who have rather high expression of PD-L1 had, indeed, a 27% response rate. That compares to a 40% response rate in the lower expressors of PD-L1, but that’s still fairly promising and better than we have done before with single-agent immune checkpoint inhibitors.

Bradley J. Monk, MD, FACS, FACOG: I like to categorize things and look at predictive biomarkers. I talked about the 3 predictors of PARP inhibitors. I think the 3 predictors of checkpoint inhibitors in ovarian cancer are PD-L1 expression, the number of neoantigens—I guess that if you could find an MSI-high patient, that would be an opportunity, and certainly on label for pembrolizumab, particularly in the endometrial and clear cell types—and tumor infiltrating lymphocytes. Unfortunately, tumor infiltrating lymphocytes in recurrent disease are relatively low, so this is a very exciting, evolving field.

Oliver Dorigo, MD, PhD: I think you’re right. I think tumor mutational burden is a readout that we get from our somatic mutation testing that has reported out. I think there is some correlation between tumor mutation and burden and response to immune checkpoint inhibition. In lung cancer, that is a stratification idea. I think we should look at this more in ovarian cancer.

Leslie M. Randall, MD, MAS: Not only is selection important, but endpoint is also important. The response rate is important, but duration of response is really important for these agents.

Transcript Edited for Clarity.

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Transcript:

Bradley J. Monk, MD, FACS, FACOG:
We’ve got earlier lines of therapy. We’ve got novel combinations. We’re not going to talk about it, but we have other tumor types. As you know, we have olaparib for breast cancer, and talazoparib has shown activity. So, it’s an exciting time. After angiogenics, PARP inhibitors, and immuno-oncology, the fourth category is antibody-drug conjugates. I can’t believe that we are now talking about the fourth area of targeted therapy, antibody-drug conjugates. The leading candidate would be mirvetuximab soravtansine. Tell us about that.

Kathleen Moore, MD: Mirvetuximab soravtansine is an antibody-drug conjugate. It’s an antibody that targets folate receptor alpha, which is highly overexpressed in epithelial ovarian cancer. We don’t really know why or what it’s doing there, but it’s there and there is relatively little to no expression on normal tissue. Conjugated to the antibody are molecules of a very potent cytotoxin called DM4, which is a microtubular toxin. These cytotoxins that are on these ADCs are active at the picomolar level. They’re really potent, but you are only getting a few molecules on each one. It’s intravenous. It’s given every 21 days. Patients have to be screened with archival tissue to make sure that they have moderate to high expression of folate receptor alpha.

Bradley J. Monk, MD, FACS, FACOG: The target, yes.

Kathleen Moore, MD: The phase I expansion was published in the Journal of Clinical Oncology. Patients with recurrent platinum-resistant ovarian cancer, who were relatively heavily pretreated, had an overall response rate of about 25%. That was good. But when we looked at that group of patients who had 1 to 3 prior lines of therapy, excluding the low expressors, the response rate was over 40%. And so, that drove the development of FORWARD I, which is the randomized phase III trial in that same population.

Bradley J. Monk, MD, FACS, FACOG: This will be, again, the fourth category of active agents. When may we have this available in clinic?

Kathleen Moore, MD: The readout of FORWARD I should happen in the first half of 2019. That’s pretty exciting. Then, the submission would go from there. There are other antibody-drug conjugates that are FDA-approved in other disease types—breast cancer and hematologic malignancies. There are a number of these in the pipeline for ovarian cancer, which has a lot of novel antigens. We don’t have a lot of mutations to target, but we have a lot of weird stuff on the surface. This may be a really fruitful line of research for our patients.

Bradley J. Monk, MD, FACS, FACOG: Great. Oliver, we haven’t really talked about what the single-agent activity is of checkpoint inhibitors. There’s a study of single-agent pembrolizumab. What could we expect from single-agent checkpoint inhibitors? Every patient that walks in the door wants a checkpoint inhibitor.

Oliver Dorigo, MD, PhD: Yes. We are very excited about the availability of checkpoint inhibitors. In gynecologic malignancy, they really haven’t shown the efficacy that we have seen in lung cancer, melanoma, and renal cell carcinoma. The first checkpoint inhibitor that was presented in 2014 demonstrated 2 complete responses in clear cell carcinoma. The patients were heavily pretreated. That generated excitement.

Pembrolizumab was studied in KEYNOTE-028. One of the many solid tumors was treated with single-agent pembrolizumab and there was some signal. It was particularly interesting to see signals in those patients whose ovarian cancers had PD-L1 expression. KEYNOTE-100 takes it a step further. It looks at 2 different cohorts of patients with more or less prior lines of chemotherapy. Those patients who have rather high expression of PD-L1 had, indeed, a 27% response rate. That compares to a 40% response rate in the lower expressors of PD-L1, but that’s still fairly promising and better than we have done before with single-agent immune checkpoint inhibitors.

Bradley J. Monk, MD, FACS, FACOG: I like to categorize things and look at predictive biomarkers. I talked about the 3 predictors of PARP inhibitors. I think the 3 predictors of checkpoint inhibitors in ovarian cancer are PD-L1 expression, the number of neoantigens—I guess that if you could find an MSI-high patient, that would be an opportunity, and certainly on label for pembrolizumab, particularly in the endometrial and clear cell types—and tumor infiltrating lymphocytes. Unfortunately, tumor infiltrating lymphocytes in recurrent disease are relatively low, so this is a very exciting, evolving field.

Oliver Dorigo, MD, PhD: I think you’re right. I think tumor mutational burden is a readout that we get from our somatic mutation testing that has reported out. I think there is some correlation between tumor mutation and burden and response to immune checkpoint inhibition. In lung cancer, that is a stratification idea. I think we should look at this more in ovarian cancer.

Leslie M. Randall, MD, MAS: Not only is selection important, but endpoint is also important. The response rate is important, but duration of response is really important for these agents.

Transcript Edited for Clarity.
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