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I/O Combination Strategies in Ovarian Cancer

Panelists: Bradley J. Monk, MD, FACOG, FACS, University of Arizona; Creighton University School of Medicine; Arizona Oncology; Kathleen N. Moore, MD, University of Oklahoma; Elena S. Ratner, MD, Yale University School of Medicine; Brian M. Slomovitz, MD, Sylvester Comprehensive Cancer Center, University of Miami Health System
Published: Friday, Jun 21, 2019



Transcript: 

Bradley J. Monk, MD, FACOG, FACS: Presented at the SGO [Society of Gynecologic Oncology] annual meeting this year, 2019, was a randomized prospective phase III trial of avelumab, another checkpoint inhibitor, versus pegylated liposomal doxorubicin, kind of as the control, and then the combination of PLD [pegylated liposomal doxorubicin] and avelumab. Elena, what does that study show?

Elena S. Ratner, MD: Well, that study was, unfortunately, not a positive study. Part of the issue with the study is that patients were not pre-selected according to their potential targeted mutations. I think that’s a lot of what we’re talking about today. So much of what we do now is based on the understanding of the biology.

Bradley J. Monk, MD, FACOG, FACS: Maybe it could have been positive.

Elena S. Ratner, MD: It would have sub-selected patients who actually had a chance of responding to it.

Bradley J. Monk, MD, FACOG, FACS: That’s what Katie said, that  maybe there is an enrichment.

Kathleen N. Moore, MD: Maybe.

Bradley J. Monk, MD, FACOG, FACS: So should our I/O [immune-oncology] therapies just have, as the endpoint, PD-L1 [programmed death-ligand 1] patients, Brian?

Brian M. Slomovitz, MD: That’s a great question. We don’t know the specific answer. We have to look at it. Maybe. You know, I think it is a predictor, or one of the multiple predictors of potential response. Again, in general these ovarian tumors are cold tumors. So I think when we’re moving forward in I/O therapy for ovarian cancer, we have to think about combination therapies. It may be combined with a radiation. It may be combined with a different type of chemotherapy or another targeted therapy. Maybe it’s before or after surgery. But a combination therapy, in general. The principle is to turn that cold tumor hot—something that will be recognized by immunotherapy. We know that it’s not just PD-1 [programmed cell death protein 1] expression.

Bradley J. Monk, MD, FACOG, FACS: So let’s talk about some of these combination trials, because it seems like they’re everywhere. You know, the frontline treatment of ovarian cancer has been defined with bevacizumab and olaparib and BRCA-mutated patients. And maybe PAOLA-1 with olaparib/bevacizumab, but there are even more combinations. You are running a study called IMagyn050?

Kathleen N. Moore, MD: Yes.

Bradley J. Monk, MD, FACOG, FACS: It just closed to enrollment here. Tell us about what IMagyn050 is and what the hypothesis is there?

Kathleen N. Moore, MD: In IMagyn050, the hypothesis is that if you combine anti-angiogenic therapy with immune checkpoint inhibitors, they will be synergistic. We know that when you block VEGF; VEGF is a really immunosuppressive molecule. In addition to being pro-angiogenic, it has both indirect and direct effects on the immune response. And one of them is that it decreases T-cell trafficking into the tumor.

So if you block VEGF through a number of ways, but hopefully with bevacizumab, you’ll increase T-cell trafficking to your tumor and improve the ability of the immune system to respond. That has been borne out in tumors that have a demonstrated response to immune therapy—renal cell cancer, lung cancer, and some in breast. Breast gives us the most hope that it will be helpful in overexpression….

Bradley J. Monk, MD, FACOG, FACS: I’m going to repeat that because it works where I/O already works.

Kathleen N. Moore, MD: Correct.

Bradley J. Monk, MD, FACOG, FACS: It’s never been shown to work where I/O doesn’t work.

Kathleen N. Moore, MD: Except there’s a signal in breast, so that’s a signal.

Bradley J. Monk, MD, FACOG, FACS: We’re hoping in ovary, too.

Kathleen N. Moore, MD: A signal in ovary too. There are signals in ovary and we can talk about those smaller studies, but that’s the hypothesis. And so, it took patients and did stratify by PD-L1.

Bradley J. Monk, MD, FACOG, FACS: Which is the only study that does that, to your point, in these combinations.

Kathleen N. Moore, MD: It was hard to do.

Bradley J. Monk, MD, FACOG, FACS: I know.

Kathleen N. Moore, MD: Because you had to wait until we did your testing. Your patient had to wait. And so, it was hard to do. It is stratified by PD-L1 expression by a different score than the CPS [combined positive score], but it is a very good assay. One arm gets chemotherapy/bevacizumab, bevacizumab maintenance; and the other gets chemotherapy/bevacizumab, bevacizumab maintenance with atezolizumab.

Bradley J. Monk, MD, FACOG, FACS: When do you think that’s going to read out, because it just finished enrollment?

Kathleen N. Moore, MD: It just finished, so I hope it doesn’t read out until 2021.

Bradley J. Monk, MD, FACOG, FACS: Because it’s an event-driven analysis.

Kathleen N. Moore, MD: It’s an event-driven analysis. I’m just sitting back and I’m hopeful that we’re going to see patients do well.

Bradley J. Monk, MD, FACOG, FACS: So that’s I/O anti-angiogenic. Certainly, within the NRG, they have olaparib and cediranib maleate—a fully oral regimen. Brian, tell us about DUO-O?

Brian M. Slomovitz, MD: DUO-O is basically an activity trial looking at a combination of durvalumab with olaparib in patients with recurrent ovarian cancer. This trial is looking to see if it can enhance activity. Right now, the academic activity part of it is spread out. I forget the exact percentage, but it’s a modest activity. The problem with those trials, intuitive head-to-head comparisons, is that we don’t know if the activity is driven by one or the other, or if it’s truly a synergy, which is what we would hope.

Bradley J. Monk, MD, FACOG, FACS: So we’ve got IMagyn050—atezolizumab, bevacizumab; DUO-O—durvalumab and olaparib; and because olaparib is shared, there’s a virtually identical trial called ENGOT-ov43 with pembrolizumab and olaparib. The difference between these 2 is that they allow bevacizumab, so it would be some triplet therapy, which would be bevacizumab, olaparib, and then pembrolizumab, or durvalumab. Talk about financial toxicity—$30,000 a cycle.

And then I run a trial called ATHENA. ATHENA is a pure maintenance trial. We were struck by the JAVELIN Ovarian 100 press release. In addition to JAVELIN Ovarian 200, which did not meet its primary endpoint, JAVELIN Ovarian 100 was avelumab in the frontline. It was with chemotherapy and in maintenance, which should have worked, or also in maintenance, who knows, but it didn’t work in either place.

And you talk about breast cancer. There’s a very large distinction between breast cancer and ovarian cancer. The classic example is the recent approval of atezolizumab and nab-paclitaxel.

Kathleen N. Moore, MD: Right.

Bradley J. Monk, MD, FACOG, FACS: So when you give single-agent chemotherapy and atezolizumab, it works. New England Journal of Medicine….

Kathleen N. Moore, MD: Yes.

Bradley J. Monk, MD, FACOG, FACS: The FDA approval is in breast. When you give PLD [pegylated liposomal doxorubicin] and avelumab, it’s negative. They say, “Maybe we should have studied PD-L1 expression.” So the JAVELIN Ovarian 100, I think, speaks to the opportunity of a pure maintenance opportunity of maybe adding chemotherapy, and I/O doesn’t have an opportunity. So that is nivolumab and rucaparib. So there are a number of trials, and I guess the final would be FIRST. Tell me about FIRST?

Kathleen N. Moore, MD: FIRST is a randomized phase III study that enrolls patients with advanced stage disease and randomizes them. Bevacizumab is optional. You have to declare it. So it’s Taxol, carboplatin, presumably bevacizumab, bevacizumab maintenance; versus Taxol, carboplatin, bevacizumab, bevacizumab maintenance, niraparib maintenance; versus Taxol, carboplatin, bevacizumab, TSR-042, which does have a name now.

Bradley J. Monk, MD, FACOG, FACS: Dostarlimab.

Kathleen N. Moore, MD: Dostarlimab, thank you. And leading into bevacizumab, niraparib, dostarlimab maintenance. That study is stratified by BRCA status. If you have a BRCA mutation, you are not randomized to a non-niraparib containing arm, because the randomization occurs in cycle 2. So it’s adaptive randomizations. It’s an interesting study. As these read out, PRIMA and other things read out, if things are positive, it will adapt and change randomizations to adapt to the new standard of care.

Transcript Edited for Clarity

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Transcript: 

Bradley J. Monk, MD, FACOG, FACS: Presented at the SGO [Society of Gynecologic Oncology] annual meeting this year, 2019, was a randomized prospective phase III trial of avelumab, another checkpoint inhibitor, versus pegylated liposomal doxorubicin, kind of as the control, and then the combination of PLD [pegylated liposomal doxorubicin] and avelumab. Elena, what does that study show?

Elena S. Ratner, MD: Well, that study was, unfortunately, not a positive study. Part of the issue with the study is that patients were not pre-selected according to their potential targeted mutations. I think that’s a lot of what we’re talking about today. So much of what we do now is based on the understanding of the biology.

Bradley J. Monk, MD, FACOG, FACS: Maybe it could have been positive.

Elena S. Ratner, MD: It would have sub-selected patients who actually had a chance of responding to it.

Bradley J. Monk, MD, FACOG, FACS: That’s what Katie said, that  maybe there is an enrichment.

Kathleen N. Moore, MD: Maybe.

Bradley J. Monk, MD, FACOG, FACS: So should our I/O [immune-oncology] therapies just have, as the endpoint, PD-L1 [programmed death-ligand 1] patients, Brian?

Brian M. Slomovitz, MD: That’s a great question. We don’t know the specific answer. We have to look at it. Maybe. You know, I think it is a predictor, or one of the multiple predictors of potential response. Again, in general these ovarian tumors are cold tumors. So I think when we’re moving forward in I/O therapy for ovarian cancer, we have to think about combination therapies. It may be combined with a radiation. It may be combined with a different type of chemotherapy or another targeted therapy. Maybe it’s before or after surgery. But a combination therapy, in general. The principle is to turn that cold tumor hot—something that will be recognized by immunotherapy. We know that it’s not just PD-1 [programmed cell death protein 1] expression.

Bradley J. Monk, MD, FACOG, FACS: So let’s talk about some of these combination trials, because it seems like they’re everywhere. You know, the frontline treatment of ovarian cancer has been defined with bevacizumab and olaparib and BRCA-mutated patients. And maybe PAOLA-1 with olaparib/bevacizumab, but there are even more combinations. You are running a study called IMagyn050?

Kathleen N. Moore, MD: Yes.

Bradley J. Monk, MD, FACOG, FACS: It just closed to enrollment here. Tell us about what IMagyn050 is and what the hypothesis is there?

Kathleen N. Moore, MD: In IMagyn050, the hypothesis is that if you combine anti-angiogenic therapy with immune checkpoint inhibitors, they will be synergistic. We know that when you block VEGF; VEGF is a really immunosuppressive molecule. In addition to being pro-angiogenic, it has both indirect and direct effects on the immune response. And one of them is that it decreases T-cell trafficking into the tumor.

So if you block VEGF through a number of ways, but hopefully with bevacizumab, you’ll increase T-cell trafficking to your tumor and improve the ability of the immune system to respond. That has been borne out in tumors that have a demonstrated response to immune therapy—renal cell cancer, lung cancer, and some in breast. Breast gives us the most hope that it will be helpful in overexpression….

Bradley J. Monk, MD, FACOG, FACS: I’m going to repeat that because it works where I/O already works.

Kathleen N. Moore, MD: Correct.

Bradley J. Monk, MD, FACOG, FACS: It’s never been shown to work where I/O doesn’t work.

Kathleen N. Moore, MD: Except there’s a signal in breast, so that’s a signal.

Bradley J. Monk, MD, FACOG, FACS: We’re hoping in ovary, too.

Kathleen N. Moore, MD: A signal in ovary too. There are signals in ovary and we can talk about those smaller studies, but that’s the hypothesis. And so, it took patients and did stratify by PD-L1.

Bradley J. Monk, MD, FACOG, FACS: Which is the only study that does that, to your point, in these combinations.

Kathleen N. Moore, MD: It was hard to do.

Bradley J. Monk, MD, FACOG, FACS: I know.

Kathleen N. Moore, MD: Because you had to wait until we did your testing. Your patient had to wait. And so, it was hard to do. It is stratified by PD-L1 expression by a different score than the CPS [combined positive score], but it is a very good assay. One arm gets chemotherapy/bevacizumab, bevacizumab maintenance; and the other gets chemotherapy/bevacizumab, bevacizumab maintenance with atezolizumab.

Bradley J. Monk, MD, FACOG, FACS: When do you think that’s going to read out, because it just finished enrollment?

Kathleen N. Moore, MD: It just finished, so I hope it doesn’t read out until 2021.

Bradley J. Monk, MD, FACOG, FACS: Because it’s an event-driven analysis.

Kathleen N. Moore, MD: It’s an event-driven analysis. I’m just sitting back and I’m hopeful that we’re going to see patients do well.

Bradley J. Monk, MD, FACOG, FACS: So that’s I/O anti-angiogenic. Certainly, within the NRG, they have olaparib and cediranib maleate—a fully oral regimen. Brian, tell us about DUO-O?

Brian M. Slomovitz, MD: DUO-O is basically an activity trial looking at a combination of durvalumab with olaparib in patients with recurrent ovarian cancer. This trial is looking to see if it can enhance activity. Right now, the academic activity part of it is spread out. I forget the exact percentage, but it’s a modest activity. The problem with those trials, intuitive head-to-head comparisons, is that we don’t know if the activity is driven by one or the other, or if it’s truly a synergy, which is what we would hope.

Bradley J. Monk, MD, FACOG, FACS: So we’ve got IMagyn050—atezolizumab, bevacizumab; DUO-O—durvalumab and olaparib; and because olaparib is shared, there’s a virtually identical trial called ENGOT-ov43 with pembrolizumab and olaparib. The difference between these 2 is that they allow bevacizumab, so it would be some triplet therapy, which would be bevacizumab, olaparib, and then pembrolizumab, or durvalumab. Talk about financial toxicity—$30,000 a cycle.

And then I run a trial called ATHENA. ATHENA is a pure maintenance trial. We were struck by the JAVELIN Ovarian 100 press release. In addition to JAVELIN Ovarian 200, which did not meet its primary endpoint, JAVELIN Ovarian 100 was avelumab in the frontline. It was with chemotherapy and in maintenance, which should have worked, or also in maintenance, who knows, but it didn’t work in either place.

And you talk about breast cancer. There’s a very large distinction between breast cancer and ovarian cancer. The classic example is the recent approval of atezolizumab and nab-paclitaxel.

Kathleen N. Moore, MD: Right.

Bradley J. Monk, MD, FACOG, FACS: So when you give single-agent chemotherapy and atezolizumab, it works. New England Journal of Medicine….

Kathleen N. Moore, MD: Yes.

Bradley J. Monk, MD, FACOG, FACS: The FDA approval is in breast. When you give PLD [pegylated liposomal doxorubicin] and avelumab, it’s negative. They say, “Maybe we should have studied PD-L1 expression.” So the JAVELIN Ovarian 100, I think, speaks to the opportunity of a pure maintenance opportunity of maybe adding chemotherapy, and I/O doesn’t have an opportunity. So that is nivolumab and rucaparib. So there are a number of trials, and I guess the final would be FIRST. Tell me about FIRST?

Kathleen N. Moore, MD: FIRST is a randomized phase III study that enrolls patients with advanced stage disease and randomizes them. Bevacizumab is optional. You have to declare it. So it’s Taxol, carboplatin, presumably bevacizumab, bevacizumab maintenance; versus Taxol, carboplatin, bevacizumab, bevacizumab maintenance, niraparib maintenance; versus Taxol, carboplatin, bevacizumab, TSR-042, which does have a name now.

Bradley J. Monk, MD, FACOG, FACS: Dostarlimab.

Kathleen N. Moore, MD: Dostarlimab, thank you. And leading into bevacizumab, niraparib, dostarlimab maintenance. That study is stratified by BRCA status. If you have a BRCA mutation, you are not randomized to a non-niraparib containing arm, because the randomization occurs in cycle 2. So it’s adaptive randomizations. It’s an interesting study. As these read out, PRIMA and other things read out, if things are positive, it will adapt and change randomizations to adapt to the new standard of care.

Transcript Edited for Clarity
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