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I-O Therapy in Advanced Ovarian Cancer

Panelists: Bradley J. Monk, MD, FACS, FACOG, University of Arizona, Creighton University, & Arizona Oncology Practice of US Oncology; Ursula Matulonis, MD, Dana-Farber Cancer Institute; David OMalley, MD, The Ohio State University; Matthew Powell, MD, Washington University; Shannon N. Westin, MD, MPH, MD Anderson Cancer Center
Published: Thursday, Apr 26, 2018



Transcript: 

Bradley J. Monk, MD, FACS, FACOG: We have 4 frontline trials that have enrolled, with data that are expected within the next year. There is the SOLO-1 trial, GOG-3005 with veliparib, PAOLA-1, and now JAVELIN Ovarian 100, with a checkpoint inhibitor. Can you tell us about that?

David O’Malley, MD: Well, PRIMA is ....

Bradley J. Monk, MD, FACS, FACOG: But it won’t report within the year.

David O’Malley, MD: You’re right.

Bradley J. Monk, MD, FACS, FACOG: I think people what to know what’s around the corner. PRIMA is around 2 corners. So, tell us about JAVELIN Ovarian 100?

David O’Malley, MD: JAVELIN Ovarian 100 is, once again, a platinum doublet with paclitaxel. We’re looking at avelumab. You receive it with a chemotherapy as maintenance, versus placebo.

Bradley J. Monk, MD, FACS, FACOG: There was no placebo, actually, but that’s OK.

David O’Malley, MD: You’re right. It was not placebo, it was open label. So, from that standpoint, that’s just the checkpoint. It’s not the bevacizumab. It’s not the PARP. So, we’re also hoping to hear about that within the next year.

Bradley J. Monk, MD, FACS, FACOG: Isn’t that great?

David O’Malley, MD: It’s going to be an exciting time.

Bradley J. Monk, MD, FACS, FACOG: Ursula, what about PD-1 or PD-L1 and PARP?

Ursula Matulonis, MD: There are some preclinical data, and now some data in the recurrent setting, that suggests that using a PARP inhibitor and an immuno-oncology (I-O) agent, PD-1 or PD-L1, is going to give you enhanced benefit. I’m not so sure that synergy has been documented to truly enhance the benefits of these agents, together. In fact, data in the recurrent setting are being presented today at the Society of Gynecologic Oncology.

Bradley J. Monk, MD, FACS, FACOG: Which is TSR-042 and niraparib?

Ursula Matulonis, MD: That’s where I think the next step is. Today is about pembrolizumab (Keytruda) plus niraparib. The safety- and tolerability-enhanced response rates have now allowed these doublets to be layered into chemotherapy. Several trials are now in development. I know that you’ve been involved in a number of them, in terms of the development of these studies, in asking questions about immuno-oncology and the use of PARP inhibitors, out back, clearly, unless you’re using a drug-line veliparib, because of that enhanced myelosuppression. And then, bevacizumab. Without that bevacizumab approval in the United States, a lot of these studies are saying “plus or minus bevacizumab.” Some are mandating bevacizumab, especially if the trial is also being done in Europe. So, a lot of really interesting questions are being posed.

Bradley J. Monk, MD, FACS, FACOG: The era of targeted therapy is here. We’ve got bevacizumab, PARP inhibitors, and now we have I-O. And combinations make sense, at least theoretically. This homologous recombination repaired deficiency might increase the neoadjuvant load.

Ursula Matulonis, MD: Correct.

Bradley J. Monk, MD, FACS, FACOG: I was really intrigued by a recent publication on uroepithelial tumors. I understand that they are intrinsically more responsive to checkpoint inhibition in ovarian cancer. But in uroepithelial tumors, HRD predicts response. HRD genes, DDR genes, same thing. And so, that seemed to add more fuel to a hypothesis that this requires future testing. You mentioned avelumab (Bavencio). Avelumab is an asset, by a particular company, that has also shown us talazoparib.

And you mentioned niraparib. Their asset is TSR-042. The company that owns olaparib has durvalumab. It’s pretty simple. I love it. So, we’re going to need your help to get these trials enrolled. There is a fourth opportunity. The company that owns rucaparib doesn’t have a checkpoint inhibitor, but the company that owns nivolumab doesn’t have a PARP inhibitor. So, maybe they should work together?

David O’Malley, MD: There are only so many patients with ovarian cancer in the United States. We have all of these unbelievable exciting combinations in clinical trial. But should we be doing HIPEC? This clearly is not ready for the big time here, right? Or should we be getting these patients on clinical trials, which may lead to a higher chance for cure rather than a 4-month progression free survival?

Bradley J. Monk, MD, FACS, FACOG: You can create a Venn diagram, right? PARP/bevacizumab and I-O/PARP. How about bevacizumab/I-O? There are 3 agents, and I’m going to ask you about all 3. But bevacizumab plus a PD-1 or a PD-L1 inhibitor, is that being done?

Shannon N. Westin, MD, MPH: Let’s keep on going. We know about IMagyn050. So, taking your chemotherapy, getting your bevacizumab, and then plus or minus atezolizumab.

Bradley J. Monk, MD, FACS, FACOG: The beauty of the FDA approval, if that happens in GOG-0218, frontline bevacizumab, it protects the control arms of PAOLA-1 and IMagyn050 because it’s chemotherapy/bevacizumab. Heretofore, they were doing a randomized trial where the control arm was not FDA approved. But if it does get FDA approved, then it simplifies that clinical trial design in a leapfrog sort of fashion. I love it.

David O’Malley, MD: It really builds upon the trials that we were talking about: GOG-0218 and ICON7. We look at using combination therapy and identifying those patients who are going to benefit the most, because these biomarkers are now ready for prime time—HRD and BRCA, obviously.

Bradley J. Monk, MD, FACS, FACOG: You may have seen bevacizumab labels in other tumor types. The atezolizumab and bevacizumab combination that is being studied in IMagyn050 is now more advanced than for other tumor types. I watch these. A classic example is renal cell carcinoma.

David O’Malley, MD: There are very exciting data.

Bradley J. Monk, MD, FACS, FACOG: In lung cancer, both of those molecules and pathways are approved. There’s also an opportunity there, where that synergy is being suggested. So, there might be something of a bevacizumab and checkpoint inhibitor combination. The science, I think, is further along, but it’s interesting.

Ursula Matulonis, MD: For atezolizumab/bevacizumab, and for or other I-O/bevacizumab combinations, there are smaller ongoing phase II concepts in recurrent cervical cancer.

Matthew Powell, MD: I think endometrial cancer is going to ....

Bradley J. Monk, MD, FACS, FACOG: For endometrial cancer, we have lenvatinib, which is an oral antiangiogenesis molecule. With pembrolizumab, it has shown really astounding, unprecedented, phase II activity in second-line endometrial cancer after failing carboplatin/paclitaxel.

Transcript Edited for Clarity 

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Transcript: 

Bradley J. Monk, MD, FACS, FACOG: We have 4 frontline trials that have enrolled, with data that are expected within the next year. There is the SOLO-1 trial, GOG-3005 with veliparib, PAOLA-1, and now JAVELIN Ovarian 100, with a checkpoint inhibitor. Can you tell us about that?

David O’Malley, MD: Well, PRIMA is ....

Bradley J. Monk, MD, FACS, FACOG: But it won’t report within the year.

David O’Malley, MD: You’re right.

Bradley J. Monk, MD, FACS, FACOG: I think people what to know what’s around the corner. PRIMA is around 2 corners. So, tell us about JAVELIN Ovarian 100?

David O’Malley, MD: JAVELIN Ovarian 100 is, once again, a platinum doublet with paclitaxel. We’re looking at avelumab. You receive it with a chemotherapy as maintenance, versus placebo.

Bradley J. Monk, MD, FACS, FACOG: There was no placebo, actually, but that’s OK.

David O’Malley, MD: You’re right. It was not placebo, it was open label. So, from that standpoint, that’s just the checkpoint. It’s not the bevacizumab. It’s not the PARP. So, we’re also hoping to hear about that within the next year.

Bradley J. Monk, MD, FACS, FACOG: Isn’t that great?

David O’Malley, MD: It’s going to be an exciting time.

Bradley J. Monk, MD, FACS, FACOG: Ursula, what about PD-1 or PD-L1 and PARP?

Ursula Matulonis, MD: There are some preclinical data, and now some data in the recurrent setting, that suggests that using a PARP inhibitor and an immuno-oncology (I-O) agent, PD-1 or PD-L1, is going to give you enhanced benefit. I’m not so sure that synergy has been documented to truly enhance the benefits of these agents, together. In fact, data in the recurrent setting are being presented today at the Society of Gynecologic Oncology.

Bradley J. Monk, MD, FACS, FACOG: Which is TSR-042 and niraparib?

Ursula Matulonis, MD: That’s where I think the next step is. Today is about pembrolizumab (Keytruda) plus niraparib. The safety- and tolerability-enhanced response rates have now allowed these doublets to be layered into chemotherapy. Several trials are now in development. I know that you’ve been involved in a number of them, in terms of the development of these studies, in asking questions about immuno-oncology and the use of PARP inhibitors, out back, clearly, unless you’re using a drug-line veliparib, because of that enhanced myelosuppression. And then, bevacizumab. Without that bevacizumab approval in the United States, a lot of these studies are saying “plus or minus bevacizumab.” Some are mandating bevacizumab, especially if the trial is also being done in Europe. So, a lot of really interesting questions are being posed.

Bradley J. Monk, MD, FACS, FACOG: The era of targeted therapy is here. We’ve got bevacizumab, PARP inhibitors, and now we have I-O. And combinations make sense, at least theoretically. This homologous recombination repaired deficiency might increase the neoadjuvant load.

Ursula Matulonis, MD: Correct.

Bradley J. Monk, MD, FACS, FACOG: I was really intrigued by a recent publication on uroepithelial tumors. I understand that they are intrinsically more responsive to checkpoint inhibition in ovarian cancer. But in uroepithelial tumors, HRD predicts response. HRD genes, DDR genes, same thing. And so, that seemed to add more fuel to a hypothesis that this requires future testing. You mentioned avelumab (Bavencio). Avelumab is an asset, by a particular company, that has also shown us talazoparib.

And you mentioned niraparib. Their asset is TSR-042. The company that owns olaparib has durvalumab. It’s pretty simple. I love it. So, we’re going to need your help to get these trials enrolled. There is a fourth opportunity. The company that owns rucaparib doesn’t have a checkpoint inhibitor, but the company that owns nivolumab doesn’t have a PARP inhibitor. So, maybe they should work together?

David O’Malley, MD: There are only so many patients with ovarian cancer in the United States. We have all of these unbelievable exciting combinations in clinical trial. But should we be doing HIPEC? This clearly is not ready for the big time here, right? Or should we be getting these patients on clinical trials, which may lead to a higher chance for cure rather than a 4-month progression free survival?

Bradley J. Monk, MD, FACS, FACOG: You can create a Venn diagram, right? PARP/bevacizumab and I-O/PARP. How about bevacizumab/I-O? There are 3 agents, and I’m going to ask you about all 3. But bevacizumab plus a PD-1 or a PD-L1 inhibitor, is that being done?

Shannon N. Westin, MD, MPH: Let’s keep on going. We know about IMagyn050. So, taking your chemotherapy, getting your bevacizumab, and then plus or minus atezolizumab.

Bradley J. Monk, MD, FACS, FACOG: The beauty of the FDA approval, if that happens in GOG-0218, frontline bevacizumab, it protects the control arms of PAOLA-1 and IMagyn050 because it’s chemotherapy/bevacizumab. Heretofore, they were doing a randomized trial where the control arm was not FDA approved. But if it does get FDA approved, then it simplifies that clinical trial design in a leapfrog sort of fashion. I love it.

David O’Malley, MD: It really builds upon the trials that we were talking about: GOG-0218 and ICON7. We look at using combination therapy and identifying those patients who are going to benefit the most, because these biomarkers are now ready for prime time—HRD and BRCA, obviously.

Bradley J. Monk, MD, FACS, FACOG: You may have seen bevacizumab labels in other tumor types. The atezolizumab and bevacizumab combination that is being studied in IMagyn050 is now more advanced than for other tumor types. I watch these. A classic example is renal cell carcinoma.

David O’Malley, MD: There are very exciting data.

Bradley J. Monk, MD, FACS, FACOG: In lung cancer, both of those molecules and pathways are approved. There’s also an opportunity there, where that synergy is being suggested. So, there might be something of a bevacizumab and checkpoint inhibitor combination. The science, I think, is further along, but it’s interesting.

Ursula Matulonis, MD: For atezolizumab/bevacizumab, and for or other I-O/bevacizumab combinations, there are smaller ongoing phase II concepts in recurrent cervical cancer.

Matthew Powell, MD: I think endometrial cancer is going to ....

Bradley J. Monk, MD, FACS, FACOG: For endometrial cancer, we have lenvatinib, which is an oral antiangiogenesis molecule. With pembrolizumab, it has shown really astounding, unprecedented, phase II activity in second-line endometrial cancer after failing carboplatin/paclitaxel.

Transcript Edited for Clarity 
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