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The Role of I-O in Platinum-Resistant Recurrent OC

Panelists: Bradley J. Monk, MD, FACS, FACOG, University of Arizona and Creighton University; Michael J. Birrer, MD, PhD The University of Alabama at Birmingham; Ursula A. Matulonis, MD, Harvard Medical School
Published: Thursday, Jan 03, 2019



Transcript:

Bradley J. Monk, MD:
All right, so we talked about checkpoint inhibitors in frontline, and how there are 5 checkpoint inhibitors and PARP [poly ADP ribose polymerase] combinations. We talked about atezolizumab [Tecentriq] being combined with bevacizumab [Avastin]. But there’s an opportunity to get checkpoint inhibitors approved in current disease and that’s what we’re talking about. You saw at ASCO [American Society of Clinical Oncology], why don’t you tell us the results of KEYNOTE-100 and this idea that maybe single-agent pembrolizumab [Keytruda] might work in what you presented very wonderfully based on the number of lines of therapy and the PD-L1 [programmed death-ligand 1] combined scores.

Ursula A. Matulonis, MD: Thanks Brad for that. I think if you take all-comers of women with recurrent ovarian cancer, and again, indiscriminate use of checkpoint blockade, the response rate is about 8% to 10%.

Bradley J. Monk, MD: Not enough for accelerated approval.

Ursula A. Matulonis, MD: Not enough for accelerated approval. And I think, importantly for the audience, not enough to give a patient off-label, even though it’s done. These drugs do have obvious toxicities. So, in KEYNOTE-100, [a] large trial nearly 400 patients, was a training set, and a larger set, patients who were less heavily pretreated versus more heavily pretreated. And the bottom line is in both of those groups, the response rates, all-comers, were about 8%, regardless of histology, regardless of number of prior lines. But that [was] when you pulled out the patients who had something called the combined positive score of 10 or higher; in a lot of trials a CPS [combined positive score] of 1 or higher [is] considered positive.

Bradley J. Monk, MD: Cervical cancer, now approved.

Ursula A. Matulonis, MD: That’s right, cervical cancer, but in here it was 10 or higher. So that’s the number of PD-L1 positive cells over the total numbers of cells.

Bradley J. Monk, MD: And only about a quarter of patients.

Ursula A. Matulonis, MD: It’s very low, exactly. And then the response rates were about 20%.

Bradley J. Monk, MD: So is that an accelerated approval opportunity?

Ursula A. Matulonis, MD: Well that’s a very good question. I think that it’s not up to me, it is up to the company who sponsored the research.

Bradley J. Monk, MD: In other words, accelerated approval opportunity for pembrolizumab in recurrent ovarian cancer with a CPS greater than 10. Obviously, we don’t know. That would be a pembrolizumab manufacturer opportunity.

Ursula A. Matulonis, MD: Because that, again, is regardless of number of prior lines. So that you would be able to sort of fill an unmet need.

Bradley J. Monk, MD: The level of false discovery is high because you’re doing all of these various analyses and you stumbled on a small subset, only a quarter of the patients where maybe it works. It’s not the typical accelerated approval approach when you do 400 patients.

Ursula A. Matulonis, MD: The only other piece of information growing forward is that in other cancers that level of CPS score, as it goes up, the response rates tend to go up as well.

Bradley J. Monk, MD: So the challenge I think is that if you look at the 3 predictors of checkpoint sensitivity, if you look at tumor infiltrating lymphocytes, which is only present in about half of ovarian cancer patients; if you look at a PD-L1 expression, maybe only two-thirds, and PD-L1 expression is a negative prognostic factor actually. And then certainly the mutational burden, which is also exclusively low except maybe in clear cell, we don’t have it. And people say, well, ovarian cancer is a cold tumor. And if it’s a cold tumor I think we’d want to give chemotherapy to create an immunogenic cell death. So tell us about JAVELIN 200, the avelumab [Bavencio], PLD [pegylated liposomal doxorubicin] study, which is interesting to test that very hypothesis.

Michael J. Birrer, MD, PhD: Yeah. So obviously that’s a hot trial.

Bradley J. Monk, MD: No pun intended.

Michael J. Birrer, MD, PhD: We expect those results in the not too distant future. So we’re very excited about that. And it has the potential, other than the KEYNOTE study, of cementing the role of immunotherapy in ovarian cancer. So it’s a very important study. It’s a study that tested the immune checkpoint inhibitor in comparison to doxorubicinol and, or pegylated liposomal doxorubicin, and in combination. Those are interesting agents because there’s been a lot of data for a long time about that particular drug in terms of what it can do to modulate the immune response. And so I think there’s combinations.

Bradley J. Monk, MD: Some ADC [antibody-drug conjugate] opportunities, which is unique.

Michael J. Birrer, MD, PhD: That’s right. And so, I think the challenge with JAVELIN 200 is this is in a platinum-resistant patient population, and always the argument has been, that’s a population where are the T-cells, or the immune system, really happy after having undergone all of that chemotherapy? We’re kind of moving away from that belief. And so I don’t know what the result of the study is going to be, but we’re excited about it.

Ursula A. Matulonis, MD: It’s an important trial, yes.

Bradley J. Monk, MD: So, JAVELIN 200 is platinum-resistant recurrent ovarian cancer up to 3 lines, all-comers, PLD alone/avelumab/PLD avelumab, 550 patients, actually enrolled 560, and your KEYNOTE-100 showed that heavily pretreated patients didn’t really do worse. There was really no T-cell exhaustion.

Ursula A. Matulonis, MD: That’s right.

Bradley J. Monk, MD: And the results of JAVELIN 200, or KEYNOTE-100 CPS 10, could be the first approval of a checkpoint inhibitor in ovarian cancer, maybe both.

Bradley J. Monk, MD: [The KEYNOTE-100] result was presented at ASCO, and the JAVELIN 200 avelumab result is imminent.

Michael J. Birrer, MD, PhD: That’s right.

Bradley J. Monk, MD: So that’s very exciting. You’ve mentioned that FORWARD I is just around the corner with mirvetuximab [soravtansine].

Michael J. Birrer, MD, PhD: First quarter.

Bradley J. Monk, MD: You’ve mentioned PAOLA-1, now frontline bevacizumab, olaparib.

Bradley J. Monk, MD: And then also PRIMA, all-comer, HRD [homologous recombination deficiency], maintenance niraparib. So that’s 4 studies. JAVELIN 200, FORWARD 1, PRIMA, and PAOLA-1, which will all report in the next 6 months.

Michael J. Birrer, MD, PhD: It’s going to be a good time.

Ursula A. Matulonis, MD: It’s a really exciting time. And it’s exciting from obviously all the trials you just mentioned, but also the increased level of interest of researchers, pharma, and really understanding that, yes, we can improve ovarian cancer treatments, and that wasn’t present 4 years ago.

Bradley J. Monk, MD: Because the prevalence though is 10 times the incidence.

Transcript Edited for Clarity.

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Transcript:

Bradley J. Monk, MD:
All right, so we talked about checkpoint inhibitors in frontline, and how there are 5 checkpoint inhibitors and PARP [poly ADP ribose polymerase] combinations. We talked about atezolizumab [Tecentriq] being combined with bevacizumab [Avastin]. But there’s an opportunity to get checkpoint inhibitors approved in current disease and that’s what we’re talking about. You saw at ASCO [American Society of Clinical Oncology], why don’t you tell us the results of KEYNOTE-100 and this idea that maybe single-agent pembrolizumab [Keytruda] might work in what you presented very wonderfully based on the number of lines of therapy and the PD-L1 [programmed death-ligand 1] combined scores.

Ursula A. Matulonis, MD: Thanks Brad for that. I think if you take all-comers of women with recurrent ovarian cancer, and again, indiscriminate use of checkpoint blockade, the response rate is about 8% to 10%.

Bradley J. Monk, MD: Not enough for accelerated approval.

Ursula A. Matulonis, MD: Not enough for accelerated approval. And I think, importantly for the audience, not enough to give a patient off-label, even though it’s done. These drugs do have obvious toxicities. So, in KEYNOTE-100, [a] large trial nearly 400 patients, was a training set, and a larger set, patients who were less heavily pretreated versus more heavily pretreated. And the bottom line is in both of those groups, the response rates, all-comers, were about 8%, regardless of histology, regardless of number of prior lines. But that [was] when you pulled out the patients who had something called the combined positive score of 10 or higher; in a lot of trials a CPS [combined positive score] of 1 or higher [is] considered positive.

Bradley J. Monk, MD: Cervical cancer, now approved.

Ursula A. Matulonis, MD: That’s right, cervical cancer, but in here it was 10 or higher. So that’s the number of PD-L1 positive cells over the total numbers of cells.

Bradley J. Monk, MD: And only about a quarter of patients.

Ursula A. Matulonis, MD: It’s very low, exactly. And then the response rates were about 20%.

Bradley J. Monk, MD: So is that an accelerated approval opportunity?

Ursula A. Matulonis, MD: Well that’s a very good question. I think that it’s not up to me, it is up to the company who sponsored the research.

Bradley J. Monk, MD: In other words, accelerated approval opportunity for pembrolizumab in recurrent ovarian cancer with a CPS greater than 10. Obviously, we don’t know. That would be a pembrolizumab manufacturer opportunity.

Ursula A. Matulonis, MD: Because that, again, is regardless of number of prior lines. So that you would be able to sort of fill an unmet need.

Bradley J. Monk, MD: The level of false discovery is high because you’re doing all of these various analyses and you stumbled on a small subset, only a quarter of the patients where maybe it works. It’s not the typical accelerated approval approach when you do 400 patients.

Ursula A. Matulonis, MD: The only other piece of information growing forward is that in other cancers that level of CPS score, as it goes up, the response rates tend to go up as well.

Bradley J. Monk, MD: So the challenge I think is that if you look at the 3 predictors of checkpoint sensitivity, if you look at tumor infiltrating lymphocytes, which is only present in about half of ovarian cancer patients; if you look at a PD-L1 expression, maybe only two-thirds, and PD-L1 expression is a negative prognostic factor actually. And then certainly the mutational burden, which is also exclusively low except maybe in clear cell, we don’t have it. And people say, well, ovarian cancer is a cold tumor. And if it’s a cold tumor I think we’d want to give chemotherapy to create an immunogenic cell death. So tell us about JAVELIN 200, the avelumab [Bavencio], PLD [pegylated liposomal doxorubicin] study, which is interesting to test that very hypothesis.

Michael J. Birrer, MD, PhD: Yeah. So obviously that’s a hot trial.

Bradley J. Monk, MD: No pun intended.

Michael J. Birrer, MD, PhD: We expect those results in the not too distant future. So we’re very excited about that. And it has the potential, other than the KEYNOTE study, of cementing the role of immunotherapy in ovarian cancer. So it’s a very important study. It’s a study that tested the immune checkpoint inhibitor in comparison to doxorubicinol and, or pegylated liposomal doxorubicin, and in combination. Those are interesting agents because there’s been a lot of data for a long time about that particular drug in terms of what it can do to modulate the immune response. And so I think there’s combinations.

Bradley J. Monk, MD: Some ADC [antibody-drug conjugate] opportunities, which is unique.

Michael J. Birrer, MD, PhD: That’s right. And so, I think the challenge with JAVELIN 200 is this is in a platinum-resistant patient population, and always the argument has been, that’s a population where are the T-cells, or the immune system, really happy after having undergone all of that chemotherapy? We’re kind of moving away from that belief. And so I don’t know what the result of the study is going to be, but we’re excited about it.

Ursula A. Matulonis, MD: It’s an important trial, yes.

Bradley J. Monk, MD: So, JAVELIN 200 is platinum-resistant recurrent ovarian cancer up to 3 lines, all-comers, PLD alone/avelumab/PLD avelumab, 550 patients, actually enrolled 560, and your KEYNOTE-100 showed that heavily pretreated patients didn’t really do worse. There was really no T-cell exhaustion.

Ursula A. Matulonis, MD: That’s right.

Bradley J. Monk, MD: And the results of JAVELIN 200, or KEYNOTE-100 CPS 10, could be the first approval of a checkpoint inhibitor in ovarian cancer, maybe both.

Bradley J. Monk, MD: [The KEYNOTE-100] result was presented at ASCO, and the JAVELIN 200 avelumab result is imminent.

Michael J. Birrer, MD, PhD: That’s right.

Bradley J. Monk, MD: So that’s very exciting. You’ve mentioned that FORWARD I is just around the corner with mirvetuximab [soravtansine].

Michael J. Birrer, MD, PhD: First quarter.

Bradley J. Monk, MD: You’ve mentioned PAOLA-1, now frontline bevacizumab, olaparib.

Bradley J. Monk, MD: And then also PRIMA, all-comer, HRD [homologous recombination deficiency], maintenance niraparib. So that’s 4 studies. JAVELIN 200, FORWARD 1, PRIMA, and PAOLA-1, which will all report in the next 6 months.

Michael J. Birrer, MD, PhD: It’s going to be a good time.

Ursula A. Matulonis, MD: It’s a really exciting time. And it’s exciting from obviously all the trials you just mentioned, but also the increased level of interest of researchers, pharma, and really understanding that, yes, we can improve ovarian cancer treatments, and that wasn’t present 4 years ago.

Bradley J. Monk, MD: Because the prevalence though is 10 times the incidence.

Transcript Edited for Clarity.
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