Advanced Ovarian Cancer: Recent Advances and Unmet Needs - Episode 14
Bradley J. Monk, MD: Let’s begin to talk about emerging therapies. I think in all of solid tumor oncology—actually, even in Hodgkin’s disease—we’re interested in anti—PD-1, PD-L1, and CTLA-4. What’s being done, Katie, in checkpoint inhibitor phase III trials in ovarian cancer?
Katie Moore, MD: I’m going to quote Dr. Rob Coleman a lot.
Bradley J. Monk, MD: Go ahead.
Katie Moore, MD: So, in frontline therapy, we have what’s called GOG-3015, which is the Genentech study that’s randomizing patients to a chemotherapy backbone and using atezolizumab, which is an anti-PD-1, as maintenance with bevacizumab. It’s looking at this question of, does the combining of a checkpoint inhibitor with an antiangiogenic strategy improve outcomes? And the rationale for that is that we think you increase T cell infiltration of the tumors by stabilizing the vessels.
Bradley J. Monk, MD: Primary debulking, interval debulking, for all-comers.
Katie Moore, MD: It’s not all-comers. It’s looking at a little bit of a higher risk population as a neoadjuvant cohort, and it has a primary cytoreduction cohort, but you can’t be a no gross residual patient.
Bradley J. Monk, MD: Because some of those patients take a long time to recur, fortunately. And this is more focused for the economy of the study.
Katie Moore, MD: Correct.
Gottfried E. Konecny, MD: I’m just asking, as devil’s advocate. The study was appropriately powered, because if you look at the single-agent activity of immune checkpoint inhibition of ovarian cancer, all data show roughly a 10% response rate.
Bradley J. Monk, MD: Not high.
Gottfried E. Konecny, MD: Not high. So, you’re using a drug in an unselected manner. Are you going to tweak out that group that really has a significant improvement?
Katie Moore, MD: Yes. Well, I believe.
Gottfried E. Konecny, MD: And do you think it’s going to apply to all patients?
Katie Moore, MD: I think that we are going to get some really good information on it, because the neoadjuvant cohort actually has planned—and the patients will have to consent—paired biopsy samples. And there’s a pretty elaborate translational science component added to that study.
Gottfried E. Konecny, MD: So, there could be some interim analysis of the neoadjuvant component, where you could amend the protocol.
Robert L. Coleman, MD: And I think that’s really important, because we know so little about what actually happens with respect to the T cell infiltration and their character and their relative spatial homology to the tumor. Those are all really critical pieces to understand. Actually, we have a similar kind of a dual approach to this in our center, where we have 2 neoadjuvant chemotherapy trials. One is using just chemotherapy as the induction surgery, followed by chemotherapy/I-O—in this case it was pembrolizumab—followed by pembrolizumab maintenance. And then, the other is looking at chemotherapy/I-O, surgery, and then chemotherapy/I-O followed by I-O alone, and that is particularly durvalumab. But the idea is to compare the pre- and post-tissue, to see what happens under those 2 stresses.
Bradley J. Monk, MD: I like to simplify things, because my mind is simple. I think that the predictors of response to checkpoints are probably tumor infiltrating lymphocytes, neoantigen load, and maybe PD-L1 expression.
Robert L. Coleman, MD: Maybe.
Bradley J. Monk, MD: So, if you look at ovarian cancer, TILs are only present if, you remember, the glucose is about 55%. The neoantigen load is also pretty low, so the idea of adding chemotherapy to checkpoint inhibition is to increase the neoantigen load. We’re fortunate that PD-L1 expression is generally pretty common, more 70% to 75%. That’s why all 5 randomized phase III trials have chemotherapy with a checkpoint. So, you talked about what I call IMagyn050; you call it GOG…
Katie Moore, MD: GOG-3015, but it is IMagyn050, you’re correct.
Bradley J. Monk, MD: And then there are 2 more atezolizumab trials, one adding it to the AURELIA regimen—again, chemotherapy/bevacizumab—and one ATALANTE trial, adding it to the platinum-sensitive backbone, all with bevacizumab, because it’s the same manufacturer. And then, there’s avelumab.
Katie Moore, MD: The JAVELIN series.
Bradley J. Monk, MD: The JAVELIN series. So, the JAVELIN series is the frontline in platinum-resistant disease, and in the platinum-resistant space it adds with PLD (pegylated liposomal doxorubicin). That study has completed enrollment.
Robert L. Coleman, MD: Amazing.
Bradley J. Monk, MD: In the last month of that study, they put in over 80 patients—in a month.
Robert L. Coleman, MD: No doubt it’s popular.
Bradley J. Monk, MD: It’s popular.
Robert L. Coleman, MD: The thing is, I like that trial a lot, because of the potential that…
Bradley J. Monk, MD: Thank you.
Robert L. Coleman, MD: I don’t know who wrote it.
Bradley J. Monk, MD: And thank you to Eric Pujade-Lauraine.
Robert L. Coleman, MD: Yes, absolutely, our international collaborators. The role of PLD in this setting is that it’s a commonly used agent to potentially induce a response for immunotherapy.
Bradley J. Monk, MD: Immunogenic cell death.
Robert L. Coleman, MD: So, it’s a nice study. What I like about all these is that they’re at least attempting to bank on what we know about the biology, and they’ll tell us what the new biology is.
Bradley J. Monk, MD: And with JAVELIN 100, which is a frontline, the challenge is that we really don’t know what the safety is of checkpoint in surgery. So, in JAVELIN 100, there are 3 arms, and 1 arm is just maintenance, because throwing in this interval debulking and all of this stuff may ruin that arm. It may not be feasible. It may increase toxicity. So, JAVELIN 100 has—as a safety net, if you will—just a maintenance phase.
Katie Moore, MD: I think that’s a great point, and we will see how the studies bear out. But we do have data from the lung setting, where they are getting thoracic resections, which is not like a big abdominal surgery, but it’s not a minor procedure.
Robert L. Coleman, MD: It’s not a minor procedure. It’s a surgical stress.
Katie Moore, MD: And it has really been shown to be a safe combination in that setting. And so, I think we’re going to get a lot of information about efficacy and safety and hopefully biomarkers.
Transcript Edited for Clarity