Panelists: Bradley J. Monk, MD, University of Arizona and Creighton University; Robert L. Coleman, MD, MD Anderson Cancer Center; Gottfried E. Konecny, MD, University of California, Los Angeles; Katie Moore, MD, University of Oklahoma; Matthew A. Powell, MD, Washington University in St. Louis
Bradley J. Monk, MD: There’s a randomized trial called FORWARD…
Katie Moore, MD: FORWARD I.
Bradley J. Monk, MD: You’re the PI of that too, right? Tell us about FORWARD I.Tell us what it is and what the design of the study is.
Katie Moore, MD: FORWARD I is a randomized phase III trial that involves patients with 1 to 3 prior therapies and platinum-resistant disease. They have had their tissue sent, usually archival tissue, for immunohistochemical testing of folate receptor alpha. And they have to have moderate to high staining. The folate receptor alpha is really robustly expressed on ovarian cancer surfaces about 75% to 80% of the time, but about 65% of the time, it’s moderate to high.
Bradley J. Monk, MD: Why does that matter?
Katie Moore, MD: Well, we actually don’t know why it matters, to be honest. We don’t know what it’s doing there. It’s not the normal folate metabolism, but it’s there and it’s not really on normal tissues. And so, the drug in FORWARD I is called mirvetuximab soravtansine, and this is an antibody–drug conjugate. An antibody–drug conjugate, in general, looks like an arrow—that’s how I picture it—and the head of the arrow is targeted to something that is hopefully tumor specific, that has a beautiful linker that keeps it all together in circulation. And then, the tail of the arrow has highly potent molecules of chemotherapy: not PLD or taxanes, they have bizarre names, but they tend to be a microtubule toxin or novel alkylating agents.
Bradley J. Monk, MD: Made by the same company that brought us T-DM1, by the way.
Katie Moore, MD: Yes.
Bradley J. Monk, MD: So, these guys have some experience.
Katie Moore, MD: There are quite a few of these in development, so they’re on the tail. They hit the folate receptor alpha, the cell thinks it’s a friend and lets it in like a Trojan horse, and you release the molecules of chemotherapy and it takes out the cell, we hope. The molecule on the tail is what’s called DM4, which is a maytansine microtubule toxin. So, in phase I expansion cohorts, the response rate in the same FORWARD I population—1 to 3 prior therapies, etc—was 47%, with a 7-month median PFS. And so, FORWARD I is comparing that drug, which is given every 3 weeks intravenously to physician’s choice chemotherapy with a PFS endpoint.
Bradley J. Monk, MD: I like it.
Gottfried E. Konecny, MD: What I think is interesting, that you were able to show, is that there’s a correlation between the level of folate receptor expression and those who have none as opposed to those who have intermediate or high, and that you really base your criteria of study entry on that intermediate to high. Because that’s, I think, where you get more drug delivery. So, it’s really a targeted drug delivery of a very potent chemotherapy now.
Robert L. Coleman, MD: And I want to give a lot of credit to the investigators that worked on this program, because there was a dosing issue, there was a toxicity issue.
Bradley J. Monk, MD: Eye issues, and we worked it all out.
Robert L. Coleman, MD: Right. And they, I think, did a very good job of taking a relatively small database to try to fashion this that would put it in the position to win in the right patient population. So, it’s a good trial.
Gottfried E. Konecny, MD: Can you comment on the side effects? Because I’ve had preliminary experience with patients, and I’m surprised how well they tolerate it. It’s very different to a patient who would expect a third- or fourth-line chemotherapy and who has access to this drug now.
Katie Moore, MD: So, patients really do well on this drug. It has a microtubule toxin, but you don’t see hair loss. You do see some worsening of neuropathy, but it tends to be low-grade and nowhere near paclitaxel. We see diarrhea as the most common toxicity, but we tell patients about it and they’re set up for success. They just start their own Imodium. The biggest thing with this antibody drug conjugate—and it actually is a class effect of a number of antibody drug conjugates with particular cytotoxans—is keratopathy.
For some reason, you get damage to the stem cells around the cornea and the limbus, and they fleck off and go centrally. So, patients come in during cycle 2 with some blurry vision. And, if you do a slit lamp, you find all these micro-cysts, which are 100% reversible. It’s just like a burn on your skin: it heals, and the patients are fine. And so, that was the toxicity you were referring to. We really worked through that. We used to dose reduce quickly and that got rid of it, of course, but now we use eye drops. If they are visually grade 1, the patient says, “Yes, I’m OK, still working,” and we keep treating. We’re not dropping the dose as quickly. So, we’re maintaining dose intensity better, but patients really like being on this class of drug and this drug in particular.
Bradley J. Monk, MD: With your indulgence, I want to talk about another molecule that we work on. It’s something that I’ve been passionate about. I think we’ve spent a lot of time talking about antiangiogenesis, the new vasculature that’s developing. But we have the opportunity to target existing vasculature, and that class of agents are called vascular disrupting agents. So, the idea would be to give a vascular disrupting agent, destroy and collapse the existing vasculature, and then give an antiangiogenesis drug so they can’t grow back. And so, in a randomized phase II trial that was important— it can prove PFS and response rate—the agent is CA4P, combretastatin or fosbretabulin. I call it CA4P. So, now there’s a randomized trial taking platinum-resistant recurrent ovarian cancer, chemotherapy/bevacizumab, all of the AURELIA trial, and then adding the vascular disrupting agent, CA4P. Hopefully we can, again, try to capitalize on the wonderful observation that Eric Pujade-Lauraine made in the AURELIA trial by giving further antivascular agents.
Robert L. Coleman, MD: This is a concept I like a lot, only because the ovarian cancer environment is a mixture of neoantigen angiogenesis, like immature blood vasculature and mature vasculature, and is not all that sensitive to anti-VEGF therapy. So, you’re taking an endothelial cell toxin that’s banking on genetic stability, which we see in endothelial cells, and going after that as a target, causing a hypoxic environment, which has a natural response to increase VEGF.
Gottfried E. Konecny, MD: But you have to be careful, because it’s a high-risk investment with maybe high gain. Ovarian cancer is different because these drugs, the vasculature-disrupting agents, haven’t really held their promise.
Robert L. Coleman, MD: As single agents?
Bradley J. Monk, MD: This is the only one.
Robert L. Coleman, MD: No doubt about it.And you’re right, there are multiple classes of VDAs that are out there.
Bradley J. Monk, MD: So, Matt, in summary, we’ve talked about genetic testing, we’ve talked about surgical trials, which are pretty rare. We’ve talked about recent approvals, angiogenesis, and immunotherapy. What are you most excited about in the near future in ovarian cancer?
Matthew Powell, MD: Well, I think, again, it’s an exciting time. You sit down with a patient who’s recently diagnosed with ovarian cancer. Before, you gave her survival based on what we were doing 10 years ago. We really think we’re at a point where we’re moving forward: we have more things to offer and much smarter molecular derived therapy. To your point, we need to correlate this much better than just saying, “Oh, I think this is the right method.” We need to actually have that documented. But it’s a very exciting time to be taking care of patients with ovarian cancer, and there’s a lot of hope for them.
Bradley J. Monk, MD: That’s right. Well, I want to thank you who have participated in this OncLive Peer Exchange®. I’d like to thank Dr. Coleman, Dr. Powell, Dr. Moore, and Dr. Konecny. Thank you for your time. I really appreciate your engagement and so long for now.