Current Role of VEGF-Targeted Therapy in Ovarian Cancer



Bradley J. Monk, MD, FACOG, FACS: Let’s transition to targeted therapy. The first targeted therapy ever to be approved in a gynecologic cancer, either cervical or ovarian, was bevacizumab—a monoclonal antibody against vascular endothelial growth factor. And that continues to evolve with the FDA approval on June 13, 2018, in the front line. Elena, you’ve followed the NCCN [National Comprehensive Cancer Network] Guidelines closely. I don’t really know how important the NCCN Guidelines are to me, but I do know they’re important to payers. So tell me about the NCCN Guidelines now for the frontline use of bevacizumab, which by the way have been updated on March 8, 2019?

Elena S. Ratner, MD: So the NCCN update really summarizes the debate regarding bevacizumab in the primary setting. And this is a debate that we’ve had now for quite a bit of time. And the debate is such: It does improve progression-free survival [PFS], but there is no overall survival benefit. And the debate becomes: How important is that to the patient—that interval of time? There are studies that show that that progression-free survival is beneficial because the patient is able, then, to get to the next platinum setting and get response with that. But a lot of people believe the overall survival is the key, and without benefit in that, bevacizumab should not be level 1 evidence.

Bradley J. Monk, MD, FACOG, FACS: Excellent summary. I’m a little—but certainly not offended by your comments, but I don’t agree with overall survival as an endpoint in frontline ovarian cancer. So Katie, tell us why the NCCN would even mention such a, what I would say, preposterous idea.

Kathleen N. Moore, MD: I honestly can’t explain it. We increasingly know, and this is true not only in the United States but in Europe, and we have data that are very convincing, although we need to publish them, that even though we struggle to show overall survival advantages with our frontline interventions, even though in both US and Europe the incidence and the mortality of ovarian cancers remain the same, the prevalence has markedly increased because women are living longer.

Bradley J. Monk, MD, FACOG, FACS: SEER [National Cancer Institute’s Surveillance, Epidemiology, and End Results Program] just showed that. That’s right.

Kathleen N. Moore, MD: We just showed that. In fact, in Europe we had to argue that it was still an orphan disease because it’s crossed the threshold by prevalence, so it’s no longer an orphan disease. But it is by incidence, so we can still say that. So these incremental, or sometimes not incremental but meaningful, improvements in progression-free survival in 1 particular study do matter over time to how long our patients are living. And bevacizumab is a part of that story. That story started developing 5 to 10 years ago, which is when we got bevacizumab. And now we have bevacizumab in every arm or every kind of setting. We’ve shown, in at least 2 separate studies, that if you keep using it, even if you progressed on it the last time, it still works again. So these improvements in PFS translate into improvements, eventually, in overall survival.

Bradley J. Monk, MD, FACOG, FACS: And they’re meaningful.

Kathleen N. Moore, MD: They’re meaningful to patients, and they’re meaningful to how long they live. So I don’t understand that decision, and I don’t agree with it.

Bradley J. Monk, MD, FACOG, FACS: Brian, who in your practice is the best candidate for frontline bevacizumab?

Brian M. Slomovitz, MD: The bevacizumab is in all arms of therapy for ovarian cancer in my practice. And right now, truthfully, all my patients with newly diagnosed ovarian cancer, if they’re not a BRCA patient, which I know we’re going to get into, are going to get maintenance therapy with bevacizumab.

Kathleen N. Moore, MD: I 100% agree.

Brian M. Slomovitz, MD: Now, the specifics of when we start the bevacizumab.… I know the studies are based on starting it right up front with cycle 1 or 2 of chemotherapy. Sometimes it takes a longer conversation with patients to tell them that they’re not just getting treated over 6 cycles, and that it’s going to be a longer treatment. But giving bevacizumab after their chemotherapy is helping them live longer, and it has a longer PFS. Remember, in ovarian cancer now, women are getting 8, 9, 10 lines of therapy. So to translate what we give in the first line to get that to overall survival…

Bradley J. Monk, MD, FACOG, FACS: So technically, the June 2018 label is postoperative. In the neoadjuvant setting, you kind of have to be careful with reimbursement. According to the label, technically you’d start it on cycle 5, not on cycle 4 while she’s healing. I think what comes into it is that that the all-comer benefit is modest—6.2 months with a hazard ratio of 0.62. But there are some patients, the stage IVs, who actually might have a survival advantage. But I think cost plays into it. Tell me what your sense is of the cost and what you think biosimilars will do if and when they become approved?

Elena S. Ratner, MD: Brad, you really pointed out the key in here and kind of the elephant in the room: There’s a lot of society cost to these drugs, which doesn’t usually stop us from using them. But yes, again, in my population, I select the patients who have the worst prognosis, and that’s what the study showed as well.

Bradley J. Monk, MD, FACOG, FACS: Ascites, stage IV.

Elena S. Ratner, MD: Ascites, stage IV.

Bradley J. Monk, MD, FACOG, FACS: And that’s reasonable.

Elena S. Ratner, MD: And I think the new addendum is that it’s not women in my practice with just BRCA deleterious mutations. It’s also women with homologous recombination deficiency.

Bradley J. Monk, MD, FACOG, FACS: Frontline PARP maintenance would be off-label unless you have a BRCA mutation, but I understand you want to do that, and we’ll come back to that.

Again, bevacizumab was approved initially in platinum-resistant disease and then platinum-sensitive with OCEANS—carboplatin-gemcitabine—and then also with GOG-0213—carboplatin-paclitaxel. And then, ultimately, as we talked about, frontline. Brian, we’re still struggling though with what the right chemotherapy backbone is in recurrent disease. I think in the AURELIA study, we’ve agreed that it’s weekly paclitaxel.

Brian M. Slomovitz, MD: Yup.

Bradley J. Monk, MD, FACOG, FACS: But in platinum-sensitive, it’s more complicated. At ESMO [the European Society of Medical Oncology 2018 Congress], Dr [Jacobus] Pfisterer reported a platinum doublet with bevacizumab, or 2 different platinum doublets. Tell us about that study.

Brian M. Slomovitz, MD: What you’re referring to, Brad, is using platinum as a backbone, with liposomal doxorubicin and bevacizumab versus platinum with gemcitabine and bevacizumab. And basically, in summary, they found there was a slight improvement, I would say, with the liposomal doxorubicin arm, or that was the experimental arm. But the [adverse] effect profile was improved in that arm as well.

Bradley J. Monk, MD, FACOG, FACS: No surprise, right? PLD [pegylated liposomal doxorubicin] is easier than gemcitabine.

Brian M. Slomovitz, MD: Limitations: They didn’t look at Taxol.

Bradley J. Monk, MD, FACOG, FACS: There you go. They did not look at GOG-0213, right?

Brian M. Slomovitz, MD: They didn’t look at GOG-0213, so how can you make a definitive conclusion without that? You can’t. In my practice, in those patients who are 6 to 12 months or 6 to 18 months, if they’ve seen taxanes within a year, I’ll probably go to 1 of the other doublets that doesn’t contain a platinum. But if they are a year and a half, 2 years out without disease, I’ll go back to carboplatin and paclitaxel.

Bradley J. Monk, MD, FACOG, FACS: Yeah. We used to have 2 opportunities in platinum-sensitive relapse—carboplatin-gemcitabine or carboplatin-paclitaxel. Now we have a third, maybe even a preferable one: carboplatin-PLD. I’m struck that the carboplatin-PLD, which is, again, pegylated liposomal doxorubicin is an ideal opportunity for the patient with unstable diabetes because you’ve got to give a lot of steroid with paclitaxel. So if you say, “Her diabetes is a challenge for hyperglycemia,” you have the opportunity to start with carboplatin-PLD in the front line.

Transcript Edited for Clarity

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