Bradley Monk, MD, FACOG, FACS: Let’s move on and talk about targeted therapy in newly diagnosed advanced ovarian cancer. The first FDA-approved targeted therapy was bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor, approved in 2014 in platinum-resistant disease but approved on June 13, 2018, for frontline. Now that’s a little unusual because the New England Journal of Medicine publication of this study called, GOG-0218, was in 2011 and it took 7 years to get it FDA approved. What do you think changed, Tom, between 2011 and 2018?

Thomas Herzog, MD: Well, I think a number of things changed, obviously. But I certainly think the aggregate of the data was just sort of overwhelming at that point.

Bradley Monk, MD, FACOG, FACS: Maybe the acceptance of PFS [progression-free survival] as an endpoint.

Thomas Herzog, MD: Yeah, I think that was probably 1 of the big things and the familiarity with BEV [bevacizumab].

Bradley Monk, MD, FACOG, FACS: That’s also true.

Thomas Herzog, MD: And seeing that BEV worked in all these multiple lines and that it was very effective. As the approval started piling up in ovary, I think it really made it even easier. I do think the PFS endpoint change was very important, because I think a lot of manufacturers were reluctant to file because they thought they had to have an OS [overall survival].

Bradley Monk, MD, FACOG, FACS: And that’s with your leadership, quite frankly, and thank you for that.

Thomas Herzog, MD: Well, thank you.

Bradley Monk, MD, FACOG, FACS: With your help in the FDA consensus panel. So that study, GOG-0218, was a PFS endpoint, 6.2-month improvement in progression-free survival, a hazard ratio of 0.62. Krish, you’ve been passionate about the overall survival, as Tom said. I think your paper that you and Bob Burger worked on together, looking at the final overall survival, is imminent in the Journal of Clinical Oncology. It’s accepted. You guys should read it any day. Summarize the overall survival results.

Krishnansu S. Tewari, MD: As you said, it took 7—actually 8—years since the PFS point was reported to be able to report the final OS. In both experimental arms, there was no significant difference compared with control. We had a median follow-up of about 103 months for this to get the number of events to trigger the final OS analysis. And we did multiple analyses. We looked at clinical stage. We looked at ascites production. We looked at crossover to BEV, patients who received second-line BEV. We also looked at CD31 status, BRCA1/BRCA2 mutational status, as well as homologous recombination deficiency.

Bradley Monk, MD, FACOG, FACS: And did any of those show an overall survival benefit?

Krishnansu S. Tewari, MD: Only stage. Stage was the only thing that tracked with the OS.

Bradley Monk, MD, FACOG, FACS: What do you mean, stage?

Krishnansu S. Tewari, MD: Patients with stage IV disease who got bevacizumab concurrent and in maintenance, so the third arm of the trial got tracked with significant improvement in OS relative to controls.

Bradley Monk, MD, FACOG, FACS: To what level?

Krishnansu S. Tewari, MD: 42 months versus 32 months.

Bradley Monk, MD, FACOG, FACS: 10 months.

Krishnansu S. Tewari, MD: Yeah.

Bradley Monk, MD, FACOG, FACS: Michael, as you know, published in the same issue of the New England Journal was this ICON7 trial. They also looked at these higher-risk advanced-stage patients. What did they show?

Michael J. Birrer, MD, PhD: Well, it was an interesting trial, I think. First of all, ICON7 for the entire group had about a 2.5 months. It was not as impressive as GOG-0218.

Bradley Monk, MD, FACOG, FACS: Shorter but at half the dose.

Michael J. Birrer, MD, PhD: That’s right. And then they teased out this high-risk group, which seemed to perform better with bevacizumab, including an OS difference. And that was a bit of an ad hoc analysis, which I never really believed. But I know that a lot of other people sort of used that to triage what patients they treat with BEV.

Bradley Monk, MD, FACOG, FACS: That’s the point. Your overall survival analysis was also post hoc. You told me about the post hoc ICON7, but they harmonize. They support each other. Jubilee, if you have 2 post hoc analyses from related trials, does that add more confidence?

Jubilee Brown, MD: Well, I think it does to me. And in practice, when I see 2 things that go together, I think that does guide patient management. Both ICON7 and GOG-0218 really showed the same thing here, that stage IV and poor-prognosis patients are probably best served with paclitaxel-carboplatin-BEV, followed by BEV maintenance.

Bradley Monk, MD, FACOG, FACS: It makes sense, too, that those large tumors are the ones that need the neovascularization, that the pleural fluid—which is the stage IV patient—really needs this opportunity to control angiogenesis. Tom, is bevacizumab only for advanced-stage and high-risk patients, or is it for everyone? Who’s the best patient for bevacizumab frontline, in other words?

Thomas Herzog, MD: Well, I think it benefits everyone in whom chemotherapy is indicated. I think that there’s certainly—if you look at statistically who benefits the most, it is those who have ascites, it is those with very advanced disease and more aggressive disease. And that’s been shown. If you’re going to limit it, that’s who you would use it on. If you’re not going to limit it, I think there are reasons not to.

Bradley Monk, MD, FACOG, FACS: Should we limit, Krish, bevacizumab to only the high-risk patients, or should we include it according to the label? So the label is after surgery with chemotherapy starting cycle 2 for 15 months because that’s what we thought the median time to progression was. So who should get BEV?

Krishnansu S. Tewari, MD: I agree with Tom. I think it’s indicated for everyone who doesn’t have a contraindication to antiangiogenesis therapy. Patients who have recovered from surgery and have no wound-healing issues or factors that would dissuade you from using it, I think they should be treated with chemotherapy plus bevacizumab. You can do genetic testing at that time. Those patients with a germline mutation can transition to PARP as maintenance. Those whose germline is negative, you should test the tumor and then transition those who are positive for somatic mutation to PARP. And the rest of them should stay on BEV, bevacizumab. I think the issue here is, as Tom mentioned, we’ve got now 9 phase III randomized trials of antiangiogenesis therapy in different populations of ovarian cancer, and they’re all positive, studying 5 different drugs that either bind to the receptor or take up the ligand. They’re all positive, and we shouldn’t ignore that.

Bradley Monk, MD, FACOG, FACS: Right. So, Michael, the FDA approval is postoperative. If you do neoadjuvant chemotherapy, technically giving it before the surgery is off-label, do you have trouble reimbursing or getting reimbursement, or you just stop it or start it after the interval debulking?

Michael J. Birrer, MD, PhD: Yeah, it’s an interesting issue, and I think it reflects where we are with the insurance coverages. I’ve never had a problem in neoadjuvant.

Bradley Monk, MD, FACOG, FACS: I haven’t either.

Jubilee Brown, MD: Right, me neither.

Michael J. Birrer, MD, PhD: I just do it and don’t even think twice, and there’s no fallout from it.

Bradley Monk, MD, FACOG, FACS: And then I guess the issue is duration. The duration is 15 months. We have a randomized prospective trial of 15 versus 30 months, called the BOOST trial, that hasn’t reported yet. What’s the duration? If we all agree that if you’re non—BRCA-mutated, you should get bevacizumab as per the label, as long as there’s not a contraindication. What’s the duration, Jubilee?

Jubilee Brown, MD: Well, I think the BOOST trial will really answer that question. And at present.

Bradley Monk, MD, FACOG, FACS: What do you do now?

Jubilee Brown, MD: Certainly at present we leave it to 15 months, but I think as we accumulate more and more data that suggest that continued bevacizumab may be useful, I think we may see the BOOST trial be positive. We’ll see.

Thomas Herzog, MD: I mean, I’m struck by the curves, the morphology of the curves in the sense of when the bevacizumab is turned off, you see a change.

Bradley Monk, MD, FACOG, FACS: Yeah, that’s good.

Transcript Edited for Clarity