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Bevacizumab for Recurrent Ovarian Cancer

Panelists: Bradley J. Monk, MD, University of Arizona and Creighton University School of Medicine at St. Joseph’s Hospital; Robert L. Coleman, MD, MD Anderson Cancer Center; Thomas Herzog, MD, University of Cincinnati; Kathleen N. Moore, MD, Stephenson Cancer Center; Angeles Alvarez Secord, MD, Duke University School of Medicine
Published: Friday, Feb 17, 2017


Transcript:

Bradley J. Monk, MD:
How many lines of therapy do ovarian cancer patients get these days?

Kathleen N. Moore, MD: I live in a different world of clinical trials, so I have patients who are in fifth-, sixth-, seventh-lines therapy and beyond. And then, you have, unfortunately, folks that have a much shorter disease trajectory, and not because we’ve had fewer options for them but just their disease, for some series of reasons, just didn’t respond.

Bradley J. Monk, MD: So, I can go to bevacizumab for patients with resistant disease in second- and third-line. For platinum-sensitive, it’s third-line, I get olaparib fourth-line and beyond. How do I figure out to treat my patient fifth-line?

Kathleen N. Moore, MD: These are different populations though.

Bradley J. Monk, MD: No, I get it. I can’t dial up the NCCN guidelines and say, “OK, this is fifth-line therapy, this is sixth-line.” How do I figure it out?

Angeles Alvarez Secord, MD: Brad, that’s where the art of medicine comes in.

Robert L. Coleman, MD: But, again, how do we guide clinicians on how to make the best treatment decisions?

Bradley J. Monk, MD: I know. Thank you. Give us some.

Angeles Alvarez Secord, MD: Well, I just think you have to take all things into context, and one of the important aspects here—and you keep driving this point home—is the platinum-free interval, and it exists on a continuum. I’ve had patients who would be platinum-resistant based on the definitions, and the original definition was based on clinically evident disease, not CA-125. It was imaging and clinically evident disease. I think people give up on reintroduction of platinum too early because of these categories. So, I do reintroduce platinum, especially if somebody did respond pretty profoundly initially. Even if they recurred within 3 months, I’ll reintroduce it.

Kathleen N. Moore, MD: Especially now that we have actually 1 maintenance agent, bevacizumab, and potentially a second next year—depending on what the FDA decides about niraparib—we have options for those patients. I totally agree with you, put them back on platinum, get them to respond again, and then our practice is stop after 6 to 8 lines, which some people agree with, some people don’t. But, you have something now that you can actually put them on instead of just stopping and letting them recur.

Angeles Alvarez Secord, MD: Can we talk about these different drugs? Then let’s come back and answer that question.

Bradley J. Monk, MD: Let’s finish the bevacizumab discussion. December 6th 2016, we got another label of bevacizumab for platinum-sensitive relapsed disease in second-line. Rob, you’re the PI of GOG-213. Summarize that study. That study has not yet been published, although the publication is imminent. Summarize that now new FDA-approved indication of bevacizumab.

Robert L. Coleman, MD: Thank you, and I have to congratulate all of the patients that participated in the trial and all the investigators. It took us 10 years to get to this point. And the trial still is ongoing with regard to surgery, and we can talk about that later if we have time. This was a trial that was set up to address a question for overall survival because we felt that was important in this patient population. We randomized patients to paclitaxel/carboplatin versus paclitaxel/carboplatin/bevacizumab. And the way the trial was set up is there was an allowance for surgery if the patients were felt to be amenable. So, that turned out to be about 15% of the patients. Also, during the context of the trial enrollment time period, they were able to be exposed to bevacizumab. About 10% of the patients in both arms of the trial were actually exposed to bevacizumab prior to going on to the study.

The eligibility criteria required a 6-month treatment-free interval from the platinum. Those that were on maintenance bevacizumab just had to have a short time off before they could be reconsidered. And so, we were very pleased to see that like most of the other trials looking at antiangiogenesis therapies, we saw a very strong effect on progression-free survival, hazard ratio around 0.6, 3 months on the median. But, most importantly, it was in the overall survival. And we saw about a 5-month, on the median, gain and it was actually an absolute value among the longest, largest OS survivorships we’ve seen—about 42 months in the experimental arm, 37 in the control arm. And so, the hazard ratio for overall survival is a two-tailed test in that study, right up around 1.0, which is the upper limit. There were some nuances in the actual FDA announcement that talked about the misclassification for the progression-free survival, which was a stratification variable. When those were corrected, we actually saw that the overall survival was statistically significant as well.

Bradley J. Monk, MD: If I heard you right, the PFS improvement was shorter than the OS improvement?

Robert L. Coleman, MD: Yes, isn’t that interesting?

Bradley J. Monk, MD: I know, it is. How is that possible?

Robert L. Coleman, MD: Well, it can be possible. We’ve seen it in multiple other trials, even today, and certainly we’ve seen it in cases of immunotherapies even more so, and we’ll get into that. I think what it gets to is that these patients who demonstrate their response, they were on bevacizumab until progression. And so, there are many patients still on bevacizumab maintenance.

Bradley J. Monk, MD: So, Tom, I’ve highlighted GOG-213 again, but now we have a fifth chemotherapy backbone with bevacizumab. We say, “Oh, we can use bevacizumab in recurrent disease, platinum-resistant and platinum-sensitive.” That’s true, but the chemotherapy backbone in resistant disease is 3 options and in sensitive, 2 options; 5 chemotherapy backbones. Tell us about the other platinum-sensitive chemotherapy backbone in the OCEANS trial.

Thomas Herzog, MD: Well, that would be comparing platinum and gemcitabine with or without bevacizumab. We saw a hazard ratio there in platinum-sensitive of 0.48, so very impressive hazard ratio with using that as well.

Bradley J. Monk, MD: But, that’s 4 months of PFS versus 5 months of OS. Is there any reason to use carboplatin/gemcitabine/bevacizumab in platinum-sensitive? I get they’re both labeled, but is the use of bevacizumab in platinum-sensitive disease really all about re-treating with carboplatin/paclitaxel?

Thomas Herzog, MD: Well, I think you have to individualize based on neuropathy, what type of alopecia the patients had, side effects...

Robert L. Coleman, MD: And also hypersensitivity reactions. So, talking about the 5 backbones, the 2 non-taxane backbones for platinum-sensitive disease both have significantly lower rates of HSR (hypersensitivity reactions). And that was actually a secondary endpoint in GOG-213, so we know the incidence rate in that study was around 27%. So, it’s not a trivial number.

Bradley J. Monk, MD: OK. We can probably put antiangiogenesis agents to rest. That’s now the third indication GYN, it’s great. So, 3 GYN indications, bevacizumab 2.5 years.

Thomas Herzog, MD: Let me just bring one thing up and that is the definition of “platinum-resistant” or “platinum-sensitive.” It varies by trial and it varies by investigator.

Bradley J. Monk, MD: It’s what you said, it’s a continuum.

Thomas Herzog, MD: Well, it is a continuum, but which platinum are you looking at? Are you looking at the first platinum? Are you looking at the penultimate platinum? There are a number of ways that that can be looked at. So, when you’re doing cross-trial comparisons which I know nobody in this panel would ever do, you need to be aware of what the methodology was. It’s very important.

Transcript Edited for Clarity
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Transcript:

Bradley J. Monk, MD:
How many lines of therapy do ovarian cancer patients get these days?

Kathleen N. Moore, MD: I live in a different world of clinical trials, so I have patients who are in fifth-, sixth-, seventh-lines therapy and beyond. And then, you have, unfortunately, folks that have a much shorter disease trajectory, and not because we’ve had fewer options for them but just their disease, for some series of reasons, just didn’t respond.

Bradley J. Monk, MD: So, I can go to bevacizumab for patients with resistant disease in second- and third-line. For platinum-sensitive, it’s third-line, I get olaparib fourth-line and beyond. How do I figure out to treat my patient fifth-line?

Kathleen N. Moore, MD: These are different populations though.

Bradley J. Monk, MD: No, I get it. I can’t dial up the NCCN guidelines and say, “OK, this is fifth-line therapy, this is sixth-line.” How do I figure it out?

Angeles Alvarez Secord, MD: Brad, that’s where the art of medicine comes in.

Robert L. Coleman, MD: But, again, how do we guide clinicians on how to make the best treatment decisions?

Bradley J. Monk, MD: I know. Thank you. Give us some.

Angeles Alvarez Secord, MD: Well, I just think you have to take all things into context, and one of the important aspects here—and you keep driving this point home—is the platinum-free interval, and it exists on a continuum. I’ve had patients who would be platinum-resistant based on the definitions, and the original definition was based on clinically evident disease, not CA-125. It was imaging and clinically evident disease. I think people give up on reintroduction of platinum too early because of these categories. So, I do reintroduce platinum, especially if somebody did respond pretty profoundly initially. Even if they recurred within 3 months, I’ll reintroduce it.

Kathleen N. Moore, MD: Especially now that we have actually 1 maintenance agent, bevacizumab, and potentially a second next year—depending on what the FDA decides about niraparib—we have options for those patients. I totally agree with you, put them back on platinum, get them to respond again, and then our practice is stop after 6 to 8 lines, which some people agree with, some people don’t. But, you have something now that you can actually put them on instead of just stopping and letting them recur.

Angeles Alvarez Secord, MD: Can we talk about these different drugs? Then let’s come back and answer that question.

Bradley J. Monk, MD: Let’s finish the bevacizumab discussion. December 6th 2016, we got another label of bevacizumab for platinum-sensitive relapsed disease in second-line. Rob, you’re the PI of GOG-213. Summarize that study. That study has not yet been published, although the publication is imminent. Summarize that now new FDA-approved indication of bevacizumab.

Robert L. Coleman, MD: Thank you, and I have to congratulate all of the patients that participated in the trial and all the investigators. It took us 10 years to get to this point. And the trial still is ongoing with regard to surgery, and we can talk about that later if we have time. This was a trial that was set up to address a question for overall survival because we felt that was important in this patient population. We randomized patients to paclitaxel/carboplatin versus paclitaxel/carboplatin/bevacizumab. And the way the trial was set up is there was an allowance for surgery if the patients were felt to be amenable. So, that turned out to be about 15% of the patients. Also, during the context of the trial enrollment time period, they were able to be exposed to bevacizumab. About 10% of the patients in both arms of the trial were actually exposed to bevacizumab prior to going on to the study.

The eligibility criteria required a 6-month treatment-free interval from the platinum. Those that were on maintenance bevacizumab just had to have a short time off before they could be reconsidered. And so, we were very pleased to see that like most of the other trials looking at antiangiogenesis therapies, we saw a very strong effect on progression-free survival, hazard ratio around 0.6, 3 months on the median. But, most importantly, it was in the overall survival. And we saw about a 5-month, on the median, gain and it was actually an absolute value among the longest, largest OS survivorships we’ve seen—about 42 months in the experimental arm, 37 in the control arm. And so, the hazard ratio for overall survival is a two-tailed test in that study, right up around 1.0, which is the upper limit. There were some nuances in the actual FDA announcement that talked about the misclassification for the progression-free survival, which was a stratification variable. When those were corrected, we actually saw that the overall survival was statistically significant as well.

Bradley J. Monk, MD: If I heard you right, the PFS improvement was shorter than the OS improvement?

Robert L. Coleman, MD: Yes, isn’t that interesting?

Bradley J. Monk, MD: I know, it is. How is that possible?

Robert L. Coleman, MD: Well, it can be possible. We’ve seen it in multiple other trials, even today, and certainly we’ve seen it in cases of immunotherapies even more so, and we’ll get into that. I think what it gets to is that these patients who demonstrate their response, they were on bevacizumab until progression. And so, there are many patients still on bevacizumab maintenance.

Bradley J. Monk, MD: So, Tom, I’ve highlighted GOG-213 again, but now we have a fifth chemotherapy backbone with bevacizumab. We say, “Oh, we can use bevacizumab in recurrent disease, platinum-resistant and platinum-sensitive.” That’s true, but the chemotherapy backbone in resistant disease is 3 options and in sensitive, 2 options; 5 chemotherapy backbones. Tell us about the other platinum-sensitive chemotherapy backbone in the OCEANS trial.

Thomas Herzog, MD: Well, that would be comparing platinum and gemcitabine with or without bevacizumab. We saw a hazard ratio there in platinum-sensitive of 0.48, so very impressive hazard ratio with using that as well.

Bradley J. Monk, MD: But, that’s 4 months of PFS versus 5 months of OS. Is there any reason to use carboplatin/gemcitabine/bevacizumab in platinum-sensitive? I get they’re both labeled, but is the use of bevacizumab in platinum-sensitive disease really all about re-treating with carboplatin/paclitaxel?

Thomas Herzog, MD: Well, I think you have to individualize based on neuropathy, what type of alopecia the patients had, side effects...

Robert L. Coleman, MD: And also hypersensitivity reactions. So, talking about the 5 backbones, the 2 non-taxane backbones for platinum-sensitive disease both have significantly lower rates of HSR (hypersensitivity reactions). And that was actually a secondary endpoint in GOG-213, so we know the incidence rate in that study was around 27%. So, it’s not a trivial number.

Bradley J. Monk, MD: OK. We can probably put antiangiogenesis agents to rest. That’s now the third indication GYN, it’s great. So, 3 GYN indications, bevacizumab 2.5 years.

Thomas Herzog, MD: Let me just bring one thing up and that is the definition of “platinum-resistant” or “platinum-sensitive.” It varies by trial and it varies by investigator.

Bradley J. Monk, MD: It’s what you said, it’s a continuum.

Thomas Herzog, MD: Well, it is a continuum, but which platinum are you looking at? Are you looking at the first platinum? Are you looking at the penultimate platinum? There are a number of ways that that can be looked at. So, when you’re doing cross-trial comparisons which I know nobody in this panel would ever do, you need to be aware of what the methodology was. It’s very important.

Transcript Edited for Clarity
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