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Upfront Systemic Therapy in Addition to Chemo?

Panelists: Bradley J. Monk, MD, FACS, FACOG, University of Arizona and Creighton University; Michael J. Birrer, MD, PhD The University of Alabama at Birmingham; Ursula A. Matulonis, MD, Harvard Medical School
Published: Saturday, Dec 22, 2018



Transcript: 

Bradley J. Monk, MD, FACS, FACOG: So, Mike, what’s the go-to chemotherapy backbone? I get that the best option is to go on a clinical trial. In the absence of a clinical trial what’s your go-to chemotherapy backbone in newly diagnosed advanced epithelial ovarian cancer?

Michael J. Birrer, MD, PhD:  Wow, interesting question. So, we’ve had a lot of twists and turns on this. I am still using a Taxol [paclitaxel] 2-3 times weekly regimen and now, frankly, with the recent approval to bevacizumab, I’m using bevacizumab.

Bradley J. Monk, MD, FACS, FACOG: So, if you have to make a chemotherapy decision, you say carboplatin-paclitaxel. You said IV [intravenous], I think?

Michael J. Birrer, MD, PhD:  Yes.

Bradley J. Monk, MD, FACS, FACOG: Every 3 weeks.

Ursula A. Matulonis, MD: So, I think as you guys have alluded to, there have been twists and turns and really an incredible evolution of the numbers or types of treatments. The backbone still is platinum and taxane, yes. With the recent bevacizumab approval, surely, the addition of bevacizumab after cycle 1 could be added with chemotherapy, then with maintenance. Q3-week carboplatin-paclitaxel; weekly carboplatin; weekly paclitaxel-carboplatin; weekly paclitaxel. Interperitoneal cisplatinum; and now the use of HIPEC [hyperthermic intraperitoneal chemotherapy] treatment after 3 cycles of neoadjuvant chemotherapy.  My go-to but saying that, selection is going to be dependent upon the patient in front of me.

Ursula A. Matulonis, MD: What is Q3-week carboplatin and paclitaxel?

Bradley J. Monk, MD, FACS, FACOG: So, this is important for our listeners. I think what I heard is, “Well, I used to give more intraperitoneal. Well, I used to give more weekly. Now typically I give every 3 weeks, carboplatin, paclitaxel.” So that’s an evolution.

Every patient who needs an operation, either in the beginning or between the third and the fourth cycle; every patient needs genetic counseling and testing from the germline, ideally a panel and maybe even the tumor. And every patient needs carboplatin-paclitaxel, and generally that’s IV every 3 weeks. And now you mentioned bevacizumab. Tell me about this trial, GOG-0218, which led to the FDA approval on June 13, 2018.

Michael J. Birrer, MD, PhD:  So before I get there, you summarized it beautifully, and I just wanted to emphasize that this evolution has been really driven by level 1 evidence. It’s not like we’re making it up. It’s very data-driven and that’s good because it’s good for our patients and for the physicians treating them.

So, GOG-0218, fascinating story, as you know Brad, you were heavily involved with it. So, this is a randomized phase III trial, placebo-controlled, which basically explored the addition of bevacizumab to carboplatin-paclitaxel upfront in the treatment of advanced ovarian cancer. And it had 3 arms, including a concurrent treatment with the placebo maintenance and then, of course, the treatment with 15 months of bevacizumab maintenance therapy.

A strongly positive trial, hazard ratio of somewhere around 0.7—we thought it was terrific at the time, and we get into PARP [poly ADP ribose polymerase] [inhibitors] on a whole different range of hazard ratios. But strongly positive. And it was matched with ICON7, which was not as positive but still statistically significant, and ICON7 was done in Europe. And so, the Europeans took actually the summation of all that, used the GOG-0218 data, and got approval.

Bradley J. Monk, MD, FACS, FACOG: [In] 2011, 7 years ago; okay, keep telling the story.

Michael J. Birrer, MD, PhD:  That’s right. And in the states, for a lot of reasons, and we can go into it, partly I think the fact the FDA was not crazy about trials that showed a PFS [progression-free survival] difference and not an OS [overall survival] difference.

We did not get approval. And so, what evolved was a patchwork use of bevacizumab upfront. I know in Massachusetts I was never able to get it approved, and I didn’t use it. But out in other areas of the country they were. And then lo and behold, as you say, just recently, the summation of all the bevacizumab data that was presented at the FDA, we got approval. And again, the label does say a hazard ratio of 0.62, I believe, with 6.2 months’ difference between the bevacizumab arm and the control. And so, I think it’s good for us. I’m a big believer in bevacizumab and this allows me to use it when I can.

Bradley J. Monk, MD, FACS, FACOG: I get asked all the time, having been heavily involved in the New England Journal of Medicine paper published in 2011 that led to the FDA approval in 2018. “So, Brad, what happened?”

Well, the first thing that happened was that we agreed through working with the FDA that PFS was an acceptable endpoint, which it wasn’t in 2011, and that about 6 months was the minimal threshold; it was only 4 in the publication. But in the publication CA-125 [cancer antigen 125] was used, and that’s really not the way we do drug development. So when you censored the CA-125 progression, just what you said, 6.2 months. It was razor thin over the agreed threshold. And, people were using it anyway in this patchwork fashion, and the FDA wanted to regulate it. And if most people are already using it, the FDA thought they had to get involved and provide black box warnings and education.

So, I think this has been an interesting story. I think we’re ready to move on. I want to know though has the approval, now it’s been 4 months later, do think that’s increased usage or not?

Ursula A. Matulonis, MD: We usually see across the US. I think for us, for me personally, I tend not to use it upfront.

Michael J. Birrer, MD, PhD:  Why?

Ursula A. Matulonis, MD: Really because of the lack of an overall survival benefit. I think that the paper, the GOG-0218 paper in the New England Journal of Medicine, did show there’s approximately a 4-month benefit. ICON7, again, different trials or different dose of bevacizumab, different duration, and there was the intent-to-treat population—no benefit in PFS, no benefit in OS.

Bradley J. Monk, MD, FACS, FACOG: So, a different dose, different duration, not placebo-controlled.

Ursula A. Matulonis, MD: Right.

Bradley J. Monk, MD, FACS, FACOG: What does that mean again?

Ursula A. Matulonis, MD: I think with ICON7, you can’t incorporate those results into decision making because it’s not necessarily reality-based.

Bradley J. Monk, MD, FACS, FACOG: Right.

Ursula A. Matulonis, MD: I think you make the decisions based upon GOG-0218. So again, there’s no biomarkers; issues around toxicities.

Bradley J. Monk, MD, FACS, FACOG: Yes, hypertension, proteinuria.

Ursula A. Matulonis, MD: Lack of a hypertension, absolutely. And now we have, as we’re going to talk about, other targeted therapies. I think we’re becoming much more sophisticated in how we think about the biology of the different histologies of ovarian cancer, and really are targeting treatment towards these patients.

Bradley J. Monk, MD, FACS, FACOG: In today’s world of conflict of interest, my conflict of interests are based on my biases, not based on an honorarium. My conflict of interest is that I think that bevacizumab is an important step forward, so I think I have to disclose that in my question.

Ursula A. Matulonis, MD: I think it’s important to support bevacizumab in the recurrent setting. And I think we’re going to for sure use bevacizumab in combinations with other biologic therapies.

Bradley J. Monk, MD, FACS, FACOG: What people say—and the problem is, again, it’s not prespecified— is that in the stage IV patients there’s a 10-month improvement in overall survival. So when you use bevacizumab post hoc, you can take a stage IV patient and turn her into the survival of a stage III, theoretically, in a hypothesis generating not hypothesis testing setting. But because the high-risk population—ICON7 supports that idea—reacts to that. Does that not resonate with you?

Ursula A. Matulonis, MD: Again, I think it’s around this kind of post hoc retrospective analysis.

Bradley J. Monk, MD, FACS, FACOG: I don’t get it.

Ursula A. Matulonis, MD: I mean that’s what bothers me about it, with a drug that doesn’t have a biomarker when you’re using it in a rather indiscriminate way.

Bradley J. Monk, MD, FACS, FACOG: I think our audience has heard both points. And I think we’re really trying, as you said, to be evidence-based, to be fair, balanced, and transparent. So, I think that’s important.

Transcript Edited for Clarity 

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Transcript: 

Bradley J. Monk, MD, FACS, FACOG: So, Mike, what’s the go-to chemotherapy backbone? I get that the best option is to go on a clinical trial. In the absence of a clinical trial what’s your go-to chemotherapy backbone in newly diagnosed advanced epithelial ovarian cancer?

Michael J. Birrer, MD, PhD:  Wow, interesting question. So, we’ve had a lot of twists and turns on this. I am still using a Taxol [paclitaxel] 2-3 times weekly regimen and now, frankly, with the recent approval to bevacizumab, I’m using bevacizumab.

Bradley J. Monk, MD, FACS, FACOG: So, if you have to make a chemotherapy decision, you say carboplatin-paclitaxel. You said IV [intravenous], I think?

Michael J. Birrer, MD, PhD:  Yes.

Bradley J. Monk, MD, FACS, FACOG: Every 3 weeks.

Ursula A. Matulonis, MD: So, I think as you guys have alluded to, there have been twists and turns and really an incredible evolution of the numbers or types of treatments. The backbone still is platinum and taxane, yes. With the recent bevacizumab approval, surely, the addition of bevacizumab after cycle 1 could be added with chemotherapy, then with maintenance. Q3-week carboplatin-paclitaxel; weekly carboplatin; weekly paclitaxel-carboplatin; weekly paclitaxel. Interperitoneal cisplatinum; and now the use of HIPEC [hyperthermic intraperitoneal chemotherapy] treatment after 3 cycles of neoadjuvant chemotherapy.  My go-to but saying that, selection is going to be dependent upon the patient in front of me.

Ursula A. Matulonis, MD: What is Q3-week carboplatin and paclitaxel?

Bradley J. Monk, MD, FACS, FACOG: So, this is important for our listeners. I think what I heard is, “Well, I used to give more intraperitoneal. Well, I used to give more weekly. Now typically I give every 3 weeks, carboplatin, paclitaxel.” So that’s an evolution.

Every patient who needs an operation, either in the beginning or between the third and the fourth cycle; every patient needs genetic counseling and testing from the germline, ideally a panel and maybe even the tumor. And every patient needs carboplatin-paclitaxel, and generally that’s IV every 3 weeks. And now you mentioned bevacizumab. Tell me about this trial, GOG-0218, which led to the FDA approval on June 13, 2018.

Michael J. Birrer, MD, PhD:  So before I get there, you summarized it beautifully, and I just wanted to emphasize that this evolution has been really driven by level 1 evidence. It’s not like we’re making it up. It’s very data-driven and that’s good because it’s good for our patients and for the physicians treating them.

So, GOG-0218, fascinating story, as you know Brad, you were heavily involved with it. So, this is a randomized phase III trial, placebo-controlled, which basically explored the addition of bevacizumab to carboplatin-paclitaxel upfront in the treatment of advanced ovarian cancer. And it had 3 arms, including a concurrent treatment with the placebo maintenance and then, of course, the treatment with 15 months of bevacizumab maintenance therapy.

A strongly positive trial, hazard ratio of somewhere around 0.7—we thought it was terrific at the time, and we get into PARP [poly ADP ribose polymerase] [inhibitors] on a whole different range of hazard ratios. But strongly positive. And it was matched with ICON7, which was not as positive but still statistically significant, and ICON7 was done in Europe. And so, the Europeans took actually the summation of all that, used the GOG-0218 data, and got approval.

Bradley J. Monk, MD, FACS, FACOG: [In] 2011, 7 years ago; okay, keep telling the story.

Michael J. Birrer, MD, PhD:  That’s right. And in the states, for a lot of reasons, and we can go into it, partly I think the fact the FDA was not crazy about trials that showed a PFS [progression-free survival] difference and not an OS [overall survival] difference.

We did not get approval. And so, what evolved was a patchwork use of bevacizumab upfront. I know in Massachusetts I was never able to get it approved, and I didn’t use it. But out in other areas of the country they were. And then lo and behold, as you say, just recently, the summation of all the bevacizumab data that was presented at the FDA, we got approval. And again, the label does say a hazard ratio of 0.62, I believe, with 6.2 months’ difference between the bevacizumab arm and the control. And so, I think it’s good for us. I’m a big believer in bevacizumab and this allows me to use it when I can.

Bradley J. Monk, MD, FACS, FACOG: I get asked all the time, having been heavily involved in the New England Journal of Medicine paper published in 2011 that led to the FDA approval in 2018. “So, Brad, what happened?”

Well, the first thing that happened was that we agreed through working with the FDA that PFS was an acceptable endpoint, which it wasn’t in 2011, and that about 6 months was the minimal threshold; it was only 4 in the publication. But in the publication CA-125 [cancer antigen 125] was used, and that’s really not the way we do drug development. So when you censored the CA-125 progression, just what you said, 6.2 months. It was razor thin over the agreed threshold. And, people were using it anyway in this patchwork fashion, and the FDA wanted to regulate it. And if most people are already using it, the FDA thought they had to get involved and provide black box warnings and education.

So, I think this has been an interesting story. I think we’re ready to move on. I want to know though has the approval, now it’s been 4 months later, do think that’s increased usage or not?

Ursula A. Matulonis, MD: We usually see across the US. I think for us, for me personally, I tend not to use it upfront.

Michael J. Birrer, MD, PhD:  Why?

Ursula A. Matulonis, MD: Really because of the lack of an overall survival benefit. I think that the paper, the GOG-0218 paper in the New England Journal of Medicine, did show there’s approximately a 4-month benefit. ICON7, again, different trials or different dose of bevacizumab, different duration, and there was the intent-to-treat population—no benefit in PFS, no benefit in OS.

Bradley J. Monk, MD, FACS, FACOG: So, a different dose, different duration, not placebo-controlled.

Ursula A. Matulonis, MD: Right.

Bradley J. Monk, MD, FACS, FACOG: What does that mean again?

Ursula A. Matulonis, MD: I think with ICON7, you can’t incorporate those results into decision making because it’s not necessarily reality-based.

Bradley J. Monk, MD, FACS, FACOG: Right.

Ursula A. Matulonis, MD: I think you make the decisions based upon GOG-0218. So again, there’s no biomarkers; issues around toxicities.

Bradley J. Monk, MD, FACS, FACOG: Yes, hypertension, proteinuria.

Ursula A. Matulonis, MD: Lack of a hypertension, absolutely. And now we have, as we’re going to talk about, other targeted therapies. I think we’re becoming much more sophisticated in how we think about the biology of the different histologies of ovarian cancer, and really are targeting treatment towards these patients.

Bradley J. Monk, MD, FACS, FACOG: In today’s world of conflict of interest, my conflict of interests are based on my biases, not based on an honorarium. My conflict of interest is that I think that bevacizumab is an important step forward, so I think I have to disclose that in my question.

Ursula A. Matulonis, MD: I think it’s important to support bevacizumab in the recurrent setting. And I think we’re going to for sure use bevacizumab in combinations with other biologic therapies.

Bradley J. Monk, MD, FACS, FACOG: What people say—and the problem is, again, it’s not prespecified— is that in the stage IV patients there’s a 10-month improvement in overall survival. So when you use bevacizumab post hoc, you can take a stage IV patient and turn her into the survival of a stage III, theoretically, in a hypothesis generating not hypothesis testing setting. But because the high-risk population—ICON7 supports that idea—reacts to that. Does that not resonate with you?

Ursula A. Matulonis, MD: Again, I think it’s around this kind of post hoc retrospective analysis.

Bradley J. Monk, MD, FACS, FACOG: I don’t get it.

Ursula A. Matulonis, MD: I mean that’s what bothers me about it, with a drug that doesn’t have a biomarker when you’re using it in a rather indiscriminate way.

Bradley J. Monk, MD, FACS, FACOG: I think our audience has heard both points. And I think we’re really trying, as you said, to be evidence-based, to be fair, balanced, and transparent. So, I think that’s important.

Transcript Edited for Clarity 
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