Select Topic:
Browse by Series:

New Options for Recurrent Ovarian Cancer

Panelists: Michael J. Birrer, MD, PhD, The University of Alabama at Birmingham; Robert L. Coleman, MD, FACOG, FACS, The University of Texas MD Anderson Cancer Center; Bradley J. Monk, MD, FACS, FACOG, The University of Arizona College of Medicine; Kathleen Moore, MD, The University of Oklahoma Health and Sciences Center; Shannon N. Westin, MD, MPH, The University of Texas MD Anderson Cancer Center
Published: Monday, Nov 25, 2019



Transcript:

Bradley J. Monk, MD, FACS, FACOG: Let’s transition to recurrent ovarian cancer. We have 3 positive, practice-changing, FDA-enabling bevacizumab trials: AURELIA, GOG-218, and OCEANS.

Robert L. Coleman, MD, FACOG, FACS: GOG-0213.

Bradley J. Monk, MD, FACS, FACOG: GOG-0213, thank you. We have 3 PARP maintenance trials. Again, your trial, Rob, ARIEL3; AVANOVA; and SOLO-2, and Study 19 comes with it. That’s really exciting, but as you said, we’re not curing patients. We need to do a better job in recurrent ovarian cancer. I get it that the best opportunity is frontline. We just spent a lot of time talking about it, but recurrent ovarian cancer is still here.

Robert L. Coleman, MD, FACOG, FACS: Yes.

Bradley J. Monk, MD, FACS, FACOG: Katie, you presented a wonderful paper here at the European Society for Medical Oncology Congress 2019 about an antibody drug conjugate that I’d like you to share with us, because I’m really excited about it, even though the study missed its primary end point.

Kathleen Moore, MD: Yes, I had the great privilege of presenting FORWARD I, which is a randomized phase III study that compared the antibody drug conjugate, mirvetuximab soravtansine, with the investigator’s choice chemotherapy in women with recurrent platinum-resistant ovarian cancer whose tumor was characterized as folate receptor alpha high or medium. Really briefly, antibody-drug conjugates target something that their programs can find, In this case, that was folate receptor alpha, which is a transmembrane protein that is almost ubiquitously expressed on ovarian cancer. It is medium to highly expressed about 60% of the time and negligible on normal tissue, so it’s an ideal target to get to the tumor.

Once the conjugate binds, it’s internalized, gets attacked by the tumor cell, and realizes that it’s made a mistake like a Trojan horse. It releases its payload, which is this highly potent microtubule toxin, and it should lead to cell death and some bystander effect. We have very robust phase I data demonstrating that. FORWARD I was designed as a confirmatory trial in that space. It was a 2:1 randomization, and the primary end point was progression-free survival [PFS] in the intention-to-treat [ITT] group, both medium and high.

Bradley J. Monk, MD, FACS, FACOG: Versus physician’s choice chemotherapy.

Kathleen Moore, MD: Versus physician’s choice chemotherapy, intention-to-treat, and then folate receptor alpha high. The assumptions we made were that the control group would have a PFS of 3.5 months, which they did, and that for the mirvetuximab group, it would be 6 months. We’re looking for a hazard ratio of 0.58. Unfortunately, what we found was that in the ITT group, there was no difference, and in the folate receptor alpha–high group, there was a difference numerically in the medians, and the hazard ratio was 0.68. However, the P value was not statistically significant, which was very surprising, and it didn’t hit the estimates that we thought it would.

One of the concerning things that we discovered when we were looking at the trial was that the percentage of patients who came on FORWARD I with high folate receptor alpha characterization was much greater than we anticipated. We wondered if there was something to do with the scoring of the assay that determined eligibility, because it was different from what was used in the phase I program. It was meant to be more of a companion diagnostic and hopefully more packageable to the community.

We went back and rescored the entire study by a blinded pathologist, and it has since been confirmed or is being confirmed using the old scoring methodology. We reran the study results in a very exploratory fashion. What we found was that a third of the patients enrolled on FORWARD I were ineligible because they had folate receptor alpha low. Of those who were characterized as high, which I’ll remind you was a key primary end point, half of them were actually medium. We diluted out our end point. When we rerun it in the correctly characterized folate receptor alpha–high subgroup, the PFS is still statistically significantly improved. Overall survival goes from 11 to 16 months. We lost power because we lost half our patients, but there’s a trend there.

Robert L. Coleman, MD, FACOG, FACS: And a response.

Kathleen Moore, MD: The response was much higher. It was 6% versus 23%. The study, on exploratory analysis, looks to be positive. That’s disappointing, but we’re coming back with a second confirmatory trial called MIRASOL, which will characterize patients with the correct assay, and we are only enrolling folate receptor alpha high. It will be a 1:1 randomization, and there’s a more conservative statistical plan and a more robust power analysis. That should launch later this year and hopefully will be positive.

Bradley J. Monk, MD, FACS, FACOG: Yes, I think the challenge is that platinum-resistant recurrent ovarian cancer is such a high unmet need that you skipped a step. You went from phase I to phase III. Generally, these sorts of things would have been figured out in the phase II, so you did a phase III trial in a phase II risk. It illustrates the value of biomarkers. I think there is a lot to learn here. Mike, how do you feel about the fact that this drug clearly works but wasn’t better than chemotherapy? Most of our other trials are versus placebo, except for PAOLA-1, right? I would say that if you can’t beat something, compete against nothing. Tell us about this idea of an antibody-drug conjugate in study design. You’ve been involved in this for a long time.

Michael J. Birrer, MD, PhD: Yes. I’ve not only been involved but I’ve also put a lot of patients on it. It was very clear that it was an active drug. We had patients on it with platinum-resistant disease for almost 2 years and very good quality of life. What was driving the whole argument is, as Katie pointed out, we had really good response rates. I don’t want to be too shrill about this, but the lesson it teaches is, don’t change the assay in the middle of the trial.

Kathleen Moore, MD: Well, it wasn’t changed in the middle of the trial. That’s an important point, just because that’s a misunderstanding. It was changed. The phase I program was developed with the PS2 scoring, and then for FORWARD I, it changed to what’s called 10X scoring.

Michael J. Birrer, MD, PhD: When you change the assay, you’ve got to very carefully validate that the new assay is the same. It turns that out in retrospective, the assay was not the same.

Bradley J. Monk, MD, FACS, FACOG: They skipped a step.

Michael J. Birrer, MD, PhD: It’s a learning curve, which threatened the development of a good agent, but I think we’re back on track.

Bradley J. Monk, MD, FACS, FACOG: I’m not being critical. I’ll explain why. Our patients are dying, so we’ve got to hurry up. I would never be critical, but I think we have to learn these lessons.

Shannon N. Westin, MD, MPH: The only other thing I would say is that when you’re going with a new novel drug against chemo, the other question you have is “What about the adverse events profile? What about the adverse events?” Actually, the adverse event profile in FORWARD I was better in the mirvetuximab group.

Bradley J. Monk, MD, FACS, FACOG: It’s tolerable.

Shannon N. Westin, MD, MPH: Yes, it’s tolerable too.

Bradley J. Monk, MD, FACS, FACOG: Let’s do another study, and thank you.

Transcript Edited for Clarity

SELECTED
LANGUAGE
Slider Left
Slider Right


Transcript:

Bradley J. Monk, MD, FACS, FACOG: Let’s transition to recurrent ovarian cancer. We have 3 positive, practice-changing, FDA-enabling bevacizumab trials: AURELIA, GOG-218, and OCEANS.

Robert L. Coleman, MD, FACOG, FACS: GOG-0213.

Bradley J. Monk, MD, FACS, FACOG: GOG-0213, thank you. We have 3 PARP maintenance trials. Again, your trial, Rob, ARIEL3; AVANOVA; and SOLO-2, and Study 19 comes with it. That’s really exciting, but as you said, we’re not curing patients. We need to do a better job in recurrent ovarian cancer. I get it that the best opportunity is frontline. We just spent a lot of time talking about it, but recurrent ovarian cancer is still here.

Robert L. Coleman, MD, FACOG, FACS: Yes.

Bradley J. Monk, MD, FACS, FACOG: Katie, you presented a wonderful paper here at the European Society for Medical Oncology Congress 2019 about an antibody drug conjugate that I’d like you to share with us, because I’m really excited about it, even though the study missed its primary end point.

Kathleen Moore, MD: Yes, I had the great privilege of presenting FORWARD I, which is a randomized phase III study that compared the antibody drug conjugate, mirvetuximab soravtansine, with the investigator’s choice chemotherapy in women with recurrent platinum-resistant ovarian cancer whose tumor was characterized as folate receptor alpha high or medium. Really briefly, antibody-drug conjugates target something that their programs can find, In this case, that was folate receptor alpha, which is a transmembrane protein that is almost ubiquitously expressed on ovarian cancer. It is medium to highly expressed about 60% of the time and negligible on normal tissue, so it’s an ideal target to get to the tumor.

Once the conjugate binds, it’s internalized, gets attacked by the tumor cell, and realizes that it’s made a mistake like a Trojan horse. It releases its payload, which is this highly potent microtubule toxin, and it should lead to cell death and some bystander effect. We have very robust phase I data demonstrating that. FORWARD I was designed as a confirmatory trial in that space. It was a 2:1 randomization, and the primary end point was progression-free survival [PFS] in the intention-to-treat [ITT] group, both medium and high.

Bradley J. Monk, MD, FACS, FACOG: Versus physician’s choice chemotherapy.

Kathleen Moore, MD: Versus physician’s choice chemotherapy, intention-to-treat, and then folate receptor alpha high. The assumptions we made were that the control group would have a PFS of 3.5 months, which they did, and that for the mirvetuximab group, it would be 6 months. We’re looking for a hazard ratio of 0.58. Unfortunately, what we found was that in the ITT group, there was no difference, and in the folate receptor alpha–high group, there was a difference numerically in the medians, and the hazard ratio was 0.68. However, the P value was not statistically significant, which was very surprising, and it didn’t hit the estimates that we thought it would.

One of the concerning things that we discovered when we were looking at the trial was that the percentage of patients who came on FORWARD I with high folate receptor alpha characterization was much greater than we anticipated. We wondered if there was something to do with the scoring of the assay that determined eligibility, because it was different from what was used in the phase I program. It was meant to be more of a companion diagnostic and hopefully more packageable to the community.

We went back and rescored the entire study by a blinded pathologist, and it has since been confirmed or is being confirmed using the old scoring methodology. We reran the study results in a very exploratory fashion. What we found was that a third of the patients enrolled on FORWARD I were ineligible because they had folate receptor alpha low. Of those who were characterized as high, which I’ll remind you was a key primary end point, half of them were actually medium. We diluted out our end point. When we rerun it in the correctly characterized folate receptor alpha–high subgroup, the PFS is still statistically significantly improved. Overall survival goes from 11 to 16 months. We lost power because we lost half our patients, but there’s a trend there.

Robert L. Coleman, MD, FACOG, FACS: And a response.

Kathleen Moore, MD: The response was much higher. It was 6% versus 23%. The study, on exploratory analysis, looks to be positive. That’s disappointing, but we’re coming back with a second confirmatory trial called MIRASOL, which will characterize patients with the correct assay, and we are only enrolling folate receptor alpha high. It will be a 1:1 randomization, and there’s a more conservative statistical plan and a more robust power analysis. That should launch later this year and hopefully will be positive.

Bradley J. Monk, MD, FACS, FACOG: Yes, I think the challenge is that platinum-resistant recurrent ovarian cancer is such a high unmet need that you skipped a step. You went from phase I to phase III. Generally, these sorts of things would have been figured out in the phase II, so you did a phase III trial in a phase II risk. It illustrates the value of biomarkers. I think there is a lot to learn here. Mike, how do you feel about the fact that this drug clearly works but wasn’t better than chemotherapy? Most of our other trials are versus placebo, except for PAOLA-1, right? I would say that if you can’t beat something, compete against nothing. Tell us about this idea of an antibody-drug conjugate in study design. You’ve been involved in this for a long time.

Michael J. Birrer, MD, PhD: Yes. I’ve not only been involved but I’ve also put a lot of patients on it. It was very clear that it was an active drug. We had patients on it with platinum-resistant disease for almost 2 years and very good quality of life. What was driving the whole argument is, as Katie pointed out, we had really good response rates. I don’t want to be too shrill about this, but the lesson it teaches is, don’t change the assay in the middle of the trial.

Kathleen Moore, MD: Well, it wasn’t changed in the middle of the trial. That’s an important point, just because that’s a misunderstanding. It was changed. The phase I program was developed with the PS2 scoring, and then for FORWARD I, it changed to what’s called 10X scoring.

Michael J. Birrer, MD, PhD: When you change the assay, you’ve got to very carefully validate that the new assay is the same. It turns that out in retrospective, the assay was not the same.

Bradley J. Monk, MD, FACS, FACOG: They skipped a step.

Michael J. Birrer, MD, PhD: It’s a learning curve, which threatened the development of a good agent, but I think we’re back on track.

Bradley J. Monk, MD, FACS, FACOG: I’m not being critical. I’ll explain why. Our patients are dying, so we’ve got to hurry up. I would never be critical, but I think we have to learn these lessons.

Shannon N. Westin, MD, MPH: The only other thing I would say is that when you’re going with a new novel drug against chemo, the other question you have is “What about the adverse events profile? What about the adverse events?” Actually, the adverse event profile in FORWARD I was better in the mirvetuximab group.

Bradley J. Monk, MD, FACS, FACOG: It’s tolerable.

Shannon N. Westin, MD, MPH: Yes, it’s tolerable too.

Bradley J. Monk, MD, FACS, FACOG: Let’s do another study, and thank you.

Transcript Edited for Clarity
View Conference Coverage
Online CME Activities
TitleExpiration DateCME Credits
Publication Bottom Border
Border Publication
x