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Antibody-Drug Conjugates for TNBC

Panelists: Adam M. Brufsky, MD, PhD, University of Pittsburgh School of Medicine; Mark E. Robson, MD, Memorial Sloan Kettering Cancer Center; Aditya Bardia, MD, MPH, Massachusetts General Hospital Cancer Center; Kimberly L. Blackwell, MD, Duke Cancer Institute
Published Online: Thursday, Mar 30, 2017



Transcript:

Adam M. Brufsky, MD, PhD:
The last thing we want to talk about in this whole series of things is that we have antibody¬–drug conjugates. And I know Kim has been very involved in development with T-DM1, which is a very successful antibody–drug conjugate for HER2. But, Aditya, you’ve been involved with some of these conjugates. Can you talk about some of the trials that we’ve done with them so far?

Aditya Bardia, MD, MPH: We were inspired by Kim and the T-DM1 story, which has been the blockbuster drug in HER2-positive breast cancer. The idea is that you have an antibody that binds to the cancer cells and then releases chemotherapy only to the cancer cells while sparing the normal cells. We can deliver very high doses of chemotherapy only to the cancer cells and have a better risk profile. Sacituzumab, or IMMU-132, is an antibody drug conjugate that is being developed for triple-negative breast cancer at this time. There is interest in other breast cancers and other solid tumors, also. And the idea is that it binds to a target called Trop2, which is overexpressed in most triple-negative breast cancers, about 85% of triple-negative breast cancers. So, the idea is the same, that the antibody would bind to Trop2 and then dump the chemotherapy only to those cells while sparing the normal cells. It was a phase I clinical trial that was started a couple years ago and then moved into phase II. Now we have data in patients with metastatic triple-negative breast cancer who received this agent. In the clinical trial, we observed an impressive objective response rate of about 30% and a median progression-free survival of about 6 months in patients who had been heavily pretreated. These patients had received a median of 5 prior lines of therapy, and, in that heavily pretreated population, to see the signal was quite encouraging. So, this drug received FDA breakthrough designation status, and there is interest in potentially looking at accelerated approval and thinking about a phase III trial as well.

Adam M. Brufsky, MD, PhD: How many triple-negative patients are Trop2-positive?

Aditya Bardia, MD, MPH: About 85%.

Adam M. Brufsky, MD, PhD: Wow! So, there’s really not a lot of selectivity against this drug, which is kind of tough.

Aditya Bardia, MD, MPH: In this trial, it was everyone with triple-negative breast cancer for this reason. And they’re trying to do subset analysis of patients who had Trop1+, 2+, 3+ to see if there are differences, and I’m sure that we’ll come up with certain biomarkers that predict who are likely to benefit the most as opposed to those who will not benefit.

Adam M. Brufsky, MD, PhD: Kind of like people will benefit most with T-DM1 who are strong HER2-positive.

Kimberly L. Blackwell, MD: I think your trial is really impressive because a lot of those patients were so heavily pretreated, needing 4 different regimens. Great drug with that trial.

Adam M. Brufsky, MD, PhD: That’s a plea. We’re pleading to pharma that you’re listening. Use this group of patients for trials. We have no standard of care. It’s not a sexy area. It’s not first line, it’s not second line, but there’s an enormous number of people that really could use this. Performance status is great.

Mark E. Robson, MD: Even first-line triple-negative, there’s plenty.

Adam M. Brufsky, MD, PhD: Right. Again, hopefully that would happen. So, I think we’re just about done. We’ve had a great conversation; covered many, many topics. I’m sure we haven’t covered them all, but hopefully, we’ve given everybody a flavor of where we are. And so, before we end the discussion, I’d like some final thoughts to summarize where you think we are with advanced breast cancer. Dr. Bardia, we’ll start with you.

Aditya Bardia, MD, MPH: I think this is an exciting time to be in breast oncology with precision medicine, a number of targets, and potential targeted therapies. And I think, actually, over the next 5 years, we might reclassify how we think about breast cancer. We initially started with ER-positive, ER-negative and we went to HER2-positive and triple-negative. But, as we are coming up with additional targets, we might actually find more positive in triple negative and potentially even reclassify this disease, which would be very exciting.

Adam M. Brufsky, MD, PhD: Very good. Kim?

Kimberly L. Blackwell, MD: My thoughts are that early-stage breast cancer, genomic predictors, are here to stay. You need to understand them in order to take care of breast cancer patients, understand what they mean, and understand how to explain them to patients. And then, I think in the metastatic arena, as was mentioned, there is lots of excitement, lots of new drugs coming down the pike. And although all of us, who have busy practices, dread the rigmarole that’s involved in putting people on trial, it’s so worth it to give these options to our patients facing metastatic disease. So, my plea is really to continue the Moonshot enthusiasm that former Vice President Joe Biden created, and it definitely is worth the effort. I think if we involve our patients in this, they’re more than willing to help us get these trials approved. So, just don’t forget about the clinical trials in the metastatic setting.

Adam M. Brufsky, MD, PhD: Very good. Mark?

Mark E. Robson, MD: I think what we’re doing is we’re trying to hone in on a true personalized or precision medicine approach. Increasingly, we have a lot of options in terms of characterization of risk in early disease and then a number of different therapies for everything except triple-negative in advanced disease. And so, our challenge is—it’s almost an embarrassment of riches—to figure out who’s going to benefit from what. We need to start sequencing, which we really didn’t talk much about. We need to perhaps start thinking about the deepest possible characterization of patients, both from a genomic level and potentially from a germline level, so that we can figure out which is the best way of putting these things together for each individual.

Adam M. Brufsky, MD, PhD: Great. Well, thank you all very much. And thank you all for your contributions to this discussion. On behalf of our panel, we thank you for joining us and we hope you have found this Peer Exchange® discussion to be useful and informative.

Transcript Edited for Clarity

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Transcript:

Adam M. Brufsky, MD, PhD:
The last thing we want to talk about in this whole series of things is that we have antibody¬–drug conjugates. And I know Kim has been very involved in development with T-DM1, which is a very successful antibody–drug conjugate for HER2. But, Aditya, you’ve been involved with some of these conjugates. Can you talk about some of the trials that we’ve done with them so far?

Aditya Bardia, MD, MPH: We were inspired by Kim and the T-DM1 story, which has been the blockbuster drug in HER2-positive breast cancer. The idea is that you have an antibody that binds to the cancer cells and then releases chemotherapy only to the cancer cells while sparing the normal cells. We can deliver very high doses of chemotherapy only to the cancer cells and have a better risk profile. Sacituzumab, or IMMU-132, is an antibody drug conjugate that is being developed for triple-negative breast cancer at this time. There is interest in other breast cancers and other solid tumors, also. And the idea is that it binds to a target called Trop2, which is overexpressed in most triple-negative breast cancers, about 85% of triple-negative breast cancers. So, the idea is the same, that the antibody would bind to Trop2 and then dump the chemotherapy only to those cells while sparing the normal cells. It was a phase I clinical trial that was started a couple years ago and then moved into phase II. Now we have data in patients with metastatic triple-negative breast cancer who received this agent. In the clinical trial, we observed an impressive objective response rate of about 30% and a median progression-free survival of about 6 months in patients who had been heavily pretreated. These patients had received a median of 5 prior lines of therapy, and, in that heavily pretreated population, to see the signal was quite encouraging. So, this drug received FDA breakthrough designation status, and there is interest in potentially looking at accelerated approval and thinking about a phase III trial as well.

Adam M. Brufsky, MD, PhD: How many triple-negative patients are Trop2-positive?

Aditya Bardia, MD, MPH: About 85%.

Adam M. Brufsky, MD, PhD: Wow! So, there’s really not a lot of selectivity against this drug, which is kind of tough.

Aditya Bardia, MD, MPH: In this trial, it was everyone with triple-negative breast cancer for this reason. And they’re trying to do subset analysis of patients who had Trop1+, 2+, 3+ to see if there are differences, and I’m sure that we’ll come up with certain biomarkers that predict who are likely to benefit the most as opposed to those who will not benefit.

Adam M. Brufsky, MD, PhD: Kind of like people will benefit most with T-DM1 who are strong HER2-positive.

Kimberly L. Blackwell, MD: I think your trial is really impressive because a lot of those patients were so heavily pretreated, needing 4 different regimens. Great drug with that trial.

Adam M. Brufsky, MD, PhD: That’s a plea. We’re pleading to pharma that you’re listening. Use this group of patients for trials. We have no standard of care. It’s not a sexy area. It’s not first line, it’s not second line, but there’s an enormous number of people that really could use this. Performance status is great.

Mark E. Robson, MD: Even first-line triple-negative, there’s plenty.

Adam M. Brufsky, MD, PhD: Right. Again, hopefully that would happen. So, I think we’re just about done. We’ve had a great conversation; covered many, many topics. I’m sure we haven’t covered them all, but hopefully, we’ve given everybody a flavor of where we are. And so, before we end the discussion, I’d like some final thoughts to summarize where you think we are with advanced breast cancer. Dr. Bardia, we’ll start with you.

Aditya Bardia, MD, MPH: I think this is an exciting time to be in breast oncology with precision medicine, a number of targets, and potential targeted therapies. And I think, actually, over the next 5 years, we might reclassify how we think about breast cancer. We initially started with ER-positive, ER-negative and we went to HER2-positive and triple-negative. But, as we are coming up with additional targets, we might actually find more positive in triple negative and potentially even reclassify this disease, which would be very exciting.

Adam M. Brufsky, MD, PhD: Very good. Kim?

Kimberly L. Blackwell, MD: My thoughts are that early-stage breast cancer, genomic predictors, are here to stay. You need to understand them in order to take care of breast cancer patients, understand what they mean, and understand how to explain them to patients. And then, I think in the metastatic arena, as was mentioned, there is lots of excitement, lots of new drugs coming down the pike. And although all of us, who have busy practices, dread the rigmarole that’s involved in putting people on trial, it’s so worth it to give these options to our patients facing metastatic disease. So, my plea is really to continue the Moonshot enthusiasm that former Vice President Joe Biden created, and it definitely is worth the effort. I think if we involve our patients in this, they’re more than willing to help us get these trials approved. So, just don’t forget about the clinical trials in the metastatic setting.

Adam M. Brufsky, MD, PhD: Very good. Mark?

Mark E. Robson, MD: I think what we’re doing is we’re trying to hone in on a true personalized or precision medicine approach. Increasingly, we have a lot of options in terms of characterization of risk in early disease and then a number of different therapies for everything except triple-negative in advanced disease. And so, our challenge is—it’s almost an embarrassment of riches—to figure out who’s going to benefit from what. We need to start sequencing, which we really didn’t talk much about. We need to perhaps start thinking about the deepest possible characterization of patients, both from a genomic level and potentially from a germline level, so that we can figure out which is the best way of putting these things together for each individual.

Adam M. Brufsky, MD, PhD: Great. Well, thank you all very much. And thank you all for your contributions to this discussion. On behalf of our panel, we thank you for joining us and we hope you have found this Peer Exchange® discussion to be useful and informative.

Transcript Edited for Clarity
View Conference Coverage
Online CME Activities
TitleExpiration DateCME Credits
Medical Crossfire®: Leveraging New Evidence in the Context of Evolving Early-Stage Treatment Standards in HER2-Positive Breast CancerJan 30, 20181.5
14th Annual School of Breast Oncology® OnlineFeb 10, 201825
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