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ADCs & Checkpoint Inhibitor Combinations in TNBC

Panelists: Joyce A. OShaughnessy, MD, Baylor Charles A. Sammons Cancer Center; Sara A. Hurvitz, MD, UCLA Jonsson Comprehensive Cancer Center; Komal Jhaveri, MD, FACP, Memorial Sloan Kettering Cancer Center; Hope S. Rugo, MD, UCSF Helen Diller Family Comprehensive Cancer Center; Debu Tripathy, MD, The University of Texas MD Anderson Cancer Center
Published: Thursday, Aug 23, 2018

 

Transcript: 

Joyce A. O’Shaughnessy, MD: The antibody-drug conjugate combinations—there’s a lot going on in that space these days, right? What were some of the updates from the ASCO Annual Meeting, in that regard?

Komal Jhaveri, MD, FACP: We are all used to T-DM1 in the HER2 space, which is our first and very important prototype antibody drug conjugate. But we now have a lot of second- and next-generation antibody-drug conjugates and are looking at different targets or cytotoxic payloads. I think an important feature is that you want an attractive target that is preferentially present in the tumor tissue, not really in the normal tissue, which is the first step that you think about when you’re thinking about a new antibody-drug conjugate.

The one that is definitely striking, that comes to mind, is the one that was presented by Aditya Bardia—sacituzumab govitecan. This is an antibody drug conjugate against the target Trop-2, which is a cell surface glycoprotein. In triple-negative breast cancer, we have breakthrough approval by the FDA. It’s present in more than 90% of the tumor tissue, but it’s also present in other beta allele tissue.

This year, at the ASCO Annual Meeting, he presented data specifically for the subset with hormone receptor–positive disease, which was interesting. This was a smaller subset compared with the triple-negative subset, which was 110 patients, and the overall response rate in the third-line setting or greater, with at least 3 prior lines of therapy, was about 34%. When we looked at the HR-positive subset, the overall response rate was also about 31%. These patients had received 3 lines of hormone therapy. They received 2 lines of chemotherapy before they got this agent. And so, I think this is certainly an upcoming and attractive molecule, or antibody-drug conjugate, even for this particular population.

We keep talking about CDK4/6 inhibitors. What was also important was that 17% of the patients had received prior CDK4/6 inhibitors before they got sacituzumab govitecan, and the response rate was still 24%. This suggests that there is, perhaps, still activity even in patients who had progressed on CDK4/6 inhibitors. We’ll see what more data show in that space.

Joyce A. O’Shaughnessy, MD: There is a really attractive payload with these topoisomerase I inhibitors. We know, very well, that there’s a track record, and we just don’t have that readily available for our patients. The phase III trial going on in the triple-negative population is really, really important, versus treatment of physician’s choice chemotherapy in the later-line setting.

Hope S. Rugo, MD: Yes. The primary toxicity of this treatment is neutropenia, which we can generally manage. I think that’s really encouraging as well. It’s intriguing to me that this ADC, along with another ADC, which is entering a phase II study—SGN-LIV1A—causes hair loss. The T-DM1, trastuzumab-emtansine, didn’t and doesn’t. That’s interesting.

There’s something different about the linker and the toxin. People do lose their hair, although some of our patients who were on the Seattle Genetic study have used scalp cooling and haven’t lost their hair, so there you go. They’re not dosed very frequently. Sacituzumab govitecan is dosed as day 1 and day 8, as opposed to the LIV1A, which is every 3 weeks. So, it’ll be interesting. Trop-2 is so universally expressed that I think it makes this a very attractive target.

Joyce A. O’Shaughnessy, MD: Yes. And ladiratuzumab, the LIV-1 antibody drug conjugate, also with an anti-tubulin payload… This is very powerful, going forward, now, when a checkpoint inhibitor is added to it.  And, going into I-SPY 2, right?

Hope S. Rugo, MD: It’s already in I-SPY 2.

Joyce A. O’Shaughnessy, MD: In I-SPY 2, in the preoperative setting. We see really rapid translation. Speaking of the checkpoint inhibitors, Debu, what’s going on in the triple-negative population? Can you give us an update?

Debu Tripathy, MD: Well, a lot is going on. The initial studies were somewhat promising even though the response rates were low. As they broadened out to treat larger populations, we saw that response rates, even in triple-negative patients, were in the 5% to 10% range. The rates were even lower in HR-positive space. And the monotherapy, or first-line therapy study, KEYNOTE-086, which presented in San Antonio, showed that the response rate was 23% as first-line therapy. This was a large, 266-patient trial.

I think this is going to give us the opportunity to further dissect which patients respond. In contrast to some of the other tumor types, it’s been hard to discern whether there are clear predictive factors, such as PD-L1. It seems that the immune infiltrates and their characters may be more important. Hope can probably comment a little bit on this. She’s been very involved in this space.

I’ll just briefly say that we’re awaiting some of the other randomized studies, such as the IMpassion130 study of nab-paclitaxel plus or minus atezolizumab. The results will hopefully be out soon, and that’s going to be very important because we’re looking at an effective therapy that may actually enhance the immune response. So, we’re all looking forward to that.

Hope S. Rugo, MD: The interesting thing about the KEYNOTE trial, in the first-, second-, or greater-line settings, was that it was a large trial. We treated a little under 90 patients—86 patients—in the first-line setting. The response rates were just under 25%—the 23% to 24% range. It’s so intriguing, just like the phase I trial that had very few patients, where we thought the response rates were higher in later lines of therapy.

The response rates in later-line therapy were less than 5% in that group. But then, when we looked at the atezolizumab dose expansion, they showed the exact same thing. They had less patients in the first-line setting. The response rates were almost identical to the KEYNOTE trial. And then, in the second- or greater-line settings, those patients also had very low response rates—almost in the same range. Both studies showed that tumor-infiltrating lymphocytes (TILs) were correlated to some degree with response, but tumor-infiltrating lymphocytes are much higher, overall, the earlier you are in your disease setting. If you’re in the first-line setting, you have more than in a later-line therapy. That predicted the response. The response numbers are smaller here. Where you had a lot of TILs, your responses were much higher—over 30%.
There are some data that suggest that the number of TILs predicts the PD-L1 status, which may be why we’re so crummy at associating PD-L1 status with response. It’s really because TILs are something you can see in more real-time than PD-L1. We have very variable data, and this is not something to be used at all to select checkpoint inhibitor therapy for patients with breast cancer right now, in my opinion.

But then, the idea is that if you could increase the TILs, you could have a better response; or if you treat very early in the course of therapy. We don’t know. There are a lot of randomized trials that are looking at this in the neoadjuvant setting. And then, I’m curious what people thought about the TONIC trial? That was updated at the ASCO Annual Meeting. It also looked at a variety of 2-week inductions with low-dose radiation and low-dose chemotherapies to see whether or not you could enhance the response. The numbers are very, very small, but the responses looked better than what we’ve seen with checkpoint inhibitors. We’ve got to be cautious, given our phase I results.

Joyce A. O’Shaughnessy, MD: Fascinating. And, of course, the preoperative setting is extremely exciting with the checkpoint inhibitors. We know about the ongoing pembrolizumab preoperative study. Hopefully we will have a good new therapy for patients. We certainly hope so. It’s enrolling very well.

Transcript Edited for Clarity 

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Transcript: 

Joyce A. O’Shaughnessy, MD: The antibody-drug conjugate combinations—there’s a lot going on in that space these days, right? What were some of the updates from the ASCO Annual Meeting, in that regard?

Komal Jhaveri, MD, FACP: We are all used to T-DM1 in the HER2 space, which is our first and very important prototype antibody drug conjugate. But we now have a lot of second- and next-generation antibody-drug conjugates and are looking at different targets or cytotoxic payloads. I think an important feature is that you want an attractive target that is preferentially present in the tumor tissue, not really in the normal tissue, which is the first step that you think about when you’re thinking about a new antibody-drug conjugate.

The one that is definitely striking, that comes to mind, is the one that was presented by Aditya Bardia—sacituzumab govitecan. This is an antibody drug conjugate against the target Trop-2, which is a cell surface glycoprotein. In triple-negative breast cancer, we have breakthrough approval by the FDA. It’s present in more than 90% of the tumor tissue, but it’s also present in other beta allele tissue.

This year, at the ASCO Annual Meeting, he presented data specifically for the subset with hormone receptor–positive disease, which was interesting. This was a smaller subset compared with the triple-negative subset, which was 110 patients, and the overall response rate in the third-line setting or greater, with at least 3 prior lines of therapy, was about 34%. When we looked at the HR-positive subset, the overall response rate was also about 31%. These patients had received 3 lines of hormone therapy. They received 2 lines of chemotherapy before they got this agent. And so, I think this is certainly an upcoming and attractive molecule, or antibody-drug conjugate, even for this particular population.

We keep talking about CDK4/6 inhibitors. What was also important was that 17% of the patients had received prior CDK4/6 inhibitors before they got sacituzumab govitecan, and the response rate was still 24%. This suggests that there is, perhaps, still activity even in patients who had progressed on CDK4/6 inhibitors. We’ll see what more data show in that space.

Joyce A. O’Shaughnessy, MD: There is a really attractive payload with these topoisomerase I inhibitors. We know, very well, that there’s a track record, and we just don’t have that readily available for our patients. The phase III trial going on in the triple-negative population is really, really important, versus treatment of physician’s choice chemotherapy in the later-line setting.

Hope S. Rugo, MD: Yes. The primary toxicity of this treatment is neutropenia, which we can generally manage. I think that’s really encouraging as well. It’s intriguing to me that this ADC, along with another ADC, which is entering a phase II study—SGN-LIV1A—causes hair loss. The T-DM1, trastuzumab-emtansine, didn’t and doesn’t. That’s interesting.

There’s something different about the linker and the toxin. People do lose their hair, although some of our patients who were on the Seattle Genetic study have used scalp cooling and haven’t lost their hair, so there you go. They’re not dosed very frequently. Sacituzumab govitecan is dosed as day 1 and day 8, as opposed to the LIV1A, which is every 3 weeks. So, it’ll be interesting. Trop-2 is so universally expressed that I think it makes this a very attractive target.

Joyce A. O’Shaughnessy, MD: Yes. And ladiratuzumab, the LIV-1 antibody drug conjugate, also with an anti-tubulin payload… This is very powerful, going forward, now, when a checkpoint inhibitor is added to it.  And, going into I-SPY 2, right?

Hope S. Rugo, MD: It’s already in I-SPY 2.

Joyce A. O’Shaughnessy, MD: In I-SPY 2, in the preoperative setting. We see really rapid translation. Speaking of the checkpoint inhibitors, Debu, what’s going on in the triple-negative population? Can you give us an update?

Debu Tripathy, MD: Well, a lot is going on. The initial studies were somewhat promising even though the response rates were low. As they broadened out to treat larger populations, we saw that response rates, even in triple-negative patients, were in the 5% to 10% range. The rates were even lower in HR-positive space. And the monotherapy, or first-line therapy study, KEYNOTE-086, which presented in San Antonio, showed that the response rate was 23% as first-line therapy. This was a large, 266-patient trial.

I think this is going to give us the opportunity to further dissect which patients respond. In contrast to some of the other tumor types, it’s been hard to discern whether there are clear predictive factors, such as PD-L1. It seems that the immune infiltrates and their characters may be more important. Hope can probably comment a little bit on this. She’s been very involved in this space.

I’ll just briefly say that we’re awaiting some of the other randomized studies, such as the IMpassion130 study of nab-paclitaxel plus or minus atezolizumab. The results will hopefully be out soon, and that’s going to be very important because we’re looking at an effective therapy that may actually enhance the immune response. So, we’re all looking forward to that.

Hope S. Rugo, MD: The interesting thing about the KEYNOTE trial, in the first-, second-, or greater-line settings, was that it was a large trial. We treated a little under 90 patients—86 patients—in the first-line setting. The response rates were just under 25%—the 23% to 24% range. It’s so intriguing, just like the phase I trial that had very few patients, where we thought the response rates were higher in later lines of therapy.

The response rates in later-line therapy were less than 5% in that group. But then, when we looked at the atezolizumab dose expansion, they showed the exact same thing. They had less patients in the first-line setting. The response rates were almost identical to the KEYNOTE trial. And then, in the second- or greater-line settings, those patients also had very low response rates—almost in the same range. Both studies showed that tumor-infiltrating lymphocytes (TILs) were correlated to some degree with response, but tumor-infiltrating lymphocytes are much higher, overall, the earlier you are in your disease setting. If you’re in the first-line setting, you have more than in a later-line therapy. That predicted the response. The response numbers are smaller here. Where you had a lot of TILs, your responses were much higher—over 30%.
There are some data that suggest that the number of TILs predicts the PD-L1 status, which may be why we’re so crummy at associating PD-L1 status with response. It’s really because TILs are something you can see in more real-time than PD-L1. We have very variable data, and this is not something to be used at all to select checkpoint inhibitor therapy for patients with breast cancer right now, in my opinion.

But then, the idea is that if you could increase the TILs, you could have a better response; or if you treat very early in the course of therapy. We don’t know. There are a lot of randomized trials that are looking at this in the neoadjuvant setting. And then, I’m curious what people thought about the TONIC trial? That was updated at the ASCO Annual Meeting. It also looked at a variety of 2-week inductions with low-dose radiation and low-dose chemotherapies to see whether or not you could enhance the response. The numbers are very, very small, but the responses looked better than what we’ve seen with checkpoint inhibitors. We’ve got to be cautious, given our phase I results.

Joyce A. O’Shaughnessy, MD: Fascinating. And, of course, the preoperative setting is extremely exciting with the checkpoint inhibitors. We know about the ongoing pembrolizumab preoperative study. Hopefully we will have a good new therapy for patients. We certainly hope so. It’s enrolling very well.

Transcript Edited for Clarity 
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