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Checkpoint Inhibitors for Triple-Negative Breast Cancer

Panelists: Joyce O Shaughnessy, MD, Baylor University Medical Center; Kevin Kalinsky, MD, MS NewYork-Presbyterian Hospital; Elizabeth Mittendorf Dana-Farber; Ruth O Regan, MD, University of Wisconsin Carbone Cancer Center; Hope S. Rugo, MD, UCSF Helen Diller Family Comprehensive Cancer Center
Published: Friday, May 03, 2019



Transcript: 

Joyce O’Shaughnessy, MD
: Let’s transition to triple-negative breast cancer and the interesting diagnostic now around PD-L1/2 [programmed death-ligand 1 and 2] and the new approval of atezolizumab in the metastatic setting and the locally advanced unresectable setting too, which is quite intriguing. This was a very interesting development, just yesterday. Hope, tell us about the IMpassion130 trial, if you would.

Hope S. Rugo, MD: It’s really exciting that we now have the first approval of a checkpoint inhibitor to treat metastatic triple-negative breast cancer. IMpassion130 randomized patients who had chemotherapy-naïve metastatic triple-negative breast cancer at least 12 months from an adjuvant or neoadjuvant taxane to receive nab-paclitaxel with either placebo or atezolizumab. The endpoints included progression-free survival [PFS] in the intent-to-treat population and also in the PD-L1–positive population, and overall survival in both populations as well. And the endpoints were tied to one another in kind of a funny, statistical design way. But because the differences were so big, we sort of overlooked that statistical design, which I think is clinically relevant because we don’t see changes in such a big difference.

About 60% of the patients had their PD-L1 testing done in the archival tumor samples versus metastatic tumor samples, and the PD-L1 was a specific test that I’ll let Beth talk about a little bit more in a moment. You know, you get on a call when you’re on a steering committee for these studies, right? You look for those results. You’re just waiting for that PFS. The PFS slide in intent-to-treat was a little under 2 months, and it was still significant. We thought, “That’s really a shame.” And then we saw, in the PD-L1–positive population, it was 2½ months. “Oh, that’s a little better. But still, it’s kind of small. That’s a lot of money, and there is the risk of immune-related AEs [adverse events]. Is it really worth it?”

And then we saw the overall survival data, [though] it’s still very much interim and we’re looking for the final data with more events later this year. But in the overall population, we saw a P value of .08. In the PD-L1–positive population, we saw a really impressive and never-before-seen overall survival difference of 9½ months. I think this is clinically relevant, even though there was this idea that you should see significance in intent-to-treat. Things change.

So I think that difference is really remarkable, and it looks so similar to CLEOPATRA. It’s so interesting to me that antibodies seem to change something about the tumor microenvironment regardless of what they’re targeting. Because in CLEOPATRA, there was about a 6-month difference in PFS but almost a 16-month difference in overall survival when you added pertuzumab to trastuzumab. So it’s really fascinating, and I think it really sets a new standard of care. Now we have to check PD-L1 in all our patients with metastatic triple-negative disease who aren’t refractory to taxanes. We’ll hopefully hear later this year about alternative chemotherapy partners. Really well tolerated also.

Joyce O’Shaughnessy, MD: Yeah. What about the diagnostics? How do we get the PD-L1 done here, Beth?

Elizabeth A. Mittendorf, MD, PhD: As Hope alluded to, there are differences in the trial that were most pronounced, of course, in the PD-L1–positive population. About 41% of patients in the study were PD-L1–positive. And so the approval that came out yesterday is for PD-L1–positive patients, and this is where I think there are some important details that we need to be aware of. So what is PD-L1–positive? The Genentech strategy for using PD-L1 as a biomarker has not been to look at PD-L1 expression on the tumor. Rather, they’re looking at PD-L1 expression on the immune cells.

This is very different [from] some of the other already-approved-in-other-histology agents. In addition, it’s a very specific antibody that they’ve used—SP142 and the Ventana system. And so one presumes that, in fact, that was also approved as a companion diagnostic, therefore we should be using the SP142 to look for PD-L1 expression on the immune cells. So I think this is going to be very interesting for groups when they go back to clinic next, because I don’t know that many institutions have kind of “set themselves up” to be testing this way. I think it’s going to be critically important for the breast cancer clinicians to work with their pathologist to recognize that this is a different PD-L1 test than what they might be using for their lung cancer patients.

I’ve heard a few people say, “Well, our group is going to use some other antibody that we use already” for, again, different histologies. An important study was done, not in breast cancer but in lung cancer, called the Blueprint project. I think we were chatting about this before. What the Blueprint project did was look in lung tumors using the 5 different antibodies that are available. Those antibodies correspond with each different pharmaceutical company and the drug that they’ve developed. And just cutting to the chase, what they found was that the antibodies are all pretty interchangeable if you’re looking for PD-L1 expression on the tumor—which, remember, is not what we looked at in the IMpassion130 trial.

Interestingly, even though they’re all fairly comparable, it’s the SP142 that’s a little less sensitive for PD-L1 expression on the tumor. But if they looked for PD-L1 expression on the immune cells, which is the biomarker from the IMpassion130 trial, there was a lot of discordance with the different antibodies. I point all this out because I think we, as a breast cancer community, are going to have to address this, and we’re going to have to address it first with respect to what we’re going to do with initial testing. But I also think there’s an opportunity to explore some of these other antibodies and see. I just gave the Blueprint data, but that was in lung tumors. Is it different in breast cancer? It might be worth looking at.

Hope S. Rugo, MD: And you have a project to do this?

Elizabeth A. Mittendorf, MD, PhD: Yes, we have our project to do that. Hope and I are involved with an effort that is going to be trying to get biospecimens from patients who will now be treated with these agents as their standard treatment in order to ask and answer some of these important questions that a clinical trial, perhaps, didn’t let us answer but real-world experience will.

Joyce O’Shaughnessy, MD: Does it make any difference whether it’s primary or metastatic disease? Should we try for 1 or the other, to try to find that PD-L1?

Elizabeth A. Mittendorf, MD, PhD: Well, I think that’s what Hope alluded to: That 60% of the tumors are archival. I presume that’s from the primary tumor.

Hope S. Rugo, MD: From the primary tumor, as far as we can tell.

Elizabeth A. Mittendorf, MD, PhD: Right. And so I just went through this whole diatribe about doing the PD-L1 testing, but then the immunologist in me questions [if] it is even that important. And the reason I say that is because PD-L1 is such a dynamic marker. There is so much going on in the microenvironment that influences PD-L1 expression. For example, if you do have an immune response, what do CD8 T cells do? Well, when they recognize something as foreign, they secrete interferon. And what does interferon do? It upregulates PD-L1. So my contention would be that the metastatic microenvironment for the patients who are on this trial and the patients we’ll see in clinic may be very different from their archival specimens.

So I think we’re going to learn more about this, and I suspect it will be this year because the KEYNOTE trial that’s looking at pembrolizumab in a very similar patient population, metastatic triple-negative breast cancer, had a little bit more rigorous of a requirement with respect to the timing of the biopsy relative to initiation of treatment. So we’ll get a little bit more information. But as a breast cancer community, we have been watching our colleagues in other histologies wrestle a bit with biomarkers. It’s now our challenge.

Hope S. Rugo, MD: Actually, this is a really important point. The other trials that we’re going to see include your own neoadjuvant trial and the pembrolizumab neoadjuvant-to-adjuvant trial, all of which will likely report in less than a year, we think.

Elizabeth A. Mittendorf, MD, PhD: Yeah, they’re mostly fully accrued, I believe.

Hope S. Rugo, MD: They’re all accrued, and maybe by the end of the year. And those trials look at PD-L1 but didn’t require PD-L1 expression, and they used different antibodies between the 2 studies. It’s going to be fascinating to see what we learn, and that may change everything.

Elizabeth A. Mittendorf, MD, PhD: You’re referring to the neoadjuvant trials. We may learn that the PD-L1 expression patterns could be quite different in that early stage disease from what we see in metastatic disease. And then I suspect we all believe, too, that PD-L1 is probably not a single biomarker. I would anticipate, and based on data that’s coming out from other histologies, that we’ll probably have multiple markers that are pulled together to have a composite biomarker, effectively.


Transcript Edited for Clarity

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Transcript: 

Joyce O’Shaughnessy, MD
: Let’s transition to triple-negative breast cancer and the interesting diagnostic now around PD-L1/2 [programmed death-ligand 1 and 2] and the new approval of atezolizumab in the metastatic setting and the locally advanced unresectable setting too, which is quite intriguing. This was a very interesting development, just yesterday. Hope, tell us about the IMpassion130 trial, if you would.

Hope S. Rugo, MD: It’s really exciting that we now have the first approval of a checkpoint inhibitor to treat metastatic triple-negative breast cancer. IMpassion130 randomized patients who had chemotherapy-naïve metastatic triple-negative breast cancer at least 12 months from an adjuvant or neoadjuvant taxane to receive nab-paclitaxel with either placebo or atezolizumab. The endpoints included progression-free survival [PFS] in the intent-to-treat population and also in the PD-L1–positive population, and overall survival in both populations as well. And the endpoints were tied to one another in kind of a funny, statistical design way. But because the differences were so big, we sort of overlooked that statistical design, which I think is clinically relevant because we don’t see changes in such a big difference.

About 60% of the patients had their PD-L1 testing done in the archival tumor samples versus metastatic tumor samples, and the PD-L1 was a specific test that I’ll let Beth talk about a little bit more in a moment. You know, you get on a call when you’re on a steering committee for these studies, right? You look for those results. You’re just waiting for that PFS. The PFS slide in intent-to-treat was a little under 2 months, and it was still significant. We thought, “That’s really a shame.” And then we saw, in the PD-L1–positive population, it was 2½ months. “Oh, that’s a little better. But still, it’s kind of small. That’s a lot of money, and there is the risk of immune-related AEs [adverse events]. Is it really worth it?”

And then we saw the overall survival data, [though] it’s still very much interim and we’re looking for the final data with more events later this year. But in the overall population, we saw a P value of .08. In the PD-L1–positive population, we saw a really impressive and never-before-seen overall survival difference of 9½ months. I think this is clinically relevant, even though there was this idea that you should see significance in intent-to-treat. Things change.

So I think that difference is really remarkable, and it looks so similar to CLEOPATRA. It’s so interesting to me that antibodies seem to change something about the tumor microenvironment regardless of what they’re targeting. Because in CLEOPATRA, there was about a 6-month difference in PFS but almost a 16-month difference in overall survival when you added pertuzumab to trastuzumab. So it’s really fascinating, and I think it really sets a new standard of care. Now we have to check PD-L1 in all our patients with metastatic triple-negative disease who aren’t refractory to taxanes. We’ll hopefully hear later this year about alternative chemotherapy partners. Really well tolerated also.

Joyce O’Shaughnessy, MD: Yeah. What about the diagnostics? How do we get the PD-L1 done here, Beth?

Elizabeth A. Mittendorf, MD, PhD: As Hope alluded to, there are differences in the trial that were most pronounced, of course, in the PD-L1–positive population. About 41% of patients in the study were PD-L1–positive. And so the approval that came out yesterday is for PD-L1–positive patients, and this is where I think there are some important details that we need to be aware of. So what is PD-L1–positive? The Genentech strategy for using PD-L1 as a biomarker has not been to look at PD-L1 expression on the tumor. Rather, they’re looking at PD-L1 expression on the immune cells.

This is very different [from] some of the other already-approved-in-other-histology agents. In addition, it’s a very specific antibody that they’ve used—SP142 and the Ventana system. And so one presumes that, in fact, that was also approved as a companion diagnostic, therefore we should be using the SP142 to look for PD-L1 expression on the immune cells. So I think this is going to be very interesting for groups when they go back to clinic next, because I don’t know that many institutions have kind of “set themselves up” to be testing this way. I think it’s going to be critically important for the breast cancer clinicians to work with their pathologist to recognize that this is a different PD-L1 test than what they might be using for their lung cancer patients.

I’ve heard a few people say, “Well, our group is going to use some other antibody that we use already” for, again, different histologies. An important study was done, not in breast cancer but in lung cancer, called the Blueprint project. I think we were chatting about this before. What the Blueprint project did was look in lung tumors using the 5 different antibodies that are available. Those antibodies correspond with each different pharmaceutical company and the drug that they’ve developed. And just cutting to the chase, what they found was that the antibodies are all pretty interchangeable if you’re looking for PD-L1 expression on the tumor—which, remember, is not what we looked at in the IMpassion130 trial.

Interestingly, even though they’re all fairly comparable, it’s the SP142 that’s a little less sensitive for PD-L1 expression on the tumor. But if they looked for PD-L1 expression on the immune cells, which is the biomarker from the IMpassion130 trial, there was a lot of discordance with the different antibodies. I point all this out because I think we, as a breast cancer community, are going to have to address this, and we’re going to have to address it first with respect to what we’re going to do with initial testing. But I also think there’s an opportunity to explore some of these other antibodies and see. I just gave the Blueprint data, but that was in lung tumors. Is it different in breast cancer? It might be worth looking at.

Hope S. Rugo, MD: And you have a project to do this?

Elizabeth A. Mittendorf, MD, PhD: Yes, we have our project to do that. Hope and I are involved with an effort that is going to be trying to get biospecimens from patients who will now be treated with these agents as their standard treatment in order to ask and answer some of these important questions that a clinical trial, perhaps, didn’t let us answer but real-world experience will.

Joyce O’Shaughnessy, MD: Does it make any difference whether it’s primary or metastatic disease? Should we try for 1 or the other, to try to find that PD-L1?

Elizabeth A. Mittendorf, MD, PhD: Well, I think that’s what Hope alluded to: That 60% of the tumors are archival. I presume that’s from the primary tumor.

Hope S. Rugo, MD: From the primary tumor, as far as we can tell.

Elizabeth A. Mittendorf, MD, PhD: Right. And so I just went through this whole diatribe about doing the PD-L1 testing, but then the immunologist in me questions [if] it is even that important. And the reason I say that is because PD-L1 is such a dynamic marker. There is so much going on in the microenvironment that influences PD-L1 expression. For example, if you do have an immune response, what do CD8 T cells do? Well, when they recognize something as foreign, they secrete interferon. And what does interferon do? It upregulates PD-L1. So my contention would be that the metastatic microenvironment for the patients who are on this trial and the patients we’ll see in clinic may be very different from their archival specimens.

So I think we’re going to learn more about this, and I suspect it will be this year because the KEYNOTE trial that’s looking at pembrolizumab in a very similar patient population, metastatic triple-negative breast cancer, had a little bit more rigorous of a requirement with respect to the timing of the biopsy relative to initiation of treatment. So we’ll get a little bit more information. But as a breast cancer community, we have been watching our colleagues in other histologies wrestle a bit with biomarkers. It’s now our challenge.

Hope S. Rugo, MD: Actually, this is a really important point. The other trials that we’re going to see include your own neoadjuvant trial and the pembrolizumab neoadjuvant-to-adjuvant trial, all of which will likely report in less than a year, we think.

Elizabeth A. Mittendorf, MD, PhD: Yeah, they’re mostly fully accrued, I believe.

Hope S. Rugo, MD: They’re all accrued, and maybe by the end of the year. And those trials look at PD-L1 but didn’t require PD-L1 expression, and they used different antibodies between the 2 studies. It’s going to be fascinating to see what we learn, and that may change everything.

Elizabeth A. Mittendorf, MD, PhD: You’re referring to the neoadjuvant trials. We may learn that the PD-L1 expression patterns could be quite different in that early stage disease from what we see in metastatic disease. And then I suspect we all believe, too, that PD-L1 is probably not a single biomarker. I would anticipate, and based on data that’s coming out from other histologies, that we’ll probably have multiple markers that are pulled together to have a composite biomarker, effectively.


Transcript Edited for Clarity
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