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Adjuvant TDM-1 and the KRISTINE Trial

Panelists:Adam M. Brufsky, MD, PhD, University of Pittsburgh Cancer Institute;Carlos L. Arteaga, MD, Vanderbilt University;Kimberly L. Blackwell, MD, Duke University Medical Center;Joyce A. O’Shaughnessy, MD, Baylor Charles A. Sammons Cancer Center;Sunil Verma, MD, MSEd, FRCPC, University of Calgary
Published: Tuesday, Aug 02, 2016


Transcript:

Adam M. Brufsky, MD, PhD:
There was a very interesting neoadjuvant abstract with T-DM1 (trastuzumab emtansine) that I want to talk about. But before we do that, I want to know, what is T-DM1? Is it a cytotoxic or is it an anti-HER agent? Carlos, what do you think?

Carlos L. Arteaga, MD: It’s both.

Adam M. Brufsky, MD, PhD: Which is more, or it’s the same? I’m trying to figure that out. I just don’t know the answer to that one.

Carlos L. Arteaga, MD: I think it’s targeted chemotherapy, but I think it also retains the antibody properties, albeit at a lower molarity.

Adam M. Brufsky, MD, PhD: That’s the point.

Carlos L. Arteaga, MD: But, in the lab, you can show that it does antibody-dependent cell-mediated cytotoxicity. So, it started as chemotherapy. It’s probably working mainly by the cytotoxic effect of DM1. It will be interesting to see what happens when tumors bypass DM1, bypass T-DM1. Are they bypassing DM1 or are they bypassing T? And we have some anecdotal observations in our practice that some patients—upon progression of T-DM1, upon rebiopsy—they don’t have any HER2 gene amplification detectable anymore. In talking to colleagues, it’s something that others have seen, but we need more information.

Adam M. Brufsky, MD, PhD: And we’ll touch on that in a few minutes when we talk about HER2 mutations in a few minutes. But I think before we get that, let’s talk a little bit just briefly about the KRISTINE trial. Does someone want to take that one?

Sunil Verma, MD, MSEd, FRCPC: Yes. So, KRISTINE is presented by Sara Hurvitz and is an important study because it’s taking a look at this concept of can we go chemotherapy-free. They looked at T-DM1/pertuzumab versus BCIRG-006 trial’s TCHP (docetaxel, carboplatin, trastuzumab, pertuzumab) regimen. And what it showed was that the pCR (pathologic complete response) rates were roughly about the same, a little bit higher in the TCHP. It was around 55% versus around 50%.

Joyce A. O’Shaughnessy, MD: Forty-four.

Sunil Verma, MD, MSEd, FRCPC: Forty-four percent. So, the TCHP wins out. More women were able to get breast conserving surgery. Coming back to that, if you take a look at equivalence, who were those patients, who with T-DM1/pertuzumab, 44% of which had a complete pCR? This is very in line with what the German group—the ADAPT trial—showed; a pCR rate, with T-DM1, alone of 40%. Who are those women and men who have HER2-positive disease—in some cases, locally advanced breast cancer—where you can give, and in Germany, it was four, shots of T-DM1? Here, it was six shots of T-DM1 plus pertuzumab. And about 40% of these patients will get complete pathological response.

If you could figure that out, if you could get a biomarker, and if we can then follow these patients, they may not be any of these patients who need chemotherapy. I think that, to me, is going to be the most important question that we need to now take in the adjuvant setting. It’s not who we can add on more treatments to, who we can give pertuzumab and the next generation of anti-HER2 therapies to, but how do we de-escalate our treatments to your point where we can actually give an ADC (antibody-drug conjugate) alone to certain women, and get a complete pathologic response, and maybe forego chemotherapy?

Carlos L. Arteaga, MD: I think you are talking about the ER-positive subgroup, I believe, right?

Sunil Verma, MD, MSEd, FRCPC: Those were ER-positive, but in KRISTINE, they’re all-comers, right?

Carlos L. Arteaga, MD: Correct. But in the ER-positive subgroup, that’s a disease that we know biologically doesn’t die quickly. So, could it be that even if we prolong the neoadjuvant therapy because it was well-tolerated, we may even see a better pathologic complete response rate—which is that surrogate you’re seeking, right—to call the therapy effective?

Sunil Verma, MD, MSEd, FRCPC: That’s right. What’s interesting about surrogacy there is that we have all established surrogacy in the context of chemotherapy and anti-HER2 therapy when we take a look at it.

Carlos L. Arteaga, MD: Good point.

Sunil Verma, MD, MSEd, FRCPC: But can we establish the same surrogacy when we are just giving a biological targeted agent? And is the meaning of surrogacy the same and the correlation the same? We just don’t know.

Carlos L. Arteaga, MD: Well, if you use the same length of therapy, it may not be necessarily.

Kimberly L. Blackwell, MD: Yes, and I think the take-home message is—at least in ER-negative patients—you still need some chemotherapy with your trastuzumab. And we know carboplatin plays a large role in ER-negative HER2-driven breast cancer. So, I think the take-home message that I’ll leave the meeting with is I’m going to still go back to my TCHP regimen in the neoadjuvant setting for those.

Adam M. Brufsky, MD, PhD: Me, too, for the time being.

Kimberly L. Blackwell, MD: For those of us who don’t think about biology on a day-to-day basis because we’re seeing so many patients, TCHP will still be my go-to. I think that’s the take-home message, and that’s unfortunate because I still think there’s so much excitement about using T-DM1 in the early-stage setting. Imagine the day when that’s all you have to give your patient, if we could sort that out.

Joyce A. O’Shaughnessy, MD: Yes, and I totally agree in the ER-negative subset in particular. It was a big differential between the TCHP and the T-DM1/P, but in the ER-positive, it wasn’t that big of a differential. It was still in favor of TCHP, but not that much. It’s very intriguing that we can kind of sneak up on some patients with just the T-DM1 and perhaps do the stress test, and see if they really get the pCR.

Kimberly L. Blackwell, MD: I’m excited about combining T-DM1 with the immunotherapies. I actually think we’ll see something there in ER-positive patients.

Sunil Verma, MD, MSEd, FRCPC: Yes, I was just thinking about that, Kim. And so there’s a metastatic trial ongoing with a checkpoint inhibitor plus T-DM1, and I think coming to the point that you were raising before, there still is potentiation of ADCC (antibody-dependent cell-mediated cytotoxicity) with T-DM1. There’s still that cell cytotoxic effect that is going to actually help generate an immune response. And if we could potentiate that by adding immune therapy, I think that’s very exciting.

Carlos L. Arteaga, MD: I was a bit surprised about the magnitude of the difference in KRISTINE in favor of TCHP unless there’s de novo resistance to DM1, which is a possibility. I think this speaks to that we may have underappreciated heterogeneity of breast cancer to begin with.

Sunil Verma, MD, MSEd, FRCPC: I think there is the heterogeneity that you can overlap and coverage through other chemotherapy that you don’t get with a direct kill.

Carlos L. Arteaga, MD: Correct.

Kimberly L. Blackwell, MD: Yes, exactly. And it might just be as simple as just HER2 expression.

Adam M. Brufsky, MD, PhD: Possibly.

Kimberly L. Blackwell, MD: I’d like to think it’s that possible.

Transcript Edited for Clarity
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Transcript:

Adam M. Brufsky, MD, PhD:
There was a very interesting neoadjuvant abstract with T-DM1 (trastuzumab emtansine) that I want to talk about. But before we do that, I want to know, what is T-DM1? Is it a cytotoxic or is it an anti-HER agent? Carlos, what do you think?

Carlos L. Arteaga, MD: It’s both.

Adam M. Brufsky, MD, PhD: Which is more, or it’s the same? I’m trying to figure that out. I just don’t know the answer to that one.

Carlos L. Arteaga, MD: I think it’s targeted chemotherapy, but I think it also retains the antibody properties, albeit at a lower molarity.

Adam M. Brufsky, MD, PhD: That’s the point.

Carlos L. Arteaga, MD: But, in the lab, you can show that it does antibody-dependent cell-mediated cytotoxicity. So, it started as chemotherapy. It’s probably working mainly by the cytotoxic effect of DM1. It will be interesting to see what happens when tumors bypass DM1, bypass T-DM1. Are they bypassing DM1 or are they bypassing T? And we have some anecdotal observations in our practice that some patients—upon progression of T-DM1, upon rebiopsy—they don’t have any HER2 gene amplification detectable anymore. In talking to colleagues, it’s something that others have seen, but we need more information.

Adam M. Brufsky, MD, PhD: And we’ll touch on that in a few minutes when we talk about HER2 mutations in a few minutes. But I think before we get that, let’s talk a little bit just briefly about the KRISTINE trial. Does someone want to take that one?

Sunil Verma, MD, MSEd, FRCPC: Yes. So, KRISTINE is presented by Sara Hurvitz and is an important study because it’s taking a look at this concept of can we go chemotherapy-free. They looked at T-DM1/pertuzumab versus BCIRG-006 trial’s TCHP (docetaxel, carboplatin, trastuzumab, pertuzumab) regimen. And what it showed was that the pCR (pathologic complete response) rates were roughly about the same, a little bit higher in the TCHP. It was around 55% versus around 50%.

Joyce A. O’Shaughnessy, MD: Forty-four.

Sunil Verma, MD, MSEd, FRCPC: Forty-four percent. So, the TCHP wins out. More women were able to get breast conserving surgery. Coming back to that, if you take a look at equivalence, who were those patients, who with T-DM1/pertuzumab, 44% of which had a complete pCR? This is very in line with what the German group—the ADAPT trial—showed; a pCR rate, with T-DM1, alone of 40%. Who are those women and men who have HER2-positive disease—in some cases, locally advanced breast cancer—where you can give, and in Germany, it was four, shots of T-DM1? Here, it was six shots of T-DM1 plus pertuzumab. And about 40% of these patients will get complete pathological response.

If you could figure that out, if you could get a biomarker, and if we can then follow these patients, they may not be any of these patients who need chemotherapy. I think that, to me, is going to be the most important question that we need to now take in the adjuvant setting. It’s not who we can add on more treatments to, who we can give pertuzumab and the next generation of anti-HER2 therapies to, but how do we de-escalate our treatments to your point where we can actually give an ADC (antibody-drug conjugate) alone to certain women, and get a complete pathologic response, and maybe forego chemotherapy?

Carlos L. Arteaga, MD: I think you are talking about the ER-positive subgroup, I believe, right?

Sunil Verma, MD, MSEd, FRCPC: Those were ER-positive, but in KRISTINE, they’re all-comers, right?

Carlos L. Arteaga, MD: Correct. But in the ER-positive subgroup, that’s a disease that we know biologically doesn’t die quickly. So, could it be that even if we prolong the neoadjuvant therapy because it was well-tolerated, we may even see a better pathologic complete response rate—which is that surrogate you’re seeking, right—to call the therapy effective?

Sunil Verma, MD, MSEd, FRCPC: That’s right. What’s interesting about surrogacy there is that we have all established surrogacy in the context of chemotherapy and anti-HER2 therapy when we take a look at it.

Carlos L. Arteaga, MD: Good point.

Sunil Verma, MD, MSEd, FRCPC: But can we establish the same surrogacy when we are just giving a biological targeted agent? And is the meaning of surrogacy the same and the correlation the same? We just don’t know.

Carlos L. Arteaga, MD: Well, if you use the same length of therapy, it may not be necessarily.

Kimberly L. Blackwell, MD: Yes, and I think the take-home message is—at least in ER-negative patients—you still need some chemotherapy with your trastuzumab. And we know carboplatin plays a large role in ER-negative HER2-driven breast cancer. So, I think the take-home message that I’ll leave the meeting with is I’m going to still go back to my TCHP regimen in the neoadjuvant setting for those.

Adam M. Brufsky, MD, PhD: Me, too, for the time being.

Kimberly L. Blackwell, MD: For those of us who don’t think about biology on a day-to-day basis because we’re seeing so many patients, TCHP will still be my go-to. I think that’s the take-home message, and that’s unfortunate because I still think there’s so much excitement about using T-DM1 in the early-stage setting. Imagine the day when that’s all you have to give your patient, if we could sort that out.

Joyce A. O’Shaughnessy, MD: Yes, and I totally agree in the ER-negative subset in particular. It was a big differential between the TCHP and the T-DM1/P, but in the ER-positive, it wasn’t that big of a differential. It was still in favor of TCHP, but not that much. It’s very intriguing that we can kind of sneak up on some patients with just the T-DM1 and perhaps do the stress test, and see if they really get the pCR.

Kimberly L. Blackwell, MD: I’m excited about combining T-DM1 with the immunotherapies. I actually think we’ll see something there in ER-positive patients.

Sunil Verma, MD, MSEd, FRCPC: Yes, I was just thinking about that, Kim. And so there’s a metastatic trial ongoing with a checkpoint inhibitor plus T-DM1, and I think coming to the point that you were raising before, there still is potentiation of ADCC (antibody-dependent cell-mediated cytotoxicity) with T-DM1. There’s still that cell cytotoxic effect that is going to actually help generate an immune response. And if we could potentiate that by adding immune therapy, I think that’s very exciting.

Carlos L. Arteaga, MD: I was a bit surprised about the magnitude of the difference in KRISTINE in favor of TCHP unless there’s de novo resistance to DM1, which is a possibility. I think this speaks to that we may have underappreciated heterogeneity of breast cancer to begin with.

Sunil Verma, MD, MSEd, FRCPC: I think there is the heterogeneity that you can overlap and coverage through other chemotherapy that you don’t get with a direct kill.

Carlos L. Arteaga, MD: Correct.

Kimberly L. Blackwell, MD: Yes, exactly. And it might just be as simple as just HER2 expression.

Adam M. Brufsky, MD, PhD: Possibly.

Kimberly L. Blackwell, MD: I’d like to think it’s that possible.

Transcript Edited for Clarity
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