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Developments in Chemotherapy for HR+ mBC

Panelists: Joyce A. OShaughnessy, MD, Baylor-Sammons Cancer Center; Andrew D. Seidman, MD, Memorial Sloan Kettering Cancer Center
Published: Tuesday, Dec 04, 2018



Transcript:

Andrew D. Seidman, MD: So, Joyce, one of the reports from ASCO [American Society of Clinical Oncology] that caught my attention, this is  thematic with the question of what to do when you progress on endocrine therapy. We’ve got all of our chemotherapeutic agents to choose from. Aditya Bardia presented some interesting data on a novel agent, particularly in the ER [estrogen receptor]-positive population. Maybe you can speak to that a little bit.

Joyce A. O’Shaughnessy, MD: Yes, that was very nice. I think we’re all getting very excited about sacituzumab, SACI for short.

Andrew D. Seidman, MD: SACI.

Joyce A. O’Shaughnessy, MD: SACI, because I wasn’t sure if it was ‘sakituzumab’ but it’s sacituzumab. It’s SACI.

Andrew D. Seidman, MD: Govitecan.

Joyce A. O’Shaughnessy, MD: Which is an SN-38 payload, so the active moiety of irinotecan. Its approximately 7 molecules of SN-38 hooked up to each antibody against the antigen TROP2, which is very ubiquitous in triple-negative and ER-positive breast cancer. We don’t have to even screen for it. Patients were not selected for these trials, and they were a heavily pretreated group of patients, whether they be triple-negative or not. And then, as you said, at ASCO, we heard about the HER2-positive, HER2-negative cohort. And the sacituzumab is given IV [intravenous] days 1 and 8 on a 21-day cycle, and it has myelosuppression as a major side effect; some diarrhea, but less than we certainly see with irinotecan; fatigue; and some mild alopecia. But in a heavily pretreated population in the ER-positive setting, the response rate was in the 30% to 35% range, similar to what we saw in a heavily pretreated triple-negative population as well. In the triple-negative population, the median PFS [progression-free survival] was a surprising 8 months or something like that. In the triple-negative heavily pretreated population, that was really amazing. But the waterfall plots look terrific with this agent.

Andrew D. Seidman, MD: Yes, so people sometimes refer to Kadcyla (trastuzumab emtansine), a T-DM1, as a smart bomb. So, here we’ve got perhaps the second antibody-drug conjugate that may be closest to widespread use in breast cancer. Do you think it’s smart and also in terms of toxicity sparing? I’ve used irinotecan. Edith Perez published this paper years ago comparing weekly with Q3 weekly irinotecan. And it’s a drug that I sometimes will use in the salvage setting. To me, this certainly seems to be a kinder, gentler agent than using irinotecan.

Joyce A. O’Shaughnessy, MD: That’s my impression, Andy. I had a patient on 15 months of sacituzumab, a very heavily pretreated woman, and I think that really is the key. I’ve used irinotecan, too, because it is really noncross resistant, and I always wished we could have a formulation of it or an FDA [Food and Drug Administration] approval and get it on the NCCN [National Comprehensive Cancer Network] guidelines, which it isn’t at present. But the thing I think about with the irinotecan is I find I keep dose reducing or spreading out the treatment interval because of toxicity. It’s just harder to get it in, particularly cumulatively. It’s very, very fatiguing. So, I think this has a better therapeutic index. If patients are benefitting, obviously, some people need dose reductions for myelosuppression in particular. But once you get them there, they can ride it, you know what I mean? And I think that’s really the key. So, I think it’s similar to the ado-trastuzumab emtansine, the T-DM1, yes.

Andrew D. Seidman, MD: That’s a big word, ado-trastuzumab.

Joyce A. O’Shaughnessy, MD: Yes.

Andrew D. Seidman, MD: Are there any other drugs, any other agents, that you’ve got your eye on not necessarily in the ER-positive space but for patients progressing on endocrine therapy?

Joyce A. O’Shaughnessy, MD: Well, you and I are both very involved in the development of tesetaxel, which I think is a really interesting agent. And this is a novel oral taxane formulation. And I think this comes at a time that is good because I’ll tell you, I’m increasingly reluctant to get to IV chemotherapy. It’s like, “Oh no, there has got to be another oral agent!” I find myself really digging deep to try to keep the women on oral agents these days.

Andrew D. Seidman, MD: So, for that 61-year-old woman who has had her 2-and-a-half years on AIs [aromatase inhibitors] and CDK4/6 inhibitors, and then you played the fulvestrant card and the exemestane/everolimus card, now she not only has 8 or 10 bone lesions and she needs more than just acetaminophen and ibuprofen, and maybe she has a couple of pulmonary nodules, you’re ready to make that leap to chemotherapy. Where do you go next and why?

Joyce A. O’Shaughnessy, MD: I always go to capecitabine. My definition of visceral crisis is getting more severe, if you will, in terms of bringing out combination chemotherapy. Someone would have to have very rapidly proliferative, very heavy tumor burden disease, particularly in the liver or lungs, for me to bring out a combination with capecitabine. Of course, we use a taxane.

Andrew D. Seidman, MD: Didn’t you study this regimen called docetaxel/capecitabine once upon a time?

Joyce A. O’Shaughnessy, MD: I did.

Andrew D. Seidman, MD: And it led to an FDA approval.

Joyce A. O’Shaughnessy, MD: Yes, yes.

Andrew D. Seidman, MD: So, that’s not what you go to first. You don’t give docetaxel/capecitabine to that woman that I just described.

Joyce A. O’Shaughnessy, MD: No, not to your woman. I also like the vinorelbine because you don’t get the hair loss, and I find that you can, for those patients with the most severe disease, even keep the doublet going for patients. Because if I do a doublet and I salvage somebody then I’m like, “Well, gee, were both drugs working, or can I stop the IV  and keep going with capecitabine?”, and I can’t always do that, I have found, when I stop the IV. So, I reluctantly do, but sometimes you have to use a doublet. But, otherwise, I go to capecitabine and learned how to try to keep the dose intensity as high as you can. I try to use as many pills as I can in that 2-week period. You guys may use some 7 days on, 7 days off. Maybe you could update me on what you’re doing.

Andrew D. Seidman, MD: Yes, we prefer the regimen that Tiffany Traina developed in terms of 7 days on, 7 days off. Granted, there are no data from a randomized trial yet comparing it with 14 days on and 7 days off. But we do think it seems to be as effective. You run into hand-foot syndrome and diarrhea, if at all, much, much later on.

Joyce A. O’Shaughnessy, MD: But you will use a higher dose, don’t you, Andy, in the…

Andrew D. Seidman, MD: Yes, for the average size woman. And I have to confess, I can’t remember the last time I prescribed the 150 mg tablet of capecitabine. But for the average size woman, I tend to start with 1500 mg/m2 orally, twice a day, 7 days on, 7 days off. And for a larger-looking woman, I’ll give her 2000 mg/m2, so 8, 4, 4, and 4.

Joyce A. O’Shaughnessy, MD: In Tiffany’s work that you guys did at Memorial Sloan Kettering Cancer Center, you could go up on the dose, couldn’t you, on the 7 days on, 7 days off?

Andrew D. Seidman, MD: Yes.

Joyce A. O’Shaughnessy, MD: I think they got up to 8 or 9 pills a day or something, as I recall.

Andrew D. Seidman, MD: Right. So, I try not to scare patients away early on.

Transcript Edited for Clarity 

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Transcript:

Andrew D. Seidman, MD: So, Joyce, one of the reports from ASCO [American Society of Clinical Oncology] that caught my attention, this is  thematic with the question of what to do when you progress on endocrine therapy. We’ve got all of our chemotherapeutic agents to choose from. Aditya Bardia presented some interesting data on a novel agent, particularly in the ER [estrogen receptor]-positive population. Maybe you can speak to that a little bit.

Joyce A. O’Shaughnessy, MD: Yes, that was very nice. I think we’re all getting very excited about sacituzumab, SACI for short.

Andrew D. Seidman, MD: SACI.

Joyce A. O’Shaughnessy, MD: SACI, because I wasn’t sure if it was ‘sakituzumab’ but it’s sacituzumab. It’s SACI.

Andrew D. Seidman, MD: Govitecan.

Joyce A. O’Shaughnessy, MD: Which is an SN-38 payload, so the active moiety of irinotecan. Its approximately 7 molecules of SN-38 hooked up to each antibody against the antigen TROP2, which is very ubiquitous in triple-negative and ER-positive breast cancer. We don’t have to even screen for it. Patients were not selected for these trials, and they were a heavily pretreated group of patients, whether they be triple-negative or not. And then, as you said, at ASCO, we heard about the HER2-positive, HER2-negative cohort. And the sacituzumab is given IV [intravenous] days 1 and 8 on a 21-day cycle, and it has myelosuppression as a major side effect; some diarrhea, but less than we certainly see with irinotecan; fatigue; and some mild alopecia. But in a heavily pretreated population in the ER-positive setting, the response rate was in the 30% to 35% range, similar to what we saw in a heavily pretreated triple-negative population as well. In the triple-negative population, the median PFS [progression-free survival] was a surprising 8 months or something like that. In the triple-negative heavily pretreated population, that was really amazing. But the waterfall plots look terrific with this agent.

Andrew D. Seidman, MD: Yes, so people sometimes refer to Kadcyla (trastuzumab emtansine), a T-DM1, as a smart bomb. So, here we’ve got perhaps the second antibody-drug conjugate that may be closest to widespread use in breast cancer. Do you think it’s smart and also in terms of toxicity sparing? I’ve used irinotecan. Edith Perez published this paper years ago comparing weekly with Q3 weekly irinotecan. And it’s a drug that I sometimes will use in the salvage setting. To me, this certainly seems to be a kinder, gentler agent than using irinotecan.

Joyce A. O’Shaughnessy, MD: That’s my impression, Andy. I had a patient on 15 months of sacituzumab, a very heavily pretreated woman, and I think that really is the key. I’ve used irinotecan, too, because it is really noncross resistant, and I always wished we could have a formulation of it or an FDA [Food and Drug Administration] approval and get it on the NCCN [National Comprehensive Cancer Network] guidelines, which it isn’t at present. But the thing I think about with the irinotecan is I find I keep dose reducing or spreading out the treatment interval because of toxicity. It’s just harder to get it in, particularly cumulatively. It’s very, very fatiguing. So, I think this has a better therapeutic index. If patients are benefitting, obviously, some people need dose reductions for myelosuppression in particular. But once you get them there, they can ride it, you know what I mean? And I think that’s really the key. So, I think it’s similar to the ado-trastuzumab emtansine, the T-DM1, yes.

Andrew D. Seidman, MD: That’s a big word, ado-trastuzumab.

Joyce A. O’Shaughnessy, MD: Yes.

Andrew D. Seidman, MD: Are there any other drugs, any other agents, that you’ve got your eye on not necessarily in the ER-positive space but for patients progressing on endocrine therapy?

Joyce A. O’Shaughnessy, MD: Well, you and I are both very involved in the development of tesetaxel, which I think is a really interesting agent. And this is a novel oral taxane formulation. And I think this comes at a time that is good because I’ll tell you, I’m increasingly reluctant to get to IV chemotherapy. It’s like, “Oh no, there has got to be another oral agent!” I find myself really digging deep to try to keep the women on oral agents these days.

Andrew D. Seidman, MD: So, for that 61-year-old woman who has had her 2-and-a-half years on AIs [aromatase inhibitors] and CDK4/6 inhibitors, and then you played the fulvestrant card and the exemestane/everolimus card, now she not only has 8 or 10 bone lesions and she needs more than just acetaminophen and ibuprofen, and maybe she has a couple of pulmonary nodules, you’re ready to make that leap to chemotherapy. Where do you go next and why?

Joyce A. O’Shaughnessy, MD: I always go to capecitabine. My definition of visceral crisis is getting more severe, if you will, in terms of bringing out combination chemotherapy. Someone would have to have very rapidly proliferative, very heavy tumor burden disease, particularly in the liver or lungs, for me to bring out a combination with capecitabine. Of course, we use a taxane.

Andrew D. Seidman, MD: Didn’t you study this regimen called docetaxel/capecitabine once upon a time?

Joyce A. O’Shaughnessy, MD: I did.

Andrew D. Seidman, MD: And it led to an FDA approval.

Joyce A. O’Shaughnessy, MD: Yes, yes.

Andrew D. Seidman, MD: So, that’s not what you go to first. You don’t give docetaxel/capecitabine to that woman that I just described.

Joyce A. O’Shaughnessy, MD: No, not to your woman. I also like the vinorelbine because you don’t get the hair loss, and I find that you can, for those patients with the most severe disease, even keep the doublet going for patients. Because if I do a doublet and I salvage somebody then I’m like, “Well, gee, were both drugs working, or can I stop the IV  and keep going with capecitabine?”, and I can’t always do that, I have found, when I stop the IV. So, I reluctantly do, but sometimes you have to use a doublet. But, otherwise, I go to capecitabine and learned how to try to keep the dose intensity as high as you can. I try to use as many pills as I can in that 2-week period. You guys may use some 7 days on, 7 days off. Maybe you could update me on what you’re doing.

Andrew D. Seidman, MD: Yes, we prefer the regimen that Tiffany Traina developed in terms of 7 days on, 7 days off. Granted, there are no data from a randomized trial yet comparing it with 14 days on and 7 days off. But we do think it seems to be as effective. You run into hand-foot syndrome and diarrhea, if at all, much, much later on.

Joyce A. O’Shaughnessy, MD: But you will use a higher dose, don’t you, Andy, in the…

Andrew D. Seidman, MD: Yes, for the average size woman. And I have to confess, I can’t remember the last time I prescribed the 150 mg tablet of capecitabine. But for the average size woman, I tend to start with 1500 mg/m2 orally, twice a day, 7 days on, 7 days off. And for a larger-looking woman, I’ll give her 2000 mg/m2, so 8, 4, 4, and 4.

Joyce A. O’Shaughnessy, MD: In Tiffany’s work that you guys did at Memorial Sloan Kettering Cancer Center, you could go up on the dose, couldn’t you, on the 7 days on, 7 days off?

Andrew D. Seidman, MD: Yes.

Joyce A. O’Shaughnessy, MD: I think they got up to 8 or 9 pills a day or something, as I recall.

Andrew D. Seidman, MD: Right. So, I try not to scare patients away early on.

Transcript Edited for Clarity 
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