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HR+ mBC: Oral Formulations of Docetaxel and Paclitaxel

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: Right. So, tesetaxel is not alone in the landscape of oral taxanes. There are some other agents that are different formulations of paclitaxel, more so than new novel taxanes. You want to comment a little bit about that?

Joyce A. O’Shaughnessy, MD: Yes. I was interested in this DHP107. It was in JCO [Journal of Clinical Oncology] in 2017 by Kang and colleagues. It’s paclitaxel but it’s lipid formulated and orally bioavailable. And there has been a phase III trial in gastric cancer in patients who were getting second-line therapy versus IV [intravenous] paclitaxel and it was a noninferiority design. And, indeed, it met its noninferiority endpoint. So, that’s really interesting but probably should lead to approval for that patient population. It’s paclitaxel, so it’s just a way to avoid the IV. And then there’s Oraxol by Athenex, which is paclitaxel mixed with a PGP inhibitor?

Andrew D. Seidman, MD: It’s paclitaxel given with a separate entity that are oral pills, which is a proprietary p-glycoprotein [PGP] inhibitor. So, the idea is that it inhibits PGP activity in the GI [gastrointestinal] mucosa. It allows paclitaxel to be absorbed more, so this is another agent that is in development. In breast cancer, it is going up against IV paclitaxel, which is a brave thing to do.

Joyce A. O’Shaughnessy, MD: Yes, again, with a clear idea of trying to displace the IV paclitaxel by giving paclitaxel but making it orally bioavailable with the PGP inhibitor.

Andrew D. Seidman, MD: So, different than tesetaxel, which has intrinsic lack of being a PGP substrate.

Joyce A. O’Shaughnessy, MD: Yes, exactly and this wonderful long half-life that is fabulous.

Andrew D. Seidman, MD: In the late 1990s when I was just a puppy, I was doing a study of an agent called VX-710. So, Vertex Pharmaceuticals had a PGP inhibitor that was parenteral that we were giving with paclitaxel in patients who had just progressed on paclitaxel. And it wasn’t a home run. It was hardly a base hit but then it never made it. But there has clearly been interest in this as a strategy to improve paclitaxel activity, and now certainly by trying to improve its oral bioavailability. So, interesting that we keep chopping away at this. There are other taxanes, too. There’s an oral version of docetaxel.

Joyce A. O’Shaughnessy, MD: Yes, yes. And that one’s through the phase I. It was a published study in 2017. ModraDoc001, so that’s through phase I. And then Spectrum Pharmaceutical also has ortataxel, which is also a paclitaxel that overcomes PGP. There’s an oral taxane that overcomes PGP resistance, and that they looked at in glioblastoma. So, there’s a number of other agents out there, particularly the DHP107 has phase III data already with the gastric. But, clearly, the CONTESSA will be the first phase III in breast cancer.

Andrew D. Seidman, MD: I just thought of another novel endpoint. I should have put this in the paper. We talked about time to chemotherapy. How about time to needing to drive to Manhattan, park my car, and go into your IV infusion room? So, this is time to parenteral chemotherapy that could conceivably be altered. These are ER [estrogen receptor]-positive patients who may spend years on endocrine therapy and then hopefully a period of time on oral agents before they ever need to see parenteral chemotherapy. So, paradigm shift.

Joyce A. O’Shaughnessy, MD: Yes, absolutely. Well, Andy, thank you so much. It has been really fun talking to you.

Andrew D. Seidman, MD: As always.

Joyce A. O’Shaughnessy, MD: We’ll have to keep doing this. We’ve been doing this for a lot of years but thank you very much; very interesting conversation. I hope this has been interesting and useful to you for your practice. Thank you very much for joining us.

Transcript Edited for Clarity

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Transcript: 

Andrew D. Seidman, MD: Right. So, tesetaxel is not alone in the landscape of oral taxanes. There are some other agents that are different formulations of paclitaxel, more so than new novel taxanes. You want to comment a little bit about that?

Joyce A. O’Shaughnessy, MD: Yes. I was interested in this DHP107. It was in JCO [Journal of Clinical Oncology] in 2017 by Kang and colleagues. It’s paclitaxel but it’s lipid formulated and orally bioavailable. And there has been a phase III trial in gastric cancer in patients who were getting second-line therapy versus IV [intravenous] paclitaxel and it was a noninferiority design. And, indeed, it met its noninferiority endpoint. So, that’s really interesting but probably should lead to approval for that patient population. It’s paclitaxel, so it’s just a way to avoid the IV. And then there’s Oraxol by Athenex, which is paclitaxel mixed with a PGP inhibitor?

Andrew D. Seidman, MD: It’s paclitaxel given with a separate entity that are oral pills, which is a proprietary p-glycoprotein [PGP] inhibitor. So, the idea is that it inhibits PGP activity in the GI [gastrointestinal] mucosa. It allows paclitaxel to be absorbed more, so this is another agent that is in development. In breast cancer, it is going up against IV paclitaxel, which is a brave thing to do.

Joyce A. O’Shaughnessy, MD: Yes, again, with a clear idea of trying to displace the IV paclitaxel by giving paclitaxel but making it orally bioavailable with the PGP inhibitor.

Andrew D. Seidman, MD: So, different than tesetaxel, which has intrinsic lack of being a PGP substrate.

Joyce A. O’Shaughnessy, MD: Yes, exactly and this wonderful long half-life that is fabulous.

Andrew D. Seidman, MD: In the late 1990s when I was just a puppy, I was doing a study of an agent called VX-710. So, Vertex Pharmaceuticals had a PGP inhibitor that was parenteral that we were giving with paclitaxel in patients who had just progressed on paclitaxel. And it wasn’t a home run. It was hardly a base hit but then it never made it. But there has clearly been interest in this as a strategy to improve paclitaxel activity, and now certainly by trying to improve its oral bioavailability. So, interesting that we keep chopping away at this. There are other taxanes, too. There’s an oral version of docetaxel.

Joyce A. O’Shaughnessy, MD: Yes, yes. And that one’s through the phase I. It was a published study in 2017. ModraDoc001, so that’s through phase I. And then Spectrum Pharmaceutical also has ortataxel, which is also a paclitaxel that overcomes PGP. There’s an oral taxane that overcomes PGP resistance, and that they looked at in glioblastoma. So, there’s a number of other agents out there, particularly the DHP107 has phase III data already with the gastric. But, clearly, the CONTESSA will be the first phase III in breast cancer.

Andrew D. Seidman, MD: I just thought of another novel endpoint. I should have put this in the paper. We talked about time to chemotherapy. How about time to needing to drive to Manhattan, park my car, and go into your IV infusion room? So, this is time to parenteral chemotherapy that could conceivably be altered. These are ER [estrogen receptor]-positive patients who may spend years on endocrine therapy and then hopefully a period of time on oral agents before they ever need to see parenteral chemotherapy. So, paradigm shift.

Joyce A. O’Shaughnessy, MD: Yes, absolutely. Well, Andy, thank you so much. It has been really fun talking to you.

Andrew D. Seidman, MD: As always.

Joyce A. O’Shaughnessy, MD: We’ll have to keep doing this. We’ve been doing this for a lot of years but thank you very much; very interesting conversation. I hope this has been interesting and useful to you for your practice. Thank you very much for joining us.

Transcript Edited for Clarity
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