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Tesetaxel: An Oral Taxane 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, this brings us to maybe the next big thing: 1994 was when paclitaxel was approved for breast cancer, 24 years ago. And not despite the lack of interest or work, we don’t have an oral taxane. Tell us about tesetaxel. How does it work? What are some potential advantages to this drug? And what do we know about it?

Joyce A. O’Shaughnessy, MD: Yes. It’s really interesting because there’s a number of oral taxanes out there. You know, there has been a big interest in this for a long time. I just think it has taken some time for some of these formulations to actually get legs, get some traction. Tesetaxel is a novel taxane. So, it’s not just paclitaxel put into a formulation that can withstand the stomach acid, such as a lipid formulation, it’s a novel taxane. It has the same taxane structure, but it has 2 moieties that are nitrogen-based, specifically to help oral bioavailability, which is quite good. About 50% to 60% of the tesetaxel is orally bioavailable compared with low single digits for the other taxanes or one is 18% for docetaxel and maybe 6% for paclitaxel or something.

But also, it’s not a substrate for p-glycoprotein [PGP], which is so important with regard to oral absorption but also, of course, some of our more resistant cancers that really have upregulation of the PGP and resistance on that basis. And also, this agent is very interesting to me because it has a really long half-life, over 8 days. And for the other taxanes, both paclitaxel and docetaxel, it’s about 11 hours, so much longer half-life, which lends itself to every-3-weekly administration. There has been some work looking at weekly, and I think there’s probably more exploration to be done there over time. But with an 8-hour half-life, it really leads itself to an every-3-week dosing interval.

Andrew D. Seidman, MD: Yes. So, in the trial that we collaborated in—and I wish Lee Schwartzberg were here to be sitting with us because Lee was also very important in that trial—we studied this drug on an every-3-week basis. And I can’t think of too many other examples where an oral agent caused tumor regression dosed every 3 weeks. I’m sure there might be other drugs in other disease entities. But with an oral agent every 3 weeks in the phase II trial that we presented at the 2017 ASCO Annual Meeting, we see 44% of patients responding to every-3-week dosing. And we did study some weekly dosing as well.  There didn’t seem to be any advantage.

Joyce A. O’Shaughnessy, MD: Be any better, right, any real advantage there. Yes, those are really exciting data to see with pills just once every 3 weeks leading to a response rate 44%. The waterfall plot is very, very impressive because very few patients progressed, I mean just a few, and everybody had some reduction in tumor volume. Whether it made the formal PR [partial response] of 44%, but others also had prolonged stable disease. So, it was very, very highly active.

Andrew D. Seidman, MD: Yes, at a tesetaxel dose of 27 mg/m2, the pill burden is quite modest, so patients aren’t taking 10 or 12 pills a day. There’s no chromophore, there’s no polysorbate, so hypersensitivity reactions weren’t common, weren’t observed. There’s less neuropathy because we don’t have a direct comparison, and some neutropenia, not a whole lot. So, this was interesting. You may know something about the history of this molecule in terms of…

Joyce A. O’Shaughnessy, MD: Yes, it was initially developed a few years back in the phase I setting. We actually participated in some of the early phase I/II to work with it, and I think it was also, of course, developed in gastric cancer as well. So, there was some initial interest and development, but then it changed hands.

Andrew D. Seidman, MD: It changed hands. It was originally, I believed, a Daiichi Sankyo drug, if I’m not mistaken.

Joyce A. O’Shaughnessy, MD: That’s right, yes, absolutely right.

Andrew D. Seidman, MD: Genta pharmaceuticals purchased and was developing it, and we were involved in that development. Genta had run into some financial difficulties. The drugs kind of sat in a closet on a shelf until a group of investors came around and thought this was worth pursuing. So, we’ve cleaned up our data from that trial, and hopefully we’ll publish that soon.

Transcript Edited for Clarity

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Transcript: 

Andrew D. Seidman, MD: So, this brings us to maybe the next big thing: 1994 was when paclitaxel was approved for breast cancer, 24 years ago. And not despite the lack of interest or work, we don’t have an oral taxane. Tell us about tesetaxel. How does it work? What are some potential advantages to this drug? And what do we know about it?

Joyce A. O’Shaughnessy, MD: Yes. It’s really interesting because there’s a number of oral taxanes out there. You know, there has been a big interest in this for a long time. I just think it has taken some time for some of these formulations to actually get legs, get some traction. Tesetaxel is a novel taxane. So, it’s not just paclitaxel put into a formulation that can withstand the stomach acid, such as a lipid formulation, it’s a novel taxane. It has the same taxane structure, but it has 2 moieties that are nitrogen-based, specifically to help oral bioavailability, which is quite good. About 50% to 60% of the tesetaxel is orally bioavailable compared with low single digits for the other taxanes or one is 18% for docetaxel and maybe 6% for paclitaxel or something.

But also, it’s not a substrate for p-glycoprotein [PGP], which is so important with regard to oral absorption but also, of course, some of our more resistant cancers that really have upregulation of the PGP and resistance on that basis. And also, this agent is very interesting to me because it has a really long half-life, over 8 days. And for the other taxanes, both paclitaxel and docetaxel, it’s about 11 hours, so much longer half-life, which lends itself to every-3-weekly administration. There has been some work looking at weekly, and I think there’s probably more exploration to be done there over time. But with an 8-hour half-life, it really leads itself to an every-3-week dosing interval.

Andrew D. Seidman, MD: Yes. So, in the trial that we collaborated in—and I wish Lee Schwartzberg were here to be sitting with us because Lee was also very important in that trial—we studied this drug on an every-3-week basis. And I can’t think of too many other examples where an oral agent caused tumor regression dosed every 3 weeks. I’m sure there might be other drugs in other disease entities. But with an oral agent every 3 weeks in the phase II trial that we presented at the 2017 ASCO Annual Meeting, we see 44% of patients responding to every-3-week dosing. And we did study some weekly dosing as well.  There didn’t seem to be any advantage.

Joyce A. O’Shaughnessy, MD: Be any better, right, any real advantage there. Yes, those are really exciting data to see with pills just once every 3 weeks leading to a response rate 44%. The waterfall plot is very, very impressive because very few patients progressed, I mean just a few, and everybody had some reduction in tumor volume. Whether it made the formal PR [partial response] of 44%, but others also had prolonged stable disease. So, it was very, very highly active.

Andrew D. Seidman, MD: Yes, at a tesetaxel dose of 27 mg/m2, the pill burden is quite modest, so patients aren’t taking 10 or 12 pills a day. There’s no chromophore, there’s no polysorbate, so hypersensitivity reactions weren’t common, weren’t observed. There’s less neuropathy because we don’t have a direct comparison, and some neutropenia, not a whole lot. So, this was interesting. You may know something about the history of this molecule in terms of…

Joyce A. O’Shaughnessy, MD: Yes, it was initially developed a few years back in the phase I setting. We actually participated in some of the early phase I/II to work with it, and I think it was also, of course, developed in gastric cancer as well. So, there was some initial interest and development, but then it changed hands.

Andrew D. Seidman, MD: It changed hands. It was originally, I believed, a Daiichi Sankyo drug, if I’m not mistaken.

Joyce A. O’Shaughnessy, MD: That’s right, yes, absolutely right.

Andrew D. Seidman, MD: Genta pharmaceuticals purchased and was developing it, and we were involved in that development. Genta had run into some financial difficulties. The drugs kind of sat in a closet on a shelf until a group of investors came around and thought this was worth pursuing. So, we’ve cleaned up our data from that trial, and hopefully we’ll publish that soon.

Transcript Edited for Clarity
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