Adam M. Brufsky, MD, PhD: There is the other one, before we talk a bit more and go back to generally summing everything up. The other one, we just saw the CONTESSA trial data, and Lee, you know these data backward and forward. You are on the abstract in the paper. What do you think of it?
Lee S. Schwartzberg, MD, FACP: I am reasonably excited about what we have seen with tesetaxel. First of all, if you look just at what we have been talking about with the pill burden, it is given once every 3 weeks because of the pharmacokinetics. Like we were talking about, it has a low Cmax [peak plasma concentration], and it has an 8-day half-life, so it lasts a long time.
For the toxicity, in our hands at West Cancer Center & Research Institute, we did phase 2 a few years ago. Andy Seidman, MD, and I basically ran that one. We treated a bunch of patients either as monotherapy or in combination with capecitabine, and we found it well tolerated. As a monotherapy, it clearly had less alopecia, and it seemed to have less neuropathy as well. Admittedly, the numbers are small, so we need a larger number of patients. In the phase 3 CONTESSA trial, there was also a small amount of grade 3 neuropathy, and there was a 3-month improvement in progression-free survival and a 30% improvement in hazard ratio.
For that combination, other than neutropenia, which was well managed once we learned about it in the first cycle in the combination with capecitabine, it is going to be a good regimen. Personally, I would initially give the every 3 week dosing in the office to make sure the patient took it because it is just once. After the patient has then taken a couple of cycles, a well-educated, compliant patient can certainly continue it at home without difficulty, certainly as monotherapy, and with capecitabine too once they got used to it.
Adam M. Brufsky, MD, PhD: The only thing that concerned me about it was the fever neutropenia rate. I am trying to figure that out from the abstract. What was it, 6% or 8%? I could not figure it out.
Lee S. Schwartzberg, MD, FACP: It was a little higher than that: about 11%.
Adam M. Brufsky, MD, PhD: Eleven percent fever neutropenia.
Lee S. Schwartzberg, MD, FACP: That was without growth factor.
Adam M. Brufsky, MD, PhD: That was without growth factors, so in a palliative setting, I am curious because I know George has been pounding at this very topic many years. In the palliative setting, we are now going to give people growth factors.
Lee S. Schwartzberg, MD, FACP: We’ve got another drug that also causes a lot of neutropenia: sacituzumab.
George W. Sledge Jr., MD: Here is a bit of a different question: why the combination as opposed to giving these 2 drugs sequentially?
Lee S. Schwartzberg, MD, FACP: That is the million-dollar question, is it not?
Adam M. Brufsky, MD, PhD: All of us asked that question to Odonate Therapeutics. They all came to us at Miami Breast Cancer Conference 2020; we said that we are doing this, and we asked why. I am sure that you had the same thing, right Lee? We said why? Why are you doing this design? They only did it because they wanted to compare it to an existing regimen. I do not know.
Lee S. Schwartzberg, MD, FACP: Yes.
George W. Sledge Jr., MD:From an FDA standpoint, from an agency standpoint, you have to demonstrate benefit above and beyond an approved therapy. Capecitabine is a standard therapy in patients who’ve had had prior anthracycline, prior taxane, so it is entirely reasonable from an FDA-approval standpoint.
I like the drug, but I hate the trial. I see no particular reason to give the drugs in combination, which requires you to give 2 drugs until progression. There is no evidence whatsoever that there is a true synergy such that you have to give the drugs together to see the benefit. You probably buy increased toxicity. You certainly buy increased costs to the health care system and probably to the patient as well.
I do not see it. Does a 3-month improvement of progression-free survival give you a significant improvement in overall survival? We will have to wait and see, but you would be surprised if there is a huge improvement in overall survival. This is E1193: it is a trial that we started in 1993. If I were king of the world, I would have run this trial with a sequential arm.
Adam M. Brufsky, MD, PhD: Right. That will be the next trial that they do.
George W. Sledge Jr., MD:Can I ask you both a related question? The trial, because they were trying to get FDA approval, used the FDA-mandated overdose of capecitabine: 2 two weeks on, 1 week off. In my clinic, Stanford Cancer Center, if I am giving a patient capecitabine, I am typically going to be giving 1 week on, 1 week off.
Adam M. Brufsky, MD, PhD: I agree.
George W. Sledge Jr., MD: This has significantly less in the way of hand-foot syndrome. Again, this is another reason I am not a big fan of the trial: it is not just that it has a problem with the combination, but there is a problem with the capecitabine that is used in the combination.
Lee S. Schwartzberg, MD, FACP: I would counter one thing that George said, which is this: if a lower dose had been used, then the trial could be criticized by saying, “Well, you compared 2 agents against the lower dose of capecitabine.” Those who want to criticize it that way could, but I agree. It was completely regulatory in nature, the design of the control arm. It had to be against a standard.
George W. Sledge Jr., MD:I have the advantage of having been the primary discussant for capecitabine approval in 1998 at ODAC [the Oncologic Drugs Advisory Committee], which I will remind you was not done based on a phase 3 trial.
Adam M. Brufsky, MD, PhD: It was phase 2, right? It was Joanne Blum, MD, PhD, FACP’s phase 2 trial, right?
George W. Sledge Jr., MD: Yes. It was a 130-patient phase 2 trial.
Adam M. Brufsky, MD, PhD: Yes, I remember that. We could never do that now. We would never get that trial passed. It would never get through.
George W. Sledge Jr., MD: It is hard to imagine.
Transcript Edited for Clarity