A discussion on a phase 3 trial using oral paclitaxel and encequidar for treatment of metastatic breast cancer.
Hope S. Rugo, MD: In this segment we're going to talk about oral taxanes, how oral therapy might play a role for us in terms of treatment, and what are the advantages of oral therapy. I'm going to talk a little bit about the Oraxol study that was presented at the San Antonio Breast Cancer Symposium. But first, I'd like to ask our panel what the advantages of oral therapy are to our patient population, and what they’re thinking about in terms of wanting oral agents. Here we're focusing on chemotherapy. We know that most of our endocrine therapy is oral on 1 IM [intramuscular] administration, but for chemotherapy we're stuck with this IV [intravenous] therapy. Tiffany, do you want to comment on that?
Tiffany A. Traina, MD: Often the perception has been that oral therapy would be simpler and easier for our patients, although I say that's perception because we've found that in the space of targeted therapy that's not always the case. Certainly having the option of oral therapy gives a woman more freedom away from the clinic, perhaps not needing central access. It depends on the adverse effect profile of the oral therapy to help in decision making over what adverse events we would otherwise see with intravenous therapy, which is sometimes really well tolerated.
Hope S. Rugo, MD: I think this is an issue, with IV access being an issue as well. Claudine, any other comments on that in terms of what your patients think about IV therapy and frequency of dosing—IV versus taking oral therapy?
Claudine J. Isaacs, MD: Absolutely. Of course you need to take the toxicity of the given agents into consideration, but I think the default from a patient perspective is that people tend to prefer oral therapies. Where we are right now in the world it’s clear that the more that we can get people away from our infusion units, and the more we can have them have the liberty of getting their treatment at home, that is clearly advantageous. But I think we need to balance that against the toxicities. The default is if we could give the same therapy orally, that would obviously be a tremendous advantage for our patients.
Hope S. Rugo, MD: Priyanka, any additional comments?
Priyanka Sharma, MD: Coming from the area that I am in, which is very rural, for us, oral therapy also has an added advantage. A lot of our patients are traveling 3 to 4 hours from where they are to come to the infusion center. From that aspect, it’s also preferable as long as the toxicity profile isn’t prohibitive.
Hope S. Rugo, MD: That’s interesting because now we'll be able to talk to them by telemedicine visits, given our experience with COVID-19 [coronavirus disease 2019]. Let's talk a little bit about the data that were recently reported from a phase 3 trial about an oral taxane. This study was conducted in Central America and South America using used a drug called Oraxol, which was compared to IV paclitaxel. Patients who had metastatic breast cancer were randomized 2 to 1 to OPE [oral paclitaxel with encequidar] or IV Taxol [paclitaxel]. The primary end point was the tumor response by week 19 that was confirmed 1 month later, so a little bit different from what we've seen in other registration trials.
In this situation they had to show that they were at least as good as IV paclitaxel, so that was a reasonable end point with tumor response by week 19. There was a total of 360 patients who were randomized in this trial, and many had received some other prior treatments for their metastatic disease. It’s important to understand what Oraxol is, and it's actually oral paclitaxel. It comes in a little gelatin capsule, so you need several of them together. Most people took 10 or 12 tablets each time. Then one of the problems with oral paclitaxel and with any oral drug is actually that you don't get absorption because you have the pump, the P-glycoprotein efflux pump is pumping it out as quickly as you get it absorbed.
They actually used another agent called encequidar, which is designed to try and prevent the P-glycoprotein pump from pumping out the chemotherapy as quickly as it is absorbed. It actually also enhances absorption, and it doesn’t have a lot of toxicity on its own. This drug is called encequidar. Basically the way people took this medication is a single tablet of encequidar, and then they took several little capsules of the oral paclitaxel. They took it for 3 days in a row every week for 3 weeks in a row, followed by 1 week off. This was compared to 175 mg/m2 of IV paclitaxel given every 3 weeks, the original way that IV paclitaxel was approved.
A lot of these patients had received some prior treatment. About a quarter had received prior chemotherapy, about a third had received prior taxane exposure in any setting, and of course quite a number had visceral disease, so they were our standard patients. They saw an improved response rate of about 15% difference favoring the Oraxol, and that showed a 40% response versus 26% response rate. They didn't see big differences in terms of subset analyses. They had the smallest number of patients who had triple negative disease, so it was a little bit harder to assess in that specific population.
They saw that the responses were quite durable with about three-quarters of the patients staying on treatment for more than 100 days, about a third of patients more than 200 days, and the follow-up is still ongoing. They did look at progression-free survival as well, and it was relatively equivalent at the first evaluation, but they have further evaluations ahead. Then overall survival actually favored the Oraxol with a hazard ratio of 0.68. Although this wasn't their primary objective, the P value is .03, and it is intriguing that you could see this improvement in overall survival.
I think one of the things that we were impressed with for these data was a difference in neuropathy. If you looked at the grade 2 or greater neuropathy, there was significantly less neuropathy over time with the Oraxol compared to IV paclitaxel—a clinically significant difference in terms of developing neuropathy. If you just looked at the total incidence, it was 31% for IV paclitaxel and only 7.6% for the Oraxol, which is very different. So it's quite intriguing, and the first encouraging data we've seen in this area. I'm interested in what everybody thinks about this. Tiffany, what do you think? What did you think about the data that were presented, and what would be a reason for you to use this over IV paclitaxel? Did you have any concerns about the study design?
Tiffany A. Traina, MD: Hope, I think you've raised some of the challenges of the design in and of itself—the control arm not being our traditional control arm, dosing, and schedule of intravenous paclitaxel, not having clarity on the different subgroups and who these patients are. But with all that being said, it does appear to be favorable in terms of that neuropathy profile. We have many women who have long-lasting neuropathy as a result of their adjuvant taxane, and that can be a limiting factor then when we need to treat them serially in metastatic disease. To be able to have a taxane that's active, that has less neuropathy, that perhaps could even partner nicely with some other oral targeted therapies and have a doublet oral regimen, and that enables women to stay out of the infusion suite, could be really advantageous.
It is a large pill burden from what you described, and so I think it will be a matter of finding the right patients for whom this is suitable. The other point that I didn't raise when we were talking about advantages of oral therapy over intravenous is a bit of a concern, that we know practices are spending a lot of time trying to get approvals and authorizations and access for oral regimens for our patients. I would love to hear some of John’s thoughts on how oral anticancer therapies such as this, how this would compare with simple IV paclitaxel.
Hope S. Rugo, MD: That's an important point that you bring up because the share of cost not just for capecitabine, our current oral drug in the United States that we have as chemotherapy, but also for CDK4/6 [cyclin-dependent kinases 4 and 6] inhibitors has been prohibitive. These are patients who have Medicare and not secondary insurers.