Unmet Needs in HR-Positive Metastatic Breast Cancer - Episode 10
Andrew D. Seidman, MD: But this has led to what I think is an exciting phase III trial. And every great trial in breast cancer has to have a good acronym. So, maybe you can tell us about CONTESSA.
Joyce A. O’Shaughnessy, MD: CONTESSA.
Andrew D. Seidman, MD: As in tesetaxel.
Joyce A. O’Shaughnessy, MD: Tesetaxel.
Andrew D. Seidman, MD: The CONTESSA of all clinical trials.
Joyce A. O’Shaughnessy, MD: CONTESSA is an ongoing phase III trial that’s enrolling very rapidly for patients with ER [estrogen receptor]-positive metastatic breast cancer because the control arm is single-agent capecitabine. So, it really makes sense to have an ER-positive group of patients.
Andrew D. Seidman, MD: The standard of care.
Joyce A. O’Shaughnessy, MD: Yes, the standard of care, exactly right. That’s the first thing you go to, and it is with or without the tesetaxel. And the patients had to have had a prior taxane because that’s the question—was tesetaxel sufficiently non—cross resistant enough with other taxanes to make it really be an impactful step forward for patients in addition to the oral advantage, which of course would be very helpful? But does it really bring improvement in PFS [progression-free survival] in the setting of a prior taxane in the adjuvant or neoadjuvant setting, not in the metastatic setting? So, it’s very simple, 1:1 randomization with progression-free survival as the primary endpoint. It’s full dose capecitabine.
Andrew D. Seidman, MD: In the single therapy.
Joyce A. O’Shaughnessy, MD: Single arm. And then it is the, I’m so glad, perfect 1650 mg/m2 divided dose, so it’s going to be 825 bid, which from all of the data in all of the combinations, that really is the perfect dose. And it’s enrolling very well without any issues that have required adjustment of the protocol. Of course, there’s flexibility in dose reduction and such. So, it’s a very, very nice trial and I really like the idea that because it’s a long half-life, you don’t get that same peak effect. And what’s cool about that is not only less neuropathy but less alopecia.
Andrew D. Seidman, MD: Right.
Joyce A. O’Shaughnessy, MD: Really cool because in the early phase I/II experience of this combination, there wasn’t any grade 2 alopecia. Now, in your single-arm study though…
Andrew D. Seidman, MD: Minimal, really minimal.
Joyce A. O’Shaughnessy, MD: In terms of grade 2, some grade 1 and a little bit of grade 2.
Andrew D. Seidman, MD: I’m not sure we saw grade 2, so minimal alopecia, yes.
Joyce A. O’Shaughnessy, MD: Minimal. That’s awesome.
Andrew D. Seidman, MD: So, this is a potentially kinder, gentler doublet therapy. It would be an all-oral regimen, hopefully control breast cancer longer than capecitabine alone. Maybe this would be the patient who I would have otherwise given vinorelbine to. These are patients who are allowed to have up to one prior chemotherapy regimen for the metastatic disease.
Joyce A. O’Shaughnessy, MD: Yes, that’s right.
Andrew D. Seidman, MD: It may be the taxane or more likely it would have a taxane in the early-stage setting. And they may have had a CDK [cyclin-dependent kinase] 4/6 inhibitor. They don’t have to have had it. So, this kind of fits with our earlier discussion about when you need to make that transition from the world of endocrine therapy for your ER [estrogen receptor]-positive, HER2-negative breast cancer, where do you go? We go to capecitabine. But this might offer another attractive option.
Joyce A. O’Shaughnessy, MD: It will be interesting. It may be a little reminiscent potentially, depending on how good the PFS is, how much better it is. Of the CDKs, we were initially a little reluctant to give everyone a drug that caused some myelosuppression, etc. But now with the incredible improvement in the PFS and the very good tolerability, it’s a standard of care. So, it will be interesting to think about whether an oral doublet may be not for everybody, of course, but those with a little bit more disease, more symptoms, it becomes the standard of care.
Andrew D. Seidman, MD: So, Joyce, in your JCO [Journal of Clinical Oncology] paper in 2002 where docetaxel/capecitabine became a new consideration, part of the motivation I think for doing that was this preclinical synergy, taxanes upregulating thymidylate synthase, perhaps making the cells more sensitive to capecitabine, etc. We do have some preclinical data with tesetaxel also that I think show the same potential.
Joyce A. O’Shaughnessy, MD: Yes, the same synergy between the 2, really impressive preclinical models where you get some improvement with the single agents. You put the 2 together and the curves just go right down the ground basically, looks very, very synergistic preclinically. I’m also thinking, of course I’ve been long interested in the docetaxel/capecitabine combination. I was gratified to see the results from the adjuvant MINDACT trial that Fatima Cardoso presented within the last year, looking at a randomization of an anthracycline/taxane-based adjuvant therapy versus docetaxel/capecitabine in the MINDACT trial.
It was about 1350 patients who were randomized. It was a secondary question in the MINDACT trial, and at least in that trial there wasn’t a difference in terms of getting that anthracycline in there. And that was a mixed group of patients, mostly ER-positive. There were some triple-negatives in there. Now, we know that that’s not always the case. The ABC trials showed that the triple-negative breast cancer patients or ER-positives with 4 or more positive nodes that the anthracycline did make a difference. But for node-negative ER-positive or 1 to 3 node-positive breast cancer patients who need chemotherapy, which increasingly is a smaller group, it’s interesting to see that docetaxel/capecitabine. So, you wonder about an all-oral regimen as a possible use for this tesetaxel/capecitabine combination, if indeed it’s a positive trial in the metastatic setting.
Transcript Edited for Clarity