CONTESSA Trial Yields Positive Results for Patients with HER2-Positive Breast Cancer

New data suggests that a combination of tesetaxel and capecitabine can help extend progress-free survival (PFS) in certain patients with breast cancer, according to a recent study. 

The phase 3 CONTESSA study (NCT03326674) compared the outcomes of tesetaxel with a reduced dose of capecitabine versus capecitabine alone in patients with hormone receptor (HR)-positive, HER2-negative metastatic breast cancer (mBC) who have been previously treated with a taxane in the neoadjuvant or adjuvant setting. The primary outcome of the study was PFS and secondary outcomes included overall survival, overall response rate, and duration of complete response.

In order to be eligible, patients were required to be at least 18-year-old, have histologically or cytologically confirmed breast cancer, HER2-negative, and HR-positive. Patients with 2 or more prior chemotherapy regimens for advanced disease or prior treatment with a taxane in the metastatic setting were not eligible to enroll.

Participants in the combination group were given 27 mg/m2 of tesetaxel orally on the first dose of each 21-day cycle plus the reduced dose of capecitabine for 14 days of the 21-day cycle. Patients in the capecitabine-only group received the recommended dose of 2500 mg/m2 dose daily for 14 days of each 21-day cycle. The 685 participants were randomized 1:1.

For the combination, the median PFS survival was 9.8 months compared to 6.9 months with capecitabine alone, achieving a 28.4% reduction in the risk of disease progression or death.

In an interview with Targeted Oncology, Joyce O’Shaughnessy, MD, chair of Breast Cancer Research and chair of Breast Cancer Prevention Research at Baylor-Sammons Cancer Center of Texas Oncology, discussed the CONTESSA stusy of tesetaxel with a reduced dose of capecitabine versus capecitabine alone in patients with HR-positive, HER2-negative breast cancer.

TARGETED ONCOLOGY: What kind of responses did you see to tesetaxel? How did the reduced capecitabine perform and how did it compare with tesetaxel alone?

O’SHANNESSY: The primary endpoint of the CONTESSA trial was PFS. At the 2020 San Antonio Breast Cancer Symposium (SABCS), we were able to show the definitive results from the PFS data from the CONTESSA trial, which showed a statistically significant improvement in PFS in favor of adding the tesetaxel to the capecitabine. It was in the order of just shy of 3 months and statistically significant. The study met its primary endpoint with acceptable safety. There was a greater proportion of patients who had febrile neutropenia with the tesetaxel because it does cause neutropenia, and there was about a 13% rate of febrile neutropenia. But there were 5 treatment-related deaths with the combination versus 3 with capecitabine alone. So, it was not a large difference in in death rate, and nothing that you wouldn’t expected to see with other combination chemotherapy strategies. Only 8% of patients had grade 2 alopecia, and about an additional 20% of patients had grade 1 alopecia with the tesetaxel. But otherwise, it was well tolerated. Also, only 4% of patients stopped the tesetaxel/capecitabine therapy because of toxicity. So, the toxicities were in fact quite manageable with dose reduction, or the addition of granulocyte colony-stimulating factor (G-CSF) onthe non-capecitabine days were was also allowed on the trial. It was good to see that it did improve PFS and safety was acceptable and highly manageable with the combination.

TARGETED ONCOLOGY: What do you feel are the implications of these findings?

O’SHANNESSY: If the combination of tesetaxel and capecitabine garners FDA approval, we hope It will become an all oral combination chemotherapy strategy for patients with HR-positive HER2-negative mBC who require a combination chemotherapy, you know, we tend to use sequential single agent cytotoxic therapy after patients become refractory to endocrine therapy. But still, there's a proportion of patients who have virulent disease who are very symptomatic with heavy tumor volume. These patients require combination chemotherapy. So, we hope that the tesetaxel/capecitabine have been will offer a new oral combination strategy for patients. And again, if it does get FDA approval, it's certainly possible that it can be used sequentially with capecitabine as well to give patients another oral option for their chemotherapy and avoiding the use of IV therapy, which is a great value to patients.

TARGETED ONCOLOGY: Are there any future research efforts planned based on the study.

O’SHANNESSY: The CONTESSA trial will certainly continue to be analyzed for overall survival. Other subsets are being looked at with regard to the older, older patient population. there are additional monotherapy trials ongoing with tesetaxel. It's also being looked at in other malignancies. So yes, I think it's just the beginning of its development because it's a very active taxane. We're also curious about whether it can penetrate the central nervous system (CNS) preclinically. It looks like it can, and so does it have activity against to patients who have CNS metastasis? There are a lot of interesting questions, because it's not extruded from the cells by P-glycoprotein, which makes it quite unique. So yes, it's got a large development program ahead of it.

TARGETED ONCOLOGY: We saw a lot of really exciting research presented at SABCS, were there any other findings that you thought were particularly exciting or promising?

O’SHANNESSY: It was an interesting and exciting SABCS. Although it was virtual, it was still very data packed. I think the most important trial to be presented at SABCS this year was the RxPONDER (NCT01272037) data in patients who had 1-3 nodes positive. Most of them have 1 or 2 nodes positive. ER-positive, HER2-negative patients looking to get adjuvant therapy and trying to understand whether chemotherapy would benefit those patients, in addition to endocrine therapy, if their recurrence score was 25 or less. Those with a recurrence score over 25 just automatically received chemotherapy. But those who were 25 and less, were randomized to endocrine therapy alone versus endocrine therapy with chemotherapy. And the bottom line of the trial was very interesting, and parallel to what we had seen in the TAILORx trial (NCT00310180), which was the same trial designed in patients with node-negative disease. And the bottom line was that in postmenopausal women with a recurrence score of 25 or less, there was no benefit at all, from the addition of chemotherapy to endocrine therapy. Contrarily, for premenopausal patients there was statistically significant and clinically meaningful absolute improvement of up to 6%. In those with a recurrence score of 14 to 25, there was more than a 6% improvement in invasive disease-free survival in favor of chemotherapy. Even in patients, the 1 to 3 node-positive premenopausal patients with recurrent scores between 0 and 14, there was still an important improvement of about 5%, as I recall. So, it really again, begs the question about whether the dominant mechanism of benefit from chemotherapy in these pre-menopausal patients is indeed ovarian suppression. Because as in the TAILORx, in the RxPONDER trial, only a small minority of patients who are pre-menopausal, had the addition of an LHRH agonist to their endocrine therapy, when they either finished their chemotherapy or didn't get chemotherapy at all.

I think, as we do now, with the TAILORx data, as patients get higher on that recurrence score, you know, closer to 25, we're going to err on the side of giving the patient chemotherapy and optimizing endocrine therapy with an LHRH agonist and an aromatase inhibitor. Whereas if they are on the lower end of the recurrence score, perhaps those 11 and under because we've seen in the ADAPT trial (NCT01779206), that patients with 0 to 3 nodes positive will have a very low recurrence score, up to 11 do very well with endocrine therapy alone. We probably would optimize endocrine therapy for those patients. So, we're going to have to really individualize it as we're doing now in the premenopausal patients with node negative disease. No one could simply take the approach that all premenopausal patients that are node positive should then just get chemotherapy plus endocrine therapy. I probably won't do that myself. In my practice, I'll get the recurrence score there at the low end of the recurrence score and the biology otherwise, looks like they'd be very endocrine therapy sensitive, strongly er-positive grade 1 or grade 2 disease, lower Ki-67. I would talk to the patient about potentially just optimizing their endocrine therapy and forgoing chemotherapy.

Overall, I think that was a very important trial and then for the postmenopausal patients with 1 to 3 nodes positive, they have a recurrence score of 25 or less. I think it's reasonable for them to just have optimal endocrine therapy, which is 10 years of an aromatase inhibitor and chemotherapy.

^REFERNCE:

^{O’Shaughnessy J, Schwartzberg L, Piccart M, et al. Results from CONTESSA: A phase 3 study of tesetaxel plus a reduced dose of capecitabine versus capecitabine alone in patients with HER2-, hormone receptor + (HR+) metastatic breast cancer (MBC) who have previously received a taxane. Presented at: 2020 San Antonio Breast Cancer Symposium; December 8-11, 2020; Virtual. Abstract GS4-01.}