Everolimus, it's an mTOR inhibitor that, in the metastatic setting demonstrated to improve outcomes on patients previously treated with aromatase inhibitor. And since we know that the mTOR/Akt pathway, it's associated with endocrine resistance, we thought it was very important to evaluate if everolimus was associated with improved outcomes in patients with early stage breast cancer.
With the SWOG 1207, to answer this question, to really tell us whether the addition of everolimus in the adjuvant setting could improve outcomes.
The design of the study, so this is a very large, phase III, randomized placebo control trial, evaluating one year of adjuvant everolimus in combination of adjuvant endocrine therapy for the treatment of patients with high-risk hormone receptor-positive, HER2-negative breast cancer.
All patients in the trial receive either adjuvant or neoadjuvant chemotherapy. We really want to capture a high-risk population and patients could have had lymph node-negative disease, but they needed to have tumors that were larger than two centimeters or had Oncotype recurring score greater than 25 or MammaPrint high. Patients with one to three positive lymph nodes also needed to have high recurring score, high score MammaPrint or grade 3 tumors. Patients with four or more positive lymph nodes were all eligible. Patients treated with neoadjuvant chemotherapy upfront needed to have residual disease with at least one or more lymph nodes involved.
So after patients completed their standard treatment, they were randomized, one-to-one, to receive endocrine therapy physicians' choice plus or minus overall everolimus or a matched placebo for a duration of one year.
The primary endpoint of the study was invasive disease free-survival, and we were powered to have 80% power for hazard ratio of 0.75.
The side effects of everolimus are well-known based on our previous experience with the drug in the metastatic setting. It's a drug that it's associated with mucositis, it's associated with lymphopenia. Therefore, side effect profile, it's different than the placebo. And while we don't believe the results of this study are compromised because of the difference in the toxicity profile compared from the study drug to placebo, we did observe that the arm of patients treated with everolimus had a higher rate of discontinuation associated with the side effect profile. So that's something that we need to take into consideration when interpreting the results. Also, it's important for us to think about the adverse safety profile of the drugs that we're giving our patients, since the tolerability of side effects might be different from what we're used to in the metastatic setting.
SWOG 1207 was associated with an important proportion of patients experiencing adverse events in the everolimus arm compared to placebo. We have observed that 35% of the patients in the everolimus arm had a grade 3 or 4 adverse event compared to only 7% in the placebo arm. And I think it's something that it's important and worth mentioning.
Everolimus is a drug that has demonstrated reactivity mainly in patients with hormone receptor-positive tumors. Therefore, thinking about using this drug in other breast cancer subtypes, I think it's unlikely that we will evaluate it there. Now, considering combining everolimus with other targeted agents, I think can be complicated based on the overlapping toxicity profile of some of these drugs.
If anything, I think we need to think about better selecting of patients, better sequencing biomarkers, predicting not only efficacy but toxicity, and maybe evaluating some other new generation of Akt or mTOR inhibitors down the line as future line of research.
Some of the things that we're very excited about, it's the translational studies that are going to be conducting using the samples of the patients participating in the study. We have blood samples and we also have tissue, we have healthy tissue. And we are collecting tissue from the recurrences of patients that develop a recurrence. And we think that this is going to really help us clarify important aspects, not only related to the observation of improvement in outcomes in premenopausal patients in an exploratory analysis, but we're going to have very important signs that hopefully will help clarify important aspects related to endocrine therapy resistance.
