Adjuvant Everolimus Plus Standard ET Does Not Significantly Improve iDFS or OS in HR+ Breast Cancer

The addition of 1 year of everolimus (Afinitor) to standard adjuvant endocrine therapy failed to significantly improve survival outcomes in patients with high-risk, hormone receptor–positive, HER2-negative breast cancer enrolled in the phase 3 SWOG S1207 trial (NCT01674140). However, future translational studies may shed much-needed light on tumor biology, resistance to endocrine therapy, and more, according to Mariana Chavez-MacGregor, MD, MSC.

Data from the final analysis of the trial were presented during the 2022 San Antonio Breast Cancer Symposium (SABCS) and showed that the estimated 5-year invasive disease-free survival (iDFS) rate with everolimus plus exemestane was 74.9% vs 74.4% with placebo plus exemestane (HR, 0.94; 95% CI, 0.77-1.14, P = .52) in the total population. Similarly, the estimated 5-year overall survival (OS) rates were 88.1% and 85.8% respectively (HR, 0.97; 95% CI, 0.75-1.26, P = .84). The regimen was associated with increased treatment-related adverse events (TRAEs) vs placebo, causing a high treatment discontinuation rate.

Data from the exploratory analysis done my menopausal status showed that in postmenopausal patients, the estimated 5-year iDFS rate in the everolimus arm was 72.0% vs 74.3% in the placebo arm (HR, 1.08; 95% CI, 0.86-1.36; P = .52). The estimated 5-year OS rates in this population were 84.6% and 85.7%, respectively (HR, 1.19; 95% CI, 0.89-1.60; P = .25). However, in premenopausal patients, the addition of everolimus to endocrine therapy resulted in an improved estimated 5-year iDFS rate vs placebo, at 81.0% and 74.7%, respectively (HR, 0.64; 95% CI, 0.44-0.94; P = .02). This finding was determined to be hypothesis generating.

“We need to continue looking for strategies [that] improve outcomes [for] our patients. Patients with hormone receptor–positive tumors can be at a very high risk of recurrence,” said Chavez-MacGregor, who is an associate professor in the Department of Health Services Research, and member of the Division of Cancer Prevention and Population Sciences at The University of Texas MD Anderson Cancer Center, Houston, TX. “Everolimus, in this trial, was not the answer, but [this can serve as] a call to action to look for other mechanisms for us to find ways to improve the outcomes of our patients.”

In an interview with OncLive^®, Chavez-MacGregor discussed key efficacy and safety data from the SWOG 1207 trial of adjuvant everolimus in postmenopausal patients with high-risk, hormone receptor–positive breast cancer.

OncLive^®: What was the rationale for evaluating the addition of everolimus to exemestane in patients with early breast cancer? What inspired this research?

Chavez-MacGregor: Everolimus is an mTOR inhibitor and we know from data in the metastatic setting that [the agent] is associated with an improvement in outcomes in patients previously treated with endocrine therapy. In the metastatic setting, the [phase 2] BOLERO-2 [NCT00863655] study confirmed that everolimus combined with exemestane improved PFS in patients previously treated with aromatase inhibitors compared [with] exemestane alone.

Since we know that [the mTOR] pathway is important in endocrine resistance, [and given the data] from BOLERO-2, [we felt] it was of great importance and relevance to evaluate whether the incorporation of everolimus in the treatment of patients with early breast cancer could improve outcomes.

Please expand on what the SWOG 1207 trial examined. What were the key efficacy data presented at the 2022 SABCS?

At the meeting, we presented the final analysis of SWOG 1207. This phase 3, randomized, placebo-controlled trial evaluated the addition of 1 year of adjuvant everolimus to adjuvant endocrine therapy in patients with high-risk, hormone receptor–positive, HER2-negative breast cancer. Our primary end point was iDFS.

Amongst patients treated with everolimus, [we observed] no improvement in outcomes. Our study [was] negative; everolimus did not improve iDFS or secondary outcomes like overall survival [OS] in the main patient population. However, an exploratory analysis [of] 571 premenopausal patients [did show] a statistically significant improvement in both iDFS and OS [with everolimus vs without]. This observation is interesting, thought-provoking, and hypothesis-generating.

What should be known about everolimus in terms of safety?

During the study, we paid a lot of attention to safety—it was a very important secondary end point in this study. We did observe a much higher rate of grade 3 and 4 adverse effects amongst patients treated with everolimus compared with those treated with placebo. We also observed that the [drug's] discontinuation rate was much higher [than placebo], and the main cause was treatment related. It does [raise] a very important issue regarding toxicity, tolerance, and the management of AEs in this patient population.

What are the clinical implications of this research, if any?

The results of our study are not going to influence practice, [or] change the way that we treat our patients. However, they add to the body of evidence [supporting the] evaluation of different treatment strategies [with the] aim of improving outcomes.

In the future, the results from our upcoming translational studies can shed some light on aspects related to the biology of hormone receptor–positive tumors and reveal important information [about] endocrine therapy resistance. We are going to further explore the results that we observed in premenopausal patients. This might be relevant for the development and evaluation of other drugs, but the reality is that I don’t see this affecting the way that we treat our patients in the clinic.

Were there any other presentations at SABCS that you found intriguing?

The meeting has been very exciting. We have seen very interesting data on the benefits of antibody-drug conjugates…like trastuzumab deruxtecan [Enhertu]. We [also saw] some interesting information on different biomarker analyses. I treat a lot of patients who are very young and desire to get pregnant, so the results of the POSITIVE trial [NCT02308085] were very interesting. In the metastatic setting, we [were] excited to hear about the [phase 2] PACE trial [NCT03147287]. Overall, it was a great meeting and there’s [more] exciting things [to come].

Editor’s Note: Dr Chavez-MacGregor reports serving as a consultant or on a paid board for Pfizer, Novartis, AstraZeneca, Lilly, Genentech/Roche, Exact Sciences; she reports receiving funding from Novartis; she reports participating in on a data safety monitoring board for AstraZeneca and Genentech.

Reference

Mariana Chavez-MacGregor M, Miao J, Pusztai L, et al. Results from a phase III randomized, placebo-controlled clinical trial evaluating adjuvant endocrine therapy +/- 1 year of everolimus in patients with high-risk hormone receptor-positive, HER2-negative breast cancer: SWOG S1207. Presented at 2022 San Antonio Breast Cancer Symposium; December 6-10, 2022; San Antonio, TX.