The invited discussant of GeparNuevo,1 Melinda L. Telli, MD, Associate Professor of Medicine at Stanford University School of Medicine, Director of the Breast Cancer Program at the Stanford Cancer Institute, and Associate Director of the Stanford Women’s Cancer Center, welcomed the additional data showing a benefit of checkpoint inhibition in early triple-negative breast cancer. However, she said the use of these drugs in the neoadjuvant setting is premature.
Melinda L. Telli, MD
As part of the “quest to further improve curative treatment for high-risk early breast cancer,” Dr. Telli said, “checkpoint inhibitors have recently begun to receive approvals for the treatment of nonmetastatic cancer. The major question is whether this strategy can hold promise in early breast cancer.”
A number of randomized phase II and III trials have evaluated checkpoint inhibitors as neoadjuvant therapy in triple-negative breast cancer. These trials have examined different chemotherapy backbones and different durations of treatment. Incorporation of a PD-1/PD-L1 inhibitor has led to absolute improvements in pathologic complete response rates, ranging from 2.7% in NeoTRIPaPDL12 to 16.5% in IMpassion0313 (both studies evaluated atezolizumab). In KEYNOTE-522, the addition of pembrolizumab boosted responses by 13.6%.4 GeparNuevo showed that durvalumab improved response rates by 9.2%.5
IMpassion031 and KEYNOTE-522 also included 1 year of continued PD-1/PD-L1 inhibition as adjuvant therapy, whereas the other studies did not. Whether the use of checkpoint inhibitors in early triple-negative breast cancer needs to extend to the adjuvant setting remains unknown, Dr. Telli added.
More Data Needed
“Our conclusions, thus far, were that there were conflicting results regarding the magnitude of pathologic complete response improvement with this approach, and we discussed many potential explanations,” she said. They include the choice of chemotherapy regimen, potential differences between PD-1 and PD-L1 antibodies, and differences in patient populations. “We concluded that we needed to wait for data on longer-term outcomes and longer-term safety.”
GeparNuevo has provided some of those data, showing that the addition of durvalumab to chemotherapy improved the key secondary endpoints of invasive disease–free survival, distant disease–free survival, and overall survival. By providing these data, GeparNuevo is a valuable study, according to Dr. Telli. “The data are important in that they give us the first glimpse into the future of this approach in early triple-negative breast cancer, with median survival that was relatively long, at more than 3.5 years,” she said.
Dr. Telli said the weaknesses of the study were the lack of stratification by stage and nodal status as well as the underpowered nature of the secondary endpoints, which had wide 95% confidence intervals. Additionally, patients on the placebo arm who did achieve pathologic complete responses had worse long-term outcomes than expected. Finally, the study lacked data on long-term safety.
“At this point, checkpoint inhibitors should not yet routinely be used in the treatment of early triple-negative breast cancer. We need robust and consistent data on long-term outcomes and safety, and cost considerations remain important,” Dr. Telli said. “We eagerly await event-free survival data from KEYNOTE-522 and findings from ongoing adjuvant studies.”
DISCLOSURE: Dr. Telli has served as a consultant or advisor to AbbVie, Blueprint Medicines, Celgene, Daiichi Sankyo, G1 Therapeutics, Genentech/Roche, Immunomedics, Lilly, Merck, Natera, OncoSec Medical, and Pfizer; has received institutional research funding from AbbVie, Bayer, Biothera, Calithera Biosciences, EMD Serono, Genentech, Medivation, Novartis, -OncoSec, Pfizer, PharmaMar, Tesaro, and Vertex; and has held other relationships with G1 Therapeutics and Immunomedics.
REFERENCES
1. Loibl S, Schneeweiss A, Huober JB, et al: Durvalumab improves long-term outcome in TNBC: Results from the phase II randomized GeparNuevo study investigating neoadjuvant durvalumab in addition to an anthracycline/taxane based neoadjuvant chemotherapy in early triple-negative breast cancer. 2021 ASCO Annual Meeting. Abstract 506. Presented June 7, 2021.
2. Gianni L, Huang C, Egle D, et al: Pathologic complete response to neoadjuvant treatment with or without atezolizumab in triple-negative, early high-risk and locally advanced breast cancer. NeoTRIPaPDL1 Michelangelo randomized study. 2019 San Antonio Breast Cancer Symposium. Abstract GS3-04. Presented December 12, 2019.
3. Harbeck N, Zhang H, Barrios CH, et al: IMpassion031: Results from a phase 3 study of neoadjuvant atezolizumab plus chemotherapy in early triple-negative breast cancer. ESMO Virtual Congress 2020. Abstract LBA11. Presented September 20, 2020.
4. Schmid P, Cortes J, Pusztai L, et al: Pembrolizumab for early triple-negative breast cancer. N Engl J Med 382:810-821, 2020.
5. Loibl S, Untch M, Burchardi N, et al: A randomised phase II study investigating durvalumab in addition to an anthracycline taxane-based neoadjuvant therapy in early triple-negative breast cancer: Clinical results and biomarker analysis of GeparNuevo study. Ann Oncol 30:1279-1288, 2019.
