Hope S. Rugo, MD, FASCO
Immunotherapy has become a potential strategy in treating triple-negative breast cancer, though many questions remain to be answered before long-term survival is achieved by all patients. This exciting field of breast cancer research was explored at the 2022 Miami Breast Cancer Conference by Giants of Cancer Care® honoree Hope S. Rugo, MD, FASCO, Professor of Medicine and Director of Breast Oncology and Clinical Trials Education at the University of California San Francisco Helen Diller Family Comprehensive Cancer Center.1 The Giants of Cancer Care recognition program celebrates the achievements of experts whose discoveries have propelled the field of oncology forward and established the building blocks for future advances.
Although this subtype is heterogeneous, triple-negative breast cancer generally carries a high risk of recurrence within 2 to 3 years. “It’s particularly important to optimize our therapy while still trying to individualize it,” Dr. Rugo said.
Triple-negative tumors seem to be good targets for immunotherapy because of their high mutation rate, expression of PD-L1, and presence of tumor-infiltrating lymphocytes. Chemotherapy can further boost the action of immunotherapy by inducing immunomodulatory changes in the tumor microenvironment. The power of this combination approach was first proven in the metastatic setting. The shift is now to the neoadjuvant setting, where the impact on long-term outcomes will be greater. To this end, neoadjuvant immunotherapy is recommended for all but the smallest triple-negative breast tumors, according to Dr. Rugo.
“I think the direction of neoadjuvant therapy now is to replace our adjuvant trials with neoadjuvant trials and power them to look at both pathologic complete response and event-free survival,” she added.
Two pivotal trials that did just that were KEYNOTE-5222 and IMpassion031.3 KEYNOTE-522 evaluated pembrolizumab given with carboplatin and paclitaxel followed by an anthracycline and cyclophosphamide. IMpassion031 evaluated atezolizumab given with albumin-bound (nab) paclitaxel followed by doxorubicin and cyclophosphamide. Patients continued the checkpoint inhibitor for 1 year.
Both trials demonstrated a marked improvement in pathologic complete response at the time of surgery. Although adverse events were increased with the checkpoint inhibitor, many patients completed treatment with pembrolizumab and atezolizumab.
“From those initial data we received fascinating information that we had not completely understood before the trials,” she said. The studies revealed that PD-L1 expression in the tumor predicts for response to chemotherapy, even in the absence of the checkpoint inhibitor. The findings also demonstrated that the benefit derived from immunotherapy in early-stage disease is independent of PD-L1 status, although PD-L1–positive tumors may be more likely to respond.
In KEYNOTE-522, event-free survival and distant recurrence–free survival were improved in patients who received pembrolizumab, with absolute differences of almost 8% and 6%, respectively—leading to regulatory approval of pembrolizumab as neoadjuvant followed by adjuvant therapy. KEYNOTE-522 also revealed that the benefit of pembrolizumab was amplified in node-positive vs node-negative disease, but the relative impact on event-free survival was independent of nodal status.
“Interestingly, the answer is likely in the impact of treatment by the stage of disease. The actual rate of pathologic complete response was much greater in patients with stage 2 vs stage 3 disease. The downward shift in residual cancer burden is a potential explanation for benefit in patients who did not achieve a pathologic complete response,” Dr. Rugo proposed.
She further noted the study showed that attainment of a pathologic complete response, regardless of treatment, heralded better outcomes. However, even without a pathologic complete response, the pembrolizumab/chemotherapy combination improved 3-year event-free survival.
Residual cancer burden can now be quantified, based on research from I-SPY2 investigators who developed a residual cancer burden index that is prognostic for better or worse outcomes.4 They have also shown that a residual cancer burden score can be lowered by neoadjuvant immunotherapy, as shown in a subset of patients whose mean residual cancer burden dropped from 1.68 to 0.46 after just four doses of pembrolizumab/paclitaxel. Such a “frame shift” was also observed in KEYNOTE-522, providing further evidence that neoadjuvant treatment with a checkpoint inhibitor may reduce the amount of tumor burden, Dr. Rugo said.
There are many unanswered questions for immunotherapy in early-stage triple-negative breast cancer.
Who needs a checkpoint inhibitor? This involves a balance of efficacy against the risk of toxicity.
What is the optimal chemotherapy backbone? Platinum improves pathologic complete response rate and event-free survival but not overall survival.
What is the optimal duration of therapy if a pathologic complete response is achieved?
What is the optimal postneoadjuvant therapy? Should pembrolizumab be combined or sequenced with other postneoadjuvant therapies?
Elaborating on some of these questions, Dr. Rugo noted that among five trials, just one—NeoTrip5—did not show at least a strong numerical improvement in pathologic complete response; the regimen in that study lacked an anthracycline. This raises the question as to whether the improvements shown in the other four studies were somewhat reliant on the anthracycline—an idea supported by research showing a quantitatively stronger immune-modulatory effect when an anthracycline is included.6 Could carboplatin also be necessary? In the neoadjuvant BrighTNess trial, the best event-free survival was achieved in patients treated with carboplatin and paclitaxel, vs paclitaxel alone (followed by doxorubicin/cyclophosphamide),7 she noted.
Trials Designed to Answer These Questions
Upcoming trials will address these questions in early-stage triple-negative breast cancer. In patients with residual disease after neoadjuvant therapy, the German Breast Group’s SASCIA trial will study sacituzumab govitecan-hziy vs treatment of physician’s choice in patients with HER2-negative disease. The Alliance for Clinical Trials in Oncology (Alliance) will compare an antibody-drug conjugate with or without pembrolizumab against pembrolizumab alone (with optional capecitabine before -pembrolizumab).
New approaches could also prove beneficial. For example, in I-SPY2, durvalumab plus olaparib “graduated” in all three eligible biomarker signatures by producing pathologic complete responses in 47% of patients vs 27% of controls.8
In the postneoadjuvant setting, to address the question of duration, the Alliance will evaluate pembrolizumab, vs observation, in patients achieving a pathologic complete response. The study will be important in determining whether longer treatment is worth the extra immunotoxicity.
“Of course, we’re interested in whether immunotherapy can benefit patients in other settings as well,” Dr. Rugo added. In HER2-positive breast cancer, ongoing multicenter trials in the neoadjuvant setting are evaluating atezolizumab. IMpassion050 will evaluate doxorubicin/cyclophosphamide with or without atezolizumab, and the APTneo trial will evaluate trastuzumab/pertuzumab/paclitaxel/carboplatin (HPTCT) vs HPTCT plus atezolizumab vs HPTCT plus atezolizumab and doxorubicin/cyclophosphamide. In the postneoadjuvant setting, for patients with residual disease, the 1,600-patient Astefania trial will study trastuzumab emtansine with and without atezolizumab.
As neoadjuvant treatment for high-risk, hormone receptor–positive breast cancer, there are two phase III trials: KEYNOTE-756, in which pembrolizumab is used in the neoadjuvant and adjuvant settings, and CheckMate 7FL, in which nivolumab is used in both settings.
Dr. Rugo’s Roadmap for Early-Stage Triple-Negative Breast Cancer
Dr. Rugo described her approach to treating patients with early-stage triple-negative breast cancer in the neoadjuvant setting:
Dr. Rugo acknowledged that evidence is lacking on some of these practices. “We want to be using olaparib in patients who have BRCA mutations. The question is whether we should give pembrolizumab as well because we don’t have data on that,” she said. Also unclear is whether pembrolizumab should be used together with capecitabine and olaparib or sequentially.
DISCLOSURE: Dr. Rugo has served as a consultant or advisor to Puma Biotechnology, Napo, and Samsung; has received institutional research funding from AstraZeneca, Ayala, Boehringer Ingelheim, Daiichi Sankyo, Genentech, Gilead, Lilly, Merck, Novartis, OBI Pharma, Pfizer, Polyphor, Sermonix, and Seattle Genetics.
2. Schmid P, Cortes J, Dent R, et al: KEYNOTE-522 study of neoadjuvant pembrolizumab + chemotherapy vs placebo + chemotherapy, followed by adjuvant pembrolizumab vs placebo for early-stage TNBC: Event-free survival sensitivity and subgroup analyses. 2021 San Antonio Breast Cancer Symposium. Abstract GS1-01. Presented December 7, 2021.
3. Mittendorf EA, Zhang H, Barrios CH, et al: Neoadjuvant atezolizumab in combination with sequential nab-paclitaxel and anthracycline-based chemotherapy versus placebo and chemotherapy in patients with early-stage triple-negative breast cancer (IMpassion031): A randomised, double-blind, phase 3 trial. Lancet 396:1090-1100, 2020.
4. Symmans WF, Yau C, Chen YY, et al: Assessment of residual cancer burden and event-free survival in neoadjuvant treatment for high-risk breast cancer: An analysis of data from the I-SPY2 randomized clinical trial. JAMA Oncol 7:1654-1663, 2021.
5. Gianni L, Huang CS, 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: NeoTRIP Michelangelo randomized study. Ann Oncol. February 17, 2022 (early release online).
6. Callari M, Barreca M, Dugo M, et al: Comparison of early modulation of biological pathways and immune microenvironment by anthracyclines- or taxane-based treatment. 2021 San Antonio Breast Cancer Symposium. Abstract PD10-09. Presented December 9, 2021.
7. Geyer CE, Sikov WM, Huober J, et al: Long-term efficacy and safety of addition of carboplatin with or without veliparib to standard neoadjuvant chemotherapy in triple-negative breast cancer: 4-year follow-up data from BrighTNess, a randomized phase III trial. Ann Oncol 33:384-394, 2022.
8. Pusztai L, Yau C, Wolf DM, et al: Durvalumab with olaparib and paclitaxel for high-risk HER2-negative stage II/III breast cancer: Results from the adaptively randomized I-SPY2 trial. Cancer Cell 39:989-998, 2021.