The results from the pivotal KEYNOTE-522 phase III clinical trial, released in May 2021, provided patients with early triple-negative breast cancer and the physicians who treat them with encouraging news. The phase III trial sought to determine if an immunotherapy agent would enhance the antitumour activity of chemotherapy in patients with metastatic triple-negative breast cancer. The results were compelling, demonstrating that the addition of an immune checkpoint inhibitor in combination with chemotherapy before surgery and continuing as a single agent after surgery showed statistically significant and clinically meaningful improvements in event-free survival compared to treatment with neoadjuvant chemotherapy alone.
The data was so promising that the study led to FDA approval in July 2021 of the first immunotherapy agent – pembrolizumab – for this indication combined with standard chemotherapy as neoadjuvant treatment for patients with early-stage triple-negative breast cancer. That same year, the American Society of Clinical Oncology (ASCO) published a guideline on neoadjuvant chemotherapy, endocrine therapy, and targeted therapy for breast cancer.
Dr. Dawn Hershman
Dawn L. Hershman, MD, MS, FASCO, is Director of Breast Oncology at NewYork-Presbyterian/
The results were compelling, demonstrating that the addition of an immune checkpoint inhibitor in combination with chemotherapy before surgery and continuing as a single agent after surgery showed statistically significant and clinically meaningful improvements in event-free survival.
The results were compelling, demonstrating that the addition of an immune checkpoint inhibitor in combination with chemotherapy before surgery and continuing as a single agent after surgery showed statistically significant and clinically meaningful improvements in event-free survival.
“The results were so impressive that the trial transformed the standard of care for patients with this high-risk breast cancer,” says Dr. Hershman, a renowned physician-scientist who has been involved in numerous clinical trials to identify new therapeutics for hard-to-treat breast cancers. “Once a trial starts to demonstrate very strong results that have the potential to keep people alive longer, physicians tend to change their practice very, very quickly, especially for a disease that doesn’t have any other satisfactory treatment.”
Subsequent to the FDA approval of pembrolizumab, results of the fourth interim analysis of data from the KEYNOTE-522 trial were published in February 2022 in The New England Journal of Medicine. This trial evaluated 1,174 patients with previously untreated, stage II or stage III TNBC, specifically comparing the addition of pembrolizumab in 784 patients versus placebo in 390 patients to neoadjuvant chemotherapy (carboplatin and paclitaxel followed by doxorubicin or epirubicin and cyclophosphamide) with completion of one year of pembrolizumab or placebo after surgery. The updated analysis, which included a 39-month median follow-up of patients, reaffirmed the benefit of pembrolizumab with a statistically significant improvement in event-free survival with three-year event-free survival rates of 84.5 percent for the pembrolizumab group and 76.8 percent for the placebo group.
These results prompted an ASCO Guideline Rapid Recommendation Update on neoadjuvant therapy for breast cancer, now published in the June 21, 2022 issue of the JCO Oncology Practice. Dr. Hershman, who has an enduring association with ASCO, served as Guideline Co-Chair of the Expert Panel. The updated guideline includes the following panel recommendations for patients with stage II or III, early-stage TNBC:
- Administer pembrolizumab (200 mg once every 3 weeks or 400 mg once every 6 weeks) in combination with neoadjuvant chemotherapy, followed by adjuvant pembrolizumab after surgery
- Adjuvant pembrolizumab may be given either concurrently with or after completion of radiation therapy
- Perform careful screening for and management of common toxicities due to immune-mediated adverse events (irAEs)
Considering the Adverse Events
In addition to recommendations provided for use of pembrolizumab, the ASCO guideline offers detailed practice recommendations in the management of adverse events in patients treated with immune checkpoint inhibitor therapy and provides an important resource for clinicians. Grade 3 or higher treatment-related events occurred in 77.1 percent and 73.3 percent of the patients in the pembrolizumab-chemotherapy group and in the placebo-chemotherapy group, respectively. The majority of these occurred during the neoadjuvant treatment phase rather than the adjuvant phase.
- The most commonly occurring grade 3 or higher treatment-related adverse events (TRAEs) in the pembrolizumab-chemotherapy and placebo-chemotherapy groups, respectively, were:
- neutropenia - 34.5 percent versus 33.4 percent
- decrease in neutrophil count - 18.6 percent versus 23.1 percent
- anemia - 18.0 percent versus 14.9 percent
- Endocrine disorders, including hypo- or hyperthyroidism, adrenal insufficiency, thyroiditis, and hypophysitis, occurred more frequently in the pembrolizumab/
chemotherapy arm (26.8 percent) than in the placebo/ chemotherapy arm (9.1 percent) - Four deaths in the pembrolizumab-chemotherapy group and one death in the placebo-chemotherapy group were attributed to TRAEs.
- TRAEs that led to discontinuation of the trial regimen occurred in 27.7 percent of patients in the pembrolizumab-chemotherapy group and 14.1 percent of patients in the placebo-chemotherapy group.
- Grade 3 or higher immune-mediated adverse events (irAEs) occurred in 12.9 percent of patients in the pembrolizumab/chemotherapy group and 1.0 percent of patients in the placebo-chemotherapy group.
“Careful attention should be paid to screening and following patients for these side effects that can be lifelong among those being treated with pembrolizumab,” says Dr. Hershman in a related article published in the ASCO Post. “The guideline specifies the need for careful screening for, and management of, common toxicities, given that immune-related adverse events from pembrolizumab can be severe and permanent.”
Succeeding Phases of Analysis
Will event-free survival benefit with neoadjuvant and adjuvant pembrolizumab translate into an improvement in overall survival? Will adjuvant pembrolizumab be needed for patients who achieve pathologic complete response? Should adjuvant pembrolizumab be used in patients with residual disease after neoadjuvant chemotherapy without pembrolizumab?
These are among the outstanding questions that remain for researchers and clinicians to answer with continued follow-up of patients in the KEYNOTE-522 trial and other clinical trials underway.
