Data further support pembrolizumab regimen for early triple-negative breast cancer
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The addition of pembrolizumab to neoadjuvant chemotherapy and as monotherapy in the adjuvant setting extended EFS for patients with early triple-negative breast cancer, according to results presented at San Antonio Breast Cancer Symposium.
Results of the randomized phase 3 KEYNOTE-522 study showed consistent benefit with this treatment approach across prespecified patient subgroups.
“We know that pembrolizumab [Keytruda, Merck] showed antitumor activity and manageable safety in patients with triple-negative metastatic breast cancer, especially in the first-line setting. We also know that neoadjuvant pembrolizumab plus chemotherapy showed manageable safety and antitumor activity among patients with early-stage disease in KEYNOTE-173 and I-SPY 2,” Peter Schmid, MD, PhD, FRCP, clinical director of St. Bartholomew Breast Cancer Centre in London and lead of the Centre for Experimental Cancer Medicine at Barts Cancer Institute, said during a presentation. “We, therefore, initiated KEYNOTE-522 as the first prospective phase 3 trial of pembrolizumab in both the neoadjuvant and adjuvant settings.”
As Healio previously reported, the primary analyses showed the addition of pembrolizumab to neoadjuvant chemotherapy and as monotherapy in the adjuvant setting resulted in a statistically significant and clinically meaningful increase in pathologic complete response (PCR).
Updated results presented in July showed the regimen conferred a statistically significant and clinically meaningful improvement in EFS.
“Based on these results, the FDA approved pembrolizumab plus chemotherapy in the neoadjuvant setting and continued as a single agent in the adjuvant setting for patients with high-risk, early-stage triple-negative breast cancer,” Schmid said.
During SABCS, Schmid presented results from five prespecified sensitivity and subgroup analyses to assess the consistency of the primary EFS results.
Median follow-up was 39.1 months.
Results showed the benefit of neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab compared with neoadjuvant chemotherapy alone was consistent with the primary EFS results across all five sensitivity analyses, Schmid said.
Data from one sensitivity analysis that employed alternative censoring rules showed a higher EFS rate among patients assigned the pembrolizumab regimen (85.3% vs. 77.9%; HR = 0.64; 95% CI, 0.48-0.84).
“This shows the robustness of EFS benefit in the pembrolizumab group,” Schmid said. “The benefit was generally consistent across a broad range of prespecified patient subgroups.”
Results of another sensitivity analysis, which removed “positive margin at last surgery” from the EFS definition, also were notable, Schmid said.
Data showed EFS rates of 84.6% among patients who received pembrolizumab and 77.5% of those who did not (HR = 0.65; 95% CI, 0.5-0.85).
“EFS again remained consistent with the primary analysis, indicating that excluding positive surgical margins from the EFS definition did not influence the conclusion of the primary analysis,” Schmid said. “The number of patients with positive margins was small, and those patients continued to be followed for other EFS events. Among the 16 patients with a positive margin at last surgery, 12 went on to experience local or distant recurrence.”
Results of subgroup analyses further indicated consistent EFS benefit with pembrolizumab in prespecified subgroups based on nodal involvement, disease stage, menopausal status, HER2 status and lactate dehydrogenase level.
The researchers observed no new safety concerns.
“As expected, patients with nodal involvement in both groups had poorer outcomes compared with those without nodal involvement,” Schmid said. “Nevertheless, patients in the pembrolizumab group still had improved outcomes compared with placebo, suggesting that pembrolizumab provides benefit regardless of nodal status. These results further support pembrolizumab plus platinum-containing neoadjuvant chemotherapy, followed by adjuvant pembrolizumab after surgery, as a new standard of care treatment regimen for patients with high-risk, early-stage triple-negative breast cancer.”
Perspective
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Hope S. Rugo, MD, FASCO
How can we explain these findings with the differential impact on stage and by node status, and the differential impact on PCR vs. EFS? Indeed, response to neoadjuvant therapy remains a predictor for long-term outcome.
Among the first 600 patients enrolled, researchers saw a left shift in residual cancer burden, suggesting that this shift is responsible for the improved EFS seen in the non-PCR group and at least in part responsible for the differential impact on PCR by node status. We hope to see residual cancer burden data from this trial next year.
With any new therapy, we need to balance efficacy against toxicity. As we have seen in other settings, the combination of a checkpoint inhibitor with chemotherapy is associated with a relative increase in immune toxicity, which then decreases with an immune checkpoint inhibitor alone. The major toxicities include the endocrine system and skin. There are, of course, a number of unanswered questions, including whether everyone needs a checkpoint inhibitor, understanding the balance between risk and toxicity, what the optimal chemotherapy backbone is and whether everyone needs 1 year of treatment with pembrolizumab.
We do not yet know the answers to those questions, but I believe T1c node-negative disease should be treated in the neoadjuvant setting because we can optimize their outcome by understanding response. However, these patients should be treated with chemotherapy alone, as we do not have data with checkpoint inhibitors in that setting. Patients with node-positive or T2 or greater disease should be treated with pembrolizumab with a chemotherapy backbone including anthracycline.
For patients with PCR or non-PCR, should we complete 1 year of pembrolizumab or stop with no further therapy? There is additional toxicity, although decreased from the neoadjuvant setting. Hopefully, we will understand more of these details in the future. There are ongoing phase 3 trials with checkpoint inhibitors in triple-negative breast cancer and we hope to see results from these trials in the near future.
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Schmid P, et al. Abstract GS1-01. Presented at: San Antonio Breast Cancer Symposium (virtual meeting); Dec. 7-10, 2021.
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