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Consistent benefit of neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab in high-risk early stage triple negative breast cancer

Previous results of the KEYNOTE-522 trial showed that pembrolizumab added to neoadjuvant chemotherapy followed by definitive surgery and adjuvant pembrolizumab significantly improves the event-free survival (EFS) in patients with high-risk early-stage triple negative breast cancer (TNBC). Results of several sensitivity analyses of this trial, presented at SABCS 2021, further solidify this finding, with subgroup analyses showing a consistent EFS benefit with this treatment strategy, irrespective of nodal status or disease stage.

Previously, pembrolizumab demonstrated clinical efficacy in the first line treatment of patients with metastatic TNBC, with a manageable safety profile. In addition to this, the KEYNOTE-173 and I-SPY2 trial also showed promising activity with a combination of pembrolizumab and chemotherapy in the neoadjuvant treatment of early stage TNBC. KEYNOTE-522 is a prospective, randomized, placebo-controlled, phase III trial evaluating pembrolizumab as neoadjuvant and adjuvant therapy for early-stage TNBC. Previous reports of this trial showed that adding pembrolizumab to neoadjuvant chemotherapy resulted in a statistically significant and clinically relevant increase in the rate of pathologic complete responses (pCR), while neoadjuvant pembrolizumab + chemotherapy followed by adjuvant pembrolizumab significantly improved the event-free survival (EFS). Based on these findings, neoadjuvant pembrolizumab + chemotherapy followed by adjuvant pembrolizumab after surgery received FDA approval for the treatment of high-risk early-stage TNBC patients.

Study design KEYNOTE-522

In KEYNOTE-522, a total of 1,174 patients with newly diagnosed TNBC stage T1c N1-2 or T2-4 N0-2 were randomized (2:1) to pembrolizumab (200 mg Q3W) or placebo, both given with 4 cycles of paclitaxel + carboplatin followed by 4 cycles of doxorubicin or epirubicin + cyclophosphamide (neoadjuvant phase). After definitive surgery, patients received pembrolizumab or placebo for 9 cycles or until recurrence or unacceptable toxicity (adjuvant phase). The co-primary endpoints of the trial were pCR assessed by the pathologists and EFS assessed by the investigator in the intent-to-treat population, with secondary study objectives including overall survival (OS) and pCR, EFS and OS in the PD-L1 positive population. In addition to this, prespecified sensitivity and subgroup analyses were performed to assess the robustness and consistency of the primary EFS result.


Just over half of the patients in the study had node-positive disease, three quarters had stage II disease and about 55% was pre-menopausal at the time of the diagnosis. In three quarters of the patients the HER2 status was scored at 0-1+ by immunohistochemistry and about one out of five patients had a lactate dehydrogenase (LDH) level above the upper limit of normal (ULN). In the primary EFS analysis, a statistically significant and clinically relevant benefit was seen for patients in the pembrolizumab arm (HR [95%CI]: 0.63 [0.48-0.82]; p=0.00031) with 36-month EFS rates of 84.5% and 76.8% for patients in the pembrolizumab and placebo arm, respectively.

In total, five prespecified sensitivity analyses were performed. One of these analyses assessed the impact of different censoring rules, while the other four assessed the impact of different event definitions. Treatment effects on EFS were also examined in prespecified patient subgroups defined by nodal involvement (positive or negative), disease stage (II or III), menopausal status (pre-menopausal or post- menopausal), HER2 status (2+ by IHC but FISH- or 0-1+ by IHC), and LDH (>ULN or ≤ULN). In brief, the benefit of neoadjuvant pembrolizumab + chemotherapy followed by adjuvant pembrolizumab compared to neoadjuvant chemotherapy alone was generally consistent with the primary EFS results in all five sensitivity analyses, underscoring the robustness of the primary EFS analysis.

In addition to the sensitivity analyses, the prespecified subgroup analyses also revealed a robust image with a consistent benefit in the pembrolizumab arm irrespective of nodal status, disease stage, menopausal status, HER2 status and LDH level. As expected, node positive patients had a worse EFS than patients without nodal involvement in both treatment arms. Nevertheless, the use of pembrolizumab in the neoadjuvant and adjuvant setting resulted in a significant EFS benefit among patients without nodal involvement. A similar image was seen in the analysis in function of the disease stage, revealing a consistent benefit of pembrolizumab irrespective of tumor size and underscoring the importance of an effective early intervention with pembrolizumab, even in small tumors.

Adverse events

In the neoadjuvant phase, the adverse event profile seen in the pembrolizumab arm was dominated by chemotherapy-related toxicity, with nausea, alopecia and anemia being the most common adverse events. In the adjuvant phase the incidence of grade ≥3 adverse events was low at only 6.3% in the pembrolizumab arm and 2.7% in the control arm. Not surprisingly, immune-related adverse events in the neoadjuvant phase were more common among patients receiving pembrolizumab than in the control arm (43.6% versus 21.9%). In the adjuvant phase immune-related adverse events were rare at 10.2% in the pembrolizumab arm and 6.0% in the control arm (grade ≥3 2.9% versus 0.3%).


The EFS sensitivity analyses performed on the data from KEYNOTE-522 showed a robust treatment benefit of neoadjuvant pembrolizumab + chemotherapy followed by adjuvant pembrolizumab for previously untreated non-metastatic TNBC. Furthermore, this benefit was consistently seen across a broad selection of patient subgroups. Most importantly, pembrolizumab prolonged the EFS irrespective of nodal status and disease stage. As such, these data further support pembrolizumab plus platinum-based neoadjuvant chemotherapy followed by definitive surgery and adjuvant pembrolizumab as a new standard of care for patients with high-risk, early-stage TNBC.


Schmid P, 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. Presented at SABCS 2021; abstract GS1-01.

Speaker Peter Schmid

Peter Schmid

Peter Schmid, MD, PhD, Barts Cancer Institute, Queen Mary University of London, London, England


See: Keyslides

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