What is the evidence for using pembrolizumab (pembrolizumab) in a patient with cT2N0 (clinical stage T2N0) triple-negative breast cancer?

Pembrolizumab for cT2N0 Triple-Negative Breast Cancer

For cT2N0 triple-negative breast cancer, pembrolizumab combined with neoadjuvant chemotherapy should be considered, as current guidelines support its use in stage II disease (which includes cT2N0), demonstrating significant improvements in event-free survival (HR 0.63, P<0.001) and overall survival (86.6% vs 81.7% at 60 months, P=0.002). 1, 2, 3

Guideline-Based Recommendations

Primary Treatment Approach

• ESMO 2024 guidelines explicitly recommend neoadjuvant chemotherapy plus pembrolizumab for cT2-4 N0 or any N-positive (stage II-III) TNBC unless there are risk factors for excessive immune-related toxicity. 1

• The St. Gallen 2023 consensus panel specifically notes that patients with cT2 cN0 were eligible for pembrolizumab in the KEYNOTE-522 trial, and recommends consideration of adding pembrolizumab for this stage. 1

• Neoadjuvant therapy is preferred over adjuvant-only treatment for cT1c-4 N0 or any N-positive TNBC to allow assessment of pathologic complete response, which remains a strong prognostic factor. 1, 4

Evidence Supporting This Recommendation

Survival Benefits from KEYNOTE-522

The pivotal KEYNOTE-522 trial, which included cT2N0 patients, demonstrated:

• Event-free survival at 36 months: 84.5% with pembrolizumab-chemotherapy versus 76.8% with chemotherapy alone (HR 0.63; 95% CI 0.48-0.82, P<0.001). 2

• Overall survival at 60 months: 86.6% with pembrolizumab-chemotherapy versus 81.7% with chemotherapy alone (P=0.002), representing a clinically meaningful mortality reduction. 3

• Pathologic complete response rates improved from 51.2% to 64.8% with pembrolizumab addition. 4

Treatment Protocol

The recommended regimen consists of: 1, 4

• Neoadjuvant phase: 4 cycles of pembrolizumab 200 mg every 3 weeks plus paclitaxel and carboplatin, followed by 4 cycles of pembrolizumab plus anthracycline-cyclophosphamide (AC or EC)

• Adjuvant phase: Pembrolizumab every 3 weeks for 9 additional cycles after surgery, regardless of pathologic response (pCR or residual disease) 1

Key Implementation Points

PD-L1 Testing Not Required

• Pembrolizumab benefit is independent of PD-L1 status in early TNBC, unlike metastatic disease where PD-L1 testing is mandatory. 4

• Testing for PD-L1 is not required to determine eligibility for pembrolizumab in early-stage TNBC. 4

Carboplatin Considerations

• While the St. Gallen panel was divided on routine carboplatin use for all stage II TNBC, some panelists favor its inclusion particularly in node-positive disease and in conjunction with pembrolizumab-based treatment. 1

• ESMO suggests carboplatin should be standard for stage II-III TNBC receiving neoadjuvant pembrolizumab, with benefit independent of germline BRCA1/2 status. 4

Dose-Dense Scheduling Controversy

• The St. Gallen panel was split on using dose-dense every-2-week AC/EC regimens versus standard every-3-week schedules with neoadjuvant pembrolizumab; 38% noted lack of safety and efficacy data for the dose-dense approach in this context. 1

Critical Safety Monitoring

Patients receiving pembrolizumab must be monitored very closely for immune-related adverse events throughout treatment, following ESMO guidelines for immunotherapy toxicity management. 1

• Grade 3-4 immune-related adverse events occur in approximately 5% of patients. 5

• The most common immune-mediated adverse event is grade 1-2 hypothyroidism. 1

• Treatment-related deaths occurred in 0.7% of pembrolizumab-treated patients in clinical trials. 5

Post-Neoadjuvant Management

For Patients with Residual Disease

• If germline BRCA1/2 wild-type: Add capecitabine for 6-8 cycles. 1, 6

• If germline BRCA1/2 mutation positive with residual disease: Add olaparib for 1 year. 1

• Continue adjuvant pembrolizumab for the full 9 cycles regardless of pathologic response. 1

Prognostic Value of Response

• Pembrolizumab shifts patients into lower residual cancer burden (RCB) categories across the entire spectrum compared with chemotherapy alone. 7

• The greatest EFS benefit was observed in patients with RCB-2 (intermediate residual disease), with HR 0.52 (95% CI 0.32-0.82). 7

Common Pitfalls to Avoid

• Do not give pembrolizumab solely in the adjuvant setting without prior neoadjuvant pembrolizumab treatment - this approach is not supported by evidence. 1

• Do not delay treatment initiation; begin neoadjuvant therapy within 2-4 weeks of diagnosis completion. 6

• Do not discontinue adjuvant pembrolizumab based on achieving pCR - continue for the full 9 adjuvant cycles as this improves outcomes even in complete responders. 1

• Ensure completion of at least 8 cycles of pembrolizumab when possible, as real-world data shows this is associated with improved pCR rates (OR 2.49, P=0.037). 8

Alternative Considerations

For patients with contraindications to pembrolizumab (significant autoimmune disease, risk factors for excessive immune toxicity), standard anthracycline-taxane chemotherapy remains appropriate, though outcomes are inferior. 1