In patients with early‑stage triple‑negative breast cancer that are PD‑L1 positive (Combined Positive Score ≥ 10), should pembrolizumab be given as neoadjuvant therapy, adjuvant therapy, or both?

Pembrolizumab in Early-Stage Triple-Negative Breast Cancer: Both Neoadjuvant and Adjuvant

For patients with early-stage triple-negative breast cancer (TNBC), pembrolizumab should be administered in BOTH the neoadjuvant and adjuvant settings—this is independent of PD-L1 status. The treatment paradigm involves pembrolizumab combined with chemotherapy during neoadjuvant therapy, followed by continuation of pembrolizumab as a single agent after surgery in the adjuvant phase.

Treatment Algorithm

Stage II-III TNBC (Standard Approach)

Neoadjuvant Phase:

• Pembrolizumab 200 mg IV every 3 weeks PLUS chemotherapy
• Chemotherapy regimen (KEYNOTE-522 protocol):
  • 4 cycles paclitaxel + carboplatin + pembrolizumab
  • Followed by 4 cycles doxorubicin/epirubicin + cyclophosphamide + pembrolizumab
• Total neoadjuvant duration: approximately 24 weeks 1

Surgical Phase:

• Definitive surgery after completion of neoadjuvant therapy

Adjuvant Phase:

• Pembrolizumab 200 mg IV every 3 weeks as monotherapy
• Continue for up to 9 additional cycles
• Critical point: Continue adjuvant pembrolizumab REGARDLESS of pathologic complete response (pCR) status 1

Stage I TNBC (Selected Cases)

For cT2 cN0 disease, consider adding pembrolizumab to chemotherapy on a case-by-case basis 1

Key Evidence Supporting Both Phases

The KEYNOTE-522 trial demonstrated that the complete regimen (neoadjuvant + adjuvant pembrolizumab) significantly improved overall survival, with 60-month OS of 86.6% versus 81.7% (P=0.002) 2. The St Gallen 2023 consensus explicitly states that "panelists favored ongoing adjuvant pembrolizumab, though the clinical value of this adjuvant phase of therapy is not known" 1. Despite uncertainty about the isolated contribution of the adjuvant phase, the FDA approval and guideline recommendations are based on the complete treatment paradigm 3.

PD-L1 Status: Not Required for Treatment Decision

The benefit from pembrolizumab is independent of PD-L1 status in the early-stage setting 1. This is a critical distinction from metastatic TNBC, where PD-L1 CPS ≥10 is required. For early-stage disease:

• No PD-L1 testing is needed before initiating treatment
• Both PD-L1-positive and PD-L1-negative patients benefit
• The ESMO 2023 guidelines recommend pembrolizumab for stage II-III TNBC without PD-L1 restriction 4

Management After Surgery Based on Response

If Pathologic Complete Response (pCR):

• Continue adjuvant pembrolizumab for 9 cycles
• No additional therapy needed 1

If Residual Disease (non-pCR):

Without germline BRCA1/2 mutation:

• Adjuvant pembrolizumab for 9 cycles PLUS
• Capecitabine for 6-8 cycles 1, 4

With germline BRCA1/2 mutation:

• Adjuvant pembrolizumab for 9 cycles PLUS
• Olaparib for 1 year 1, 4

The combination of pembrolizumab with capecitabine or olaparib is increasingly used in practice, though optimal sequencing data are limited 5, 6.

Safety Considerations

Common pitfalls to avoid:

1. Do not omit the adjuvant pembrolizumab phase even if pCR is achieved—the trial design included continuation regardless of response 1

2. Monitor closely for immune-related adverse events (irAEs) throughout both treatment phases and after completion. Grade ≥3 treatment-related AEs occur in approximately 78% of patients, but pembrolizumab-specific toxicity is manageable 2, 7

3. Do not use pembrolizumab solely in the adjuvant setting without prior neoadjuvant exposure—this approach is explicitly not recommended 4

4. Dose-dense chemotherapy schedules with pembrolizumab remain controversial; the St Gallen panel was split, with 38% noting lack of safety data for every-2-week regimens 1

Alternative Regimen (Limited Use)

An anthracycline-free option (docetaxel/carboplatin/pembrolizumab for 6 cycles) exists but is designated as "useful in certain circumstances" by NCCN 8. This should be reserved for patients with contraindications to anthracyclines or node-negative disease, as pCR rates are lower in node-positive patients (45% vs 65% in node-negative) compared to the standard KEYNOTE-522 regimen.

Quality of Life

Patient-reported outcomes from KEYNOTE-522 showed no substantial differences in quality of life, emotional functioning, or physical functioning between pembrolizumab and placebo groups during either neoadjuvant or adjuvant phases 9. This supports the tolerability of the complete treatment paradigm.