What is the recommended use of pembrolizumab immunotherapy for PD‑L1 (programmed death‑ligand 1)‑positive triple‑negative breast cancer (TNBC) in metastatic and neoadjuvant settings, and are there approved indications for HER2‑positive or hormone‑receptor‑positive breast cancer?

Immunotherapy in Breast Cancer

Triple-Negative Breast Cancer: The Primary Indication

Pembrolizumab combined with chemotherapy is the standard of care for PD-L1-positive (CPS ≥10) metastatic triple-negative breast cancer in the first-line setting, and pembrolizumab with neoadjuvant chemotherapy followed by adjuvant pembrolizumab is the standard for high-risk early-stage TNBC regardless of PD-L1 status. 1, 2, 3

Metastatic TNBC: First-Line Treatment Algorithm

Step 1: Mandatory PD-L1 Testing

• All patients with locally recurrent unresectable or metastatic TNBC must undergo PD-L1 testing using an FDA-approved companion diagnostic before treatment decisions 1, 2
• For pembrolizumab: Use the 22C3 assay with Combined Positive Score (CPS) ≥10 cutoff 1, 2
• For atezolizumab: Use the SP142 assay with ≥1% immune cell staining cutoff 1, 2
• Critical pitfall: These assays are NOT interchangeable—different antibodies and scoring systems yield different results 1, 2

Step 2: Treatment Selection Based on PD-L1 Status

For PD-L1-Positive Disease (CPS ≥10):

• Pembrolizumab 200 mg every 3 weeks plus chemotherapy (nab-paclitaxel, paclitaxel, or gemcitabine-carboplatin) 1, 3
  • Improves median PFS from 5.6 to 9.7 months (HR 0.65, P=0.0012) 1, 2
  • Improves overall survival from 16.1 to 23.0 months (HR 0.73, P=0.0093) 4
• Alternative: Atezolizumab plus nab-paclitaxel for PD-L1 ≥1% on immune cells 1, 2
  • Improves PFS from 5.0 to 7.5 months (HR 0.62, P<0.001) 2
  • Improves OS from 15.1 to 25 months (7-month absolute benefit) 2, 4

For PD-L1-Negative Disease:

• Single-agent chemotherapy is preferred—taxanes if not previously used in adjuvant setting 1, 5
• Do NOT use immunotherapy 1

Step 3: Critical Timing Restriction

• Immunotherapy is ONLY indicated if metastatic disease developed de novo OR at least 12 months after completion of (neo)adjuvant chemotherapy 2, 5
• If disease recurred within 12 months of completing adjuvant therapy, immunotherapy is contraindicated—proceed directly to chemotherapy alone 2

Early-Stage TNBC: Neoadjuvant/Adjuvant Setting

Pembrolizumab 200 mg every 3 weeks combined with neoadjuvant chemotherapy, followed by adjuvant pembrolizumab monotherapy after surgery for up to 9 cycles total 3, 6, 7

• This is the standard of care for high-risk early-stage TNBC 2, 8
• Key difference from metastatic setting: PD-L1 testing is NOT required—benefit is independent of PD-L1 status 2, 8
• Improves event-free survival regardless of tumor PD-L1 expression 6, 8

Later-Line Treatment for Metastatic TNBC

Pembrolizumab monotherapy is NOT recommended in second-line or beyond 1, 2

• The KEYNOTE-119 trial showed no OS benefit for pembrolizumab monotherapy versus chemotherapy in second/third-line setting (HR 0.97,95% CI 0.82-1.15) 1
• Even in PD-L1 CPS ≥10 subgroup, no significant OS improvement (HR 0.78, P=0.057) 1
• Immunotherapy MUST be combined with chemotherapy in first-line setting only 2

After ≥2 prior therapies, switch to sacituzumab govitecan (not immunotherapy), which improves median PFS to 5.6 months versus 1.7 months with chemotherapy (HR 0.41, P<0.0001) 5, 4

Immune-Related Adverse Events: Monitoring Requirements

• Grade 3+ immune-related adverse events occur in 5% of patients receiving pembrolizumab-chemotherapy versus 0% with chemotherapy alone 1
• Any-grade immune-mediated events occur in 26% with pembrolizumab-chemotherapy versus 6% with placebo-chemotherapy 1
• Thyroid disease occurs in 23% of patients receiving atezolizumab 4
• Monitor vigilantly for immune-related toxicities affecting any organ system 4

HER2-Positive Breast Cancer: No Approved Indication

Immunotherapy should NOT be used in routine clinical practice for HER2-positive breast cancer outside clinical trials 1, 2

• ESMO provides Level III evidence, Grade D recommendation with 85% consensus against routine use 2
• Pembrolizumab plus trastuzumab produced objective responses in PD-L1-positive tumors with trastuzumab-resistant disease in early studies, but this remains investigational 2
• No survival benefit has been demonstrated to support routine use 1, 2

Hormone Receptor-Positive Breast Cancer: No Approved Indication

Immunotherapy should NOT be used in routine clinical practice for hormone receptor-positive breast cancer outside clinical trials 1, 2

• ESMO provides Level III evidence, Grade D recommendation with 85% consensus against routine use 2
• Several ongoing trials are evaluating immunotherapy in this population, but current evidence does not support use 2
• Standard endocrine therapy with or without CDK4/6 inhibitors remains the backbone of treatment 1

Common Pitfalls to Avoid

Pitfall 1: Using Wrong PD-L1 Assay

• SP142 assay is ONLY for atezolizumab (≥1% immune cell staining cutoff) 2
• 22C3 assay is ONLY for pembrolizumab (CPS ≥10 cutoff) 2
• These are not interchangeable—using the wrong assay invalidates treatment eligibility 1, 2

Pitfall 2: Ignoring Timing Restrictions

• Do NOT initiate immunotherapy if disease recurred within 12 months of completing (neo)adjuvant chemotherapy 2, 5
• This is an absolute exclusion criterion for immunotherapy benefit 2

Pitfall 3: Using Immunotherapy Monotherapy in Later Lines

• Pembrolizumab monotherapy has low response rates in second/third-line setting 1, 2
• Immunotherapy MUST be combined with chemotherapy and used in first-line setting only 2

Pitfall 4: Requiring PD-L1 Testing in Neoadjuvant Setting

• For early-stage TNBC receiving neoadjuvant pembrolizumab, PD-L1 testing is NOT required 2, 8
• Benefit is independent of PD-L1 status in the curative setting 2, 8

Pitfall 5: Using Immunotherapy in Non-TNBC Subtypes

• There is no approved indication for immunotherapy in HER2-positive or hormone receptor-positive breast cancer outside clinical trials 1, 2
• Do not extrapolate TNBC data to other breast cancer subtypes 1, 2