Is Keytruda (pembrolizumab) effective for metastatic breast cancer and ovarian cancer?

Pembrolizumab (Keytruda) Efficacy for Metastatic Breast and Ovarian Cancer

Pembrolizumab is not broadly effective for most metastatic breast or ovarian cancers, but may benefit specific subgroups with certain biomarkers like PD-L1 expression, MSI-H/dMMR, or high tumor mutation burden.

Efficacy in Metastatic Breast Cancer

Triple-Negative Breast Cancer (TNBC)

• Pembrolizumab shows efficacy in TNBC with PD-L1 expression (CPS ≥10) when combined with chemotherapy in first-line treatment 1
  • Demonstrated significant improvement in progression-free survival (9.7 vs 5.6 months) compared to chemotherapy alone
  • FDA approved for this specific indication

Hormone Receptor-Positive Breast Cancer

• Limited evidence supports pembrolizumab in HR-positive metastatic breast cancer
• Not a standard of care treatment option per NCCN and ESMO guidelines 2
• Case reports suggest potential benefit when combined with endocrine therapy in selected patients with high T-cell receptor repertoire, but this is not standard practice 3

Biomarker-Specific Indications

• Pembrolizumab is FDA approved for solid tumors with:
  • Microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) tumors that have progressed after prior treatment 2
  • High tumor mutation burden (≥9 mutations/megabase) in heavily pretreated patients 2

Efficacy in Metastatic Ovarian Cancer

• Limited evidence for pembrolizumab in ovarian cancer
• In heavily pretreated platinum-resistant ovarian cancer, combination of pembrolizumab with bevacizumab and cyclophosphamide showed modest activity:
  • Overall response rate of only 13%
  • Disease control rate of 33%
  • Median progression-free survival of just 3.5 months 4
• Not currently recommended as standard therapy for ovarian cancer by major guidelines

Treatment Algorithm for Metastatic Breast Cancer

1. First, determine breast cancer subtype:

   • Triple-negative
   • HR-positive/HER2-negative
   • HER2-positive

2. For triple-negative breast cancer:

   • Test for PD-L1 expression (CPS score)
   • If CPS ≥10: Consider pembrolizumab + chemotherapy as first-line therapy
   • If CPS <10: Standard chemotherapy approaches are preferred

3. For HR-positive metastatic breast cancer:

   • Standard approach is endocrine therapy ± targeted agents (CDK4/6 inhibitors, PI3K inhibitors, or mTOR inhibitors) 5
   • Pembrolizumab is not recommended outside clinical trials

4. For all breast cancer subtypes, test for biomarkers:

   • MSI-H/dMMR status
   • Tumor mutation burden
   • If positive for either and patient has progressed on standard therapies, pembrolizumab may be considered

Important Considerations

• Toxicity profile: Immune-related adverse events can occur with pembrolizumab, including fatigue, pruritus, hypothyroidism, and potentially serious immune-mediated reactions
• Patient selection: Response rates are higher in biomarker-selected populations
• Combination approaches: Ongoing research is evaluating pembrolizumab in combination with other agents to enhance efficacy

Common Pitfalls to Avoid

1. Using pembrolizumab as monotherapy in unselected breast cancer patients

   • The KEYNOTE-119 trial showed pembrolizumab monotherapy did not significantly improve overall survival versus chemotherapy in previously treated metastatic TNBC 6

2. Assuming efficacy across all breast cancer subtypes

   • Evidence primarily supports use in TNBC with high PD-L1 expression or tumors with specific biomarkers (MSI-H/dMMR or high TMB)

3. Overlooking biomarker testing

   • PD-L1 testing is essential before considering pembrolizumab in TNBC
   • MSI-H/dMMR and TMB testing should be performed in patients who have progressed on standard therapies

4. Expecting high response rates in ovarian cancer

   • Current evidence shows limited efficacy in ovarian cancer outside of specific biomarker-selected populations

In conclusion, pembrolizumab should be considered primarily for metastatic triple-negative breast cancer with high PD-L1 expression (CPS ≥10) in combination with chemotherapy, or in any breast or ovarian cancer with MSI-H/dMMR or high TMB that has progressed on standard therapies. For most patients with metastatic HR-positive breast cancer or ovarian cancer, other standard treatment approaches remain preferred.