Is pembrolizumab (pembrolizumab) effective in treating brain metastases (brain mets)?

Pembrolizumab's Effectiveness in Treating Brain Metastases

Pembrolizumab may be offered to patients with asymptomatic brain metastases from certain cancers, particularly PD-L1-positive NSCLC when combined with chemotherapy, and melanoma, with evidence showing meaningful intracranial activity. 1

Effectiveness by Cancer Type

Non-Small Cell Lung Cancer (NSCLC)

• For patients with asymptomatic brain metastases from immunotherapy-naïve, PD-L1-positive NSCLC:
  • Pembrolizumab combined with pemetrexed and platinum chemotherapy is recommended 1
  • Significant survival benefit observed in patients with brain metastases (median OS 19.2 months vs 7.5 months with chemotherapy alone) 1
  • In a pooled analysis of KEYNOTE trials, patients with stable brain metastases receiving pembrolizumab plus chemotherapy had:
    • Improved OS (18.8 vs 7.6 months; HR 0.48) compared to chemotherapy alone
    • Improved PFS (6.9 vs 4.1 months; HR 0.44) 2

Melanoma

• Pembrolizumab shows activity in melanoma brain metastases:
  • 26% brain metastasis response rate in a phase II trial 3
  • Durable responses with all ongoing at 24 months 3
  • 48% of patients alive at 24 months 3
  • For melanoma with brain metastases, ipilimumab plus nivolumab is also recommended and may allow deferral of local therapy until intracranial progression 1

Important Clinical Considerations

Patient Selection

1. Asymptomatic brain metastases: Pembrolizumab is primarily studied in patients with asymptomatic brain metastases not requiring corticosteroids 1, 3, 4
2. Size limitations: Most studies included brain metastases between 5-20mm in diameter 3, 4
3. PD-L1 status: For NSCLC, PD-L1 expression is an important biomarker:
   • Responses in NSCLC brain metastases were seen only in patients with PD-L1 expression ≥1% 5

Treatment Approach

• For symptomatic brain metastases: Local therapy (surgery/radiation) should be offered regardless of systemic therapy 1
• For asymptomatic brain metastases:
  • In select cases (as outlined in ASCO-SNO-ASTRO guidelines), pembrolizumab may be used with deferral of local therapy until progression 1
  • For most other cases, local therapy should not be deferred 1

Safety Profile

• Neurologic adverse events occur in approximately 65% of patients, but most are grade 1-2 3
• Potential neurologic complications include:
  • Seizures (requiring anticonvulsants) 3
  • Cognitive dysfunction (usually transient) 3, 4
• Overall safety profile is generally acceptable, with similar treatment-related adverse events in patients with or without brain metastases 2

Biomarkers and Response Prediction

• Higher pretreatment tumor CD8 cell density and PD-L1 expression correlate with better response 3
• Brain and extracranial responses tend to be concordant, suggesting systemic response may predict brain response 3

Pitfalls and Caveats

1. Multidisciplinary approach is essential: Decisions about deferring local therapy require input from neuro-oncology, medical oncology, neurosurgery, and radiation oncology 1
2. Radiation may still be needed: Consider radiation for large or symptomatic lesions, which were excluded from most pembrolizumab trials 3
3. Corticosteroid use: Most trials excluded patients requiring corticosteroids, which may reduce immunotherapy efficacy
4. Response assessment: Regular brain imaging is required to monitor response and detect progression 2

In conclusion, pembrolizumab demonstrates meaningful activity against brain metastases in select patients, particularly those with PD-L1-positive NSCLC when combined with chemotherapy, and those with melanoma. The decision to use pembrolizumab for brain metastases should be made in the context of cancer type, PD-L1 status, symptom status, and in consultation with a multidisciplinary team.