What is the best course of action for patients with non-small cell lung (NSCL) cancer who have completed Keytruda (pembrolizumab) treatment and are found to have brain metastasis?

Management of NSCLC Patients with Brain Metastases After Completing Pembrolizumab

For NSCLC patients who develop brain metastases after completing pembrolizumab, local therapy with stereotactic radiosurgery (SRS) or whole-brain radiation therapy (WBRT) should be offered based on the number and size of metastases, with consideration for resuming pembrolizumab if the patient has high PD-L1 expression (≥50%) and good performance status. 1, 2

Initial Assessment and Prognostic Stratification

When brain metastases are discovered after pembrolizumab completion, immediately assess:

• Performance status using Karnofsky Index (KI): Patients with KI <70% should receive best supportive care only, as median survival is <2 months and treatment offers no benefit 1, 2
• RPA classification: Determine if patient is Class I (<65 years, KI ≥70%, no extracranial metastases, controlled primary), Class II (KI ≥70%, other features), or Class III (KI <70%) 1, 2
• Number and size of brain metastases: This determines the local therapy approach 1, 2
• Symptom burden: Symptomatic patients require immediate local therapy regardless of systemic therapy plans 1

Local Therapy Algorithm

For 1-4 Brain Metastases (RPA Class I-II):

• SRS alone is the preferred treatment for lesions <3-4 cm diameter 1, 2
• Surgery followed by SRS may be considered for single, large (>3 cm) lesions causing mass effect 1
• WBRT should be avoided in this setting to preserve neurocognitive function 1

For >4 Brain Metastases (RPA Class I-II):

• WBRT is recommended when more than 3-4 metastases are present 1, 2
• Consider hippocampal-avoidance WBRT with memantine for neuroprotection if available 1

For Asymptomatic Brain Metastases:

• Local therapy should NOT be routinely deferred unless specific molecular indications exist 1, 2
• Multidisciplinary discussion (neuro-oncology, neurosurgery, radiation oncology) is required before any deferral decision 1

Systemic Therapy Considerations After Local Treatment

Resuming Pembrolizumab:

Pembrolizumab can be resumed after local therapy if:

• PD-L1 expression is ≥50%: Phase 2 data shows 29.7% intracranial response rate in PD-L1 ≥1% patients, with higher responses expected in ≥50% expressors 3
• Patient had prior clinical benefit from pembrolizumab: Those who experienced immune-related adverse events (IRAEs) during initial treatment had significantly longer intracranial time-to-treatment-failure (14 vs 5 months, p=0.001) 4
• Performance status remains 0-2 3, 4

Combination Therapy Option:

• Pembrolizumab plus pemetrexed and platinum may be offered for asymptomatic or controlled brain metastases in immunotherapy-naïve patients with PD-L1 expression, though this applies primarily to treatment-naïve settings 1

Alternative Systemic Options:

If pembrolizumab is not appropriate:

• EGFR-mutant tumors: Osimertinib (if not previously used) can be initiated with local therapy deferred until intracranial progression 1
• ALK-rearranged tumors: Alectinib, brigatinib, or ceritinib with deferred local therapy 1
• Standard chemotherapy: Pemetrexed (non-squamous) or docetaxel as second-line options 1, 5

Supportive Care Management

Corticosteroids:

• Dexamethasone 4 mg/day (or equivalent) for symptomatic metastases or significant edema 1, 2
• Early tapering after radiotherapy is essential to minimize long-term side effects 1, 2
• Do NOT use corticosteroids for asymptomatic metastases as they may impair immunotherapy efficacy 2

Monitoring Strategy

• Brain MRI every 6-8 weeks initially after local therapy to assess response 5
• Circulating tumor DNA (ctDNA) monitoring if available, as negative ctDNA correlates with sustained remission 6
• Clinical assessment for neurological symptoms at each visit 1, 2

Critical Pitfalls to Avoid

1. Do not withhold local therapy in asymptomatic patients based solely on prior pembrolizumab response—local control is essential for preventing neurological deterioration 1

2. Do not assume pembrolizumab lacks CNS activity—case reports and phase 2 data demonstrate complete responses in brain metastases with pembrolizumab monotherapy in high PD-L1 expressors 7, 3, 8

3. Do not treat RPA Class III patients (KI <70%) with aggressive therapy—best supportive care is the only appropriate option 1, 2

4. Do not delay molecular testing—EGFR and ALK status may fundamentally change the treatment approach even after prior pembrolizumab 1, 5

Evidence for Pembrolizumab Activity in Brain Metastases

Recent case reports demonstrate that pembrolizumab can achieve complete radiographic resolution of brain metastases as monotherapy in PD-L1-high patients, with one case showing sustained response >50 months when combined with surgery 8, 6. The phase 2 trial by Goldberg et al. showed 29.7% intracranial response rate in PD-L1 ≥1% NSCLC patients with median follow-up of 8.3 months 3. Patients who developed IRAEs during pembrolizumab had significantly improved intracranial control (median TTF 14 vs 5 months) 4. These data support considering pembrolizumab continuation or resumption in appropriately selected patients after local therapy.