What is the best treatment for a patient with progressive brain metastases (brain Mets) despite previous treatment with etoposide (VP-16)/carboplatin, radiation, and durvalumab (Imfinzi) who developed pneumonitis due to immunotherapy?

Treatment for Progressive Brain Metastases After Immunotherapy-Related Pneumonitis

Given the immunotherapy-induced pneumonitis, durvalumab must be permanently discontinued, and the focus should shift to local brain-directed therapy (stereotactic radiosurgery or surgical resection if feasible) combined with non-immunotherapy systemic options. 1

Immediate Management Priorities

Discontinue Immunotherapy Permanently

• Durvalumab must be stopped immediately and permanently due to the development of pneumonitis, as grade ≥2 pneumonitis from prior immunotherapy is an absolute contraindication to further immune checkpoint inhibitor therapy 1
• Pneumonitis occurred in 38.2% of patients receiving durvalumab in the ADRIATIC trial, with 2.7% treatment-related deaths, making rechallenge unsafe 1
• The patient is now ineligible for any further immunotherapy, including alternative checkpoint inhibitors 1

Assess Symptom Burden and Steroid Requirements

• Determine if brain metastases are symptomatic or causing mass effect requiring dexamethasone 1
• Patients requiring significant steroids (>4 mg dexamethasone daily) have dramatically reduced responses to systemic therapy, with intracranial response rates dropping to only 16.7% in symptomatic/steroid-dependent patients 1
• If symptomatic, initiate dexamethasone 16 mg/day in divided doses for moderate to severe symptoms 2

Primary Treatment Strategy: Local Brain-Directed Therapy

Stereotactic Radiosurgery (SRS) as First-Line Local Therapy

• SRS should be offered as the primary treatment for progressive brain metastases, regardless of number of lesions, as it provides superior cognitive outcomes compared to whole-brain radiation 1
• SRS alone is recommended for patients with 1-4 unresected brain metastases, with tumors generally <3-4 cm in diameter 1
• For symptomatic or steroid-dependent patients, local brain-directed therapy combined with systemic therapy is the most reasonable approach 1

Surgical Resection Considerations

• Neurosurgical management should be considered for bulky or symptomatic lesions causing significant mass effect 1
• Surgery can quickly decompress metastases and reduce steroid dependence, potentially improving subsequent systemic therapy efficacy 1
• Post-operative SRS to the resection cavity should follow within 2-4 weeks of surgery 1, 3

Systemic Therapy Options (Non-Immunotherapy)

Second-Line Chemotherapy Regimens

Since the patient has progressed on platinum/etoposide and cannot receive further immunotherapy:

• Topotecan or lurbinectedin are FDA-approved options for relapsed small cell lung cancer (if this is SCLC based on the etoposide/carboplatin/durvalumab regimen) 1
• Tarlatamab (bispecific T-cell engager) is FDA-approved for relapsed SCLC after ≥2 prior systemic regimens, with a 40% overall response rate and 9.7-month median duration of response 1
  • Notably, tarlatamab showed 52% response rate in platinum-resistant disease 1
  • Critical exclusion: Patients with grade ≥2 pneumonitis due to previous immunotherapy are NOT eligible for tarlatamab 1

Alternative Considerations Based on Primary Tumor Type

If the primary tumor is NSCLC (less likely given the regimen but possible):

• Molecular testing should guide treatment if not already performed 3
• For EGFR-mutant NSCLC: osimertinib has CNS activity 1
• For ALK-rearranged NSCLC: alectinib, brigatinib, or lorlatamab have excellent CNS penetration 1, 4

Treatment Algorithm

1. Immediately discontinue durvalumab due to pneumonitis 1
2. Obtain contrast-enhanced brain MRI to assess extent and characteristics of progressive brain metastases 1, 2
3. Initiate dexamethasone if symptomatic (16 mg/day divided doses) 2
4. Urgent multidisciplinary evaluation (neuro-oncology, neurosurgery, radiation oncology) 1
5. Proceed with local therapy:
   • SRS for limited metastases (<3-4 cm, ≤4 lesions preferred) 1
   • Surgical resection for large symptomatic lesions causing mass effect 1, 3
   • Post-operative SRS within 2-4 weeks if surgery performed 1, 3
6. Initiate non-immunotherapy systemic therapy between radiation cycles 3:
   • Topotecan or lurbinectedin for SCLC 1
   • Molecular-targeted therapy if actionable mutations present in NSCLC 1
7. Serial brain MRI every 3 months to monitor response and detect new lesions 3

Critical Pitfalls to Avoid

Do Not Rechallenge with Immunotherapy

• Any further immune checkpoint inhibitor therapy is absolutely contraindicated given the pneumonitis history 1
• This includes switching to alternative checkpoint inhibitors (nivolumab, pembrolizumab, ipilimumab) 1
• Tarlatamab is also excluded due to the grade ≥2 pneumonitis history 1

Do Not Delay Local Therapy

• Systemic therapy alone is insufficient for progressive brain metastases, particularly in symptomatic or steroid-dependent patients 1
• Deferral of local therapy should only occur in highly selected asymptomatic patients with small metastases receiving systemic agents with proven CNS activity 1
• This patient has already progressed through systemic therapy, making local therapy essential 1

Steroid Management

• Taper steroids slowly as clinical situation allows to minimize toxicity (personality changes, immunosuppression, metabolic derangements) 2
• Avoid enzyme-inducing anticonvulsants as they affect chemotherapy metabolism 2

Monitoring Considerations

• Up to 90% of patients with brain metastases experience neurocognitive effects requiring close monitoring 2
• Watch for radiation necrosis as a delayed complication of SRS, particularly if prior radiation was administered 1