Management of Mixed Response to Immunotherapy in Lung Adenocarcinoma with Brain Metastases
Continue immunotherapy while adding stereotactic radiosurgery (SRS) to the new brain metastasis, as this mixed response pattern (two sites shrinking, one new site emerging) represents localized progression rather than systemic treatment failure and does not warrant discontinuation of an otherwise effective systemic therapy. 1, 2
Understanding Mixed Response Patterns
This clinical scenario represents what is termed "pseudoprogression" or "oligoprogression" during immunotherapy, where most disease sites respond while isolated new lesions develop. 3, 4
The shrinkage of two existing brain metastases indicates the immunotherapy is achieving intracranial activity, which is particularly important given that brain metastases historically showed reduced response to systemic therapy. 5
Research demonstrates that later progression of disease can still respond to continuing immunotherapy due to dynamic adaptations between the immune system and tumor, with documented cases showing marked improvement after apparent progression. 4
The emergence of a single new brain metastasis does not constitute systemic progression and should be managed with local therapy while maintaining systemic control. 1, 3
Recommended Treatment Algorithm
Immediate Management
Continue current immunotherapy without interruption, as discontinuation would risk losing systemic and existing intracranial disease control. 1
Refer urgently to radiation oncology for stereotactic radiosurgery (SRS) to the new brain metastasis, which is the preferred local therapy for limited brain metastases (1-4 lesions). 1, 2
SRS should be performed between immunotherapy cycles, allowing systemic therapy to continue with minimal interruption. 3
Molecular Testing Considerations
If not already performed, molecular testing for actionable mutations is critical as it may alter the treatment approach entirely. 1
For EGFR-mutant disease: Addition of EGFR TKIs to radiation therapy improves OS, PFS, and intracranial PFS. 1
For ALK-rearranged disease: Alectinib, brigatinib, or lorlatinib are recommended to delay intracranial tumor progression (Level I-II evidence). 1
For patients without actionable mutations: Continue immunotherapy as the backbone of systemic therapy. 1
Rationale for Continuing Immunotherapy
Evidence Supporting Treatment Continuation
ESMO guidelines explicitly state that patients with localized progression and ongoing systemic control should continue systemic therapy with local treatment of progressing sites. 1
The 2022 ASCO-SNO-ASTRO guidelines support deferring local therapy in asymptomatic patients receiving CNS-active systemic therapy, but when progression occurs, local therapy should be added rather than systemic therapy discontinued. 1
Pembrolizumab may be offered to patients with asymptomatic brain metastases from immunotherapy-naïve, PD-L1-expressing NSCLC, and the current scenario shows the drug is working systemically. 1
Brain-Specific Immunotherapy Considerations
Research shows that PD-1+ tumor-infiltrating lymphocytes are significantly decreased in brain metastases compared to primary lung lesions (P = 0.034), which may explain discordant responses. 5
Despite reduced PD-1+ TIL infiltration in brain tissue, immunotherapy can still achieve intracranial responses, as evidenced by the two shrinking lesions in this patient. 5
The blood-brain barrier and unique tumor microenvironment of brain metastases create challenges, but combination with local therapy (SRS) overcomes these limitations. 3, 5
Monitoring and Follow-Up
Imaging Schedule
MRI brain should be performed 1 month after SRS and every 3 months thereafter to assess treatment response and surveillance for additional lesions. 3
Continue systemic imaging (CT chest/abdomen/pelvis) per standard protocols to monitor extracranial disease. 3
Symptomatic Management
If the new brain metastasis is symptomatic or causing significant edema, initiate dexamethasone 4 mg/day (or equivalent corticosteroid). 2
Early tapering after SRS is essential to minimize corticosteroid-related complications. 2
Corticosteroids are NOT recommended for asymptomatic brain metastases as they may interfere with immunotherapy efficacy. 2
When to Consider Treatment Change
Criteria for Systemic Therapy Modification
Discontinue or change immunotherapy only if:
Multiple new brain metastases develop (>4 lesions), making SRS impractical and suggesting true systemic progression. 2
Extracranial disease progresses simultaneously with intracranial progression. 1
The patient develops unacceptable immunotherapy-related toxicity. 1, 6
Performance status deteriorates to PS 3-4, at which point best supportive care becomes appropriate. 2, 6
Second-Line Options if Needed
If progression after first-line immunotherapy occurs, platinum-based chemotherapy is recommended as second-line treatment. 1
Nintedanib/docetaxel or ramucirumab/docetaxel are treatment options for adenocarcinoma progressing after immunotherapy. 1, 7
Critical Pitfalls to Avoid
Do not discontinue immunotherapy based solely on a single new brain metastasis when other sites are responding—this represents oligoprogression, not systemic failure. 1, 3
Do not delay SRS while "waiting to see" if immunotherapy controls the new lesion—early local therapy prevents neurological deterioration and irreversible damage. 3
Do not use whole-brain radiation therapy (WBRT) for a single new metastasis—SRS is preferred due to reduced cognitive side effects and morbidity. 2, 3
Do not assume brain metastases will respond identically to extracranial disease—the brain tumor microenvironment differs significantly from systemic sites. 5