What is the appropriate treatment regimen for a patient with advanced or metastatic cancer, potentially non-small cell lung cancer, and a history of adrenal insufficiency, using docetaxel, Keytruda (pembrolizumab), carboplatin, and dexamethasone?

Treatment Regimen for Advanced NSCLC with Adrenal Insufficiency

For patients with advanced/metastatic non-small cell lung cancer and adrenal insufficiency, pembrolizumab plus carboplatin and paclitaxel (or nab-paclitaxel) is the preferred first-line regimen, with mandatory dexamethasone premedication serving dual purposes: hypersensitivity prophylaxis for docetaxel/paclitaxel and glucocorticoid replacement for adrenal insufficiency. 1, 2

Critical Pre-Treatment Requirements

Molecular Testing

• EGFR mutation and ALK translocation testing must be completed before initiating any immunotherapy to exclude activating mutations that would contraindicate pembrolizumab. 2
• PD-L1 testing is not required for combination chemo-immunotherapy, as benefit is observed across all PD-L1 expression levels (though diminished in PD-L1-negative patients). 1

Adrenal Insufficiency Management

• Establish baseline cortisol and ACTH levels before treatment, as pembrolizumab can induce adrenal insufficiency (median onset 4.63 months from treatment start). 3
• Initiate physiologic glucocorticoid replacement (hydrocortisone 15-25 mg daily in divided doses or equivalent) if adrenal insufficiency is confirmed, as this significantly improves symptoms and quality of life. 4
• The dexamethasone premedication protocol (see below) provides supraphysiologic coverage on treatment days but does not replace daily physiologic replacement therapy. 5

Recommended First-Line Regimen

For Non-Squamous NSCLC (Adenocarcinoma)

Pembrolizumab 200 mg IV + carboplatin AUC 5-6 + pemetrexed 500 mg/m² every 3 weeks for 4 cycles, followed by pembrolizumab + pemetrexed maintenance. 1, 6

• This regimen demonstrates superior overall survival across all PD-L1 expression levels compared to chemotherapy alone. 1
• Mandatory vitamin supplementation: Folic acid 0.4-1.0 mg PO daily starting ≥1 week before first dose, and vitamin B12 1000 μg IM starting ≥1 week before first dose and every 9 weeks thereafter. 6

For Squamous Cell Carcinoma

Pembrolizumab 200 mg IV + carboplatin AUC 5-6 + paclitaxel 200 mg/m² (or nab-paclitaxel 100 mg/m² on days 1,8,15) every 3 weeks for 4 cycles, followed by pembrolizumab maintenance. 1, 2

• This combination is the standard of care for metastatic squamous NSCLC with PS 0-1. 1
• Pemetrexed is contraindicated in squamous histology. 1

Dexamethasone Premedication Protocol

Dexamethasone 8 mg PO twice daily for 3 days (starting the day before chemotherapy) is mandatory for all patients receiving docetaxel or paclitaxel-based regimens. 5, 7

Dual Purpose in Adrenal Insufficiency

• Hypersensitivity prophylaxis: Prevents severe hypersensitivity reactions to taxanes (required per FDA labeling). 5
• Stress-dose glucocorticoid coverage: The 48 mg total dexamethasone dose (equivalent to ~320 mg hydrocortisone) provides supraphysiologic coverage during the chemotherapy stress period. 5
• Critical caveat: This premedication does NOT replace daily physiologic glucocorticoid replacement between treatment cycles. 4

Alternative Regimen Considerations

If Pembrolizumab is Contraindicated

Carboplatin AUC 5-6 + paclitaxel 200 mg/m² (or docetaxel 75 mg/m²) every 3 weeks for 4-6 cycles remains an acceptable platinum-based doublet. 1

• Docetaxel 100 mg/m² as monotherapy is contraindicated in previously treated NSCLC patients due to increased treatment-related mortality. 5
• For first-line combination therapy, docetaxel 75 mg/m² with cisplatin is FDA-approved, but carboplatin is preferred for better tolerability. 1, 5

Carboplatin vs. Cisplatin

Carboplatin is strongly preferred over cisplatin in patients with adrenal insufficiency due to:

• Better tolerability with less nausea/vomiting (critical in patients with baseline cortisol deficiency). 1, 6
• Outpatient administration feasibility without mandatory hydration. 1, 6
• Equivalent efficacy in paclitaxel/gemcitabine-based regimens. 1

Monitoring Requirements

Hematologic Monitoring

• Complete blood counts on days 8 and 15 of each cycle to assess nadir blood counts, as 62% of patients experience grade 3-4 adverse events with pemetrexed-carboplatin. 6
• Grade 4 neutropenia occurs in 79% of patients receiving docetaxel-carboplatin combinations. 8

Immune-Related Adverse Events (irAEs)

Pembrolizumab can cause adrenal insufficiency even in patients without pre-existing disease, with median onset at 4.63 months. 3

• Monitor for new/worsening fatigue, hypotension, hyponatremia, or hypoglycemia throughout treatment. 3, 4
• Obtain morning cortisol and ACTH if symptoms develop, as prompt corticosteroid replacement is critical. 3
• Other irAEs requiring immediate evaluation: pneumonitis (dyspnea, cough), colitis (diarrhea, abdominal pain), hepatitis, and endocrinopathies. 6

Adrenal Crisis Prevention

Patients with known adrenal insufficiency require stress-dose glucocorticoids during acute illness, surgery, or severe irAEs (typically hydrocortisone 100 mg IV every 8 hours, then taper). 4

Treatment Duration and Maintenance

• Four cycles of platinum-based chemotherapy followed by maintenance therapy is the standard approach. 1
• Pembrolizumab maintenance continues until disease progression, unacceptable toxicity, or maximum 24 months (35 cycles). 9
• For non-squamous NSCLC, pemetrexed continuation maintenance significantly improves progression-free survival. 1

Performance Status Considerations

• PS 0-1: Full-dose combination chemo-immunotherapy as outlined above. 1, 2
• PS 2: Consider carboplatin-based doublet chemotherapy without immunotherapy, or single-agent chemotherapy if combination not tolerated. 1
• PS 3-4: Best supportive care only; systemic therapy is contraindicated. 2

Common Pitfalls to Avoid

1. Do not use docetaxel 100 mg/m² in previously treated patients due to increased mortality risk. 5
2. Do not omit vitamin supplementation with pemetrexed, as this significantly increases severe toxicity risk. 6
3. Do not assume dexamethasone premedication provides adequate daily glucocorticoid replacement in patients with adrenal insufficiency. 4
4. Do not delay corticosteroid replacement if pembrolizumab-induced adrenal insufficiency develops, as this can be fatal. 3
5. Do not use pemetrexed in squamous cell histology, as it worsens outcomes. 1