What is the evidence-based management of ALK (Anaplastic Lymphoma Kinase) positive polymetastatic adenocarcinoma of the lung using pharmacotherapy, including dosing and toxicity management?

Management of ALK-Positive Polymetastatic Adenocarcinoma Lung

Alectinib (600 mg orally twice daily with food) is the preferred first-line treatment for ALK-positive polymetastatic adenocarcinoma lung due to superior efficacy, better CNS penetration, and lower toxicity compared to other ALK inhibitors. 1

First-Line Treatment Algorithm

1. Confirm ALK positivity using an FDA-approved test (FISH, IHC, or NGS)

2. Initiate alectinib 600 mg orally twice daily with food until disease progression or unacceptable toxicity 2

   • Superior progression-free survival (PFS) compared to crizotinib (median PFS 25.7 months vs 10.4 months) 1
   • Significantly lower CNS progression (12% vs 45% with crizotinib) 1, 3
   • Higher response rate (83% vs 75%) 1
   • Lower grade 3-5 adverse events (41% vs 50%) 1, 3

3. Alternative first-line options (if alectinib is not tolerated or unavailable):

   • Ceritinib (category 1) 1
   • Crizotinib (category 1, but less preferred due to inferior efficacy) 1
   • Brigatinib (category 1, superior to crizotinib) 1, 4

Monitoring and Toxicity Management

Regular Monitoring

• Liver function tests: Every 2 weeks during first 3 months, then monthly 2
• Renal function: Regularly monitor serum creatinine 2
• Heart rate and blood pressure: Regular monitoring for bradycardia 2
• CPK levels: Every 2 weeks during first month, then as needed 2
• Brain imaging: Regular surveillance for CNS progression, especially important in ALK+ disease 1
• Therapeutic drug monitoring: Consider monitoring alectinib plasma concentrations (target Cmin ≥435 ng/mL) 5

Dose Modifications for Toxicities

Hepatotoxicity (Most Common)

• ALT/AST >5× ULN with bilirubin ≤2× ULN: Temporarily withhold until recovery to ≤3× ULN, then resume at reduced dose 2
• ALT/AST >3× ULN with bilirubin >2× ULN: Permanently discontinue alectinib 2
• Total bilirubin >3× ULN: Temporarily withhold until recovery to ≤1.5× ULN, then resume at reduced dose 2

Interstitial Lung Disease/Pneumonitis

• Any grade: Permanently discontinue alectinib 2

Renal Impairment

• Grade 3: Temporarily withhold until serum creatinine recovers to ≤1.5× ULN, then resume at reduced dose 2

Bradycardia

• Symptomatic, non-life-threatening: Withhold until recovery to asymptomatic bradycardia or heart rate ≥60 bpm, then resume at reduced dose 2
• Life-threatening: Permanently discontinue if no contributing concomitant medication 2

Severe Myalgia/CPK Elevation

• Grade 3: Temporarily withhold until improvement to ≤Grade 1, then resume at same dose 2
• Grade 4: Temporarily withhold until improvement to ≤Grade 1, then resume at reduced dose 2

Dose Reduction Schedule

• Starting dose: 600 mg twice daily
• First reduction: 450 mg twice daily
• Second reduction: 300 mg twice daily
• Discontinue if unable to tolerate 300 mg twice daily 2

Management of Disease Progression

Progression on First-Line Alectinib

1. Molecular testing of a biopsy to identify resistance mechanisms 1
2. Treatment options:
   • Cytotoxic chemotherapy (carboplatin/pemetrexed) 1
   • Consider lorlatinib or brigatinib if available (especially for patients with ALK secondary mutations) 1
   • In selected cases, continuing alectinib may be appropriate 1

Isolated CNS Progression

• Continue ALK TKI plus local therapy (radiation) for isolated CNS progression 1, 6
• Consider switching to a next-generation ALK TKI with better CNS penetration if available 1

Progression on First-Line Crizotinib

• Switch to alectinib, ceritinib, or brigatinib 1
• Alectinib and ceritinib showed significant improvement in PFS compared to chemotherapy in crizotinib-resistant disease 1

Special Considerations

CNS Metastases

• ALK+ NSCLC has high propensity for brain metastases 1
• Alectinib has superior CNS efficacy compared to crizotinib (CNS ORR 83% vs 40%) 3
• For patients with baseline CNS metastases, alectinib is strongly preferred 1

Immunotherapy

• Immunotherapy appears less effective in ALK+ NSCLC regardless of PD-L1 expression 1
• ALK TKIs should be prioritized over immunotherapy 1

Elderly Patients

• Crizotinib may have lower response rates in patients ≥60 years (40% vs 71.9% in younger patients) 6
• Consider starting with alectinib in elderly patients due to better tolerability 1, 3

By following this evidence-based approach to management of ALK-positive polymetastatic adenocarcinoma lung, clinicians can optimize outcomes for patients with this molecular subtype of NSCLC.