What is the best course of action for a patient with a history of non-small cell lung cancer (NSCLC) presenting with persistently elevated Anaplastic Lymphoma Kinase (ALK) levels?

Management of Persistently Elevated ALK in NSCLC

For a patient with NSCLC and persistently elevated ALK levels (indicating ALK-positive disease), initiate first-line treatment with alectinib 600 mg orally twice daily with food, as this is the preferred Category 1 recommendation that provides superior progression-free survival, better CNS control, and improved tolerability compared to other ALK inhibitors. 1, 2, 3

Understanding "Persistently Elevated ALK"

The question likely refers to ALK rearrangement-positive NSCLC detected by molecular testing, not a serum "ALK level" (which doesn't exist as a clinical test). Approximately 5% of NSCLC patients harbor ALK gene rearrangements leading to oncogenic fusion proteins. 1

First-Line Treatment Algorithm

Preferred First-Line Option: Alectinib

• Alectinib demonstrates superior efficacy with median PFS of 25.7 months versus 10.4 months with crizotinib (HR 0.47, P<0.001) in the ALEX trial. 1, 2
• Response rates are higher at 82.9% compared to 75.5% with crizotinib. 1
• CNS disease control is markedly superior, with only 12% experiencing CNS progression versus 45% with crizotinib. 1, 2
• Five-year overall survival is 62.5% with alectinib versus 45.5% with crizotinib. 1
• Safety profile is better, with fewer grade 3+ adverse events (41% vs 50%) and no treatment-related deaths. 1, 2

Alternative First-Line Options

• Lorlatinib is another Category 1 preferred option for ALK-positive metastatic NSCLC. 1
• Brigatinib is a Category 1 preferred first-line option. 1
• Ceritinib and crizotinib are acceptable but less preferred alternatives. 1

Critical Management Considerations

Avoid Immunotherapy in First-Line

• Do NOT use immunotherapy as first-line treatment in ALK-positive NSCLC, as targeted therapy yields higher response rates and is better tolerated. 1
• PD-1/PD-L1 inhibitors are less effective in ALK-positive disease regardless of PD-L1 expression levels. 4, 2
• The only exception is IMpower150 (atezolizumab + bevacizumab + carboplatin + paclitaxel) after targeted therapies are exhausted. 1, 4

Monitoring Requirements with Alectinib

• Monitor liver function tests every 2 weeks during the first 3 months, then monthly and as clinically indicated. 3
• Assess CPK levels every 2 weeks during the first month and in patients with unexplained muscle pain, tenderness, or weakness. 3
• Monitor heart rate and blood pressure regularly for bradycardia. 3

Common Adverse Events to Anticipate

The most common adverse reactions (≥20% incidence) include hepatotoxicity, constipation, fatigue, myalgia, edema, rash, and cough. 3

Management at Disease Progression

If Progression Occurs on First-Line Alectinib

Obtain tissue or liquid biopsy to identify resistance mechanisms before selecting next therapy. 4

For symptomatic systemic progression with multiple lesions:

• Platinum-pemetrexed combination chemotherapy is the standard recommendation. 4

For oligoprogressive disease (limited sites of progression):

• Continue alectinib and add definitive local therapy (stereotactic radiotherapy, surgery, or thermal ablation). 4, 2
• This approach is appropriate for asymptomatic progression with 1-3 sites. 4

If Progression Occurs on First-Line Crizotinib

• Switch to a second-generation ALK inhibitor (alectinib, ceritinib, or brigatinib). 1, 2
• Alectinib achieves 50% response rate and 83% CNS disease control rate in crizotinib-refractory disease. 2

After Second-Generation ALK Inhibitor Failure

• Next-generation ALK inhibitors (brigatinib or lorlatinib) if not previously used. 1
• Platinum-pemetrexed chemotherapy if ALK inhibitors exhausted. 1, 4

Critical Pitfalls to Avoid

• Never use EGFR inhibitors in ALK-positive disease, as these mutations are mutually exclusive. 2
• Do not switch between agents with similar mechanisms at progression without molecular profiling. 1
• Do not delay re-biopsy at progression, as resistance mechanisms guide optimal sequencing. 4, 5
• Monitor for pneumonitis with any ALK inhibitor, which can be life-threatening and requires immediate discontinuation. 2, 6, 3

Special Populations

CNS Involvement

• Alectinib is strongly preferred due to superior CNS penetration, achieving complete CNS responses in 27% of patients with baseline brain metastases. 1, 2
• Ceritinib is an alternative for CNS disease. 1

Adjuvant Setting (Completely Resected Disease)

• Alectinib is FDA-approved for adjuvant treatment in adult patients following tumor resection of ALK-positive NSCLC (tumors ≥4 cm or node positive). 3

Contraception Requirements

• Advise females of reproductive potential to use effective contraception, as alectinib can cause fetal harm. 3
• Do not breastfeed during treatment. 3