What is the upfront management for a 50-70 year old adult patient with stage 4 anaplastic lymphoma kinase (ALK)-positive lung cancer, possibly with a history of smoking or exposure to carcinogens, and with consideration of performance status and comorbidities such as cardiovascular disease or diabetes?

Upfront Management of Stage 4 ALK-Positive Lung Cancer

Alectinib 600 mg orally twice daily with food is the preferred first-line treatment for stage 4 ALK-positive non-small cell lung cancer, based on superior progression-free survival, lower toxicity, and excellent CNS activity compared to crizotinib. 1, 2

First-Line ALK Inhibitor Selection

Preferred Option: Alectinib

• Alectinib demonstrates the best overall profile with longer PFS and lower toxicity than crizotinib, plus demonstrated activity against CNS disease in previously untreated patients 1
• The standard dose is 600 mg orally twice daily, administered with food 2
• Alectinib is associated with longer PFS (median not reached vs 9.2 months for crizotinib in some comparisons) and superior intracranial disease control 1
• The FDA has approved alectinib for treatment of adult patients with ALK-positive metastatic NSCLC 2

Alternative First-Line Options

• Brigatinib represents another first-line option, showing improved PFS compared with crizotinib (HR 0.49; 95% CI 0.33–0.74; P < 0.001) 1

• In patients with baseline CNS metastases, intracranial objective response rate was 78% for brigatinib versus 29% for crizotinib 1

• Brigatinib is FDA-approved for ALK-positive metastatic NSCLC 3

• Lorlatinib may be considered as first-line therapy, with 3-year PFS of 64% versus 19% for crizotinib 1

• However, lorlatinib has a less favorable safety profile with increased neurocognitive and mood disorders, grade 3-4 hypercholesterolemia, hypertriglyceridemia, weight gain, and hypertension 1

• Despite excellent intracranial control (71% complete response), the adverse event profile makes alectinib preferred over lorlatinib for most patients 1

• Ceritinib is also approved for first-line use but is generally considered less favorable than alectinib or brigatinib 1

• Crizotinib is no longer recommended as first-line therapy given the superiority of second-generation ALK inhibitors 1

Pre-Treatment Requirements

Molecular Confirmation

• ALK rearrangement must be confirmed by an FDA-approved test before initiating ALK-targeted therapy 2
• Testing should be performed on tumor tissue or, when tissue is insufficient, validated liquid biopsy methods may be considered 1

Baseline Staging and Assessment

• Contrast-enhanced CT scan of chest and upper abdomen including liver and adrenal glands is required 1
• Brain MRI is mandatory at diagnosis for all patients with metastatic disease, as MRI is more sensitive than CT for detecting CNS metastases 1
• Bone imaging with bone scan or PET-CT should be performed if bone metastases are clinically suspected 1
• Performance status (PS) assessment is essential, as systemic therapy should be offered to all stage IV patients with PS 0–2 1

Baseline Laboratory Monitoring

• Liver function tests (ALT, AST, bilirubin) must be obtained at baseline, as alectinib requires monitoring every 2 weeks during the first 3 months, then monthly 2
• Creatine phosphokinase (CPK) should be assessed at baseline and every 2 weeks during the first month 2
• Heart rate and blood pressure should be documented at baseline due to bradycardia risk 2

Treatment Strategy Considerations

Performance Status-Based Approach

• PS 0-2 patients: Offer ALK inhibitor therapy (alectinib preferred) 1
• PS 3-4 patients: ALK inhibitors may still be considered given the dramatic responses possible with targeted therapy, unlike in EGFR-negative disease where best supportive care is recommended 1

Patients with CNS Metastases

• Alectinib or ceritinib are specifically recommended for patients with CNS involvement at diagnosis 1
• Alectinib represents the better treatment option than crizotinib for CNS disease 1
• Systemic ALK inhibitor therapy is effective for brain metastases, and delaying whole brain radiotherapy (WBRT) after front-line therapy does not modify overall survival 1

Comorbidity Considerations

• Treatment strategy must consider age, PS, comorbidities (cardiovascular disease, diabetes), and patient preferences 1
• In patients with cardiovascular disease, monitor for bradycardia with alectinib, as dose reduction or discontinuation may be required for symptomatic bradycardia 2
• Hepatic function must be adequate; more frequent monitoring is required in patients with baseline liver abnormalities 2

Critical Management Principles

What NOT to Do

• Do not use immunotherapy (pembrolizumab, atezolizumab, nivolumab) as first-line treatment in ALK-positive NSCLC 1
• Immunotherapy is explicitly contraindicated in patients with EGFR or ALK mutations in the first-line setting 1
• Do not use chemotherapy as first-line treatment when ALK inhibitors are available and accessible 1
• Do not delay molecular testing; it should be completed before initiating any systemic therapy 1

Smoking Cessation

• Smoking cessation should be highly encouraged in any stage of NSCLC, as it improves outcomes 1

Response Monitoring

Imaging Schedule

• Response evaluation is recommended after 6–9 weeks of systemic therapy using the same radiographic investigation that initially demonstrated tumor lesions 1
• Measurements and response assessment should follow RECIST criteria v1.1, though the adequacy of RECIST in evaluating response to ALK TKI is debatable 1
• Follow-up with PET is not routinely recommended due to high sensitivity and relatively low specificity 1

Laboratory Monitoring on Alectinib

• Liver function tests every 2 weeks during the first 3 months, then monthly and as clinically indicated 2
• CPK every 2 weeks during the first month and in patients reporting unexplained muscle pain, tenderness, or weakness 2
• Heart rate and blood pressure regularly to monitor for bradycardia 2

Management of Oligoprogressive Disease

• In ALK-rearranged NSCLC patients with localized distant progression and ongoing systemic control, continuation of treatment with ALK TKI in combination with local treatment (radiation, ablation) of the progressing metastatic sites may be considered 1
• This approach allows patients to remain on effective systemic therapy while addressing isolated sites of progression 1

Dose Modifications for Toxicity

Hepatotoxicity

• For severe ALT, AST, or bilirubin elevations, withhold alectinib, then reduce dose or permanently discontinue 2

Interstitial Lung Disease/Pneumonitis

• Immediately withhold alectinib in patients diagnosed with ILD/pneumonitis and permanently discontinue if no other potential causes have been identified 2

Severe Myalgia/CPK Elevation

• For severe CPK elevations, withhold alectinib, then resume at reduced dose or permanently discontinue 2

Bradycardia

• If symptomatic bradycardia develops, withhold alectinib, then reduce dose or permanently discontinue 2

Contraception and Pregnancy Considerations

• Alectinib can cause fetal harm; advise females of reproductive potential of the potential risk to a fetus and to use effective contraception during treatment 2
• Do not breastfeed while taking alectinib 2