For a patient with advanced ALK‑positive non‑small cell lung cancer receiving lorlatinib 100 mg orally daily, what are the appropriate next management options if the disease is responding, stable, or progressing?

Management of ALK-Positive NSCLC on Lorlatinib

If the patient progresses on lorlatinib, transition to platinum-pemetrexed combination chemotherapy as the standard next-line treatment. 1

Disease Progression on Lorlatinib

Obtain Molecular Profiling First

• Re-biopsy progressing tumor tissue or obtain plasma cfDNA analysis to identify resistance mechanisms before selecting next therapy. 1
• If plasma testing is negative, tissue-based testing with re-biopsy material is strongly recommended. 1
• Broad genomic testing at progression determines resistance mechanisms and guides subsequent therapy selection. 1

Standard Treatment: Platinum-Pemetrexed Chemotherapy

• Platinum-pemetrexed combination chemotherapy is the guideline-recommended treatment for symptomatic systemic progression with multiple lesions. 1
• This represents the standard approach following lorlatinib failure per ESMO 2023 guidelines. 1
• The NCCN explicitly recommends this regimen for patients with widespread progressive disease. 1

Immunotherapy: Limited Role

• PD-1/PD-L1 inhibitor monotherapy is less effective in ALK-positive NSCLC regardless of PD-L1 expression. 1
• ALK-positive patients were excluded from most immune checkpoint inhibitor trials, making the benefit uncertain. 1
• One exception: IMpower150 (atezolizumab + bevacizumab + carboplatin + paclitaxel) showed benefit in a small ALK-positive subgroup. 1

Oligoprogressive Disease: Consider Local Therapy

• For limited/oligoprogressive disease, definitive local therapy should be considered before changing systemic therapy. 1
• Stereotactic ablative radiotherapy (SABR) or surgery for limited systemic lesions may allow continuation of lorlatinib. 1
• Image-guided thermal ablation (cryotherapy, microwave ablation, radiofrequency ablation) represents additional options for select patients. 1

Continuing Lorlatinib: Highly Selective Scenarios Only

• Continuing lorlatinib may be considered ONLY for asymptomatic progression or oligoprogression amenable to local therapy. 1
• This is NOT recommended for symptomatic systemic progression with multiple lesions. 1

Stable or Responding Disease on Lorlatinib

Continue Current Therapy

• Continue lorlatinib 100 mg orally daily in continuous 21-day cycles until disease progression, unacceptable toxicity, or patient withdrawal. 2, 3
• Lorlatinib demonstrates substantial long-term activity with median OS not reached in treatment-naïve patients and prolonged survival even in heavily pretreated populations. 3

Monitor for Adverse Events

• Common grade 3-4 treatment-related adverse events include hypertriglyceridemia (19%) and hypercholesterolemia (14%). 2
• Unique manageable adverse events include edema, cognitive effects, weight gain, and diarrhea. 4
• Dose reductions occur in approximately 28% of patients, temporary discontinuation in 57%, and permanent discontinuation in only 13%. 3

Response Monitoring Schedule

• Evaluate response after 6-9 weeks of therapy using the same radiographic modalities that initially demonstrated tumor lesions. 5
• Use RECIST criteria v1.1 for measurements and response assessment. 5
• Brain MRI should be included for patients with baseline CNS involvement. 5

Critical Context: Lorlatinib's Position in ALK-Positive NSCLC

Lorlatinib is typically used after progression on first-generation (crizotinib) and second-generation (alectinib or brigatinib) ALK inhibitors. 6 The drug demonstrates significant intracranial efficacy and encouraging systemic responses despite prior exposure to 1-3 ALK inhibitors. 6 In patients previously treated with second-generation ALK TKIs, those harboring ALK secondary mutations respond better to lorlatinib (ORR: 61%) compared to those without detectable mutations (ORR: 26%). 6