What is the next line of targeted therapy for a patient with non-small cell lung cancer (NSCLC) who has progressed on lorlatinib (Crizotinib)?

Next-Line Therapy After Lorlatinib Progression in ALK-Positive NSCLC

Platinum-pemetrexed combination chemotherapy is the standard treatment following lorlatinib progression in ALK-positive NSCLC patients. 1

Immediate Action: Obtain Molecular Profiling

Before initiating next-line therapy, re-biopsy of progressing tumor tissue or plasma cell-free DNA (cfDNA) analysis must be performed to identify specific resistance mechanisms that may guide subsequent treatment selection. 1 This molecular profiling via broad genomic testing is critical at progression to determine resistance mechanisms. 1 If plasma-based testing returns negative, tissue-based testing with re-biopsy material is strongly recommended. 1

Primary Recommendation: Platinum-Based Chemotherapy

For patients with symptomatic systemic progression and multiple lesions, platinum-pemetrexed chemotherapy is the guideline-recommended treatment. 1 This recommendation comes from both the European Society for Medical Oncology (ESMO) 2023 guidelines and the National Comprehensive Cancer Network (NCCN). 1 The ASCO 2022 guidelines similarly recommend standard therapy following the non-driver mutation guideline for patients who have progressed on lorlatinib. 2

Key Considerations for Chemotherapy:

• This applies specifically to patients with performance status 0-2 who have received prior lorlatinib in second or third-line settings 2
• The combination of platinum with pemetrexed is preferred over single-agent therapy 1

Role of Immunotherapy: Limited Benefit

PD-1/PD-L1 inhibitor monotherapy is less effective in ALK-positive NSCLC regardless of PD-L1 expression levels. 1 The additional value of immune checkpoint inhibitors remains uncertain because ALK-positive patients were systematically excluded from most immunotherapy clinical trials. 1

Exception for Immunotherapy Consideration:

The IMpower150 trial demonstrated benefit in a small subgroup of ALK-positive NSCLC patients using the combination of atezolizumab + bevacizumab + carboplatin + paclitaxel. 1 However, this represents the only positive immunotherapy data in this population and should be considered carefully.

Alternative Strategy: Local Therapy for Oligoprogression

For patients with limited or oligoprogressive disease (typically 3-5 metastatic sites), definitive local therapy should be considered. 1 This approach is particularly relevant for patients with asymptomatic progression or progression limited to specific anatomic sites.

Local Therapy Options Include:

• Stereotactic ablative radiotherapy (SABR) or surgical resection for limited systemic lesions 1
• Image-guided thermal ablation (cryotherapy, microwave ablation, or radiofrequency ablation) for select patients 1
• These interventions may allow continuation of lorlatinib in carefully selected cases 1

Continuation of Lorlatinib: Highly Selective

Continuing lorlatinib may be considered only for patients with asymptomatic progression or oligoprogression who can receive definitive local therapy. 1 This strategy is NOT recommended for patients with symptomatic systemic progression and multiple lesions. 1 The rationale is that local therapy can address limited sites of resistance while maintaining systemic control with lorlatinib.

Common Pitfalls to Avoid

• Do not use immunotherapy monotherapy as standard next-line therapy after lorlatinib—the evidence shows limited efficacy in ALK-positive disease 1
• Do not skip molecular profiling at progression—resistance mechanisms may reveal actionable targets or inform prognosis 1
• Do not continue lorlatinib in patients with widespread symptomatic progression—this delays effective systemic therapy 1
• Do not assume all ALK inhibitors are exhausted—while lorlatinib is the most potent third-generation ALK inhibitor, re-biopsy may reveal non-ALK resistance mechanisms amenable to other targeted therapies 1

Clinical Context

The recommendation for chemotherapy after lorlatinib reflects the reality that lorlatinib represents the most advanced ALK-targeted therapy currently available, with activity against most known ALK resistance mutations. 3, 4 When patients progress on lorlatinib, they have typically exhausted the ALK-directed therapeutic pathway, making chemotherapy the most appropriate next step for most patients. 2, 1