Alternative Targeted Therapy After Lorlatinib Progression in ALK-Positive Lung Cancer
Following progression on lorlatinib in ALK-positive NSCLC, platinum-pemetrexed chemotherapy is the recommended standard treatment, as there are currently no effective alternative ALK-targeted therapies available after lorlatinib failure. 1
Primary Recommendation: Chemotherapy
- Platinum-pemetrexed combination chemotherapy is the guideline-recommended treatment following lorlatinib progression 1
- This represents the standard systemic therapy option when patients develop symptomatic systemic progression with multiple lesions 1
- The ESMO 2023 guidelines explicitly state that "Following progression on lorlatinib, ChT with a platinum-pemetrexed-based combination is recommended" 1
Why No Alternative ALK-Targeted Therapy?
Lorlatinib is the most potent third-generation ALK inhibitor with the broadest coverage of resistance mutations, and no subsequent ALK-targeted therapy has demonstrated efficacy after lorlatinib failure 2, 3, 4
- Lorlatinib was specifically designed to overcome resistance mutations (including ALK G1202R and L1196M) that emerge after second-generation ALK TKIs 1
- Compound resistance mutations (e.g., both L1196M and G1202R together) that develop on lorlatinib are not effectively targeted by any currently available ALK inhibitor 1
- Brigatinib showed only 34-40% response rates after alectinib progression, but has not demonstrated meaningful activity post-lorlatinib 1
Critical Step: Obtain Tissue or Liquid Biopsy
Re-biopsy of progressing tumor tissue or plasma cfDNA analysis should be performed to identify resistance mechanisms and guide subsequent therapy selection 1
- Molecular profiling via broad genomic testing is recommended at progression to determine resistance mechanisms 1
- If plasma-based testing is negative, tissue-based testing with re-biopsy material is strongly recommended 1
- This may identify alternative resistance mechanisms beyond ALK mutations that could inform treatment decisions 1
Role of Immunotherapy: Limited and Uncertain
- PD-1/PD-L1 inhibitor monotherapy is less effective in ALK-positive NSCLC regardless of PD-L1 expression 1
- The additional value of immune checkpoint inhibitors is uncertain, as ALK-positive patients were excluded from most ICI trials 1
- One exception: IMpower150 showed benefit in a small subgroup of ALK-positive NSCLC patients using atezolizumab + bevacizumab + carboplatin + paclitaxel 1
- This combination might be considered in select patients with good performance status (0-1) after targeted therapies are exhausted 1
Local Therapy Options for Oligoprogression
For patients with limited/oligoprogressive disease (asymptomatic or limited symptomatic progression), definitive local therapy should be considered 1
Oligoprogression Management:
- Stereotactic ablative radiotherapy (SABR) or surgery for limited systemic lesions 1
- Image-guided thermal ablation (cryotherapy, microwave ablation, radiofrequency ablation) may be considered for select patients 1
CNS-Specific Progression:
- Stereotactic radiosurgery (SRS) with or without surgical resection for symptomatic CNS lesions 1
- SRS should be considered for asymptomatic lesions at risk for symptomatic progression based on size, location, and edema 1
Option to Continue Lorlatinib in Select Cases
- Continuing lorlatinib may be considered for patients with asymptomatic progression or oligoprogression who can receive local therapy 1
- This is NOT recommended for patients with symptomatic systemic progression and multiple lesions 1
Common Pitfall to Avoid
Do not attempt to sequence back to earlier-generation ALK inhibitors (crizotinib, alectinib, ceritinib, brigatinib) after lorlatinib failure - these agents lack activity against lorlatinib-resistant mutations and will not provide meaningful clinical benefit 2, 5. The resistance mechanisms that emerge on lorlatinib, particularly compound ALK mutations, are not effectively targeted by prior-generation inhibitors 5.