2L Lorlatinib, phase II trials

Background

Phase II study. N=228 ALK-positive and 47 ROS1-positive advanced NSCLC (with or without CNS mets) in six expansion cohorts (EXP1–6) by ALK/ROS1 status and prior therapy.

Interventions and follow up

Regimen: Lorlatinib 100 mg PO daily, 21-day cycles
Primary endpoint: ORR and intracranial response by independent central review, pooled ALK+ subgroups
mFollow up: NR

Results

mPFS EXP1 (treatment-naive): NR (95% CI 11.4–NR)
mPFS EXP2–3A (prior crizotinib ± chemo): NR (95% CI 12.5–NR)
mPFS EXP3B (prior 2nd-gen TKI ± chemo): 5.5 mo (95% CI 2.7–9.0)
mPFS EXP4–5 (2–3 prior TKI lines ± chemo): 6.9 mo (95% CI 5.4–9.5)
mPFS pooled EXP2–5: 7.3 mo (95% CI 5.6–11.0)

Adverse events

Lab changes: Hypercholesterolemia 96% (grade 3–4 16%), hypertriglyceridemia 90%
Constitutional: Edema 51%
CNS effects: Peripheral neuropathy 47%; cognitive/mood/speech/psychotic effects ~21% combined
Dose modification: Dose reductions in 31%

Conclusions

Lorlatinib showed significant activity in ALK-positive NSCLC progressing on crizotinib or a 2nd-generation TKI, including durable CNS responses, supporting its role after prior ALK TKI failure.

Key Limitations

Single-arm phase II, no randomized comparator. Heterogeneous, pooled cohorts by line of therapy. ORR/intracranial response surrogate endpoints; OS not assessed. Resistance-mutation-driven activity varies. Now lorlatinib is increasingly used 1L (CROWN), shifting its post-TKI positioning.

Clinical Context

FDA granted accelerated approval (2018) for lorlatinib after prior ALK TKI based on this study, later expanded to 1L (2021). ESMO endorses lorlatinib after progression on a 2nd-generation ALK TKI when not used 1L. Resistance-mutation profiling can guide selection.

References