Neoadjuvant lorlatinib in stage III NSCLC harboring ALK fusion: A phase 2 multicenter study (LORIN).

Abstract

8002 Background: While adjuvant alectinib has established itself as the new standard for resected anaplastic lymphoma kinase (ALK) fusion non-small cell lung cancer (NSCLC), there is limited data on neoadjuvant treatment for locally advanced ALK fusion NSCLC. Given the groundbreaking efficacy of lorlatinib in advanced NSCLC, it is worth exploring its clinical feasibility as neoadjuvant treatment for stage III ALK+ NSCLC. Methods: This study is an open-label, phase 2 multi-center prospective trial (ClinicalTrials.gov NCT05740943) utilizing a Simon two-stage design. Patients diagnosed with potentially resectable or unresectable stage III ALK+ NSCLC were enrolled, with up to 3 cycles of lorlatinib administered, followed by optional local treatment and consolidation lorlatinib for up to 2 years. The primary endpoint was the pathological complete response (pCR) (H0≤20%, H1≥40%, α=0.05, β=0.2, at least 12 pCR events for 43 patients enrolled), while secondary endpoints included major pathological response (MPR), event-free survival (EFS), overall survival (OS), and safety profile. Xenium as well as spatial proteomics was performing on paired samples collected before and after lorlatinib. Results: As of January 1, 2026, 43 patients with stage III ALK-fusion NSCLC (19 evaluated as potentially resectable and 24 as unresectable) were consecutively enrolled and received 3 cycles neoadjuvant lorlatinib, with 32 completing surgery (including neck dissection and/or contralateral lymph node dissection), 9 continuing TKI therapy, and 2 undergoing radiotherapy. The most common treatment-related adverse events (TRAEs) included hypertriglyceridemia, hypercholesterolemia, and edema. The confirmed objective response rate (ORR) was 83.7% (36/43), without progressive disease (PD). Among patients who underwent surgery, the R0 resection rate was 96.9% (31/32) and 3 patients experiencing conversion to thoracotomy. pCR and MPR rates were 46.9% (15/32) and 81.3% (26/32), respectively, reaching the primary endpoint. Pathological nodal downstaging was seen in 90.6% (29/32) patients. For those with initially unresectable stage III disease, 75.0% (18/24) achieved conversion surgery through multidisciplinary evaluation after neoadjuvant lorlatinib, while others continued TKI or underwent radiotherapy. With a median follow-up of 13 months, the 1-year EFS rate was 97.1% (95% CI, 91.5-100) and no OS events were observed. Only 3 patients experienced local relapse (regional lymph nodes and/or intrapulmonary metastasis) without distant metastasis; all had initially presented with N3 disease and did not receive adjuvant lorlatinib after surgery. Conclusions: Neoadjuvant lorlatinib unveiled overwhelming pathological response and could lead to high conversion surgery for unresectable stage III disease. Further large-scale prospective trial was warranted to testified such treatment modality. Clinical trial information: NCT05740943 .