Clinical Summary:

• Design/Population: In this open-label trial, patients with unresectable or potentially resectable advanced ALK-positive non-small cell lung cancer received neoadjuvant lorlatinib followed by surgery or other local therapy and consolidation lorlatinib.
• Key Outcomes: Neoadjuvant lorlatinib produced high objective response, major pathologic response, and pathologic complete response rates, with substantial conversion to surgery among patients with initially unresectable disease.
• Clinical Relevance: These findings support neoadjuvant lorlatinib as a promising treatment strategy for locally advanced ALK-positive non-small cell lung cancer and suggests potential for expanding surgical eligibility in unresectable disease. 

Results from a multicenter phase 2 trial demonstrated that neoadjuvant lorlatinib induced high pathological response and enabled substantial conversion to surgery among patients with advanced ALK-positive non-small cell lung cancer (NSCLC).

These results were presented by Chao Zhang, MD, Guangdong Lung Cancer Institute, Guangzhou, China, at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, Illinois.

In this open-label trial, 43 patients with unresectable (n = 24) or potentially resectable (n = 19) stage 3 ALK-positive NSCLC received up to 3 cycles of neoadjuvant lorlatinib followed by optional local therapy and lorlatinib consolidation for up to 2 years. The study used a Simon two-stage design and specified pathologic complete response (pCR) as the primary end point. Key secondary end points included objective response rate (ORR), major pathological response, event-free survival (EFS), overall survival (OS), and safety. Investigators also performed Xenium and spatial proteomic analyses on paired tumor samples collected before and after treatment.

At analysis, all patients had received 3 cycles of neoadjuvant lorlatinib. Following treatment, 32 patients underwent surgery, 9 continued tyrosine kinase inhibitor therapy, and 2 received radiotherapy. The most common treatment-related adverse events included hypertriglyceridemia, hypercholesterolemia, and edema.

The confirmed ORR was 83.7%, and no patients experienced progressive disease during neoadjuvant therapy. Among patients who underwent surgery, the R0 resection rate was 96.9%, with 3 patients requiring conversion to thoracotomy. pCR and major pathological response rates were 46.9% and 81.3%, respectively. Pathological nodal downstaging occurred in  90.6% of surgically treated patients.

Among patients considered initially unresectable, 75% underwent conversion surgery following multidisciplinary reassessment after neoadjuvant lorlatinib therapy. The remaining patients either continued tyrosine kinase inhibitor therapy or underwent radiotherapy. At a median follow-up of 13 months, the 1-year EFS rate was 97.1%, and no OS events had occurred. Local relapse occurred in 3 patients, all involving regional lymph nodes or intrapulmonary metastases, with no distant metastatic recurrences observed. All patients who experienced relapse initially presented with N3 disease and did not receive adjuvant lorlatinib after surgery. 

“Neoadjuvant lorlatinib unveiled overwhelming pathological response and could lead to high conversion surgery for unresectable stage 3 disease,” concluded Dr Zhang. “Further large-scale prospective trials [are] warranted to testified such treatment modality.”

Source:

Zhang C, Hu Y, Jiang BY, et al. Neoadjuvant lorlatinib in stage III NSCLC harboring ALK fusion: A phase 2 multicenter study (LORIN). Presented at the ASCO Annual Meeting. May 29 - June 2, 2026. Chicago, Illinois. Abstract 8002.