Clinical outcomes with low-dose lorlatinib in <i>ALK</i> mutation–positive metastatic lung adenocarcinoma: Experience from a tertiary care center in a developing country.

Abstract

e20764 Background: Lorlatinib is a highly effective third-generation ALK inhibitor, with a 5-year progression-free survival (PFS) of 60% reported in the CROWN study. However, high cost limits its use in low-resource settings, with fewer than 1% of eligible patients at our center receiving full-dose therapy. Preclinical and early clinical data suggest activity at lower doses. We report real-world outcomes of lorlatinib 25 mg daily administered on a compassionate basis in patients with advanced ALK-rearranged non-small cell lung cancer (NSCLC). Methods: Between August 2024 and April 2025, 35 patients with metastatic ALK-positive NSCLC were treated with lorlatinib 25 mg orally once daily. Median age was 42 years (range, 22–68), 63% were male, and median ECOG performance status was 1 (range, 0–2). Thirty-one percent had a smoking history. ALK rearrangement and fusion variants were assessed using immunohistochemistry and next-generation sequencing. Treatment was continued until progression or unacceptable toxicity. Results: Thirty-two patients (91%) had received at least one prior ALK tyrosine kinase inhibitor. Median follow-up was 10.3 months (95% CI, 9.7–12.8). Overall response rate was 42.9% and disease control rate was 71%. Eighteen patients (51%) had baseline intracranial metastases; prior local therapy included stereotactic radiosurgery in 10% and whole-brain radiotherapy in 77%. Intracranial response and disease control rates were 25% and 37%, respectively. Estimated 1-year overall survival and PFS rates were 68.7% (95% CI, 54.2–87.2) and 66.6% (95% CI, 52.0–85.2). Treatment-related adverse events occurred in 65% of patients, all grade 1–2; hyperlipidemia was most common (57%). Patients experiencing adverse events had higher response rates (45% vs. 14%). No PFS difference was observed between ALK fusion variants 1 and 3. Conclusions: Low-dose lorlatinib demonstrates clinically meaningful systemic and intracranial activity with acceptable toxicity in heavily pretreated ALK-positive metastatic NSCLC in a resource-limited setting. This strategy may offer a pragmatic treatment option when full-dose lorlatinib is not feasible. Demographic and clinical characteristics of patients. Characteristics Count (n=35), in number (%) Age, Mean (SD) 43.23 (10.19) Sex Male 22 (62.9) Female 13 (37.1) Comorbidities Yes 8 (22.9) No 27 (77.1) Hypertension Yes 2 (5.7) No 33 (94.3) Diabetes Mellitus Yes 6 (17.1) No 29 (82.9) COPD No 35 (100) Other Comorbidities Bronchial asthma 2 (5.7) HbCIgG + 1 (2.9) HbSAg + 1 (2.9) Ischemic Herat disease 1 (2.90 No 29 (82.9) TB 4years back 1 (2.9) ECOG PS Baseline 0 1 (2.9) 1 31 (88.6) 2 3 (8.6) Addictions Yes 11 (31.4) No 24 (68.6) Presence of mucin pools Yes 7 (20.0) No 28 (80.0)