The phase II ALNEO trial has demonstrated promising activity for perioperative alectinib in patients with potentially resectable stage III ALK-positive non-small cell lung cancer (NSCLC), meeting its primary endpoint with a 46% major pathological response rate. Results from the final analysis were presented at the 2025 ASCO Annual Meeting by Dr. Alessandro Leonetti and colleagues from the Italian GOIRC consortium.
First-in-Class Perioperative Approach
The ALNEO study represents the first prospective trial to assess the role of alectinib in the perioperative setting for locally advanced ALK-positive NSCLC, addressing a population with limited data and significant therapeutic need. The multicenter, open-label, single-arm phase II trial enrolled 33 treatment-naïve patients across 20 oncology centers in Italy between May 2021 and July 2024.
Patients received neoadjuvant alectinib 600 mg twice daily for 2 cycles (8 weeks), followed by surgical resection and adjuvant alectinib for up to 24 cycles (96 weeks). Eligible participants had stage IIIA or IIIB ALK-positive NSCLC considered potentially resectable, with ECOG performance status ≤1.
Patient Demographics and Disease Characteristics
The study population had a median age of 62 years (interquartile range: 49-74), with 70% female patients and 52% never-smokers—a clinical profile commonly associated with ALK-positive lung cancer. Staging revealed 64% of patients had stage IIIA disease and 36% had stage IIIB. The most frequently observed substage was T3N2 (24%), followed by T1aN2, T2aN2, T4N0, and T4N2, each accounting for 12% of the study population.
Strong Pathological and Surgical Outcomes
All 33 patients successfully completed neoadjuvant therapy, and 28 patients (85%) proceeded to surgery. Treatment with neoadjuvant alectinib led to a major pathological response (MPR)—defined as ≤10% viable tumor cells in the resected specimen—in 15 patients (46%), as assessed by Blinded Independent Central Review (BICR). The 90% confidence interval for this response ranged from 31% to 61%.
Additionally, 4 patients (12%) achieved a complete pathological response (pCR), with no viable tumor cells detected in the surgical specimen (95% CI: 3%-28%). Radiographic evaluations revealed an objective response in 22 patients (67%), supporting strong preoperative tumor shrinkage with targeted therapy.
Among the 28 patients who underwent resection, surgical outcomes were favorable: 21 patients (64%) received a lobectomy, 3 patients (9%) underwent pneumonectomy, and 4 patients (12%) had other types of surgery. Importantly, 24 of the 28 operated patients (86%) achieved an R0 resection, meaning there was no residual microscopic tumor at the surgical margins. Additionally, 48% of patients experienced nodal downstaging.
Survival and Long-term Outcomes
Following surgery, 26 patients (79%) began adjuvant treatment with alectinib, typically initiated within 5.1 weeks post-surgery (IQR: 3.6-6.0). At a median follow-up of 15.2 months (IQR: 6.8-27.8), 94% of patients were alive, and 5 patients (19%) had completed the full 2-year course of adjuvant therapy.
Median event-free survival (EFS) and overall survival (OS) have not yet been reached, reflecting encouraging durability of disease control. Only 6 patients (18%) experienced disease progression or recurrence during the study period. With extended follow-up of 20.3 months, 91% of patients remained alive.
Favorable Safety Profile
Treatment with alectinib was well tolerated in both the neoadjuvant and adjuvant settings. During the preoperative phase, grade 3 or higher adverse events were observed in 3 patients (9%), while during adjuvant therapy, 2 patients (8%) experienced grade ≥3 adverse events.
In the neoadjuvant phase, treatment-emergent adverse events included increased alanine aminotransferase levels (grade 1/2: 12%; grade 3: 3%), increased aspartate aminotransferase levels (15%), asthenia (15%), and diarrhea (3% grade 1/2; 3% grade 3). During adjuvant treatment, common adverse events included asthenia (23% grade 1/2), increased bilirubin levels (23%), increased ALT levels (15% grade 1/2; 4% grade 3), and neutropenia (4% grade 3).
No grade 4/5 or treatment-related serious adverse events were observed in either the neoadjuvant or adjuvant phases. These low toxicity rates are consistent with the known safety profile of alectinib in the metastatic setting.
Clinical Implications
The ALNEO trial results suggest that alectinib represents an active and feasible perioperative therapy option in patients with resectable stage III ALK-positive NSCLC, offering a potential alternative to cytotoxic chemotherapy in this molecularly defined population. As noted by the study authors, "With the limitation of a small phase 2 nonrandomized trial, [the] ALNEO study suggests alectinib as an active and feasible perioperative option in patients with resectable, stage III, ALK-positive NSCLC."
The strong response rates and favorable surgical outcomes provide a compelling case for further exploration in larger, randomized trials to establish the role of targeted therapy in the perioperative management of locally advanced ALK-positive NSCLC.
