In a phase III, randomised ALINA study, patients with resected ALK-positive non-small cell lung cancer (NSCLC) who received adjuvant alectinib had significantly longer disease-free survival (DFS) than those who received the standard adjuvant platinum-based chemotherapy. The hazard ratio (HR) for disease recurrence or death was 0.24 among patients with stage II or IIIA NSCLC and in the intention-to-treat (ITT) population, which corresponds to a 76% lower risk with adjuvant alectinib than with chemotherapy.
DFS benefit was seen consistently across prespecified subgroups, including those defined according to disease stage, race, sex, and smoking status. The findings are published by Drs. Yi-Long Wu of the Guangdong Lung Cancer Institute, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University in Guangzhou, China, Benjamin J. Solomon of the Department of Medical Oncology, Peter MacCallum Cancer Centre in Melbourne, Australia and colleagues in the 10th April 2024 issue of The New England Journal of Medicine.
Approximately 4-5% of patients with NSCLC have ALK-positive disease. Patients with ALK-positive NSCLC are more likely to be younger, non-smokers, and receive a diagnosis with more advanced disease than those with ALK-negative NSCLC. They are also at high risk for brain metastases, which are seen in up to 50-60% of patients.
The current recommended adjuvant treatment for patients with resected ALK-positive NSCLC is platinum-based combination chemotherapy. However, adjuvant chemotherapy is associated with only modest improvements in patient outcomes and with a high risk of adverse events. Although the treatment landscape for early-stage NSCLC is rapidly evolving with the approval of immunotherapy and targeted therapy regimens, adjuvant targeted therapy in patients with resectable NSCLC harbouring a rearrangement in ALK gene warrants evaluation.
The authors wrote in the background that data in advanced NSCLC support investigation of alectinib in resected ALK-positive NSCLC to determine whether it can reduce the risk of disease recurrence, improve outcomes after surgery, and reduce the incidence of recurrence in the central nervous system (CNS).
The ALINA investigators conducted a global, phase III, open-label, randomised study in which patients with completely resected, ALK-positive NSCLC of stage IB (tumours ≥4 cm), II, or IIIA as classified according to the 7th edition of the Cancer Staging Manual of the American Joint Committee on Cancer and Union for International Cancer Control were randomly assigned in a 1:1 ratio to receive oral alectinib 600 mg twice daily for 24 months or intravenous platinum-based chemotherapy in four 21-day cycles. The primary endpoint was DFS, tested hierarchically among patients with stage II or IIIA disease and then in the ITT population. Other endpoints included CNS DFS, overall survival (OS), and safety. Follow-up is ongoing.
In total, 257 patients were randomly assigned to receive alectinib (130 patients) or chemotherapy (127 patients). The percentage of patients alive and disease-free at 2 years was 93.8% in the alectinib group and 63.0% in the chemotherapy group among patients with stage II or IIIA disease (HR for disease recurrence or death 0.24; 95% confidence interval [CI] 0.13 to 0.45; p < 0.001) and 93.6% and 63.7% in the ITT population (HR 0.24; 95% CI 0.13 to 0.43; p < 0.001).
Patients with ALK-positive NSCLC are at high risk for brain metastases, which are associated with poor prognosis and have a substantial effect on health-related quality-of-life. Alectinib was associated with a clinically meaningful benefit with respect to CNS DFS as compared with chemotherapy (HR for CNS disease recurrence or death 0.22; 95% CI 0.08 to 0.58). These early data suggest that adjuvant alectinib can prevent or delay CNS recurrence, findings consistent with the intracranial efficacy of alectinib in advanced NSCLC. Data for OS were immature.
The safety profile of adjuvant alectinib was consistent with that in previous reports in the context of advanced disease, with laboratory abnormalities and constipation being the most frequent adverse events, and no new safety concerns were identified. Although treatment duration with adjuvant alectinib was much longer than with chemotherapy, median of 2 years versus 2 months, similar numbers of adverse events were observed in the two groups, and the percentage of patients who discontinued treatment owing to adverse events was lower with alectinib (5.5%) than with chemotherapy (12.5%). Long-term follow-up will be needed to assess any potential long-term toxic effects of adjuvant alectinib.
An open-label trial design was used to make a head-to-head comparison between a chemotherapy-free regimen of 2 years of adjuvant oral alectinib and standard adjuvant intravenous chemotherapy, for which blinding would not be feasible. In the ALINA, the choice of treatment after disease recurrence was at the discretion of the investigators, because the study did not have a formal crossover design.
The authors commented that the data from the ALINA study reinforce the need for rapid biomarker testing for ALK alterations across all stages of NSCLC. Currently, biomarker testing for ALK alterations in resectable NSCLC is mainly performed to exclude patients from receiving immunotherapy, but routine ALK testing should also support identification of patients who are likely to benefit from adjuvant alectinib.
In an accompanied editorial article, Drs. Antonio Passaro of the Division of Thoracic Oncology, European Institute of Oncology IRCCS in Milan, Italy and Solange Peters of the Lausanne University Hospital in Lausanne, Switzerland wrote that DFS results in the ALINA study should be regarded as highly meaningful, given the rarity of the clinical scenario and the magnitude of the benefit reported. The effect of alectinib on the risk of CNS disease recurrence positions it as a therapeutic breakthrough. However, more mature data on OS, a critical endpoint after curative-intent surgery and adjuvant treatments, are still expected.
The promising developments highlighted by the ADAURA and ALINA underscore the potential of adjuvant targeted therapy in patients with tumours harbouring actionable molecular alterations, potentially expanding beyond EGFR and ALK inhibitors. Currently, LIBRETTO-432 is evaluating such a strategy in the rare occurrence of RET-rearranged NSCLC.
In the ALINA, the study investigators intentionally omitted chemotherapy for patients in the experimental group, which highlights the clinically significant efficacy of alectinib and suggests its potential as a sufficient stand-alone treatment. The question of whether a chemotherapy-free approach can be safely and universally applied across disease stages or whether platinum-based chemotherapy still holds relevance, particularly for patients at higher risk for relapse before starting biologic therapy, is open to debate.
The uncertainty also resides in the most effective duration of tyrosine kinase inhibitor (TKI) therapy in this context. The financial and health system–related sustainability of a long duration of exposure to TKI therapy in up to a third of patients with non-squamous NSCLCs who have actionable molecular alterations should be carefully analyzed.
According to the editorialists, the conclusive findings from the ADAURA and ALINA studies highlight the critical need to prioritise multiplex molecular profiling through next-generation sequencing for all patients with resected NSCLC. Furthermore, transition from treating metastatic disease with curative intent in early-stage cancers introduces new dynamics in the risk–benefit analysis.
The study was funded by F. Hoffmann–La Roche.
