SUMMARY: The FDA on April 18, 2024, approved ALECENSA® (Alectinib) for adjuvant treatment following tumor resection in patients with Anaplastic Lymphoma Kinase (ALK)-positive Non Small Cell Lung Cancer (NSCLC), as detected by an FDA-approved test. Lung cancer is the second most common cancer in both men and women and accounts for about 12% of all new cancers and 21% of all cancer deaths. The American Cancer Society estimates that for 2024 about 234,580 new cases of lung cancer will be diagnosed and about 125,070 patients will die of the disease. Non Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Of the three main subtypes of Non Small Cell Lung Cancer (NSCLC), 25% are Squamous cell carcinomas, 40% are Adenocarcinomas and 10% are Large cell carcinomas.
The discovery of rearrangements of the Anaplastic Lymphoma Kinase (ALK) gene in some patients with advanced NSCLC and adenocarcinoma histology, led to the development of agents such as XALKORI® (Crizotinib), ZYKADIA® (Ceritinib), ALECENSA® (Alectinib), ALUNBRIG® (Brigatinib) and LORBRENA® (Lorlatinib), with promising results. It has become clear that appropriate molecularly targeted therapy for tumors with a molecular abnormality, results in the best outcomes. According to the US Lung Cancer Mutation Consortium (LCMC), two thirds of patients with advanced adenocarcinoma of the lung, have a molecular driver abnormality. The most common oncogenic drivers in patients with advanced adenocarcinoma of the lung are, KRAS in 25%, EGFR in 21% and ALK in 5%, as well as other mutations in BRAF, HER2, AKT1, fusions involving RET and ROS oncogenes and MET gene alterations. These mutations are mutually exclusive and the presence of two simultaneous mutations, are rare.
Patients with ALK-positive NSCLC tend be younger nonsmokers and present with more advanced disease. Approximately 50-60% of these patients develop brain metastases. These patients are often treated with ALK TKIs that cross the blood brain barrier. Patients with early stage resected ALK-positive NSCLC receive adjuvant treatment with platinum-based combination chemotherapy, with 5-year survival ranging from 70% for Stage IB disease to about 35% for Stage IIIA disease, with associated chemotherapy related toxicities.
Alectinib is a potent, second-generation ALK Tyrosine Kinase Inhibitor, and is effective against several ALK mutations that confer resistance to Crizotinib. In the Phase III, randomized ALEX trial, treatment naïve patients with advanced ALK-positive NSCLC who received Alectinib had significantly longer Progression Free Survival and 5-year Overall Survival, compared to those who received Crizotinib, with substantial CNS activity.
The ADAURA trial investigated adjuvant TAGRISSO® (Osimertinib), a third-generation EGFR TKI, in patients with resected EGFR-mutated NSCLC of stage IB, II, or IIIA. Results showed benefits in Disease-Free and Overall Survival, along with reduced CNS recurrence. The ALINA trial similarly assessed the efficacy of Alectinib, in resected ALK-rearranged NSCLC.
ALINA is a global, open-label, randomized, Phase III trial, conducted to investigate the efficacy and safety of adjuvant Alectinib as compared with standard chemotherapy in patients with resected ALK-positive NSCLC. In this study, 257 eligible enrolled patients (N=257) were randomly assigned 4-12 weeks after patients had undergone complete surgical resection (lobectomy, sleeve lobectomy, bilobectomy, or pneumonectomy) in a 1:1 ratio to receive Alectinib 600 mg orally twice daily or platinum-based chemotherapy IV every 21 days for 4 cycles. Alectinib was given for 24 months. Chemotherapy consisted of Cisplatin 75 mg/m2 IV on day 1 of each cycle, plus Vinorelbine 25 mg/m2 IV on days 1 and 8, Gemcitabine 1250 mg/m2 IV on days 1 and 8, or Pemetrexed 500 mg/m2 on day 1. In the event of Cisplatin intolerance, Carboplatin AUC 5 or 6 IV was substituted. Eligible patients had completely resected, histologically confirmed Stage IB (tumors 4 cm or more), II, or IIIA NSCLC, and randomization was stratified according to disease stage and race (Asian versus non-Asian). A total of 231 patients had Stage II or IIIA disease, 116 in the Alectinib group and 115 in the chemotherapy group. The Primary end point was Disease Free Survival (DFS), tested hierarchically among patients with Stage II or IIIA disease and then in the Intention-To-Treat (ITT) population. Secondary end points included CNS Disease Free Survival, Overall Survival, and Safety. The median duration of follow up was 28 months.
The DFS among patients with Stage II or IIIA disease at 2 years was 93.8% in the Alectinib group and 63.0% in the chemotherapy group, and 88.3% and 53.3% respectively at 3 years. The Hazard Ratio for disease recurrence or death was 0.24 (P<0.001), which corresponds to a 76% lower risk with adjuvant Alectinib than with chemotherapy. This DFS benefit was seen consistently across prespecified subgroups, including those defined according to disease stage, race, sex, and smoking status. An exploratory analysis showed a clinically meaningful prolongation of CNS Disease Free Survival with Alectinib. Fewer patients in the Alectinib group had CNS recurrence compared to the chemotherapy group (3.1% versus 11%), consistent with the intracranial efficacy of Alectinib in advanced NSCLC. Overall Survival data were immature at the time of data-cutoff.
The authors concluded that Adjuvant Alectinib significantly improved Disease Free Survival, as compared with platinum-based chemotherapy, among patients with resected ALK-positive NSCLC of Stage IB, II, or IIIA, with few discontinuations due to adverse events. The researchers added that this study reinforces the need for implementation of biomarker testing for ALK alterations, across all stages of NSCLC.
Alectinib in Resected ALK-Positive Non–Small-Cell Lung Cancer. Wu Y-L, Dziadziuszko R, Ahn JS, et al. for the ALINA Investigators. N Engl J Med 2024;390:1265-1276.
