SUMMARY: Lung cancer is the second most common cancer in both men and women and accounts for about 13% of all new cancers and 27% of all cancer deaths. The American Cancer Society estimates that for 2017 about 222,500 new cases of lung cancer will be diagnosed and over 155,000 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) and now ALUNBRIG® (Brigatinib), 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 8% as well as other mutations in BRAF, HER2, AKT1 and fusions involving RET and ROS oncogenes. These mutations are mutually exclusive and the presence of two simultaneous mutations, are rare.
Patients with advanced NSCLC harboring ALK gene rearrangements often receive XALKORI® as first line therapy and can expect a median Progression Free Survival of approximately 11 months. These patients however are at a high lifetime risk of CNS metastases. ALECENSA® (Alectinib) is a potent ALK Tyrosine Kinase Inhibitor, and is effective against several ALK mutations that confer resistance to XALKORI® Further, unlike XALKORI®, ALECENSA® can cross the blood-brain barrier and is not a substrate of P-glycoprotein, a key efflux transporter located at the blood-brain barrier.
The ALEX trial is an international, randomized, open-label, phase III study which compared ALECENSA® with XALKORI®, in patients with previously untreated, advanced ALK-positive NSCLC, including those with asymptomatic CNS disease. In this trial, 303 previously untreated patients were randomly assigned in a 1:1 ratio to receive ALECENSA® at 600 mg twice daily (N=152) or XALKORI® at 250 mg PO twice daily (N=151). Treatment was continued until disease progression or unacceptable toxicities. Patients with isolated asymptomatic CNS progression could receive a local therapy at the investigator’s discretion, followed by continued trial treatment until systemic disease progression. Patients were stratified and the primary end point was Investigator-assessed Progression Free Survival. Secondary end points were Independent Review Committee (IRC)–assessed Progression Free Survival, time to CNS progression, Objective Response Rate, and Overall Survival.
At the time of primary analysis, ALECENSA® was significantly superior to XALKORI®, reducing the risk of progression/death by 53% (HR= 0.47; P<0.0001). The median PFS for ALECENSA® was Not Reached versus 11.1 months for XALKORI®. The median Progression Free Survival assessed by the IRC was 25.7 months for ALECENSA® vs 10.4 months for XALKORI® (HR=0.50, P< 0.001). The magnitude of the benefit with ALECENSA® was generally consistent across all the subgroups although this benefit was lower in the subgroups of active smokers and patients with poor Performance Status. Objective Response Rate was 82.9% in the ALECENSA® group versus 75.5% in the XALKORI® group (P=0.09). The rate of CNS progression was 12% in the ALECENSA® group compared with 45% in the XALKORI® group (HR=0.16; P<0.001). Among patients with measurable or non-measurable CNS lesions at baseline, a CNS response occurred in 59% of the patients in the ALECENSA® group versus 26% in the XALKORI® group. Further, 45% of the patients in the ALECENSA® group had a complete CNS response, as compared with 9% in the XALKORI® group. Grade 3-5 adverse events were less frequent with ALECENSA® (41%) versus 50% with XALKORI®.
It was concluded that ALECENSA® showed superior efficacy and lower toxicity compared with XALKORI®, and should be a new standard of care for treatment-naïve patients with ALK-positive NSCLC. Alectinib versus crizotinib in treatment-naive advanced ALK-positive non–small cell lung cancer (NSCLC): primary results of the global phase III ALEX study. Shaw AT, Peters S, Mok T, et al. J Clin Oncol. 2017;35 (suppl; abstr LBA9008).