Adjuvant alectinib significantly improves the disease-free survival of patients with early-stage non-small cell lung cancer harbouring ALK rearrangements
Patients with resected, stage IB–IIIA, non-small cell lung cancer (NSCLC) harbouring ALK rearrangements are currently treated with adjuvant chemotherapy (CT), resulting in a modest improvement in survival. In the phase III ALINA trial, adjuvant alectinib was shown to significantly improve the disease-free survival (DFS) and the central nervous system (CNS)-DFS compared to CT, while maintaining a well-tolerated safety profile. Consequently, adjuvant alectinib emerges as an important new treatment strategy for patients with resected, stage IB-IIIA, ALK+ NSCLC.
Despite treatment, the risk of disease recurrence remains high in patients with resectable non-small cell lung cancer (NSCL). ALK rearrangements are found in 4-5% of NSCLC patients and are associated with a high risk of brain metastases, which affect 50-60% of patients over the course of the disease. For patients with resected, stage IB–IIIA, ALK+ NSCLC, the recommended treatment after surgery consists of platinum-based chemotherapy (CT). However, this therapeutic strategy is associated with only a modest survival improvement. In advanced ALK+ NSCLC, the ALK inhibitor alectinib demonstrated statistically significant and clinically meaningful improvements in progression-free survival (PFS) and high levels of intracranial activity compared to crizotinib in three phase III trials (ALEX, J-ALEX and ALESIA). Building on these encouraging findings, the global phase III ALINA trial was conducted to evaluate the effectiveness and safety of adjuvant alectinib vs. CT for patients with completely resected ALK-positive NSCLC. The primary results from the pre-specified interim analysis were presented at ESMO 2023.
Methods
The phase III ALINA trial enrolled adult patients (≥18 years) with completely resected, stage IB (≥4 cm)-IIIA, ALK+ NSCLC (per UICC/AJCC 7th edition). These patients had to be eligible to receive platinum-based CT and did not receive prior systemic cancer therapy. In total, 257 participants were randomly assigned (1:1) to receive oral alectinib 600 mg twice daily for two years (n=130), or intravenous platinum-based CT for four cycles (n=127). The primary endpoint was investigator-assessed disease-free survival (DFS), tested hierarchically first in stage II–IIIA and then in the intention-to-treat (ITT) population (stage IB–IIIA). Other endpoints included central nervous system (CNS)-DFS, overall survival (OS) and safety.
Results
After a median follow-up of 27.8 months, 2-years of adjuvant alectinib led to a significant improvement in DFS compared to CT in stage II–IIIA patients (HR[95%CI]: 0.24[0.13–0.45]; p<0.0001). The median DFS was not reached in the alectinib arm, while it was reported at 44.4 months in the CT arm. Two-year DFS rates were 93.8% and 63.0% for patients in the alectinib and CT arms, respectively (88.3% vs. 53.3% after 3 years). In the ITT population (stage IB-IIIA), treatment with alectinib also resulted in a DFS benefit compared to CT (HR[95%CI]: 0.24[0.13-0.43]; p<0.0001). The median DFS was not reached in the alectinib arm as compared to 41.3 months with CT. In this population, the 2- and 3-year DFS rates were reported at 93.6% vs. 63.7% and 88.7% vs. 54.0%, respectively. At the data cutoff, OS data were immature with only six (2.3%) OS events reported. The benefit of alectinib was observed across all subgroups, including a consistent effect across the different stages, with HRs of 0.21, 0.24 and 0.25 for stages IB, II and IIIA, respectively. A clinically meaningful CNS-DFS benefit was observed in the ITT population (HR[95%CI]: 0.22[0.08–0.58]). Moreover, treatment with alectinib resulted in a low incidence of local and regional recurrences. The effect on distant recurrences was particularly profound, including low recurrence rates in the brain (4 vs. 14 patients in the alectinib and CT arms, respectively) and in extracranial sites, including the bone (1 vs. 8 patients). Incidence of grade 3/4 adverse events (AEs) was similar in the alectinib and CT arm (30 vs. 31%, respectively), and no grade 5 events were reported. AEs leading to treatment withdrawal were observed in 5% vs. 13% of patients in the alectinib and CT arms, respectively. The most common AEs for alectinib included increased blood creatine phosphokinase, constipation and increased aspartate aminotransferase, consistent with the previously reported safety profile of this drug.
Conclusions
ALINA is the first and only positive phase III trial evaluating an adjuvant ALK inhibitor in resected stage IB-IIIA NSCLC patients. Treatment with alectinib resulted in a statistically significant improvement in DFS and CNS-DFS compared with CT, with a tolerable safety profile. Based on these results, adjuvant alectinib represents an important new treatment strategy for patients with resected, stage IB-IIIA, ALK+ NSCLC.
Reference
Solomon BJ. LBA2 - ALINA: Efficacy and safety of adjuvant alectinib versus chemotherapy in patients with early-stage ALK+ non-small cell lung cancer (NSCLC). Presented at ESMO 2023; Abstract LBA2.
