Adjuvant Alectinib Is Associated With a Tolerable Safety Profile in ALK+ NSCLC

Hidehito Horinouchi, MD, PhD

The safety profile of adjuvant alectinib (Alecensa) was shown to be tolerable and manageable in patients with resected ALK-positive non–small cell lung cancer (NSCLC), despite a longer median treatment duration with the agent vs chemotherapy, according to an oral presentation of safety findings from the phase 3 ALINA trial (NCT03456076) that were presented at the 2024 IASLC World Conference on Lung Cancer.¹

At a data cutoff date of June 26, 2023, the median treatment durations were 23.9 months and 2.1 months in the alectinib (n = 128) and chemotherapy (n = 120) arms, respectively. Any-grade adverse effects (AEs) were observed in 98% and 93% of patients in the respective arms. Grade 3 or 4 AEs were accounted for in 30% and 31% of patients, respectively; grade 3 or 4 treatment-related AEs were seen in 18% and 28% of patients, respectively. Serious AEs occurred in 13% and 8% of patients, respectively; 2% and 7% of patients, respectively, experienced treatment-related serious AEs. Of note, no grade 5 AEs were reported in either arm.

“The safety profile of adjuvant alectinib was consistent with the known profile of alectinib in patients with metastatic, ALK-positive NSCLC,” Hidehito Horinouchi, MD, PhD, a medical oncologist in the Department of Thoracic Oncology at National Cancer Center Hospital in Tokyo, Japan, said during the oral presentation.

Recapping the ALINA Trial Design

The ALINA trial included 257 total patients with resected stage IB to IIIA ALK-positive NSCLC (intent-to-treat [ITT] population) who were randomly assigned 1:1 to receive either alectinib at 600 mg twice daily for 2 years or platinum-based chemotherapy for 4 cycles, both until disease recurrence, at which point further treatments were administered at investigator’s choice and survival follow-up was conducted. Chemotherapies used in the trial included cisplatin, vinorelbine, gemcitabine, pemetrexed, and carboplatin. Key eligibility criteria included complete tumor resection, an ECOG performance status of 0 or 1, eligibility to receive platinum-based chemotherapy, adequate end-organ function, and no prior receipt of systemic cancer therapy. Stratification factors included tumor stage (IB vs II vs IIIA) and race (Asian vs non-Asian).

The primary end point was investigator-assessed disease-free survival (DFS) tested hierarchically in the population of patients with stage II to IIIA disease and then in the ITT population. Secondary end points included central nervous system (CNS) DFS, overall survival, and safety.

Revisiting Initial Efficacy Findings From ALINA

Findings from the primary analysis of ALINA showed that treatment with adjuvant alectinib led to a DFS benefit compared with platinum-based chemotherapy. At a median follow-up of 27.8 months, the DFS rates in patients with stage IB to IIIA disease at 24 months were 93.6% and 63.7% in the alectinib and chemotherapy arms, respectively; at 36 months, the DFS rates were 88.7% and 54.0% in the respective arms (HR, 0.24; 95% CI, 0.13-0.43; P < .0001). The CNS DFS rates in patients with stage IB to IIIA disease at 24 months were 98.4% and 85.8% in the respective arms; at 36 months, the respective CNS DFS rates were 95.5% and 79.7% (HR, 0.22; 95% CI: 0.08-0.58).

Based on these findings, in April 2024, the FDA approved alectinib as the first adjuvant treatment for patients with ALK-positive, early-stage (tumors 4 cm or larger or node positive) NSCLC, as detected by an FDA-approved test.² 

Expanding on the ALINA Safety Findings

AEs leading to dose reductions occurred in 26% and 10% of patients from the alectinib and chemotherapy arms, respectively.¹ AEs that led to dose interruptions occurred in 27% and 18% of patients, respectively; 5% and 13% of patients, respectively, had AEs that led to treatment withdrawal.

The most common AEs observed in patients in the alectinib arm were low-grade lab abnormalities, which were consistent with the known safety profile of the drug. AEs that occurred in at least 15% of patients across both arms included increased blood creatine phosphokinase (CPK), constipation, increased aspartate aminotransferase (AST), increased alanine aminotransferase (ALT), and increased blood bilirubin.

The AEs that were observed in at least 15% of patients in the alectinib arm mostly occurred during the first month of receiving alectinib. AEs that persisted for a longer duration were typically grade 1 or 2, were manageable, and did not lead to treatment discontinuation.

The most clinically relevant AEs seen in patients in the alectinib arm included liver function abnormalities (all grade, 60.9%; grade 3 or 4, 4.7%), increased blood CPK (43.0%; 6.3%), constipation (42.2%; 0.8%), myalgia (28.1%; 0.8%), anemia (23.4%; 0%), renal impairment (15.6%; 0.8%), rash (14.1%; 0.8%), and peripheral edema (10.2%; 0%).

Most AEs in the alectinib arm did not require dose reduction or modification and were resolved by the data cutoff date. The median dose intensity was 99.4%, and AEs leading to dose interruption occurred in 35 patients (27.3%), most commonly due to increased blood CPK (n = 7; 5.5%), increased ALT (n = 7; 5.5%), increased AST (n = 6; 4.7%), COVID-19 (n = 6; 4.7%), increased blood bilirubin (n = 5; 3.9%), and myalgia (n = 3; 2.3%).

“Alectinib has a tolerable and manageable safety profile, despite a quite longer treatment duration with alectinib vs chemotherapy. Together with the DFS [findings], these safety data support [the use of] adjuvant alectinib as an important new standard treatment strategy for patients with resected ALK-positive NSCLC,” Horinouchi concluded.

References

1. Horinouchi H, Solomon B, Wu YL, et al. ALINA safety results: adjuvant alectinib vs chemotherapy in patients with resected ALK+ non-small cell lung cancer (NSCLC). Presented at: 2024 IASLC World Conference on Lung Cancer; September 7-10, 2024; San Diego, CA. Abstract OA13.04.
2. FDA approves Genentech's Alecensa as first adjuvant treatment for people with ALK-positive early-stage lung cancer. News release. Genentech. April 18, 2024. Accessed September 10, 2024. https://www.gene.com/media/press-releases/15023/2024-04-18/fda-approves-genentechs-alecensa-as-firs