ALESIA 5-Year Update: Alectinib at 600 mg Twice Daily Gives Lorlatinib a Run for Its Money in Asia

Abstract

Alectinib, a next-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI), has demonstrated superior progression-free survival over crizotinib with both 300 mg twice daily (J-ALEX) or 600 mg twice daily (ALEX, ALESIA) dosing in three pivotal clinical trials. Given the similar median PFS achieved in the J-ALEX trial and the Asian subgroup of the ALEX trial, there remains debate about the optimal alectinib dose for Asians. The third pivotal alectinib trial, ALESIA, which was conducted exclusively in Asia to support the registration of alectinib in China, utilized 600 mg alectinib twice daily. The mature PFS was not reached at the initial publication of ALESIA. At ESMO Asia 2022, the 5-year update of ALESIA was presented with an impressive mature investigator-assessed PFS of 41.6 months (95% CI 33.1–58.9), which is numerically longer than the mature PFS of 34.1 months achieved by alectinib at 300 mg twice daily in the J-ALEX trial. Based on these results, as well as retrospective pharmacokinetic and responses and PFS data, Alectinib at 600 mg twice daily is the optimal dose for Asians. This has been based on the ALESIA trial and on the retrospective pharmacokinetic and responses and PFS data and has set the benchmark for ALK TKI as the first-line treatment for advanced ALK+ NSCLC in Asia. Importantly, lorlatinib, another next generation ALK TKI, also achieved an impressive hazard ratio with a still immature PFS in all patients, including Asian patients, in a recent subgroup analysis after a median follow-up time of 36.7 months. We await the final mature PFS of lorlatinib overall and for Asian patients in the CROWN trial to see if lorlatinib will set a new standard.

Keywords:

• ALESIA
• CROWN
• alectinib
• lorlatinib
• brigatinib
• pharmacokinetics
• dose response
• ALK fusion
• NSCLC

Executive Summary

1. ALESIA 5-year follow-up data demonstrated impressive median PFS survival data for ALK+ Asian patients treated with alectinib. Alectinib at 600 mg twice daily is the optimal dose of alectinib globally for Asians and non-Asians alike. Alectinib at 600 mg twice daily sets the current benchmark for ALK TKI as the first-line treatment for advanced ALK+ NSCLC.

2. Lorlatinib seems to project an even longer median PFS among ALK+ NSCLC Asian and non-Asian patients alike. However, without mature PFS, it will take time for oncologists to realize the magnitude of PFS, which could potentially exceed 60 months.^2,17

Disclosure

Dr Saihong Ignatius Ou reports personal fees from Pfizer, personal fees from JNJ/Janssen, personal fees from DAVA Oncology LLP, personal fees from Lilly, personal fees, stock holder of Elevation Oncology, stock holder of Turning Point Therapeutics, personal fees from BeiGene, outside the submitted work. The authors report no other conflicts of interest in this work.