Ensartinib vs Crizotinib for Patients With Anaplastic Lymphoma Kinase-Positive Non-Small Cell Lung Cancer: A Randomized Clinical Trial

Abstract

Importance: Ensartinib, an oral tyrosine kinase inhibitor of anaplastic lymphoma kinase (ALK), has shown systemic and central nervous system efficacy for patients with ALK-positive non-small cell lung cancer (NSCLC).

Objective: To compare ensartinib with crizotinib among patients with advanced ALK-positive NSCLC who had not received prior treatment with an ALK inhibitor.

Design, setting, and participants: This open-label, multicenter, randomized, phase 3 trial conducted in 120 centers in 21 countries enrolled 290 patients between July 25, 2016, and November 12, 2018. Eligible patients were 18 years of age or older and had advanced, recurrent, or metastatic ALK-positive NSCLC.

Interventions: Patients were randomized (1:1) to ensartinib, 225 mg once daily, or crizotinib, 250 mg twice daily.

Main outcomes and measures: The primary end point was blinded independent review committee-assessed progression-free survival (PFS). Secondary end points included systemic and intracranial response, time to central nervous system progression, and overall survival. Efficacy was evaluated in the intent-to-treat (ITT) population as well as a prespecified modified ITT (mITT) population consisting of patients with central laboratory-confirmed ALK-positive NSCLC.

Results: A total of 290 patients (149 men [51.4%]; median age, 54 years [range, 25-90 years]) were randomized. In the ITT population, the median PFS was significantly longer with ensartinib than with crizotinib (25.8 [range, 0.03-44.0 months] vs 12.7 months [range, 0.03-38.6 months]; hazard ratio, 0.51 [95% CI, 0.35-0.72]; log-rank P < .001), with a median follow-up of 23.8 months (range, 0-44 months) for the ensartinib group and 20.2 months (range, 0-38 months) for the crizotinib group. In the mITT population, the median PFS in the ensartinib group was not reached, and the median PFS in the crizotinib group was 12.7 months (95% CI, 8.9-16.6 months; hazard ratio, 0.45; 95% CI, 0.30-0.66; log-rank P < .001). The intracranial response rate confirmed by a blinded independent review committee was 63.6% (7 of 11) with ensartinib vs 21.1% (4 of 19) with crizotinib for patients with target brain metastases at baseline. Progression-free survival for patients without brain metastases was not reached with ensartinib vs 16.6 months with crizotinib as a result of a lower central nervous system progression rate (at 12 months: 4.2% with ensartinib vs 23.9% with crizotinib; cause-specific hazard ratio, 0.32; 95% CI, 0.16-0.63; P = .001). Frequencies of treatment-related serious adverse events (ensartinib: 11 [7.7%] vs crizotinib: 9 [6.1%]), dose reductions (ensartinib: 34 of 143 [23.8%] vs crizotinib: 29 of 146 [19.9%]), or drug discontinuations (ensartinib: 13 of 143 [9.1%] vs crizotinib: 10 of 146 [6.8%]) were similar, without any new safety signals.

Conclusions and relevance: In this randomized clinical trial, ensartinib showed superior efficacy to crizotinib in both systemic and intracranial disease. Ensartinib represents a new first-line option for patients with ALK-positive NSCLC.

Trial registration: ClinicalTrials.gov Identifier: NCT02767804.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Horn reported receiving grants and/or personal fees from Xcovery Holdings Inc, Amgen, AstraZeneca, Merck, Bristol Myers Squibb, Incyte, EMD Serono, Pfizer, and AbbVie, while affiliated with Vanderbilt University; currently an employee of AstraZeneca. Dr Mok reported receiving personal fees, grants, or other fees from AbbVie, ACEA Pharma, Alpha Biopharma Co Ltd, Amgen, Amoy Diagnostics Co Ltd, AstraZeneca, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Blueprint Medicines Corporation, CStone Pharmaceuticals, Daiichi Sankyo, Eisai, Fishawack Facilitate Ltd, geneDecode, Gritstone Oncology Inc, Guardant Health, Hengrui Therapeutics, Ignyta Inc, IQVIA, Incyte Corporation, InMed Medical Communication, Janssen, Lilly, Loxo-Oncology, Lunit Inc, MD Health (Brazil), Medscape/WebMD, Merck Serono, Merck Sharp & Dohme, Mirati Therapeutics Inc, MORE Health, Novartis, OrigiMed, PeerVoice, Physicians’ Education Resource, Permanyer SL, Pfizer Inc, PrIME Oncology, Puma Technology Inc, Research to Practice, Roche, Sanofi-Aventis R&D, Takeda, Touch Medical Media, Virtus Medical Group, Yuhan Corporation, AstraZeneca PLC, Hutchison Chi-Med, Sanomics Ltd, Clovis Oncology, SFJ Pharmaceuticals, Xcovery, Curio Science, Inivata, Berry Oncology, G1 Therapeutics Inc, and Aurora. Dr Reck reported receiving personal or other fees from Amgen, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Lilly, Merck, MSD, Novartis, Pfizer, and Roche. Dr Wakelee reported receiving fees from advisory boards, grants, or other fees from ACEA Biosciences, Arrys Therapeutics, AstraZeneca/Medimmune, Blueprint Oncology, Bristol Myers Squibb, Celgene, Clovis, Daiichi Sankyo, Exelixis, Genentech/Roche, Gilead, Helsinn, Janssen, Merck, Mirati, Novartis, Pharmacyclics, Seattle Genetics, and Xcovery Holdings Inc. Dr Chiappori reported receiving fees for speakers bureaus and/or advisory boards from Genentech, Takeda, Merck, Celgene, Novartis, AstraZeneca, Pfizer, Jazz, Amgen, AbbVie, and Bristol Myers Squibb. Dr Lee reports receiving personal fees from AbbVie, AstraZeneca, Boehringer Ingelheim, Takeda, Bristol Myers Squibb, ChongKunDang, CJ Healthcare, Eli Lilly, Janssen, Merck, MSD, Mundipharma, Novartis, Ono, Pfizer, Roche, Samyang Biopharm, ST Cube, Green Cross, and Genexine. Dr Breder reports receiving personal fees or nonfinancial support from AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Lilly, MSD, Takeda, Roche, and Ipsen. Dr Whisenant reported having a patent with Anasys Instruments with royalties paid. Dr Zhou reported being an employee of Xcovery Holdings Inc. Mr Oertel reported being an employee of Xcovery Holdings Inc. Ms Harrow reported receiving personal fees from Xcovery Holdings Inc during the conduct of the study; and currently being an employee of EQRx. Dr Liang reported being an employee and shareholder of Xcovery Holdings Inc. Dr Mao reported being a former employee and shareholder of Xcovery Holdings Inc; and currently an employee of Sino Biopharmaceutical Limited. Dr Selvaggi reported being an employee and shareholder of Xcovery Holdings Inc. Dr Y.-L. Wu reported receiving grants and/or personal fees from AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Eli Lilly, Hengrui, MSD, Pfizer, Roche, and Sanofi. No other disclosures were reported.

Figures

Figure 1.. Screening, Enrollment, Randomization, and Follow-up

Data reported as of the cutoff for the first interim analysis (July 1, 2020) are shown. In the ensartinib group, 49 patients had documented disease progression according to the Response Evaluation Criteria in Solid Tumours (RECIST), version 1.1. In the crizotinib group, 100 patients had documented disease progression according to RECIST, version 1.1. ALK indicates anaplastic lymphoma kinase gene; ITT, intent to treat.

Figure 2.. Efficacy of Ensartinib and Crizotinib Among Patients With Non–Small Cell Lung Cancer

Kaplan-Meier estimates of progression-free survival by blinded independent review committee among patients in the intent-to-treat population. Tick marks indicate censored data. mPFS indicates median progression-free survival; NR, not reached.

Figure 3.. Efficacy of Ensartinib and Crizotinib Among Patients With Centrally Confirmed Anaplastic Lymphoma Kinase−Positive Non–Small Cell Lung Cancer

A, Kaplan-Meier estimates of progression-free survival (PFS) by blinded independent review committee in the modified intent-to-treat (mITT) population. B, The presence of brain metastases at baseline was assessed by the investigator. C, Kaplan-Meier estimates of PFS by blinded independent review committee. D, Overall survival in the mITT population. ECOG indicates Eastern Cooperative Oncology Group; mITT, modified intent-to-treat; mOS, median overall survival; mPFS, median progression-free survival; NA, not applicable; and NR, not reached.

Figure 4.. Treatment-Related Adverse Events Reported in 10% or More of All Patients

ALT indicates alanine aminotransferase; AST, aspartate aminotransferase; and γ-GT, γ-glutamyltransferase.