Next-Generation ALK Inhibitor Ensartinib Outperforms Crizotinib in ALK-Positive NSCLC


Ensartinib, an investigational ALK inhibitor, significantly extended progression-free survival versus crizotinib in patients with advanced disease in the phase 3 eXalt3 randomized clinical trial.

Leora Horn, MD, MS

Leora Horn, MD, MS

The investigational ALK-inhibitor ensartinib (X-396) outperformed standard-of-care crizotinib (Xalkori) in patients with advanced ALK-positive non–small cell lung cancer (NSCLC), findings from the phase 3 eXalt3 show.

Patients who received ensartinib experienced a median progression-free survival (PFS) of 25.8 months compared to only 12.7 months in the crizotinib group. The Hazard ratio (HR) was 0.51, meaning that ensartinib was associated with a 49% lower risk of disease progression or death (95% Confidence Interval [CI], 0.35-0.72). These interim results from the phase 3 eXalt3 randomized clinical trial were published recently in JAMA Oncology.

Ensartinib also had a confirmed intracranial response rate of 64% among patients who had baseline brain metastases. This compares with a 21% intracranial response rate among patients in the crizotinib group.

Led by Leora Horn, MD, MS, Vanderbilt-Ingram Cancer Center, Nashville, Tenn., the authors concluded: “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.”

The open-label eXalt3 trial was conducted at 120 centers in 21 countries. It enrolled 290 patients with advanced, recurrent, or metastatic ALK-positive NSCLC who had not received prior treatment with an ALK inhibitor. Patient sex distribution was well balanced, and the median patient age was 54, with an age range of 25 to 90 years.

Participants were randomized 1:1 to receive either 225 mg of oral ensartinib once daily or 250 mg of crizotinib twice daily. The trial design called for patients to receive treatment until disease progression or unacceptable toxicity, but no crossover was permitted. At the physician’s discretion, treatment could continue beyond progression.

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 (OS).

At the July 2020 data cutoff, many more patients in the ensartinib group continued to receive treatment: 64 patients (44.8%) versus 25 patients (17.0%) in the crizotinib group. The median follow-up was 23.8 months (range, 0-44 months) for the ensartinib group and 20.2 months (range, 0-38 months) for the crizotinib group.

EXalt3 also included a prespecified modified intention-to-treat (mITT) group that consisted of ALK-positive patients whose status was confirmed by central testing. 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; HR, 0.45; 95% CI, 0.30-0.66; log-rank P < .001).

Progression-free survival for patients without brain metastases was not reached with ensartinib. “[This compares with] 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),” Horn et al. wrote.

The safety profiles of each drug were manageable and consistent with previous studies. About two-thirds of patients in the ensartinib group experienced a grade 1, 2, or 3 rash. Of these, 16 patients (11.2%) had a grade 3 rash; all responded when the study drug dose was withheld or reduced. Additionally, about half the patients in the ensartinib group developed elevated alanine aminotransferase levels and about one third developed elevated transaminase levels.

Only 3 patients in the ensartinib group developed grade 4 treatment-related adverse events (AEs): one each with increased bilirubin level, increased creatine phosphokinase level, and hyponatremia. In the crizotinib group, the most common AEs were liver toxic effects, nausea, edema, and constipation. There were no treatment-related deaths in either group.

Horn et al. noted some limitations with the study. One concern is that eXalt3 included some patients whose ALK status was confirmed only at the local level, which could have affected efficacy outcomes in the ITT population. Additionally, the OS data may be confounded by the fact that study participants could have received other ALK inhibitors when their disease progressed. Finally, the OS data are not yet mature; when they are, they may“help to better contextualize the role of ensartinib compared with other next-generation ALK inhibitors.”

Additionally, Horn et al. believe that researchers should look more closely at drug resistance in this disease setting: “A more precise understanding of primary and acquired resistance mechanisms is warranted to establish the optimal sequence of ensartinib and other available second- and third-generation ALK inhibitors in the first-line setting.”


Horn L, Wang Z, Wu G et al. Ensartinib vs Crizotinib for Patients With Anaplastic Lymphoma Kinase−Positive Non–Small Cell Lung Cancer: A Randomized Clinical Trial. JAMA Oncol. doi:10.1001/jamaoncol.2021.3523. Published online September 2, 2021.

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