Betta Pharmaceuticals' ALK Inhibitor Ensartinib Outperforms Xalkori in Phase 3 NSCLC Trial, Reaches Primary Endpoint

Compiled by Keke

Recently, Xcovery Holdings, a subsidiary of Betta Pharmaceuticals, presented the interim analysis results of the international, multicenter, Phase 3 eXalt3 clinical trial at the Presidential Symposium of the World Conference on Lung Cancer (IASLC WCLC). The study compared the next-generation ALK inhibitor ensartinib hydrochloride (Ensartinib, X-396) with the同类 drug Pfizer’s Xalkori (crizotinib). The results demonstrated that the median progression-free survival (mPFS) in patients with ALK-positive non-small cell lung cancer (NSCLC) treated with ensartinib was significantly longer than that in patients treated with crizotinib, thereby meeting the primary endpoint.

It is reported that the eXalt3 study enrolled a total of 290 patients with ALK-positive non-small cell lung cancer (NSCLC), who were randomly assigned to receive either ensartinib or crizotinib. As of the data cutoff date of July 1 this year, progression events accounted for 73% of the prespecified progression events for the final analysis, as assessed by the Blinded Independent Review Committee (BIRC). The data indicated that the median progression-free survival (mPFS) was 25.8 months in the ensartinib group versus 12.7 months in the crizotinib group, demonstrating a statistically significant difference between the two groups. Survival analysis (Kaplan-Meier curves) showed that at the 36-month time point post-treatment, less than 40% of patients in the ensartinib group had experienced disease progression, compared to 75% of patients in the crizotinib group.

Furthermore, ensartinib reduced tumor size in 75% of treatment-naïve lung cancer patients, surpassing the 67% rate observed with crizotinib; it also delayed disease progression by approximately two years, more than double that of crizotinib. Currently, the eXalt3 study continues to follow up on patients receiving treatment.

In a small subset of patients with ALK-positive NSCLC whose disease had metastasized to the brain, ensartinib also demonstrated superior therapeutic efficacy. In the ensartinib treatment group, tumor shrinkage was observed in all 11 patients who had large brain tumors with clearly visible lesions on scanning. Among them, 7 patients (64%) achieved a response, defined as a significant reduction in brain tumor size. In contrast, only one-fifth (approximately 4) of the 19 patients in the crizotinib treatment group responded.

In terms of safety, the most common adverse effect observed in the study with ensartinib was a sunburn-like rash, which represents a “novel toxicity” associated with ALK inhibitors.

Furthermore, at the initiation of this study, approximately 40 enrolled patients underwent ALK mutation testing at local laboratories. Subsequently, centralized testing of enrolled patients was conducted at large reference laboratories. This approach was adopted to minimize false-positive results from local testing facilities. It is reported that among the 43 patients tested at local laboratories, 11 had false-positive ALK results; seven of these patients received ensartinib treatment, and two received crizotinib treatment.

Since ensartinib targets only the ALK protein, it cannot achieve the therapeutic effect of slowing tumor growth in ALK-negative patients. Understandably, false-positive results can skew the data; therefore, researchers also reported outcomes for what they termed the “modified intent-to-treat population,” which comprised patients who underwent central testing. The median progression-free survival (PFS) for this patient cohort had not been reached at the time of the data cutoff, indicating that more than half of the patients had not experienced cancer progression by then. In contrast, the corresponding figure for patients treated with crizotinib was 12.7 months.

Anaplastic lymphoma kinase (ALK) is one of the important oncogenic drivers in non-small cell lung cancer (NSCLC). Statistics show that the positivity rate of ALK fusion genes in this patient population is approximately 5%, and it is more commonly seen in young patients with lung adenocarcinoma who are non-smokers or light smokers. Activation of ALK can lead to the activation of downstream signaling pathways, thereby promoting tumor development and survival. ALK inhibitors can effectively suppress ALK activity, thus inhibiting tumor growth. Crizotinib was the first drug approved by the U.S. FDA for targeted therapy against ALK, belonging to the first generation of ALK inhibitors.

Ensartinib is a novel, potent, and highly selective next-generation ALK inhibitor with fully independent intellectual property rights, jointly developed by Betta Pharmaceuticals and its controlled subsidiary, Xcovery. The drug exhibits strong binding affinity to ALK. The Phase 2 registrational clinical trial conducted in China aimed to evaluate the efficacy and safety of ensartinib in patients with ALK-positive non-small cell lung cancer (NSCLC) who had progressed on crizotinib, as well as to analyze biomarkers. The results demonstrated an objective response rate (ORR) of 52% and a disease control rate (DCR) of 93%. The intracranial ORR and DCR were 70% and 98%, respectively, indicating that the overall efficacy met the expected endpoints.

Mechanism of Action of Ensartinib (Source: Company Website)

Moving forward, based on the results of the eXalt3 study, Xcovery will discuss the data with regulatory authorities and actively prepare for the marketing approval applications of ensartinib as a first-line treatment for ALK-positive NSCLC in China and the United States. This drug may become the first lung cancer targeted innovative therapy led by a Chinese company to be launched globally.

If ensartinib is approved, it will face increased competition in the same therapeutic area. In addition to Xalkori, competitors include Roche’s Alecensa and Zykadia, both of which surpassed Xalkori in 2017 by securing approvals for first-line treatment indications; Alecensa is currently the sales leader in this drug class. Meanwhile, Pfizer’s Lorbrena (lorlatinib), a third-generation ALK inhibitor following Xalkori, has also released recent results, showing promise in outperforming Xalkori and reclaiming a significant share of this market.

Reference Source:

1、WCLC: Xcovery's Xalkori challenger shines in phase 3 lung cancer showdown

2. Company Website