Ensartinib Tops Crizotinib in ALK-Positive NSCLC

The investigational ALK inhibitor ensartinib demonstrated better efficacy than crizotinib (Xalkori) against systemic and intracranial disease in patients with ALK-positive non-small cell lung cancer (NSCLC), according to the eXalt3 randomized clinical trial.

With a median follow-up of 23.8 months for patients treated with ensartinib and 20.2 months for those treated with crizotinib, patients on ensartinib had a median progression-free survival (PFS) that was about twice that of crizotinib (25.8 vs 12.7 months; HR 0.51, 95% CI 0.35-0.72), reported Yi-Long Wu, MD, of Guangdong Lung Cancer Institute in Guangzhou, China, and colleagues.

In addition, ensartinib had a confirmed intracranial response rate of 64% compared with just 21% with crizotinib in patients with brain metastases at baseline.

“In this randomized clinical trial, ensartinib showed superior systemic and intracranial efficacy compared with crizotinib and an overall favorable safety profile that is distinct from that of other agents in this class,” wrote Wu and colleagues in JAMA Oncology. “Ensartinib represents a new first-line treatment option for patients with ALK-positive NSCLC.”

In an editorial accompanying the study, Ibiayi Dagogo-Jack, MD, of Massachusetts General Hospital in Boston, observed that the eXalt3 study provides further evidence that next-generation ALK tyrosine kinase inhibitor (TKI) should be the standard of care for patients with advanced ALK-positive NSCLC.

“To continue to build on the successes of the past decade, future clinical trials and translational efforts will need to embrace designs that help guide prioritization and sequencing of available ALK TKIs while also informing the rational development of the next wave of therapies for ALK-positive NSCLC,” wrote Dagogo-Jack.

The open-label eXalt3 trial enrolled 290 patients in 21 countries who had recurrent or metastatic ALK-positive NSCLC and had not received previous treatment with an ALK inhibitor. Of these patients, 143 were randomized to receive ensartinib, 225 mg once daily, and 147 to receive crizotinib, 250 mg twice daily.

The primary endpoint of the the trial was PFS, while secondary endpoints included systemic and intracranial response, time to central nervous system progression, and overall survival. Efficacy was evaluated for both the intent-to-treat (ITT) population, as well as a modified intent-to-treat (mITT) population of 247 patients randomly assigned to the trial based on positive results of local testing for ALK and subsequently confirmed by central laboratory analysis as required by a protocol amendment.

As for the primary endpoint, Wu and colleagues noted that the median PFS demonstrated with ensartinib was consistent with studies comparing other ALK TKIs, such as brigatinib (Alunbrig) and alectinib (Alecensa), against crizotinib.

In addition, in the ITT group, the confirmed objective response rate was 74% (95% CI 66%-81%) in the ensartinib group and 67% (95% CI 58%- 74%) in the crizotinib group The median duration of complete or partial response was not reached in the ensartinib group and was 27.3 months in the crizotinib group.

In the mITT population, median PFS was not reached in the ensartinib group compared with 12.7 months in the crizotinib group (HR 0.45, 95% CI 0.30-0.66). The confirmed objective response rate in the mITT population was 75% (95% CI 66.5%-82.6%) in the ensartinib group and 68% (95% CI 58.5%-75.5%) in the crizotinib group. The median duration of response in this population was not reached in the ensartinib group, with 59% of patients having durable responses lasting 36 months or more.

Eleven patients receiving ensartinib and 19 patients receiving crizotinib had measurable brain metastases at baseline. Among this population, the intracranial response rate was 63.6% on ensartinib versus 21.1% on crizotinib.

PFS among patients without brain metastases was not reached with ensartinib and was 16.6 months with crizotinib. While just 4.2% of patients without brain metastases at baseline in the ensartinib group developed brain metastases at 12 months, 23.9% of patients in the crizotinib group did.

Serious treatment-related adverse events (AEs) were similar in the ensartinib and crizotinib groups (7.7% vs 6.1%, respectively), as were dose reductions (23.8% vs 19.9%) and drug discontinuations (9.1% vs 6.8%).

The most common ensartinib-related AEs were rash (67.8%), elevated aspartate aminotransferase (37.8%) and alanine aminotransferase levels (48.3%) and pruritus (26.6%). Most of these events were grade 2 or less.

In her editorial, Dagogo-Jack noted that several toxic effects associated with ensartinib – particularly pyrexia and the high frequency of dermatological toxic effects – distinguishes the drug from other ALK TKIs.

“These classes of toxic effects, while relatively rare for ALK targeted therapies, are commonly encountered with other lung cancer targeted therapies including epidermal growth factor receptor inhibitors (dermatologic toxicities) and BRAF inhibitors (pyrexia),” she pointed out. “Guidelines for management of these adverse events, including recommendations regarding supportive medications to ameliorate symptoms, will be important if ensartinib is to have a future in the ALK therapeutic space.”