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The investigational ALK inhibitor ensartinib improved oncologic outcomes over crizotinib (Xalkori) for the first-line treatment of patients with advanced non-small cell lung cancer (NSCLC) and ALK gene alterations, an interim analysis of a phase III study found.

Among nearly 300 ALK-positive NSCLC patients in the so-called eXalt3 study, those assigned to ensartinib saw their median progression-free survival (PFS) double, at 25.8 months compared with 12.7 months with crizotinib, a first-generation ALK inhibitor (HR 0.51, 95% CI 0.35-0.72, P=0.0001), reported Leora Horn, MD, of the Vanderbilt-Ingram Cancer Center in Nashville, Tennessee.

Overall response rates (ORRs) were slightly improved with ensartinib (75% vs 67% with crizotinib), and more than twice as many patients achieved a complete response (14% vs 6%), with a duration of response not reached in the ensartinib group compared to 27.3 months with crizotinib, according to findings presented at the . Due to the ongoing global pandemic, the full 2020 WCLC meeting in Singapore has been postponed to January 2021.

Preclinical work demonstrated that ensartinib was a more potent ALK inhibitor than crizotinib, as well as other FDA-approved agents for ALK-positive NSCLC such as alectinib (Alecensa) and ceritinib (Zykadia).

showed promise in patients with crizotinib-resistant disease, and also carried a different toxicity profile than currently available drugs, with lower observed rates of gastrointestinal adverse events, but higher rates of rash, a new toxicity for ALK inhibitors that manifests as a sunburn or skin sensitivity.

"Ensartinib showed a favorable safety profile with low-grade rash and transaminitis as the most frequent treatment-related adverse events, and represents a new first-line treatment option for patients with ALK-positive non-small cell lung cancer," said Horn.

The novel, next-generation ALK inhibitor also demonstrated a substantially higher level of central nervous system (CNS) activity, with an intracranial ORR of 64% versus 21% with crizotinib among patients with brain lesions at baseline. For patients without brain metastases at baseline, ensartinib significantly reduced the time-to-treatment-failure rate in the brain, with 4% of patients on ensartinib developing new brain lesions at 12 months versus 24% of those on crizotinib (P=0.0011).

"Now we have a drug that clearly has activity in the CNS, and we've seen this with some of the other next-generation drugs like alectinib and brigatinib," said Horn.

At the time of the present analysis, overall survival data were immature, with a 2-year survival of 78% for both arms.

"While this is clearly a positive trial, ensartinib has demonstrated superiority to a now obviated prior standard of care in crizotinib," noted H. Jack West, MD, of City of Hope Comprehensive Cancer Center in Duarte, California. "Alectinib and brigatinib have both demonstrated superiority over crizotinib in the same setting, and we've just learned in a just this week that lorlatinib [Lorbrena] has also beaten crizotinib first line in the CROWN trial."

"Today, alectinib is very widely adopted as a current standard of care and demonstrating very favorable efficacy and good tolerability overall," added West, who was not involved in the study. "The clinical relevance of these findings is likely to be very limited, as there appears to be no aspect of the results with ensartinib that should tempt us to favor it over alectinib."

The open-label eXalt3 study randomized 290 patients with locally advanced or metastatic ALK-positive disease 1:1 to either 225 mg ensartinib daily or 250 mg crizotinib twice daily. This pre-planned interim analysis was conducted after 75% of PFS events, with treatment ongoing in 45% of those on ensartinib and 17% of those on crizotinib. Median follow-up was 23.8 and 20.2 months, respectively.

Median patient age was 54 years, and just over half were never smokers. Participants were stratified by baseline performance status, presence of brain metastases, receipt of prior chemotherapy (26%), and geographic region (about 50% were recruited from Asia).

Presence of ALK alterations was initially determined locally, but the study protocol was amended to determine ALK status centrally with an Abbott FISH test. In the modified intent-to-treat analysis, median PFS had not been reached among the 121 patients who received ensartinib, as compared to 12.7 months for the 126 who received crizotinib (HR 0.45, 95% CI 0.30-0.66, P<0.0001). In landmark analyses, PFS rates at 3 years were 51% in patients treated with ensartinib and 19% in those who received crizotinib.

About a third of patients had brain metastases at baseline. Median PFS in this population was not reached in the investigational arm compared with 16.6 months in the control arm (HR 0.40, 95% CI 0.23-0.70, P=0.0009), and PFS rates at 3 years were 61% and 25%, respectively.

This was done in part in order to have a companion diagnostic, Horn explained, but also because of variability in results of ALK alterations. "We wanted to make sure that we had a true population that was indeed ALK positive," she added.

Fewer grade 3/4 adverse events (AEs) were reported in the ensartinib arm, said Horn, and serious AEs occurred in 8% of patients on ensartinib and 6% of those on crizotinib. In the two arms, respectively, 9% and 7% of patients discontinued treatment due to toxicity.

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