Ensartinib Effective, Well-Tolerated in Patients With ALK+, TKI-Naive NSCLC

Heather A. Wakelee, MD

Ensartinib, a potent small molecule tyrosine kinase inhibitor (TKI), has shown promise and meaningful intercranial activity in anaplastic lymphoma kinase (ALK)-positive, TKI-naïve patients with non—small cell lung cancer (NSCLC), according to study results presented at the IASLC 18th World Conference on Lung Cancer in Yokohama, Japan.

The compound was also well tolerated by patients in the study, in which the primary endpoint was safety. The most serious adverse event (AE) was development of a rash, which was successfully managed by dose reduction and topical or oral steroids, said Heather Wakelee, MD, lead presenter and a professor of medicine/oncology at Stanford University Medical Center, Stanford, California.

In results presented last month in Chicago at the IASLC Multidisciplinary Symposium on Thoracic Oncology, ensartinib (X-396; Xcovery) was shown to be safe and effective in patients with ALK-positive NSCLC.

Wakelee, whose presentation expanded upon that study disclosure, noted that ensartinib has demonstrated broad antitumor activity in a range of ALK-positive patients, including those with multiple resistance mechanisms who have been heavily pretreated, and with at least 1 second-generation ALK TKI.

The positive outcomes extend to patients who have been previously treated with first-generation ALK inhibitor crizotinib (Xalkori) (objective response rate [ORR] 72%), while in the post-alectinib (Alecensa) setting, ensartinib has achieved an ORR of 20%, to name a few, Wakelee said.

Besides ALK, “we also see activity with this compound against multiple other mutations,” she said, listing MET, ABL, Axl, EPHA2, LTK, ROS1, and SLK.

Patient enrollment criteria included stage IIIb/IV NSCLC, ALK-positive status by immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH) testing, an ECOG performance status of 0 or 1, measurable disease, and central nervous system (CNS) target lesions of 2 to 3 mm. Dosage was 225 mg daily with or without food, on a 28-day cycle. After the primary endpoint of safety, secondary goals were response rate by RECIST v1.1 criteria, progression-free survival (PFS), and CNS response.

Wakelee said that of 69 patients evaluable for efficacy, the ALK-positive TKI-naïve subpopulation numbered 15 patients, of whom 11 (73%) had no prior systemic treatment and 4 were previously treated with chemotherapy.

In that subgroup, the median age was 58 (range 34-79), the gender divide was slightly female predominant (53%), and ethnicity was mostly Caucasian (87%). Wakelee said 53% reported never having smoked, and the remainder were a mix of former and current smokers. Those patient characteristics were not unexpected for the ALK-positive TKI-naïve population, she said. Three patients were positive for target brain lesions, and 10 (67%) had none.

In the broader patient group (n = 110), the median age was 55; the gender was 51% male; and ethnicity was also strongly Caucasian at 76%, with 14% Asian, and 5% African American.

In terms of response to ensartinib among the ALK-positive TKI-naïve patients, there were 12 partial responses, 1 stable disease, and 2 progressive disease, with PFS for this subgroup extending to 23.8 months (95% CI, 6.2-40.5). The ORR for the 3 patients with CNS target lesions was 100%, including 1 complete response. “So, small numbers, good responses,” Wakelee noted.

AEs were reported in greater than 10% of all patients (n = 110), with the rash being most prominent—predominantly erythematous and maculopapular (n = 59). The rash was primarily grade 1 to 2, although 14 patients suffered a grade 3 rash that was determined mostly by total body surface area rather than severity, Wakelee said. “For patients who do develop the rash, usually a 1-step-down dose reduction allows it to be quite tolerable.” Other leading all-grade AEs were nausea (34%), pruritis (26%), vomiting (26%), fatigue (22%), and decreased appetite (17%). “In general, ensartinib has been fairly well tolerated,” she said.

These results add up to promising activity in ALK-positive patients, Wakelee concluded. The response rate was 92% for next-generation sequencing-confirmed disease, and 80% for FISH only. Intercranial activity from this compound was “meaningful,” as responses were seen in patients who were previously treated. There also is an ongoing head-to-head phase III first-line study of ensartinib versus crizotinib (Xalkori), she added.

For more information on ensartinib, including ongoing phase III studies for patients with ALK-positive NSCLC, visit xcovery.com.

Wakelee H, Sanborn R, Nieva J, et al. Response to ensartinib in TKI naïve ALK+ NSCLC patients. Presented at: IASLC 18th World Conference on Lung Cancer; October 15-18, 2017; Yokohama, Japan. Abstract MA 07.02.