Novel ALK Inhibitor Shows Encouraging Activity in Early NSCLC Study

Leora Horn, MD, MSc

Ensartinib (X-396), a novel small-molecule tyrosine kinase inhibitor (TKI) developed to target patients with ALK-positive non—small cell lung cancer (NSCLC), demonstrated promising clinical activity in that subset of patients who are crizotinib (Xalkori)-naïve or crizotinib-resistant, according to results of a phase I/II study.¹

In the first-in-human dose-escalation trial, patients with stage IIIB/IV NSCLC were treated with ensartinib starting at 25 mg orally once or twice daily. Enrolled patients were also tested positive for ALK via immunohistochemistry testing (IHC) or fluorescence in situ hybridization (FISH).

“The fact that we are seeing such amazing responses and durable responses in ALK-positive patients, we know that this drug is hitting its target,” said Leora Horn, MD, MSc, in an interview withTargeted Therapies in Oncologyduring the 2016 International Association for the Study of Lung Cancer (IASLC) Multidisciplinary Symposium on Thoracic Oncology.

Cohorts separated patients who were crizotinib-naïve (27%), had prior crizotinib (48%), had a different prior second-generation ALK TKI (25%), and patients who had central nervous system (CNS) disease (46%), but patients could have overlapped into more than one cohort. Prior second-generation ALK TKIs included brigatinib (AP26113), alectinib (Alecensa), and ceritinib (Zykadia).

Patients were treated until disease progression or unacceptable toxicity developed. In this portion of the study, in which safety was the primary endpoint, 225 mg was established as the phase II dose. Secondary endpoints included response rate, pharmacokinetics, and correlatives.

Treatment-related adverse events (AEs) occurred in 84% (n = 72) of patients. The only grade 3/4 AE was rash at 10% (n = 9). Most AEs were grade 1/2, including rash (46%), nausea (35%), pruritus (25%), vomiting (27%), fatigue (20%), decreased appetite (17%), edema (15%), and dry skin (11%).

“The drug is very well tolerated,” explained Horn, an associate professor of Medicine (Hematology and Oncology), assistant director, Educator Development Program, clinical director, Thoracic Oncology Program, medical oncologist, Vanderbilt-Ingram Cancer Center. “The most common toxicity that we saw, initially, was nausea that seems to go away when taking the agent with food. We have also seen some rash, which is treated by withholding the drug for a few days. Some patients require dose modification.”

The phase II portion of the study was an expansion phase, which was aimed at assessing the preliminary antitumor activity of ensartinib. The updated findings were presented at the 2016 IASLC Multidisciplinary Symposium on Thoracic Oncology.²

In the 52 evaluable ALK-positive patients who received 200 mg or higher of ensartinib, 56% of patients (n = 29) had a partial response (PR) and 25% (n = 13) had stable disease (SD). The duration of treatment was up to more than 34 months.

Of those who had a PR, 10% were ALK TKI-naïve, 64% received prior crizotinib, and 23% previously received a second-generation ALK TKI. There were 3 PRs in 5 patients with measurable CNS lesions; 2 patients with CNS lesions had SD.

“The drug has some very promising activity in patients who were crizotinib-naïve,” said Horn. “We saw 7 out of 9 responders, and it actually turned out that 2 patients who did not respond on central testing were not ALK-positive, so we can say that it is very effective in the first-line setting. In the second-line setting, we are also seeing responses of over 60%, and we’re also seeing very durable responses where patients are on the drug not for months, but for years for some.”

Additional data presented in conjunction with efficacy findings related the concordance between plasma via next-generation sequencing (NGS) with the Resolution ctDx blood-based platform, and tissue via FISH, and how this correlates with responses to ensartinib. Results showed that the overall concordance of ALK fusions in tissue via FISH and plasma via NGS is 74% (n = 31 variants).

The median age of patients was 55 (n = 86) with the median age of ALK-positive patients at 53 (n = 52). Sixty-three percent of patients were never smokers, 33% were former smokers, and 4% were current smokers.

Ensartinib also has additional activity against receptors of MET, ABL, Axl, EPHA2, LTK, ROS1, and SLK, Horn noted.

An ongoing phase III trial is comparing ensartinib with crizotinib in TKI-naïve, ALK-positive patients with NSCLC (NCT02767804). The trial is currently open in the United States and will soon open worldwide, Horn noted.

Ensartinib has a more manageable safety profile compared with the other ALK inhibitors available, Horn explained. While its efficacy is similar, she added that second-line ALK-positive NSCLC is where response rates get trickier to achieve.

“We know that when patients get treated with crizotinib, there are multiple different mechanisms of resistance to crizotinib,” Horn said. “L1196 is probably the most common that we hear about—that’s a gatekeeper mutation. What sets these different second-generation inhibitors apart is they don’t all target the same resistance mechanism. What we’re going to see more commonly is that patients on these first-line ALK inhibitors will progress and hopefully get re-biopsied or get a liquid biopsy so that we can determine their mechanism of resistance and, in the second-line setting, determine which agent is the most appropriate drug to give at that time.”

References:

1. Horn L, Wakelee H, Reckamp K, et al. Phase I/II trial of ensartinib (X-396), a novel anaplastic lymphoma kinase (ALK) inhibitor, in patients with ALK+ non—small cell lung cancer (NSCLC).J Clin Oncol.2016;34 (suppl;abstr 9056).
2. Horn L, Wakelee H, Reckamp K, et al. Phase I/II trial of ensartinib (X-396), a novel anaplastic lymphoma kinase (ALK) inhibitor, in patients with ALK+ non—small cell lung cancer (NSCLC). Presented at: 2016 IASLC Multidisciplinary Symposium on Thoracic Oncology; Chicago, Illinois, September 22-24, 2016.