Lazertinib Shows Promising Antitumor Activity in Patients With EGFR+ NSCLC

Article

With the inevitability of resistance to first- and second-generation EGFR tyrosine kinase inhibitors in patients with EGFR-mutant non–small cell lung cancer, novel options like lazertinib, an irreversible, third-generation, mutant-selective, EGFR TKI are being explored. Lazertinib has shown promise for the treatment of this patient population, according to a phase I/II dose-escalation study published in The Lancet Oncology.

With the inevitability of resistance to first- and second-generation EGFR tyrosine kinase inhibitors (TKIs) in patients withEGFR-mutant non—small cell lung cancer (NSCLC), novel options like lazertinib (YH25448), an irreversible, third-generation, mutant-selective, EGFR TKI are being explored. Lazertinib has shown promise for the treatment of this patient population, according to a phase I/II dose-escalation study (NCT03046992) published inTheLancet Oncology.1

As assessed by independent central review (ICR), 69 (54%, 95% CI; 46—63) of the 127 in the study patients had an objective response to lazertinib. Of those patients, 52% had confirmed partial responses (PRs) and 2% confirmed complete responses (CRs). Additionally, there were 41 patients with stable disease, and 110 had disease control (87%, 95% CI; 81–93).

The data according to investigator assessment showed 76 patients with an objective response (60%, 95% CI; 51—68) and 114 with disease control (90%, 84–95).

The overall median duration of response (DoR) was 15.2 months (95% CI; 8.6—15.2), and the progression-free survival (PFS) was 9.5 months (6.9–16.4), by ICR.

In a subgroup of 108 patients harboring aTM90Mmutation, 62 patients achieved an objective response. In another subgroup of patients whose tumors were negative for TM90M, 7 out of 19 patients achieved objective responses, according to ICR. The investigator assessment showed 69 objective responses in patients withTM90M-positive tumors (64%, 95% CI; 55—73), and the number of objective responses in patients with TM90M-negative tumors was consistent with the ICR assessment.

Eighteen out of 127 patients had measurable brain metastases, including 15 patients withT790M-positive and 3T790M-negative tumors. Objective cranial responses were observed in 8 of those patients with measurable brain metastases (44%, 95% CI 22—69).

Patients withTM90M-positive tumors also had longer PFS than those withTM90M-negative tumors.

Adverse events (AEs) of any grade occurred in 119 patients in the study. The most common AEs were grade 1/2 rash or acne (30%) and pruritus (27%). AEs varied according to the dose level of lazertinib. Among participants who received 20 mg of the drug, 33% experienced grade 1/2 rash or acne (n = 1), and the same percentage of patients had constipation, decreased appetite, nausea, paraesthesia, headache, vomiting, and dyspnea. Of 27 patients given 40 mg of lazertinib, 26% had rash or acne (n = 7), 19% had pruritus (n = 5), and 19% experienced constipation most commonly.

At 80 mg, 10% of patients developed rash or acne (n = 2), 20% of them had pruritis (n = 4), and 35% had constipation (n = 7). In the patients who received 120 mg of lazertinib, 40% had rash or acne (n = 10), 24% developed pruritis (n = 6), and constipation occurred in another 24% (n = 6). With 160 mg doses of lazertinib, 35% percent of patients had rash/acne (n =8) and 35% experienced pruritis (n = 8), while 13% had constipation (n = 3).

In the cohort of patients treated with 240 mg of lazertinib, most patients who experienced AEs (42%) developed pruritis (n = 10). In 33% of these patients, rash or acne occurred (n = 8), and 13% had constipation (n = 3). In the 320 mg cohort, which included only 5 patients, 40% had rash or acne (n =2), while another 40% had either pruritis or constipation (n = 2).

Grade 3/4 AEs were observed in 16% of patients (n = 20). Among these patients, the most common AE was grade 3 pneumonia (n = 4). Some serious AEs occurred in 17% of patients in the overall study population (n = 21). Only 5% of the serious AEs observed were considered to be treatment-related. A total of 5 patients discontinued treatment due to AEs like pneumonitis (n = 2), gallbladder cancer (n = 1), and nausea (n = 1). No AEs led to death in any cohort.

Although the incidence of AEs climbed as the dose level of lazertinib increased, the drug was determined to be well-tolerated in the study subjects, and the toxicities were considered to be consistent with other EGFR inhibitors. One patient in the 160 mg lazertinib cohort had disease progression which ultimately led to death.

In a post hoc analysis, objective responses were seen in 37 of the patients withT790M-positive tumors given 120 mg of lazertinib or higher. This group of patients had a median PFS of 12.3 months (8.3—not reached), and 25 of these patients experienced disease progression, according to ICR assessment. At lower doses levels of 80 mg or below, 46 of the patients withT790M-positive tumors had an objective response and a median PFS of 6.9 months.

Based on investigator assessment, post hoc, the median PFS was 8.1 months in all patients (95% CI; 6.7—11.0; 76). Patients included in this analysis who originally presented with measurable brain metastases were evaluated for intracranial PFS (iPFS), which was not reached according to the ICR assessment.

The dose-escalation evaluation showed that high and durable responses would more likely to be achieved at 160 mg dose of lazertinib.

The study authors explained their determinations of lazertinib activity, writing, ” Lazertinib showed promising anti-tumor activity across multiple doses in patients with tumors harboring activatingEGFRmutations andT790Mresistance mutations. Responses tended to be rapid and durable. Because only a small number of patients withT790M-negative tumors were included in our study, we could not fully assess the activity of lazertinib in this subgroup.”

The phase I/II first-in-human, open-label, multicenter study, was divided into 3 parts; dose-escalation, dose-expansion, and dose extension. The study operated on a rolling 6 design and enrolled patients to 7 separate cohorts based on dose levels of 20 mg, 40 mg, 80 mg, 120 mg, 160 mg, 240 mg, and 320 mg. The drug was administered orally, once daily for 21-day cycles.

The coprimary endpoints of the study were objective response rate and the safety and tolerability of lazertinib. Secondary endpoints included DoR, disease control rate, PFS, overall survival, tumor shrinkage, objective intracranial response rate (OIRR), duration of OIRR, and iPFS.

Individuals required a histologically or cytologically confirmed diagnosis ofEGFR-mutant NSCLC, and Eastern Cooperative Group (ECOG) status of 0 or 1, and a minimum of 1 extracranial lesion. TheT790Mmutation status must have also been determined before beginning treatment in the study.2

Patients were excluded from the study due to spinal cord compression, brain metastases, known intracranial hemorrhage, complications in the central nervous system, leptomeningeal metastasis, cardiovascular disease, and having a history of interstitial lung disease.

The study investigators concluded that lazertinib has potential as a third-generation EGFR TKI for the treatment ofEGFR-mutant NSCLC and may be used either alone or in combination with other agents.

References

  1. Ahn MJ, Han JY, Hyeong K, et al. Lazertinib in patients with EGFR mutation-positive advanced non-small-cell lung cancer: results from the dose escalation and dose expansion parts of a first-in-human, open-label, multicentre, phase 1
Related Videos
Related Content