Telisotuzumab Vedotin Shows Durable Responses in EGFR Wild-type, c-MET+ NSCLC

Results from the LUMINOSITY trial show an enriched overall response rate for telisotuzumab vedotin among patients with c-Met high overexpressing tumors.

Telisotuzumab vedotin was associated with durable responses in c-Met protein-overexpressing nonsquamous EGFR wild-type non–small cell lung cancer (NSCLC), particularly in patients with high c-Met overexpression, according to results from the phase 2 LUMINOSITY trial (NCT03539536) published in the Journal of Clinical Oncology.1

Findings showed that the overall response rate (ORR) was 28.6% (95% CI, 21.7%-36.2%), with a 34.6% ORR (95% CI, 24.2%-46.2%) in patients with high c-Met overexpression vs those with intermediate c-Met overexpression (22.9%; 95% CI, 14.4%-33.4%). The median duration of response (DOR) was 8.3 months (95% CI, 5.6-11.3), with a 9.0-month median DOR for c-Met high overexpression (95% CI, 4.2-13.0) vs 7.2 months for c-Met intermediate overexpression (95% CI, 5.3-11.5). The 6-month or greater DOR rate was observed in 56.5% of c-Met total patients, including 63.0% of those who were c-Met high and 47.4% of c-Met intermediate.

“The phase II LUMINOSITY study aimed to determine which c-Met protein–overexpressing NSCLC patient population would most benefit from treatment with [telisotuzumab vedotin] and to further evaluate the efficacy within those patients,” lead study author D. Ross Camidge, MD, PhD, professor of medicine-medical oncology at the University of Colorado Anschutz Medical Campus in Aurora, and coinvestigators wrote in the study. “The nonsquamous EGFR wild-type NSCLC cohort met criteria for expansion, whereas the squamous and nonsquamous EGFR-mutant cohorts met protocol-specified criteria for futility… Currently, no therapies specifically for patients with c-Met protein–overexpressing NSCLC are available. In LUMINOSITY, [telisotuzumab vedotin] was associated with durable responses in c-Met protein–overexpressing nonsquamous EGFR-wildtype NSCLC, with ORRs enriched in patients with high c-Met expression.”

The multicenter, nonrandomized, 2-stage phase 2 study enrolled 270 patients with NSCLC. In stage I of the trial, 245 patients received telisotuzumab vedotin at 1.9 mg/kg once every 2 weeks, in patients who were c-Met high (n = 130), c-Met intermediate (n = 107), and c-Met negative (n = 5). Patients had a median of 1 prior therapy (range, 1-3), with 98% and 82% having undergone previous platinum-based therapy or receipt of an immune checkpoint inhibitor, respectively.

Patients in stage I were disaggregated into 3 cohorts: c-Met protein–overexpressing, nonsquamous EGFR wild-type NSCLC; c-Met protein–overexpressing, nonsquamous EGFR-mutant NSCLC; and c-Met protein–overexpressing, squamous NSCLC. In the stage II portion, investigators enrolled patients with EGFR wild-type NSCLC with sufficient c-Met expression. The dosing regimen was the same in both stages.

A China extension cohort at the same dosing regimen and another supplementary cohort at 1.6 mg/kg once every 2 weeks were added after completion of stage II enrollment. Data from the supplementary cohort were not included in the analysis, and the efficacy analysis includes 7 patients from the China extension cohort. All patients received telisotuzumab vedotin until progression, unacceptable toxicity, or meeting of study discontinuation criteria.

The primary end point of the study was ORR. Secondary end points included DOR, disease control rate (DCR), progression-free survival (PFS), and overall survival (OS).

At the data cutoff date of September 28, 2023, 92.4% (n = 152) of patients with nonsquamous EGFR wild-type NSCLC had discontinued treatment, most commonly due to progression (47.7%) or adverse events (AEs, 27.9%). Median duration of treatment exposure was 19.7 weeks (range, 0.1-104), with 20.3% of patients receiving at least 20 doses of telisotuzumab vedotin.

Among those eligible for efficacy analysis, DCR for c-Met overexpressing total was 59.0% (95% CI, 51.0%-66.7%); it was 60.3% for c-Met high (95% CI, 48.5%-71.2%) and 57.8% of c-Met intermediate (95% CI, 46.5%-68.6%) patients. The median PFS was 5.5 months (95% CI, 4.1-8.3) and 6.0 months (95% CI, 4.5-8.1) for c-Met high and intermediate patients, respectively; the median PFS was 5.7 months (95% CI, 4.6-6.9) for c-MET overexpressing overall. Six-month PFS rates were 48.0% (95% CI, 39.5%-56.1%), 45.8% (95% CI, 33.8%-57.1%), and 50.1% (95% CI, 37.9%-61.1%) overall, c-Met high, and c-Met intermediate, respectively.

Furthermore, median OS was 14.6 months (95% CI, 9.2-25.6) and 14.2 months (95% CI, 9.6-16.6) for c-Met high and intermediate patients, respectively; the median OS was 14.5 months (95% CI, 9.9-16.6) in c-MET overexpressing overall. One-year OS rates were 56.0% (95% CI, 47.7%-63.4%), 57.0% (95% CI, 45.0%-67.4%), and 55.0% (95% CI, 43.5%-65.2%) in the overall, high, and intermediate populations, respectively.

Regarding safety, any-grade treatment-emergent AEs (TEAEs) were observed in 97.1% of patients, including a 56.4% grade 3 or greater occurrence. Furthermore, any-grade treatment-related AEs (TRAEs) and grade 3 or greater TRAEs were observed in 81.4% and 27.9% of patients, respectively. Treatment discontinuation-resultant TRAEs occurred in 21.5% of patients, and 1 death was related to a grade 3 instance of interstitial lung disease. The most common any-grade TRAEs were peripheral sensory neuropathy (30%), peripheral edema (16%), and fatigue (14%); the most common grade 3 or higher AE was peripheral sensory neuropathy (7%).

Reference

Camidge DR, Bar J, Horinouchi H, et al. Telisotuzumab vedotin monotherapy in patients with previously treated c-Met protein–overexpressing advanced nonsquamous EGFR-wildtype non–small cell lung cancer in the phase II LUMINOSITY trial. J Clin Oncol. Published online June 6, 2024. doi:10.1200/JCO.24.00720