Telisotuzumab Vedotin Demonstrates Efficacy and Tolerability in Previously Treated c-MET+ NSCLC

Telisotuzumab vedotin monotherapy demonstrated a promising objective response rate and has a tolerable safety profile in patients with previously treated c-Met–positive advanced non–small cell lung cancer.

Single-agent telisotuzumab vedotin (teliso-v; ABBV-399) induced an encouraging objective response rate (ORR) with a tolerable safety profile in patients with previously treated non–small cell lung cancer (NSCLC) who were c-MET positive, according to data from a phase 2 study (NCT03539536) presented in a virtual poster during the AACR Annual Meeting 2021.

The study explored the safety and efficacy of teliso-v, an anti-c-Met antibody conjugated with a tubulin inhibitor MMAE, in previously treated patients with c-Met–positive advanced NSCLC.

The ongoing phase 2 study is expecting to enroll about 233 patients across 2 stages and has an estimated completion date of January 2025. During the open-label, single-arm study, patients received teliso-v at 1.9 mg/kg intravenously every 14 days. Patients with nonsquamous histology were separated into cohorts by EGFR mutations and then into subgroups based on level of c-Mt expression; intermediate c-Met was defined as staining on ≥25% to <50% of tumor cells at 3+ intensity, and high c-Met was considered ≥50% staining at 3+ intensity. For patients with squamous histology, c-Met positivity was defined as staining on ≥75% of tumor cells at 1+ intensity.

The primary outcome of the study was ORR with a time frame of up to approximately 3 years. Secondary outcomes included duration of response (DoR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS).

In order to participate, patients must be 18 years old or older and have locally advanced or metastatic NSCLC. Additionally, they must be c-Met-positive by immunohistochemistry assay and have received no more than 2 lines of prior systemic therapy. Patients with adenosquamous histology or major surgery within 21 days prior to the first dose of teliso-v are not eligible to participate.

The poster presentation highlighted results from 93 evaluable patients from stage 1 of the study. Of these patients, age ranged from 33 to 81 across the 3 cohorts. The majority of patients were male and had an ECOG performance status of 1. MET amplifications were reported in 8.6% and MET exon 14 skipping mutations were observed in 4.3% of patients, all in the nonsquamous EGFR wild-type (WT) cohort. Patients had received a median of 2 prior therapies (range, 1-4), which included platinum-based therapies in the majority of patients, immunotherapy for most of the patients with EGFR WT and EGFR tyrosine kinase inhibitors for all of the patients with EGFR mutations.

For the non-squamous EGFR WT cohort (n = 37), the ORR by independent central review was 35.1% (95% CI, 20.2%-52.5%). For the c-Met–high subgroup (n = 13), the ORR was 53.8% (95% CI, 25.1%-80.8%) and 25.0% (95% CI, 9.8%-46.7%) for the c-Met–intermediate subgroup. The DoR for this cohort was 6.9 months. For the EGFR-mutant (MU) group (n = 30), the ORR was 13.3% (95% CI, 3.8%-30.7%), with responses only in those with high c-Met (n = 22). DoR data for this cohort was not available. For the squamous cohort (n = 21), the ORR was 14.3% (95% CI, 3.0%-36.3%). The DoR was 4.4 months. All responses were partial responses.

Grade 3 or higher treatment-emergent adverse events (AEs) occurred in 53.8% of the evaluated patients, the most common of which was malignant neoplasm progression; this occurred in 7.5% of the patients. Grade 3 or higher pneumonia occurred in 6.5% and hyponatremia occurred in 5.4%. AEs that were possibly related to treatment with teliso-v and led to death were reported in 3 patients, 2 with squamous NSCLC and 1 with nonsquamous EGFR WT NSCLC.

According to the presentation, many of the AEs were related to duration of exposure to teliso-v. So while AEs did occur, the patient was still receiving a benefit from the drug.

“This is particularly true for some of the things like neuropathy,” said presenter D. Ross Camidge, MD, PhD, director of the Thoracic Oncology Clinical and Clinical Research Programs and professor of medical oncology, University of Colorado Medicine. “How often did these side effects lead to discontinuation? Somewhere between 20% and 30% of the time.”

Camidge also noted that higher rates of peripheral edema and peripheral sensory neuropathy events were observed in the cohort with the greater efficacy.

Ultimately, the nonsquamous EGFR WT cohort met the prescribed safety criteria to go onto phase 2. Enrollment in the EGFR MU cohort will continue until the next analysis and enrollment into the squamous cohort was stopped. According to Camidge, this agent is also being explored in combination with osimertinib (Tagrisso) in the EGFR MU cohort.

“I think the idea of what is exactly the right cut point, when exactly you may use these agents based on that cut point is going to be interesting to explore in the future,” Camidge said. “There are obvious similarities between the PD-L1 expression level and how we use that for prioritizing therapy on deciding who gets this agent versus other agents.”

Reference

  1. Camidge DR, Moiseenko F, Cicin I, et al. Telisotuzumab vedotin (teliso-v) monotherapy in patients with previously treated c-Met+ advanced non-small cell lung cancer. Poster presented at the American Association for Cancer Research Annual Meeting 2021; April 10-15, 2021; Virtual. Abstract CT179. Accessed April 12, 2021. https://bit.ly/32lwmvX