A phase II LUMINOSITY study aimed to determine which patients with c-Met protein–overexpressing non-small cell lung cancer (NSCLC) would most benefit from treatment with telisotuzumab vedotin. The non-squamous EGFR-wild-type NSCLC cohort met criteria for expansion, while the squamous and non-squamous EGFR-mutated cohorts met protocol-specified criteria for futility. The highest overall response rate (ORR) was observed among patients with c-Met protein–overexpressing, non-squamous EGFR-wild-type NSCLC, and ORR was enriched among patients with c-Met high overexpressing tumours.
Although ORR was increased in the c-Met–high population, disease control rate, progression-free survival (PFS), and overall survival (OS) were comparable between c-Met high, c-Met intermediate, and c-Met total overexpression, indicating telisotuzumab vedotin was efficacious in patients with c-Met–overexpressing tumours regardless of the level of expression. The findings are reported by Dr. D Ross Camidge of the University of Colorado Cancer Center in Aurora, Colorado, US and colleagues on 6 June 2024 in the JCO.
Aside from any role in acquired resistance to targeted therapies, primary MET gene dysregulation can occur through amplification or mutation in approximately 5% and around 2-4% of patients with NSCLC. c-Met tyrosine kinase inhibitors have been successfully developed for patients with MET exon 14 skipping mutations and are in development for MET amplification.
Approximately 25-39% of patients with NSCLC have tumours that overexpress the c-Met protein, which may co-exist with MET genomic alterations. Overexpression prevalence is around 25% in patients with non-squamous EGFR-wild-type NSCLC. c-Met protein overexpression is a negative prognostic factor for survival in early and advanced NSCLC.
The authors wrote in the background that although numerous clinical trials are evaluating targeted therapies against cancers with MET genomic alterations, there are currently no therapies available to specifically target c-Met protein overexpression. Telisotuzumab vedotin is a first-in-class c-Met–directed antibody-drug conjugate using c-Met protein overexpression as a biomarker to target the cytotoxic payload to tumour cells. It has shown promising activity and an acceptable safety profile in patients with c-Met protein–overexpressing NSCLC in a phase I study.
The phase II LUMINOSITY study evaluated efficacy and safety of telisotuzumab vedotin in patients with c-Met protein–overexpressing locally advanced/metastatic NSCLC with aim to identify the population best suited for treatment with telisotuzumab vedotin in the second- or third-line (stage 1), and further assess efficacy and safety in the selected population (stage 2). The c-Met protein–overexpressing, non-squamous EGFR-wild-type NSCLC population was selected for further evaluation in stage 2. The study team reports findings from primary efficacy and safety analyses.
Eligible patients had locally advanced/metastatic c-Met protein–overexpressing NSCLC and at least two prior lines of therapy, including at least one line of systemic chemotherapy. c-Met protein overexpression in non-squamous EGFR-wild-type NSCLC was defined as ≥25% tumour cells with 3+ staining, defined as high in case ≥50% 3+, intermediate ≥25%–<50%. Primary endpoint was ORR by independent central review.
In total, 172 patients with non-squamous EGFR-wild-type NSCLC received telisotuzumab vedotin in stages 1 and 2; ORR was 28.6% (95% confidence interval [CI] 21.7–36.2); in c-Met high 34.6% (95% CI 24.2–46.2); in c-Met intermediate 22.9% (95% CI 14.4–33.4). Median duration of response was 8.3 months (95% CI 5.6–11.3); in c-Met high 9.0 (95% CI 4.2–13.0); in c-Met intermediate 7.2 (95% CI 5.3–11.5). Median OS was 14.5 months (95% CI 9.9–16.6); in c-Met high 14.6 (95% CI 9.2–25.6); in c-Met intermediate 14.2 (95% CI 9.6–16.6). Median PFS was 5.7 months (95% CI 4.6–6.9); in c-Met high 5.5 (95% CI 4.1–8.3); in c-Met intermediate 6.0 (95% CI 4.5–8.1).
Most common any-grade treatment-related adverse events were peripheral sensory neuropathy (30%), peripheral oedema (16%), and fatigue (14%); the most common grade ≥3 was peripheral sensory neuropathy (7%).
The authors commented that this phase II study is limited by the lack of a comparator arm. The ongoing global, randomised phase III TeliMET NSCLC-01 study compares telisotuzumab vedotin monotherapy with docetaxel in patients with previously treated locally advanced/metastatic, c-Met protein–overexpressing, non-squamous EGFR-wild-type NSCLC. Given the potential overlap of some genomic markers of MET activation with c-Met protein overexpression, retrospective analyses of the current study data on available tissue or blood for these markers will be of interest.
The study was funded by AbbVie.
Reference
Camidge DR, Bar J, Horinouchi H, et al. Telisotuzumab vedotin monotherapy in patients with previously treated c-Met protein– overexpressing advanced non-squamous EGFR-wildtype NSCLC in the Phase 2 LUMINOSITY trial. JCO; Published online 6 June 2024. DOI: 10.1200/JCO.24.00720