Telisotuzumab vedotin (teliso-v) is an anti-c-Met antibody conjugated with a tubulin inhibitor. The aim of a recent phase II trial is to explore the safety and efficacy of teliso-V in cohorts (based on histopathology and EGFR mutation) and subgroups (based on c-Met expression) of patients with c-Met overexpressing advanced non-small cell lung cancer (stage 1), followed by expansion into an appropriately selected population for further evaluation of safety and efficacy (stage 2).
Telisotuzumab vedotin (teliso-v; formerly ABBV-399) is a first-in-class anti-c-MET antibody-drug conjugate (ADC) composed of the humanised recombinant IgG1κ antibody ABT-700 (telisotuzumab) conjugated to the microtubule inhibitor and cytotoxin monomethyl auristatin E (MMAE) via a valine-citrulline linker. Preliminary data from a phase I/Ib study (NCT02099058) suggest that teliso-v monotherapy has anti-tumour activity and a tolerable safety profile that warrants further investigation in a phase II study (NCT03539536). This ongoing trial evaluates the safety and efficacy of teliso-v in cohorts (based on histopathology and epidermal growth factor receptor [EGFR] mutation) and subgroups (based on c-Met expression) of patients with previously treated, locally advanced or metastatic non-small cell lung cancer (NSCLC) and c-Met protein overexpression (c-Met+).
The trial is a phase II multicentre, non-randomised, single-arm, 2-stage, adaptive study. Patients had ECOG ≤ 1 with 1-2 prior lines of therapy including cytotoxic chemotherapy, immunotherapy and targeted therapy. c-Met status was determined centrally by IHC (SP44 antibody). Membrane staining on ≥ 25% of tumour cells at 3+ intensity or ≥ 75% of tumour cells at 1+ intensity was considered positive for non-squamous and squamous, respectively. Teliso-v dose was 1.9 mg/kg once every two weeks. Primary endpoint was objective response rate (ORR) per central review in patients with ≥ 12 weeks follow-up. Secondary endpoints were duration of response, disease control rate, PFS and OS. Stage 1 of the study assesses the efficacy of teliso-v monotherapy in three NSCLC cohorts (based on histopathology and EGFR mutation status) and adaptively enriches into five groups (based on intermediate vs. high c-Met expression levels) to identify those with the highest ORR to be included in Stage 2. Stage 2 of the study aims to expand and further evaluate efficacy of teliso-v in specific group(s) that demonstrated the most promising results in Stage 1 according to prespecified criteria.
As of December 2020, 841 patients were screened with evaluable c-Met IHC data. C-Met+ rates were generally lower in the EGFR wildtype (25%) vs. EGFR mutant (37%) non-squamous cohorts. Furthermore, 39% of patients in the squamous cohort had c-Met+ tumours. Approximately 50-60% of Met+ cases within the non-squamous NSCLC groups had high c-Met protein levels as opposed to intermediate levels.
In total, 113 patients with c-Met+ NSCLC were enrolled in Stage 1; 90 patients met efficacy-evaluable criteria and had ≥ 12 weeks of follow-up. c-Met expression, based on H-score, was generally lower in squamous vs. non-squamous cohorts. In the non-squamous cohorts, a greater frequency of patients with wild type EGFR had intermediate c-Met expression (65% vs. 29%), while a greater frequency of patients with mutated EGFR had high c-Met expression (35% vs. 71%). Patients in the non-squamous EGFR mutant cohort had a longer median duration of prior systemic cancer therapy than the other two cohorts. Prior treatment with platinum-based therapies was most common in all cohorts (>80%). The majority of patients in the non-squamous EGFR wild type and squamous cohorts (73% and 91%, respectively) received prior therapy with immune checkpoint inhibitors; all patients in the non-squamous EGFR mutant cohort received prior therapy with an EGFR TKI. ORR was 13/37 (35.1%) in the non-squamous EGFR wild type cohort (7/13 [53.8%] in c-Met high group and 6/24 [25.0%] in c-Met intermediate group), but was modest in the non-squamous EGFR mutant (13.3%) and squamous cohorts (14.3%). At the time of this interim analysis, no patients had achieved a complete response, 30% had achieved a partial response, and 10% experienced disease progression.
In total, 96% of patients experienced a treatment-emergent adverse event (TEAE), and 72% experienced a TEAE related to teliso-v as assessed by investigators. Grade ≥3 TEAEs occurred in 50 (44%) patients with the most common being malignant neoplasm progression (6.2%), pneumonia (5.3%), hyponatremia (4.4%), anaemia (2.7%), dyspnoea (2.7%), fatigue (2.7%), increased gamma-glutamyltransferase (2.7%), peripheral sensory neuropathy (2.7%), and pneumonitis (2.7%). Three patients died as a result of a TEAE considered possibly related to teliso-V by investigators (sudden death, dyspnoea, pneumonitis, N= 1 each).
ORR in non-squamous EGFR WT NSCLC patients treated with teliso-v at a dose of 1.9 mg/kg every two weeks was encouraging with a tolerable safety profile, and this cohort met prespecified criteria to transition to stage 2. In this cohort, ORR was highest in the c-Met high group, though also clinically meaningful in the intermediate group. Based on prespecified criteria, enrolment into the squamous cohort was stopped while enrolment into the EGFR mutated cohort will continue until the next interim analysis.
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. Presented at the 2021 World Conference on Lung Cancer; Abstract OA15.04.