Phase 3 Randomized Study of Telisotuzumab Vedotin vs. Docetaxel in c-Met Overexpressing EGFR Wildtype Non-Squamous NSCLC

Trial ID: 2023-505749-14-00
Protocol: M18-868
Sponsor: AbbVie Deutschland GmbH & Co. KG

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Diseases & Conditions

Non-small cell lung cancer

Objectives

The primary objective of this study is to evaluate the **efficacy** of telisotuzumab vedotin compared with docetaxel in terms of **progression-free survival** and/or **overall survival** in patients with c-Met overexpressing, EGFR wildtype, non-squamous non-small cell lung cancer (NSCLC). This is clinically relevant as it aims to determine the potential of telisotuzumab vedotin to improve survival outcomes in this specific patient population, which could lead to more effective treatment options.

Secondary objectives include:

Objective Response Rate (ORR) by BICR.
Duration of Response (DoR) by BICR.
Progression Free Survival per investigator assessment.
Change from baseline to week 12 in physical functioning as measured by the physical functioning domain of the EORTC-QLQ-Core 30 (EORTC QLQC30).
Change from baseline to Week 12 in quality of life as measured by the global health status/quality of life domain of the EORTC QLQ-C30.

Participants

The clinical trial involves a total of **480 participants** diagnosed with **c-Met overexpressing EGFR wildtype non-squamous non-small cell lung cancer**. The study population includes both male and female subjects, with an age range corresponding to categories 3 and 4, which typically includes adults and older adults. Participants were selected based on specific criteria, including the requirement for c-Met overexpression as assessed by an AbbVie designated IHC laboratory. The trial does not include a vulnerable population. Participants must have progressed on at least one line of prior therapy for locally advanced or metastatic non-small cell lung cancer (NSCLC) and must be considered appropriate for docetaxel therapy. Additionally, subjects are required to have adequate bone marrow, renal, and hepatic function, and an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 1. Lifestyle factors such as diet and physical activity are not specified as part of the selection criteria. The trial does not include subjects with known active severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or those with serious SARS-CoV-2 infection complications unresolved at the time of prescreening.

Plans and Procedures

The clinical trial is designed as a **randomized**, controlled, open-label, Phase III study to evaluate the efficacy of **telisotuzumab vedotin** compared to **docetaxel** in subjects with previously treated **c-Met overexpressing EGFR wildtype non-squamous non-small cell lung cancer**. The primary objective is to assess progression-free survival and overall survival in two nested populations: subjects with high c-Met overexpression and all subjects with c-Met overexpression. The trial is expected to run from March 2022 to March 2028, with a maximum treatment period of 24 months for each participant.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as c-Met overexpression and prior treatment history. Follow-up visits will occur regularly to monitor the participants' health status, treatment efficacy, and any adverse events. The end-of-study visit will conclude the trial for each participant, assessing final outcomes and collecting data for analysis.

The expected length of participant involvement is up to 24 months, depending on individual response and disease progression. Conditions that may lead to early termination from the study include significant adverse events, disease progression, or withdrawal of consent. The trial will adhere to rigorous scientific standards to ensure the reliability and validity of the results, contributing valuable insights into the treatment of this specific type of lung cancer.

Treatment

The clinical trial involves the administration of **Telisotuzumab Vedotin**, an experimental medication, which is a **solution for injection**. This investigational drug is administered via **intravenous infusion**. The dosing regimen for Telisotuzumab Vedotin is set at a maximum daily dose of 1.9 mg/kg, with a total maximum dose of 98.8 mg/kg over the treatment period. The treatment duration is capped at 24 weeks. Telisotuzumab Vedotin is a protein-based therapeutic agent developed by ABBVIE DEUTSCHLAND GMBH & CO. KG, and it is not formulated for pediatric use. Participant compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the protocol.

In this study, **Docetaxel** serves as the comparator treatment. Docetaxel is provided as a **concentrate for solution for infusion** and is also administered via **intravenous infusion**. The dosing for Docetaxel is established at a maximum daily dose of 75 mg/m², with a total maximum dose of 2600 mg/m² over the course of the 24-week treatment period. Docetaxel is a chemically derived therapeutic agent and is not intended for pediatric use. As with the experimental treatment, participant adherence to the dosing regimen will be closely monitored to ensure protocol compliance.

Efficacy

The efficacy of Telisotuzumab Vedotin compared to Docetaxel in subjects with previously treated c-Met overexpressing, EGFR wildtype, locally advanced or metastatic non-squamous non-small cell lung cancer (NSCLC) will be assessed through several endpoints. The co-primary endpoints are **Progression-Free Survival (PFS)** and **Overall Survival (OS)**, both evaluated by blinded independent central review (BICR). Secondary endpoints include Objective Response Rate (ORR) and Duration of Response (DoR), also assessed by BICR. Additionally, changes from baseline to Week 12 in physical functioning and quality of life will be measured using the EORTC QLQ-C30 questionnaire, specifically focusing on the physical functioning domain and the global health status/quality of life domain. PFS will also be assessed per investigator evaluation.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Subject must have c-Met overexpressing NSCLC as assessed by an AbbVie designated IHC laboratory using the VENTANA MET (SP44) RxDx assay
Subject must have progressed on at least 1 line of prior therapy for locally advanced/metastatic NSCLC: - Subjects WITHOUT an actionable gene alteration: subjects must have progressed on (or be considered ineligible for) platinum-based chemotherapy and immune checkpoint inhibitor (as monotherapy or in combination with chemotherapy). - Subjects WITH an actionable gene alteration for which immune checkpoint inhibitor therapy is not standard of care (e.g., anaplastic lymphoma kinase [ALK] translocation): subjects must have progressed on (or be considered ineligible for) anti-cancer therapy targeting driver gene alterations and platinum-based chemotherapy. - Subjects with actionable gene alterations for which immune checkpoint inhibitor is standard of care must have also progressed on (or be considered ineligible for) immune checkpoint inhibitor (as monotherapy or in combination with chemotherapy).
Subject must be considered appropriate for docetaxel therapy based on the assessment of the treating physician.
Archival or fresh tumor material must be submitted for assessment of c-Met protein expression levels by an AbbVie designated IHC laboratory during the Pre-Screening period. Tumor material from the primary tumor site and/or metastatic sites are allowed. If archival tissue is negative for c-Met overexpression, fresh biopsy material may be submitted for reassessment of c-Met expression (see Operations Manual Section 3.7). - If a subject was prescreened for Study M14-239 but did not enroll, tumor material previously submitted for Study M14-239 may be used for Study M18-868 Pre-Screening upon confirmation from AbbVie that sufficient evaluable tumor material is available
Subject has adequate bone marrow, renal, and hepatic function
Subject must have histologically or cytologically documented non-squamous cell NSCLC that is locally advanced or metastatic.
Subjects must have a known EGFR activating mutation status. - Subjects with EGFR activating mutations are not eligible.
Subjects with actionable alterations in genes other than EGFR are eligible.
Subject must have measurable disease per RECIST version 1.1.
Subject must have an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 1.
Subject must have received no more than 1 line of prior systemic cytotoxic chemotherapy in the locally advanced or metastatic setting. -Neoadjuvant and adjuvant systemic cytotoxic chemotherapy would count as a prior line for eligibility purposes if progression occurred within 6 months of the end of therapy.

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Exclusion Criteria

Subject has adenosquamous or neuroendocrine histology, or sarcomatoid features
Subject has received prior c-Met-targeted antibodies, prior telisotuzumab vedotin, or prior antibody-drug conjugates either targeting c-Met or consisting of monomethylauristatin E.
Subject has received prior docetaxel therapy.
Subjects with metastases to the central nervous system (CNS) are eligible only after adequate treatment (such as surgery, radiotherapy or drug therapy) is provided and: - They are asymptomatic and off or on a stable or reducing dose of systemic steroids (on no more than 10 mg QD prednisone or equivalent) and/or anticonvulsants for at least 2 weeks prior to randomisation; - There is no evidence of new, untreated CNS metastases or progressing CNS metastases after treatment; - There is no evidence of leptomeningeal disease.
Subjects with a history of other malignancies except: Malignancy treated with curative intent and with no known active disease present for ≥ 2 years before the first dose of study drug and felt to be at low risk for recurrence by investigator. Additionally, subjects must not be receiving any ongoing anti-cancer therapy, including maintenance therapy, prior to randomization; Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease; Adequately treated carcinoma in situ without current evidence of disease.
Subject with a history of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan.
History of prior radiation pneumonitis in the radiation field (fibrosis) is not permitted.
Subject with unresolved clinically significant AE ≥ Grade 2 from prior anticancer therapy, except for alopecia or anemia. Subjects with hormone deficiencies caused by prior anticancer therapy who are asymptomatic and on a stable dose of replacement hormone are eligible for study.
Subject has had major surgery within 21 days prior to randomisation.
Subjects with the following: - Known human immunodeficiency virus (HIV) infection. Note: HIV testing is not required for eligibility for this protocol unless mandated by local regulatory authority or ethics committee/institutional review board. - Active hepatitis B virus (HBV) infection, defined by HBV DNA ≥ 500 IU/mL or hepatitis B surface antigen (HBsAG) positivity associated with HBV DNA ≥ 500 IU/mL. In subjects with known HBV infection, the presence of active infection must be tested locally. If HBV status is unknown, it must be tested locally at screening if required by local regulatory authority or ethics committee/institutional review board. - Active hepatitis C virus (HCV) infection, defined by HCV RNA positivity. Subjects cured of HCV infection may be included in the study. In subjects with known HCV infection, the presence of active infection must be tested locally. If HCV status is unknown, it must be tested locally at screening if required by local regulatory authority or ethics committee/institutional review board. - Uncontrolled autoimmune disease.
Subject has clinically significant condition(s) including but not limited to the following: Clinically significant vascular disease, including: - Myocardial infarction within 1 year or stroke within 6 months prior to first dose of study drug, or unstable or uncontrolled disease/condition related to or affecting cardiac function (e.g., unstable angina, congestive heart failure, New York Heart Association Class III-IV), cardiac arrhythmia (CTCAE Version 5 Grade 2 or higher), or clinically significant electrocardiogram (ECG) abnormalities. - Screening 12-lead ECG showing a baseline QT interval as corrected by Fridericia's formula (QTcF) > 450 msec; Clinically significant liver disease, including hepatitis, current alcohol abuse, or cirrhosis; Grade ≥ 2 edema or lymphedema; Grade ≥ 2 ascites or pleural effusion; Grade ≥ 2 neuropathy; Active uncontrolled bacterial or viral infection; Active corneal disorder.
Subject has a history of major immunologic reaction to any immunoglobulin G (IgG)-containing agent. Subject has hypersensitivity to docetaxel or polysorbate 80.
Subjects have received any live vaccine within 30 days of the first dose of study drug.
Treatment with any of the following therapies within the noted time intervals prior to randomisation: - Within 2 weeks (14 days): radiation therapy not involving the lungs. - Within 4 weeks (28 days) or 5 half-lives (whichever is shorter): systemic cytotoxic chemotherapy; small molecule targeted agents; monoclonal antibodies, antibody-drug conjugates, radioimmunoconjugates, or T-cell or other cell-based therapies.
Subjects must not have had radiation therapy to the lung within 6 months prior to the first dose of study drug and until study drug is permanently discontinued.

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Austria	Recruiting	27 Mar 2022	18
Belgium	Recruiting	27 Mar 2022	22
Bulgaria	Recruiting	27 Mar 2022	9
Czechia	Recruiting	27 Mar 2022	6
Denmark	Recruiting	27 Mar 2022	5
France	Recruiting	27 Mar 2022	13
Germany	Recruiting	27 Mar 2022	16
Greece	Recruiting	27 Mar 2022	11
Italy	Recruiting	27 Mar 2022	26
The Netherlands	Recruiting	27 Mar 2022	—