Pemetrexed-free vs. Pemetrexed-based Immunochemotherapy in Metastatic TTF-1 Negative Lung Adenocarcinoma (ANTELOPE)

Atezolizumab/Carboplatin/Nab-Paclitaxel vs. Pembrolizumab/Platinum/Pemetrexed in Metastatic TTF-1 Negative Lung Adenocarcinoma

This is an open-label randomized, controlled, multicenter, phase II trial with two arms. Patients with metastatic TTF-1 negative, treatment-naive lung adenocarcinoma without actionable genomic alterations are randomized in a 1:1 manner to investigate the efficiency of atezolizumab, carboplatin and nab-paclitaxel (Arm A) versus pembrolizumab, cis-/carboplatin and pemetrexed (Arm B) as first-line treatment.

Study Overview

• Status: Recruiting
• Conditions: Non-Small Cell Lung Cancer Metastatic
• Intervention / Treatment: Drug: Atezolizumab; Drug: Nab paclitaxel; Drug: Carboplatin; Drug: Pembrolizumab; Drug: Cisplatin; Drug: Pemetrexed

Detailed Description

Thyroid transcription factor 1 (TTF-1) is expressed in the majority of lung adenocarcinoma and has a clear prognostic value. Pemetrexed-based immunochemotherapy is a standard of care for advanced lung adenocarcinoma. However, real-world data suggest that TTF-1 negative patients might derive superior outcome using pemetrexed-free regimens. The aim of this study is to compare a pemetrexed-free (Arm A) vs. a pemetrexed-based immunochemotherapy (Arm B) as first-line treatment for metastatic TTF-1 negative lung adenocarcinoma without actionable genomic alterations.

• Study Type: Interventional
• Enrollment (Estimated): 136
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Nikolaj Frost, PD Dr.; Phone Number: +49 30 450 565 005; Email: nikolaj.frost@charite.de
• Study Contact Backup: Name: Daniel Müller, Dr.; Phone Number: +49 69 7601 125; Email: mueller.daniel@ikf-khnw.de

Study Locations

• Germany
  • Amberg, Germany, 92224
    • Not yet recruiting
    • Klinikum St. Marien
    • Contact: Ludwig Fischer von Weikersthal, Dr. med.
  • Bad Homburg, Germany, 61352
    • Recruiting
    • MVZ Taunus GmbH
    • Contact: Migle Link, Dr. med.
  • Berlin, Germany, 13125
    • Recruiting
    • Evangelische Lungenklinik
    • Contact: Christian Grohé, Prof. Dr.
  • Berlin, Germany, 13353
    • Recruiting
    • Charité Universitätsmedizin
    • Contact: Nikolaj Frost, Dr.
  • Berlin, Germany, 14165
    • Recruiting
    • Helios Klinikum Emil Von Behring
    • Contact: Jens Kollmeier, Dr.
  • Berlin, Germany, 13125
    • Recruiting
    • Evangelische Lungenklinik Krankenhausbetriebs gGmbH
    • Contact: Christian Grohé, Prof. Dr.
  • Bielefeld, Germany, 33604
    • Recruiting
    • Klinikum Bielefeld
    • Contact: Martin Görner, Dr.
  • Dresden, Germany, 01307
    • Recruiting
    • Technische Universität Dresden Medizinische Fakultät Carl Gustav Carus
    • Contact: Felix Saalfeld, Dr.
  • Essen, Germany, 45136
    • Recruiting
    • KEM Evang. Kliniken Essen-Mitte
    • Contact: Daniel Christoph, Dr.
  • Esslingen, Germany, 73730
    • Recruiting
    • Klinikum Esslingen GmbH
    • Contact: Martin Faehling, PD Dr.
  • Frankfurt, Germany, 60488
    • Recruiting
    • Krankenhaus Nordwest
    • Contact: Akin Atmaca, PD DR.
  • Frankfurt am Main, Germany, 60590
    • Not yet recruiting
    • Universitätsklinikum Frankfurt am Main
    • Contact: Martin Sebastian, Dr. med.
  • Gauting, Germany, 82131
    • Recruiting
    • Asklepios Klinik Gauting GmbH
    • Contact: Niels Reinmuth, Prof. Dr.
  • Großhansdorf, Germany, 22927
    • Recruiting
    • LungenClinic Grosshansdorf GmbH
    • Contact: Martin Reck, Prof. Dr.
  • Göttingen, Germany, 37075
    • Recruiting
    • Universitatsmedizin Gottingen
    • Contact: Tobias Overbeck, Dr.
  • Hamburg, Germany, 21075
    • Recruiting
    • Asklepios Klinkum Hamburg
    • Contact: Claas Wesseler, Dr.
  • Heidelberg, Germany, 69126
    • Recruiting
    • Thoraxklinik Heidelberg gGmbH
    • Contact: Farastuk Bozorgmehr, Dr.
  • Hemer, Germany, 58675
    • Recruiting
    • Lungenklinik Hemer
    • Contact: Karsten Schulmann, PD Dr. med.
  • Krefeld, Germany, 47805
    • Recruiting
    • Helios Klinikum Krefeld
    • Contact: Benoit Krämer
  • Köln, Germany, 51109
    • Recruiting
    • Kliniken der Stadt Köln GmbH
    • Contact: Carolin Groß-Ophoff-Müller, Dr. med.
  • Landshut, Germany, 84036
    • Recruiting
    • ÜBAG- Medizinisches Versorgungszentrum Dr. Vehling-Kaiser GmbH
    • Contact: Florian Kaiser, Dr.
  • Lemgo, Germany, 32657
    • Recruiting
    • Klinikum Lippe GmbH
    • Contact: Christian Constantin, Dr.
  • Ludwigsburg, Germany, 71640
    • Recruiting
    • Klinikum Ludwigsburg
    • Contact: Matthias Ulmer, Dr.
  • Lübeck, Germany, 23538
    • Recruiting
    • UKSH, Campus Lübeck
    • Contact: Sabine Bohnert, Dr.
  • Mannheim, Germany, 68167
    • Recruiting
    • Medizinische Fakultät Mannheim der Universität Heidelberg
    • Contact: Melanie Janning, Dr.
  • München, Germany, 80336
    • Recruiting
    • LMU Klinikum
    • Contact: Amanda Tufman, Prof. Dr.
  • Münster, Germany, 48149
    • Not yet recruiting
    • Unversitätsklinikum Münster
    • Contact: Annalen Bleckmann, Prof. Dr.
  • Münster, Germany, 48153
    • Recruiting
    • Überörtliche Gemeinschaftspraxis für Hämatologie und Onkologie
    • Contact: Rüdiger Liersch, PD Dr.
  • Oldenburg, Germany, 26121
    • Recruiting
    • Pius Hospital
    • Contact: Frank Griesinger, Prof. Dr.
  • Regensburg, Germany, 93049
    • Recruiting
    • Barmherzige Brüder Krankenhaus Regensburg
    • Contact: Veronika Berberich, Dr.
  • Riesa, Germany, 01589
    • Recruiting
    • Elblandkliniken Stiftung & Co. KG Elblandklinikum Riesa
    • Contact: Jörg Schubert, Prof. Dr.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Patient has provided written informed consent
2. Patient* 18 years or older at time of signing the informed consent form
3. Histologically or cytologically confirmed metastatic stage IV non-squamous NSCLC
4. Negative local testing for TTF-1
5. Negative molecular testing for EGFR mutations and ALK rearrangements (tested locally)
6. PD-L1 tumor proportion score (TPS) < 50%, tested locally by QUiP®-certified immunohistochemistry
7. ECOG performance status ≤ 1
8. Measurable lesions according to RECIST v1.1
9. Life expectancy ≥ 12 weeks

10. Adequate hepatic, renal and bone marrow function

    1. Hemoglobin ≥ 8.0 g/dL
    2. Absolute neutrophil count ≥ 1.5 x 109/L
    3. Platelets ≥ 100 x 109/L
    4. Calculated creatine clearance ≥ 50 mL/min as determined by the Cockcroft-Gault equation and/or creatinin ≤ 1,5x upper limit of normal (ULN)
    5. Serum bilirubin ≤ 1.5 x institutional ULN
    6. AST/ ALT and alkaline phosphatase ≤ 2.5 x ULN
    7. International normalized ratio (INR)/ Activated partial thromboplastin time (aPTT) ≤1.5 × ULN unless participant is receiving anticoagulant therapy as long as PTT is within therapeutic range of intended use of anticoagulants
11. The patient is willing and able to comply with the protocol for the duration of the study, including hospital visits for treatment and scheduled follow-up visits and examinations.
12. Female patients who are considered as woman of childbearing potential (WOCBP) must use any contraceptive method with a failure rate of less than 1% per year during the treatment as well as up to 6 months after the last dose of study treatment. Male patients who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year during the treatment as well as at least 6 months after the last dose of IMP. Female patients who are not of childbearing potential (i.e., who are postmenopausal or surgically sterile) as well as azoospermic male patients do not require contraception

Exclusion Criteria:

1. Mixed histologies (small-cell and non-small cell or non-squamous and squamous; patients exhibiting the latter expression pattern may be eligible if the non-squamous part predominates)

2. Patients having received:

   1. Systemic treatment for metastatic or locally advanced disease
   2. prior PD-1/PD-L1 immunotherapies (prior treatment with CD137 agonists or immune checkpoint blockade therapies, including, but not limited to, anti-cytotoxic T lymphocyte associated protein 4 [anti-CTLA-4], anti T cell immunoreceptor with Ig and tyrosine-based inhibition motif domains [anti-TIGIT], anti-PD-1 and anti-PD-L1 therapeutic antibodies)
3. Symptomatic, neurologically unstable central nervous system (CNS) metastases or requiring increasing doses of steroids to manage CNS symptoms within 2 weeks prior to study entry (maximal acceptable dose must be ≤ 10 mg of prednisolone)
4. Leptomeningeal disease
5. History of interstitial lung disease
6. Severe infection within 2 weeks prior to study entry. Clinical signs must have been resolved to CTCAE grade ≤ 1
7. Active infection with hepatitis B or C virus (HBV, HCV), human immunodeficiency virus (HIV) or Mycobacterium tuberculosis
8. Known additional malignancies other than NSCLC, either untreated or having required active treatment within the past 3 years
9. Significant cardiovascular disease (≥ NYHA 3)

10. Active or prior documented autoimmune or inflammatory disorders (including but not limited to diverticulitis [with the exception of diverticulosis], celiac disease, systemic lupus erythematosus, Sarcoidosis, or Wegener's syndrome [granulomatosis with polyangiitis], Graves' disease, rheumatoid arthritis, hypophysitis, uveitis). The following are exceptions to this criterion:

    1. Patients with vitiligo or alopecia
    2. Patients with hypothyroidism (e.g., following Hashimoto's disease) stable on hormone replacement
    3. Patients with controlled Type I diabetes mellitus on an insulin regimen
    4. Any chronic skin condition that does not require systemic therapy
    5. Patients without active disease in the last 5 years may be included but only after consultation with the study physician

11. Current or prior use of immunosuppressive medication within 14 days before the first dose of atezolizumab/pembrolizumab. The following are exceptions to this criterion:

    1. Intranasal, inhaled, topical steroids, or local steroid injections (e.g. intra articular injection)
    2. Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent
    3. Steroids as premedication for hypersensitivity reactions (e.g. CT scan premedication)
12. Treatment with systemic immunostimulatory agents (including, but not limited to, interferon and IL-2) within 4 weeks or 5 drug-elimination half-lives (whichever is longer) prior to initiation of study treatment
13. Live vaccine within 30 days prior to first dose of trial treatment
14. Known allergy or hypersensitivity to any component of the chemotherapy regimen or to atezolizumab or pembrolizumab or any constituents of the products
15. Any co-existing medical condition that in the investigator's judgement will substantially increase the risk associated with the patient's participation in the study.
16. Patient who has been incarcerated or involuntarily institutionalized by court order or by the authorities.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Pemetrexed-free Immunochemotherapy (Arm A); Atezolizumab 1200 mg q3w, carboplatin AUC 5-6 q3w, nab-paclitaxel 100 mg/m2 qw (administered for 4 cycles with subsequent maintenance with atezolizumab monotherapy 1200 mg q3w until loss of clinical benefit or occurrence of unacceptable toxicity)	Drug: Atezolizumab; 1200 mg i.v. q3w; Other Names: Tecentriq; Drug: Nab paclitaxel; 100 mg/m² i.v. qw; Other Names: Abraxane; Drug: Carboplatin; AUC 5-6 i.v. q3w
Active Comparator: Pemetrexed-based Immunochemotherapy (Arm B); Pembrolizumab 200 mg q3w, cisplatin 75 mg/m2 q3w OR carboplatin AUC 5-6 (each) q3w, pemetrexed 500 mg/m2 q3w (administered for 4 cycles with subsequent maintenance with pembrolizumab 200 mg AND pemetrexed 500 mg/m2 (each) q3w until loss of clinical benefit or occurrence of unacceptable toxicity)	Drug: Carboplatin; AUC 5-6 i.v. q3w; Drug: Pembrolizumab; 200 mg i.v. q3w; Other Names: Keytruda; Drug: Cisplatin; 75 mg/m² i.v. q3w; Drug: Pemetrexed; 500 mg/m² i.v. q3w

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival (OS)	time from randomization to the date of death due to any case	30 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objectice Response Rate (ORR)	proportion of subjects with best response of complete or partial response (CR & PR) according to RECIST v1.1	30 months
Progression-Free Survival (PFS)	time from randomization until progression defined by RECIST v1.1 or death due to any cause	30 months
One-Year Overall Survival Rate	percentage of patients alive at 12 months after randomization	30 months
Time to Next Treatment or Death (TNTD)	time from initial study randomization to the start of next subsequent treatment or death, whichever occurs first	30 months
Progression-Free Survival 2 (PFS2)	time from initial study randomization to second disease progression or death from any cause to assess efficacy post-trial-treatment anti-cancer therapy	30 months
Health-related quality of life 1 (HRQoL)	assessed with the QoL questionnaire QLQ-C30 on general health conditions in lung cancer patients using numeric scales ranging from 1-4. Lower numbers indicate no, higher numbers high agreement.	Assessed after randomization at cycle 1 day 1, after completion of cycle 4 (each cycle is 21 days) of the chemoimmunotherapy and at progressive disease (if occurring within the maximum time frame of 30 months)
Health-related quality of life 2 (HRQoL)	assessed with the lung cancer symptom-specific QoL questionnaire QLQ-LC13 using numeric scales ranging from 1-4. Lower numbers indicate no, higher numbers high agreement.	Assessed after randomization at cycle 1 day 1, after completion of cycle 4 (each cycle is 21 days) of the chemoimmunotherapy and at progressive disease (if occurring within the maximum time frame of 30 months)

Collaborators and Investigators

• Sponsor: Nikolaj Frost MD
• Collaborators: Roche Pharma AG; Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest
• Investigators: Principal Investigator: Nikolaj Frost, PD Dr., Charite University, Berlin, Germany

Publications and helpful links

General Publications

• Frost N, Zhamurashvili T, von Laffert M, Klauschen F, Ruwwe-Glosenkamp C, Raspe M, Brunn M, Ochsenreither S, Temmesfeld-Wollbruck B, Suttorp N, Grohe C, Witzenrath M. Pemetrexed-Based Chemotherapy Is Inferior to Pemetrexed-Free Regimens in Thyroid Transcription Factor 1 (TTF-1)-Negative, EGFR/ALK-Negative Lung Adenocarcinoma: A Propensity Score Matched Pairs Analysis. Clin Lung Cancer. 2020 Nov;21(6):e607-e621. doi: 10.1016/j.cllc.2020.05.014. Epub 2020 May 22.

Helpful Links

• Study description on the webpage of the "Oncology in Internal Medicine Working Group" (AIO) within the German Cancer Society

Study record dates

Study Major Dates

• Study Start (Actual): December 6, 2023
• Primary Completion (Estimated): October 1, 2025
• Study Completion (Estimated): October 1, 2026

Study Registration Dates

• First Submitted: November 30, 2022
• First Submitted That Met QC Criteria: January 18, 2023
• First Posted (Actual): January 19, 2023

Study Record Updates

• Last Update Posted (Actual): April 3, 2024
• Last Update Submitted That Met QC Criteria: April 2, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: NSCLC; immunochemotherapy; checkpoint inhibitors
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Carcinoma; Neoplasms, Glandular and Epithelial; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Neoplasms; Adenocarcinoma; Adenocarcinoma of Lung; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Folic Acid Antagonists; Carboplatin; Paclitaxel; Pembrolizumab; Pemetrexed; Atezolizumab
• Other Study ID Numbers: SAP131705; 2022-002990-27 (EudraCT Number); AIO-TRK-0122 (Other Identifier: Arbeitsgemeinschaft Internistische Onkologie)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes