Treatment in Patients With Advanced Non-Small Cell Lung Carcinoma and Interstitial Lung Disease

Official title

Phase II Trial Assessing 1st Line and 2nd Line Treatment in Patients With Advanced Non-Small Cell Lung Carcinoma and Interstitial Lung Disease

Overview

Lung cancer is a leading cause of cancer-related death worldwide. Interstitial Lung Diseases are closely associated with lung cancer either as complications or comorbidities to be considered for treatment. Recently, a survey concerning the management of lung cancer in patients with ILDs was conducted by the Interstitial Lung Diseases and Thoracic Oncology Assemblies of the European Respiratory Society. Out of 494 practitioners, mostly pulmonologists, this survey showed that the majority of metastatic patients with pulmonary fibrosis would not be treated (69%), but that 25% and 31% of clinicians would offer chemotherapy or immunotherapy, respectively. The systemic therapy is not clearly codified. There is a risk of worsening of ILDs with most of the treatments used in lung cancer including surgery, radiation therapy or certain systemic therapies. The Japanese Society of Pneumology has recently published proposals for care. However, the Asian population is unique in its incidence of ILDs and the frequency of drug toxicities and these recommendations may not be relevant for other populations. Thus, data are still needed to validate carboplatin and weekly paclitaxel as the best regimen for first-line treatment of NSCLC patients with ILD in a caucasian population. In 2nd line setting, immune checkpoint blocker (ICB) in monotherapy or associated with chemotherapy has become an essential part of the therapeutic arsenal in advanced NSCLC. Several agents have been shown to be superior to docetaxel, following platinum-based chemotherapy failure, and have resulted in several marketing authorizations for PD-1 inhibitors (nivolumab, pembrolizumab) and PD-L1 inhibitors (atezolizumab). The long-term benefits of using ICBs as a second-line therapy are now clear. Survival at 5 years is 10% higher than that obtained with docetaxel alone. The safety profile is well known in particular with a risk of pulmonary toxicity. It should be noted that in most trials, patients with ILDs were not included. Therefore, we do not have trial data from these pivotal trials in patients with concomitant ILD. Two prospective studies are available on the use of nivolumab in the second-line setting in patients with idiopathic ILDs. The first, in an Asian population, included 6 patients. It showed an interesting response rate of 50% without grade III or IV pulmonary toxicity or worsening of at 12 weeks. Following this, the same team proposed a multicenter phase 2 study. Included patients had mild ILDs (VCf \>80%) and were treated with nivolumab in 2nd line. The primary objective was PFS at 6 months. 18 patients were treated. 3 patients developed toxicity leading to discontinuation of nivolumab including 2 patients with grade 2 pneumonitis. PFS at 6 months was 56%, response rate was 39% and disease control achieved for 72% of patients. In a recent prospective study in Asia, atezolizumab was administered to patients with moderate IPF and advanced NSCLC. The study was stopped prematurely due to a high incidence of inflammatory pneumonitis. Thus, data are still needed to assess the safety of ICB in NSCLC patients with ILD in second line setting.

Interventions

• Drug Paclitaxel
  Paclitaxel 90 mg/m² D1, D8, D15 Q4W
• Drug Bevacizumab
  Bevacizumab 10 mg/kg D1, D15 Q4W
• Drug Carboplatin
  Carboplatin AUC D1 Q4W
• Drug Pemetrexed
  Pemetrexed 500 mg/m² D1 Q3W
• Drug Vinorelbine
  Vinorelbine 25 mg/m² D1, D8 Q3W
• Drug Nivolumab
  Nivolumab 240 mg D1 Q2W
• Drug Pembrolizumab
  Pembrolizumab 200 mg D1 Q3W
• Drug Gemcitabine
  Gemcitabine 1150 mg/m² D1, D8 Q3W

Primary outcome measures

• 1st line part: disease Control Rate at 8 weeks [Time frame: 8 weeks from date of inclusion]
• 2nd line part: Treatment related respiratory worsening leading to discontinuation of treatment during the first 6 months [Time frame: 6 months from randomisation]

Secondary outcome measures (12)

• Progression-free survival [Time frame: About 6 months]
• Duration of response [Time frame: About 6 months]
• Overall Survival [Time frame: About 20 months]
• Best overall response [Time frame: About 6 months]
• 1st line part: Disease control rate at 8 weeks [Time frame: 8 weeks]
• 2nd line part: Disease control rate at 8 weeks [Time frame: 8 weeks]
• Progression-free survival according to ILDs pattern on CT scan [Time frame: About 6 months]
• Duration of response according to ILDs pattern on CT scan [Time frame: About 6 months]
• Overall Survival according to ILDs pattern on CT scan [Time frame: About 20 months]
• Best overall response according to ILDs pattern on CT scan [Time frame: About 6 months]
• Progression-free survival according to ILDs severity (FVC/DLCO) [Time frame: About 6 months]
• Duration of response according to ILDs severity (FVC/DLCO) [Time frame: About 6 months]

Eligibility criteria

Inclusion Criteria for both parts:

• Informed, written and signed consent: Patients must have signed and dated the written informed consent form approved by the ethics committee in accordance with the legal and institutional framework. It must have been signed before protocol-related procedures that are not part of normal patient management are performed. Patients should be willing and able to adhere to the schedule of visits, treatment and laboratory tests.
• Patients with radiological ILDs. All cases should be presented in a multidisciplinary board dedicated to ILD to confirm eligibility. In centres without a local multidisciplinary board dedicated to ILD, the national multidisciplinary board CAPID can be used.
• NSCLC proven histologically. Cytological evidence is allowed if a cytoblock has been prepared.
• Age ≥ 18 years old.
• Performance status ≤ 2.
• Stage IIIB or IIIC non-eligible to radiation therapy or IV (8th TNM classification, UICC 2015). For other less advanced stages but rejected for any local treatment, possible inclusion discussion with the sponsor.
• Disease measurable according to RECIST criteria 1.1 per investigator assessment.
• Adequate biological function: Creatinine clearance ≥ 45 mL/min (Cockroft or MDRD or CKD-epi); neutrophils ≥ 1500/mm3; platelets ≥ 100,000/mm3; Haemoglobin ≥ 9 g/dL; liver enzymes< 3x ULN except for patients with liver metastases (< 5x ULN); total bilirubin ≤ 1.5x ULN except for patients with proven Gilbert's syndrome (≤ 5x ULN) or patients with liver metastases (≤ 3.0 mg/dL).
• Life expectancy of at least 12 weeks.
• For female patients of childbearing potential and patients with a partner of childbearing potential, agreement (by the patient and/or partner) to use one or more highly effective contraceptives (failure rate < 1% per year when used correctly and regularly) and to continue using it for 7 months after the last dose of treatment. Men should not donate their sperm for the duration of the study and for at least 7 months after the last dose of treatment. Oral contraception should always be combined with another method of contraception because of potential interactions with treatment. Patients should always use a condom.
• Patient covered by national health insurance.
• Protected adults may participate in the study if they can make decisions regarding their medical treatment in accordance with the guardianship judgment.

Inclusion Criteria for first-line part:

• Patient must be treatment naive for advanced or metastatic disease. Treatment for non-metastatic stage is not considered as a line if there is a time interval of at least 6 months between the last dose of treatment for non-metastatic stage and recurrent disease.
• ILD criteria: any type of ILD and any level of severity are allowed Inclusion criteria specific to second-line part
• Patients must have received one but no more than one platinum-based therapy for advanced or metastatic disease. Treatment for non-metastatic stage is not considered as a line if there is a time interval of at least 6 months between the last dose of treatment for non-metastatic stage and recurrent disease.
• ILD severity criteria: Patients with ILDs with mild to moderate alteration of pulmonary function, defined by Forced Vital Capacity (FVC) ≥ 50% of the predicted value AND DLCO≥ 35% of the of the predicted value. All cases should be presented in a multidisciplinary board dedicated to ILD to confirm eligibility. In centers without a local multidisciplinary board dedicated to ILD, the national multidisciplinary board CAPID can be used.
• ILD type criteria: Patient with idiopathic interstitial pneumonia (including IPF and NSIP) or secondary ILDs (including hypersensitivity pneumonia, pneumoconiosis, radiation pneumonitis) could be included. Will be excluded patients with ILDs secondary to connective tissue disease, vasculitis or granulomatosis (including but not limited to granulomatosis with polyangiitis, rheumatoid arthritis, Sjogren's syndrome, scleroderma, myositis/dermatomyositis, anti-synthetase syndrome). For sarcoidosis and for Interstitial pneumonia with autoimmune features (IPAF) inclusion could be confirmed based on a case-by-case discussion with the sponsor.
• Available results for Immunoassay including antinuclear antibodies tested by immunofluorescence, rheumatoid factor, anti-CCP, Anti-dsDNA, Anti-Ro (SS-A), Anti-La (SS-B), Anti-ribonucleoprotein, Anti-Smith, Anti-topoisomerase (Scl-70), Anti-tRNA synthetase (Jo-1, PL-7, PL-12, Anti-PM-Scl, Anti-MDA-5), ANCA.

Exclusion criteria for both parts

• Small cell lung cancer or tumor with mixed histology including a small cell component.
• Known EGFR activating mutation or ALK or ROS rearrangements. Inclusion of patients with any other oncogene addiction (excluding KRAS mutations) should be discussed with the sponsor on a case-by-case level.
• History of cancer or cancer active within 3 years except those with a negligible risk of metastasis or death treated curatively (such as adequately treated cervical cancer in situ, basal or squamous cell skin cancer or ductal carcinoma in situ curatively treated. For other types of cancer, please contact the IFCT). Patients with a history of prostate cancer in the last 5 years may be included in cases of localized prostate cancer of good prognosis according to the Amico classification (≤ T2a and Gleason score ≤ 6 and PSA ≤ 10 ng/mL) and if they have been treated curatively (surgery or radiotherapy ± hormone therapy, without chemotherapy).
• Acute exacerbation of interstitial lung disease less than 6 months ago. Exclusion criteria specific to first line part
• Previous systemic therapy (including but not limited to chemotherapy, targeted therapy, immunotherapy). Treatment for non-metastatic stage is not considered as a line if there is a time interval of at least 6 months between the last dose of treatment for non-metastatic stage and recurrent disease.

Exclusion criteria specific to second line part

• History of severe allergy, anaphylactic or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins. Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary cells or any component of the pembrolizumab/nivolumab formulation.
• Diagnosis of interstitial lung disease with manifestations of autoimmunity (IPAF) according to ATS/ERS criteria39 Inclusion may be considered on a case-by-case basis following discussion with the sponsor.
• More than one line of treatment.
• Any prior immunotherapy.
• History of autoimmune disease, connective tissue disease, vasculitis or granulomatosis associated with but not limited to myasthenia gravis, myositis, autoimmune hepatitis, inflammatory bowel disease, vascular thrombosis associated with anti-phospholipid syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis or glomerulonephritis.
• Diagnosis of ILDs due to connective tissue disease, vasculitis or granulomatosis including but not limited to granulomatosis with polyangiitis, rheumatoid arthritis, Sjogren's syndrome, scleroderma, myositis/dermatomyositis, anti-synthetase syndrome. For sarcoidosis and for Interstitial pneumonia with autoimmune features (IPAF) inclusion could be confirmed based on a case-by-case discussion with the sponsor.
• Corticosteroid therapy > 10 mg daily oral prednisone or equivalent.
• Immunosuppressive therapy within two weeks prior to randomization.
• Patients who have had major surgery ≤ 3 weeks before randomization.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

France · 31 centers

• Angers - CHU — Angers
• Besançon - CHU — Besançon
• Bobigny - APHP - Hôpital Avicenne — Bobigny
• Boulogne - APHP Ambroise Paré — Boulogne-Billancourt
• Boulogne-Sur-Mer - CH — Boulogne-sur-Mer
• Brest - CHU — Brest
• Caen - CHU Côte de Nacre — Caen
• Clermont-Ferrand - CHU — Clermont-Ferrand
• … and 23 more centers

Identifiers

NCT: NCT07420439 · IFCT-2502 LIMPID · 2025-522790-10-00

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗