Anti-PD-L1 Antibody MEDI4736 in Addition to Neoadjuvant Chemotherapy in Patients With Stage IIIA(N2) Non-small Cell Lung Cancer (NSCLC). A Multicenter Single-arm Phase II Trial.
Overview
- Phase
- Phase 2
- Intervention
- MEDI4736 (anti-PD-L1)
- Conditions
- NSCLC Non-small Cell Lung Cancer
- Sponsor
- Swiss Cancer Institute
- Enrollment
- 68
- Locations
- 19
- Primary Endpoint
- Event-free Survival (EFS) Rate
- Status
- Completed
- Last Updated
- 6 months ago
Overview
Brief Summary
The objective of the trial is to demonstrate that the addition of neoadjuvant and adjuvant immunotherapy (with the anti-PD-L1 antibody MEDI4736) to standard neoadjuvant chemotherapy (with cisplatin/docetaxel) in primary resectable stage IIIA(N2) NSCLC is efficacious and feasible.
Detailed Description
Despite multimodal therapy, the cure rate of patients with stage IIIA NSCLC is poor and therapy outcome failed to improve during the past years. The addition of immunotherapy with the anti-PD-L1 antibody MEDI4736 as a novel treatment modality has the potential to improve the outcome without adding substantial toxicity to an otherwise intensive multimodality treatment, as MEDI4736 has been generally well tolerated. Based on the current evidence on immune checkpoint inhibition, there is a strong rationale to test this novel treatment modality also in the curative setting in order to improve local tumor control and prevent distant metastasis to improve the cure rate in this patient population. The trial investigates the addition of pre- and post-operative immune checkpoint inhibition with MEDI4736 to the previously established standard of care for stage IIIA(N2) patients, which is based on the trials SAKK16/96 and SAKK16/00. Patients whose tumor is deemed resectable at diagnosis will receive 3 cycles (21 days each) of standard chemotherapy with cisplatin (100 mg/m2) / docetaxel (85 mg/m2), followed by 2 cycles (14 days each) of neoadjuvant immunotherapy with MEDI4736 750 mg. Following surgery, patients with complete resection (R0) of their tumor will be administered adjuvant treatment with MEDI4736 750 mg for up to one year or until recurrence, death, unacceptable toxicity or consent withdrawal (whichever occurs first). Patients with incomplete R1/R2 resection, including patients with extracapsular spread of mediastinal lymph node metastases, may undergo standard radiotherapy prior to adjuvant treatment with MEDI4736.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Written informed consent according to ICH-GCP regulations before patient registration and any protocol-related procedures.
- •Pathologically proven NSCLC (adeno-, squamous-, large cell carcinoma or NSCLC not otherwise specified) irrespective of genomic aberrations or PD-L1 expression status.
- •Tumor tissue is available for the mandatory translational research (preferably histology, cytology allowed).
- •Tumor stage T1-3N2M0 (stage IIIA(N2)) according to the TNM classification, 7th edition, (October 2009). Mediastinal lymph node staging has to follow the process chart.
- •Tumor is considered resectable based on a multidisciplinary tumor board decision made before neoadjuvant treatment. Resectable is when a complete resection can be achieved according to Rami-Porta {Rami-Porta, 2005 #88}.
- •Measurable disease according to RECIST 1.1 criteria (non-nodal lesions ≥10 mm in longest diameter, lymph nodes ≥15 mm in short axis) by PET/CT with contrast enhanced CT-scan.
- •WHO performance status 0-
- •Age 18-75 years at time of registration.
- •Appropriate lung function based on the ESTS guidelines {Brunelli, 2009 #19}:
- •For pneumonectomy: FEV1 and DLCO ≥80%. If one of both \<80% an exercise test peak VO2 \>75% or 20ml/kg/min is needed,
Exclusion Criteria
- •Presence of any distant metastasis or N3 disease. Brain metastases have to be excluded by CT or MRI.
- •Sulcus superior tumors (Pancoast tumors).
- •Previous or concomitant malignancy within 5 years prior registration with the exception of adequately treated localized non-melanoma skin cancer or cervical carcinoma in situ.
- •Any previous treatment for NSCLC.
- •Any previous treatment with a PD-1 or PD-L1 inhibitor, including MEDI
- •Previous radiotherapy to the chest.
- •Absolute contraindications for the use of corticosteroids as premedication.
- •Concurrent treatment with other experimental drugs or other anti-cancer therapy, treatment in a clinical trial within 30 days prior to registration.
- •Current or prior use of immunosuppressive medication within 28 days before the first dose of MEDI4736, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses (i.e. which must not exceed 10 mg/day of prednisone or an equivalent corticosteroid) and the premedication for chemotherapy.
- •Severe or uncontrolled cardiac disease requiring treatment, congestive heart failure NYHA III or IV, unstable angina pectoris even if medically controlled, history of myocardial infarction during the last 3 months, serious arrhythmias requiring medication (with exception of atrial fibrillation or paroxysmal supraventricular tachycardia).
Arms & Interventions
MEDI4736
Patients whose tumor is deemed resectable at diagnosis will receive 3 cycles (21 days each) of standard chemotherapy with cisplatin/docetaxel followed by 2 cycles (14 days each) of neoadjuvant immunotherapy with MEDI4736 750 mg. Following surgery, patients with complete resection (R0) of their tumor will be administered adjuvant treatment with MEDI4736 750 mg for up to one year or until recurrence, death, unacceptable toxicity or consent withdrawal (whichever occurs first). Patients with incomplete R1/R2 resection, including patients with extracapsular spread of mediastinal lymph node metastases, may undergo standard radiotherapy prior to adjuvant treatment with MEDI4736.
Intervention: MEDI4736 (anti-PD-L1)
Outcomes
Primary Outcomes
Event-free Survival (EFS) Rate
Time Frame: at 12 months
Measured using the Kaplan-Meier method
Secondary Outcomes
- Median Event-free Survival (EFS)(up to 7 years from registration)
- Overall Survival (OS) Rate(at 1, 2, 3, 4 & 5 years after registration)
- Objective Response (OR) After Neoadjuvant Chemotherapy (FAS)(After Neoadjuvant Chemotherapy, up to 3 months)
- Objective Response (OR) After Neoadjuvant Immunotherapy (FAS II)(After Neoadjuvant immunotherapy, up to 3 months)
- Adverse Events (AEs) (According to NCI CTCAE v4.0)(Adverse events were recorded from registration up to 13 months after surgery, up to 17 months. Deaths were reported up to 8 years from registration)
- Pathological Responses (pCR)(at 12 months)