Anti-PD-L1 in Stage IIIA(N2) Non-small Cell Lung Cancer (NSCLC)

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.

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.

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.

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 0-1.

• 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,
  • For resection less than pneumonectomy (resection up to the calculated extent): exercise test peak VO2 ≥35% or ≥10ml/kg/min, with predicted postoperative FEV1 and DLCO ≥ 30%.

• Adequate hematological values: hemoglobin ≥ 90 g/L, absolute neutrophils count ≥ 1.5 x 109/L, platelets count ≥ 100 x 109/L.

• Adequate hepatic function: bilirubin ≤ 1.5 x ULN, AST/ALT ≤ 1.5 x ULN, AP ≤ 2.5 x ULN.

• Adequate renal function: calculated creatinine clearance ≥ 60 mL/min, according to the formula of Cockcroft-Gault.

• Women with child-bearing potential are using effective contraception are not pregnant or lactating and agree not to become pregnant during participation in the trial and during 90 days after the last treatment. A negative serum pregnancy test performed within 7 days before registration into the trial is required for all women with child-bearing potential. Men agree not to father a child during participation in the trial and during 90 days after the last treatment.

• Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow-up.

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 MEDI4736.
• 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).
• Mean QT interval corrected for heart rate (QTc) ≥470 ms calculated from 3 electrocardiograms (ECGs) using Bazett's Correction.
• Preexisting peripheral neuropathy (> grade 1).
• Body weight less than 30 kg.
• Active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease or a syndrome that requires systemic steroids or immunosuppressive agents. Exceptions: - Vitiligo or resolved childhood asthma/atopy - Hypothyroidism stable on hormone replacement or Sjorgen's syndrome
• Active or prior documented inflammatory bowel disease (e.g. Crohn's disease, ulcerative colitis).
• Known evidence of acute or chronic hepatitis B, hepatitis C or human immunodeficiency virus (HIV) infection.
• History of primary immunodeficiency.
• History of allogeneic organ transplant.
• Known history of previous clinical diagnosis of tuberculosis.
• Receipt of live attenuated vaccination any time during trial therapy with MEDI4736 and within 30 days of receiving the last dose of MEDI4736.
• Any concomitant drugs contraindicated for use with MEDI4736: this includes systemic corticosteroids, methotrexate, azathioprine, and tumor necrosis factor (TNF)-α blockers. Any concomitant drugs contraindicated for use with the other trial drugs according to the locally approved product information.
• Known hypersensitivity to trial drugs (cisplatin and docetaxel), to the IMP or to any excipient.
• Any other serious underlying medical (e.g. uncontrolled diabetes mellitus, active uncontrolled infection, active gastric ulcer, uncontrolled seizures, severe hearing impairment), psychiatric, psychological, familial or geographical condition that, in the judgment of the investigator, may interfere with the planned staging, treatment and follow-up, affect patient compliance or place the patient at high risk from treatment-related complications.