Phase II clinical trial of chemotherapy + atezolizumab for stage IIIa and IIIb non-small cell lung cancer followed by atezolizumab as adjuvant treatment after surgery and atezolizumab as maintenance treatment for non-resected patients after chemoradiotherapy

Prior treatment

• Positive test for HIV. All patients will be tested for HIV prior to inclusion into the study; patients who test positive for HIV will be excluded from the clinical study.
• Severe infections within 4 weeks prior to be included in the study, including but not limited to hospitalization for complications of infection, bacteremia, or severe pneumonia.
• Received therapeutic oral or IV antibiotics within 2 weeks prior to be included in the study. Patients receiving prophylactic antibiotics are eligible.
• Significant cardiovascular disease, such as New York Heart Association cardiac disease (Class II or greater), myocardial infarction, or cerebrovascular accident within 3 months prior to inclusion, unstable arrhythmias, or unstable angina.
• Major surgical procedure other than for diagnosis within 28 days prior to inclusion or anticipation of need for a major surgical procedure during the course of the study.
• Prior allogeneic bone marrow transplantation or solid organ transplant.
• Administration of a live, attenuated vaccine within 4 weeks before inclusion or anticipation that such a live attenuated vaccine will be required during the study.
• Treatment with any other investigational agent with therapeutic intent within 28 days prior to initiation of study treatment.
  • "27. Treatment with systemic immunosuppressive medications (including but not limited to corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti−tumor necrosis factor [anti-TNF] agents) within 2 weeks prior to inclusion. Patients who have received acute, low-dose (≤ 10 mg oral prednisone or equivalent), systemic immunosuppressant medications may be enrolled in the study. The use of corticosteroids (≤ 10 mg oral prednisone or equivalent) for chronic obstructive pulmonary disease, mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic hypotension, and low-dose supplemental corticosteroids for adrenocortical insufficiency is allowed."
• Weight loss >10% within the previous 3 months.
• Patients that receive previous treatment with antineoplasic drugs, chest radiotherapy, or previous surgery for lung cancer.
• Malignancies other than NSCLC within 3 years prior to enrolment, with the exception of those with a negligible risk of metastasis or death (e.g., expected 3-year OS > 90%) treated with expected curative outcome
• Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary cells or any component of the Atezolizumab or Tiragolumab formulation.
  • "8. History of autoimmune disease, including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener’s granulomatosis, Sjögren’s syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis. Patients with a history of autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone are eligible for this study. Patients with controlled Type 1 diabetes mellitus on a stable dose of insulin regimen are eligible for this study. Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis would be excluded) are permitted provided that they meet the following conditions: ▪ Rash must cover less than 10% of body surface area (BSA). ▪ Disease is well controlled at baseline and only requires low-potency topical steroids. ▪ No acute exacerbations of underlying condition within the previous 12 months"

Other illness

• Patients with active hepatitis B (chronic or acute; defined as having a positive hepatitis B surface antigen [HBsAg] test at screening) or hepatitis C.
• Patients with past hepatitis B virus (HBV) infection or resolved HBV infection (defined as the presence of hepatitis B core antibody [HBcAb] and absence of HBsAg) are eligible only if they are negative for HBV DNA (vaccinated patients are excluded).
• Patients positive for hepatitis C virus (HCV) antibody are eligible only if PCR is negative for HCV RNA.
• Active tuberculosis.
• Patients with a superior vena cava syndrome.
• Patients with medical, mental, neurological or psychological condition which in the opinion of the investigator would not permit the patient to understand the patient information sheet or comply with study procedures.
• Pleural or pericardial effusion, both will be considered indicative of metastatic disease unless proven otherwise. Patients with pleural effusion not visible on chest-X-ray or too small to perform diagnostic puncture safely may be included.
• History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan.

Lab values

• Patients with known sensitizing mutation or an amplification in the epidermal growth factor receptor (EGFR) gene, ALK fusion oncogene.
• Patients with known coronary artery disease, congestive heart failure not meeting the above criteria, or left ventricular ejection fraction < 50% must be on a stable medical regimen that is optimized in the opinion of the treating physician, in consultation with a cardiologist if appropriate.
• Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or renders the patient at high risk from treatment complications.

Other

• Symptomatic neuropathy (sensory) grade > 1 according to the NCI Common Toxicity Criteria for Adverse Events v5.0 and that were not related to the tumor
• Known STK-11 ligand alterations, MDM2 amplifications or ROS1 translocations.
• Patients with uncontrolled comorbidities that may affect the clinical trial compliance.
• Women who are pregnant or in the breastfeeding period.
• Sexually active women of childbearing potential who are not willing to use an effective contraceptive method during the study.

• Previously untreated patients with histologically- or cytologically- documented NSCLC who present stage IIIA – IIIB disease (according to 8th version of the International Association for the Study of Lung Cancer Staging Manual in Thoracic Oncology)
• Adequate lung function: Forced Expiratoy Volumen in 1 second (FEV1) >50% of normal volume and Diffusion Capacity of the Lungs for Carbon Monoxide (DLCO) >40% of normal value
• Patients aged > 18 years
• For female patients of childbearing potential, agreement (by patient and/or partner) to use a highly effective form(s) of contraception that results in a low failure rate (< 1% per year) when used consistently and correctly, and to continue its use for 6 months after the last dose of trial treatment.
• For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods, and agreement to refrain from donating sperm, as defined below: • With a female partner of childbearing potential who is not pregnant, men must remain abstinent or use a condom plus an additional contraceptive method that together result in a failure rate of < 1% per year during the treatment period and for 180 days after the final dose of chemotherapy. Men must refrain from donating sperm during this same period. • With a pregnant female partner, men must remain abstinent or use a condom during the treatment period and for 180 days after the final dose of chemotherapy to avoid exposing the embryo. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not adequate methods of contraception
• Women who are not postmenopausal (≥ 12 months of non−therapy-induced amenorrhea) or surgically sterile must have a negative serum pregnancy test result within 8 days prior to initiation of study drug.
• Patient capable of proper therapeutic compliance and accessible for correct follow-up
• Presence of at least one measurable lesion by CT-SCAN, as defined by RECIST v1.1.
• Patients with a life expectancy ≥12 weeks
• PET scan and brain CT or MRI at baseline to confirm the absence of distant disease. Positive mediastinal lymph nodes by PET scan must be confirmed histologically by mediastinoscopy/EBUS/EUS.
• ECOG (Performance status) 0-1
• Adequate hematologic and organ function defined by laboratory results obtained within 14 days prior to enrollment
• All patients are notified of the investigational nature of this study and signed a written informed consent in accordance with institutional and national guidelines, including the Declaration of Helsinki prior to any trial-related intervention.