Tocilizumab and Atezolizumab for the Treatment of Patients with Refractory, Locally Advanced or Metastatic Non-small Cell Lung Cancer

Inclusion Criteria

• Signed informed consent form
• Age >= 18 years at time of signing informed consent form
• Ability to comply with the study protocol, in the investigator’s judgment
• Histologically or cytologically confirmed non-small cell lung cancer
• No evidence of an EGFR, ALK, ROS1, BRAF or other driver mutation for which targeted therapy would be preferable or standard of care (consult principal investigator if there is a question of the nature of the mutation)
• Prior exposure and disease progression during at least 1 line of therapy including a checkpoint inhibitor. This may include a single checkpoint inhibitor, therapy with two checkpoint inhibitors simultaneously, or chemotherapy and immunotherapy combined or in sequence and must be the line immediately prior to enrollment on the trial. Prior PD-L1 inhibitors are permitted, since the goal of the study is to see if interleukin (IL) 6 inhibition can relieve resistance to immune checkpoint inhibitors
• No greater than CTCAE v5 grade 3 toxicity on prior immune checkpoint inhibitor therapy that was at least possibly attributable to prior immune checkpoint therapy, in the investigator’s opinion
• Resolution of all immune related adverse events on prior immunotherapy to grade 1 or less
• Measurable disease, per RECIST v1.1. Previously irradiated lesions may be considered as measurable disease only if progressive disease has been unequivocally documented at that site since radiation
• Availability of a representative paraffinized tumor specimen for exploratory biomarker research. A formalin-fixed paraffin-embedded (FFPE) tumor specimen in a paraffin block (preferred) or at least 10-15 slides containing unstained, freshly cut, serial sections should be submitted along with an associated pathology report prior to study enrollment. PDL1 status, which should be done as a standard of care for first line immunotherapy, will be recorded on a case report form. A biopsy may also be performed at screening if a patient's archival tissue test results do not meet eligibility criteria
• Eastern Cooperative Oncology Group performance status of 0-2
• Absolute neutrophil count (ANC) >= 1.5 x 10^9/lL (1500/L) without growth factor support
• Lymphocyte count 0.5 x 10^9/L (500/uL)
• Platelet count >= 100 x 10^9/L (100,000/uL) without transfusion
• Hemoglobin >= 90 g/L (9 g/dL). Patients may be transfused to meet this criterion
• Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) =< 2.5 x upper limit of normal (ULN), with the following exceptions: * Patients with documented liver metastases: AST and ALT =< 5 x ULN * Patients with documented liver or bone metastases: ALP =< 5 x ULN
• Serum bilirubin =< 1.5 x ULN with the following exception: * Patients with known Gilbert disease: serum bilirubin level =< 3 x ULN
• Serum creatinine =< 1.5 x ULN or Creatinine clearance >= 60 mL/min (calculated using the Cockcroft-Gault formula)
• Serum albumin >= 30 g/L (3.0 g/dL)
• For patients not receiving therapeutic anticoagulation: International normalized ratio (INR) or activated partial thromboplastin time (aPTT) =< 1.5 x ULN
• For patients receiving therapeutic anticoagulation: stable anticoagulant regimen
• No untreated or actively progressing central nervous system (CNS) metastases. Patients with a history of treated CNS lesions are eligible, provided that all of the following criteria are met: * Measurable disease, per RECIST v1.1, must be present outside the CNS * The patient has no history of intracranial hemorrhage or spinal cord hemorrhage * Metastases are limited to the cerebellum or the supratentorial region (i.e., no metastases to the midbrain, pons, medulla, or spinal cord) * There is no evidence of interim progression between completion of CNS-directed therapy and the screening brain scan * The patient has not received stereotactic radiotherapy within 7 days prior to initiation of study treatment or whole-brain radiotherapy within 14 days prior to initiation of study treatment * The patient has no ongoing requirement for corticosteroids as therapy for CNS disease. Anticonvulsant therapy at a stable dose is permitted * Asymptomatic patients with CNS metastases newly detected at screening are eligible for the study after receiving radiotherapy or surgery, with no need to repeat the screening brain scan
• No active leptomeningeal disease or history of leptomeningeal disease
• No uncontrolled tumor-related pain * Patients requiring pain medication must be on a stable regimen at study entry * Symptomatic lesions amenable to palliative radiotherapy (e.g., bone metastases or metastases causing nerve impingement) should be treated prior to enrollment. Patients should be recovered from the effects of radiation. There is no required minimum recovery period * Asymptomatic metastatic lesions that would likely cause functional deficits or intractable pain with further growth (e.g., epidural metastasis that is not currently associated with spinal cord compression) should be considered for loco-regional therapy if appropriate prior to enrollment
• No active or history of autoimmune disease or immune deficiency, including, but not limited to: myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, or multiple sclerosis, with the following exceptions: * Patients with a history of autoimmune-related hypothyroidism who are on thyroid-replacement hormone are eligible for the study * Patients with controlled type 1 diabetes mellitus who are on an insulin regimen are eligible for the study * Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for the study provided all of following conditions are met: ** Rash must cover < 10% of body surface area ** Disease is well controlled at baseline and requires only low-potency topical corticosteroids ** No occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high-potency or oral corticosteroids within the previous 12 months
• No history of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan * History of radiation pneumonitis in the radiation field (fibrosis) is permitted
• Negative human immunodeficiency virus (HIV) test at screening
• No evidence of hepatitis B virus (HBV) infection (chronic or acute), defined as having a positive hepatitis B surface antigen (HBsAg) test at screening * Patients with a past or resolved HBV infection, defined as having a negative HBsAg test and a positive total hepatitis B core antibody (HBcAb) test at screening, are eligible for the study
• No evidence of active hepatitis C virus (HCV) infection, defined as having a positive HCV antibody test followed by a positive HCV ribonucleic acid (RNA) test at screening * The HCV RNA test will be performed only for patients who have a positive HCV antibody test
• No active or latent tuberculosis by Quantiferon assay
• No active infection with Epstein-Barr virus (EBV), as defined by EBV viral load >= 10,000 copies per mL of whole blood
• No active infection with cytomegalovirus (CMV), as defined by CMV viral load >= 10,000 copies per mL of whole blood
• No significant cardiovascular disease, such as New York Heart Association Class II or greater cardiac disease, myocardial infarction, or cerebrovascular accident within 3 months prior to initiation of study treatment, unstable arrhythmia, or unstable angina
• No major surgical procedure other than for diagnosis within 4 weeks prior to initiation of study treatment, or anticipation of need for a major surgical procedure during the course of the study
• No other presently active malignancy that requires systemic treatment
• No severe infection within 4 weeks prior to initiation of study treatment, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia
• No treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment. Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection or chronic obstructive pulmonary disease exacerbation) are eligible for the study
• No other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug, may affect the interpretation of the results, or may render the patient at high risk from treatment complications
• No prior allogeneic stem cell or solid organ transplantation
• No treatment with investigational therapy within 28 days prior to initiation of study treatment
• No treatment with systemic immunostimulatory agents (including, but not limited to, interferon and interleukin 2 [IL-2]) within 4 weeks prior to initiation of study treatment
• No treatment with systemic immunosuppressive medication (including, but not limited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti−TNF-⟨agents) within 2 weeks prior to initiation of study treatment, or anticipation of need for systemic immunosuppressive medication during the course of the study, with the following exceptions: * Patients who received acute, low-dose systemic immunosuppressant medication or a one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of corticosteroids for a contrast allergy) are eligible for the study, after obtaining principal investigator approval * Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids for chronic obstructive pulmonary disease (COPD) or asthma, or low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible for the study
• No requirement for use of denosumab during the study. Patients who are receiving denosumab for any reason (including hypercalcemia) must be willing and eligible to receive a bisphosphonate instead while in the study
• No history of severe allergic anaphylactic reactions to chimeric or humanized antibodies or fusion proteins
• No known allergy or hypersensitivity to Chinese hamster ovary cell products or to any component of the atezolizumab or tocilizumab formulations
• Not pregnant, not breastfeeding, and not intending to become pregnant during the study or within 5 months after the last dose of study treatment. Women of childbearing potential must have a negative serum pregnancy test result within 14 days prior to initiation of study treatment
• Agreement to follow appropriate contraception guidelines: Requirements for contraception and pregnancy testing for a clinical trial should encompass all investigational medicinal products (IMPs) as well as protocol-mandated non-investigational medicinal products (NIMPs) such as background therapy, and the measures to be followed should be based on the medicinal product with the highest risk. Contraception requirements for marketed IMPs or NIMPs should be based on recommendations in the Summary of Product Characteristics (SmPC) or, if there is no SmPC, national prescribing information. Length of time required for abstinence or use of contraceptives should take into account the reproductive toxicity profile, including genotoxicity and teratogenicity, the size of the molecule, and the number of doses. In the absence of specific delayed-toxicity concerns or safety hypotheses, the following guidelines should be used: * Single dose studies: ** Small molecules: 5 elimination half-lives or 14 days after the last dose, whichever is longer ** Large molecules: 2 elimination half-lives or 28 days after the last dose, whichever is longer * Multiple dose studies: ** Small molecules: 5 elimination half-lives or 28 days after the last dose, whichever is longer ** Large molecules: 2 elimination half-lives or 28 days after the last dose, whichever is longer
• For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods, as defined below: Women must remain abstinent or use contraceptive methods with a failure rate of < 1% per year during the treatment period and for 5 months after the final dose of atezolizumab. A woman is considered to be of childbearing potential if she is post-menarche, has not reached a postmenopausal state (>= 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus) or another cause as determined by the investigator (e.g., Müllerian agenesis). Per this definition, a woman with a tubal ligation is considered to be of childbearing potential. The definition of childbearing potential may be adapted for alignment with local guidelines or requirements. Examples of contraceptive methods with a failure rate of < 1% per year include bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices. 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 post-ovulation methods) and withdrawal are not acceptable methods of contraception. If required per local guidelines or regulations, locally recognized adequate methods of contraception and information about the reliability of abstinence will be described in the local informed consent form For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom, and agreement to refrain from donating sperm, as defined below: With a female partner of childbearing potential or pregnant female partner, men must remain abstinent or use a condom during the treatment period and for 5 months after the final dose of atezolizumab to avoid exposing the embryo. Men must refrain from donating sperm during this same period. 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 preventing drug exposure. If required per local guidelines or regulations, information about the reliability of abstinence will be described in the local informed consent form