Atezolizumab and Pirfenidone for the Treatment of Non-small Cell Lung Cancer

Inclusion Criteria

• Participant or legal representative is able to provide written informed consent prior to performing any protocol-related procedures
• Is willing and able to comply with scheduled visits, treatment schedule, laboratory testing and other requirements of the study
• Men or women at least 18 years of age with histologically or cytologically confirmed non-small cell lung cancer
• Previous history of cancer other than lung cancer is allowed if no active treatment for that cancer within 1 year
• Life expectancy of at least 6 months, in the opinion of the investigator
• De novo stage IV or recurrent NSCLC without actionable mutation (e.g. EGFR/ ALK/ ROS-1) that was previously treated with either PD-1 / PD-L1 or the combination of PD1/PDL1 and cytotoxic chemotherapy, no more than 2 systemic regimens for metastatic disease with measurable disease *. Maintenance therapy will be considered part of 1 regimen
• PDL1 Tumor Proportion Score (TPS) score 1%+: first-line must be either single agent pembrolizumab or PD1/PDL1 in combination with chemotherapy. Second-line must include chemotherapy if not used in first-line
• PDL1 TPS score < 1% or unknown: first-line must be PD1/PDL1 inhibitor in combination with chemotherapy
• Early stage (I-III) NSCLC treated with adjuvant or neoadjuvant chemotherapy with PD1/PDL1 inhibitor with recurrent disease if disease progression is confirmed within 12 months from the last treatment
• Recurrent unresectable stage III NSCLC treated with prior chemoradiation followed by maintenance PD1/PDL1 inhibitor with measurable disease
• At least 1 measurable lesion per RECIST version (v)1.1 confirmed via screening imaging within 30 days prior to start of treatment * {Previously irradiated lesions can be considered as measurable disease only if progressive disease has been unequivocally documented at that site since radiation.}
• Eastern Cooperative Group (ECOG) performance status 0 - 2
• Is able to swallow oral medications
• Absolute neutrophil count >= 1.5 K / UL
• Hemoglobin (hgb) >= 9 g/dl
• Platelets >= 100,000/uL
• Lymphocyte count ≥ 0.5 x 10^9/L (500/µL)
• Serum albumin ≥ 25 g/L (2.5 g/dL)
• For patients not receiving therapeutic anticoagulation: International normalized ratio (INR) or activated partial thromboplastin time (aPTT) ≤ 1.5 x upper limit of normal (ULN) * For patients receiving therapeutic anticoagulation: stable anticoagulant regimen
• Total bilirubin =< 1.5 x upper limit of normal (ULN) (Patients with known Gilbert disease: serum bilirubin level =< 3 x ULN)
• 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: alkaline phosphatase =< 5 x ULN
• Serum creatinine =< 1.5 mg/dL (133 umol/L) OR calculated creatinine clearance >= 30 mL/min as calculated by Cockcroft and Gault Formula
• Women of child-bearing potential and men with partners of child-bearing potential must agree to practice sexual abstinence, or to use two forms of adequate contraception (hormonal AND barrier method of birth control) prior to study entry, for the duration of study participation, and for 180 days following completion of study drug combination treatment
• Men of child-bearing potential must agree not to father a baby or donate sperm while on this study and for 240 days after their last study drug combination treatment
• For women of child-bearing potential: Has undergone a hysterectomy or bilateral oophorectomy
• For women of child-bearing potential: Has been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months) and is > 45 years of age
• For women of child-bearing potential: OR List type of contraception to be used
• Tumor PD-L1 expression results (If more than one results are available, use the one that is closer to the time of consent)
• Tumor Mutation Burden results (If more than one results are available, use the one that is closer to the time of consent)

Exclusion Criteria

• The presence of any other concurrent severe and/or uncontrolled medical condition that would, in the investigator or treating physician's judgement, cause unacceptable safety risks, contraindicate patient participation in the clinical study or compromise compliance with the protocol
• Has received investigational agents within 14 days or 5 half-lives of the compound or active metabolites, whichever is longer, before the first dose of study treatment
• Has a known hypersensitivity to atezolizumab or pirfenidone. History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or fusion proteins. Known hypersensitivity to Chinese hamster ovary cell products or to any component of the atezolizumab formulation
• Has active medical or psychiatric illness that would, in the investigator or treating physician’s judgement, interfere with the study treatment
• Has uncontrolled diabetes per treating investigator’s discretion
• Has any of the following cardiac diagnoses: * Unstable angina * Significant cardiovascular disease (such as New York Heart Association Class II or greater cardiac disease, myocardial infarction, or cerebrovascular disease) within 6 months * Unstable arrhythmia * Uncontrolled congestive heart failure * Left ventricular ejection fraction < 35%
• Has a history of any grade 3 or 4 toxicities to a prior checkpoint inhibitor treatment
• Is pregnant or breast feeding
• Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study treatment, or anticipation of need for such a vaccine during atezolizumab treatment or within 5 months after the final dose of atezolizumab
• Treatment with systemic immunostimulatory agents (including, but not limited to, interferon and interleukin 2 [IL-2]) within 4 weeks or 5 half-lives of the drug (whichever is longer) prior to initiation of study treatment
• Uncontrolled tumor-related pain * Patients requiring pain medication must be on a stable regimen at study entry * Symptomatic lesions (e.g., bone metastases or metastases causing nerve impingement) amenable to palliative radiotherapy 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
• Uncontrolled human immunodeficiency virus (HIV) (viral load > 400 copies/ml) or active acquired immunodeficiency syndrome (AIDS) defined opportunistic infection or any AIDS defining within 2 weeks of enrollment
• Clinically diagnosed with grade 2 or 3 radiation-induced lung injury within the last 3 months prior to registering for the study
• Has a history of idiopathic pneumonitis that required systemic agent including steroid
• Has drug-induced pneumonitis (e.g. from amiodarone, methotrexate or nitrofurantoin)
• Has evidence of active pneumonitis on screening chest computed tomography (CT) scan
• Current smoker of more than 1 pack / day
• Has active peptic ulcer diagnosed within 4 weeks of enrollment
• Patients with active tuberculosis. Patients with other active infections requiring systemic treatment
• Current use of systemic antibacterial or antifungal agent (Exception: Patients with hepatitis B or C not requiring active treatment are eligible)
• Prior monoclonal antibody within 4 weeks before study day 1 Exception: The use of denosumab
• Patient not recovered to =< grade 1 from adverse events (AEs) due to agents administered more than 4 weeks earlier
• Concurrent use of other investigational agents
• Uncontrolled or symptomatic brain metastasis or leptomeningeal disease that requires use of steroids. Patients with treated brain metastasis without need of steroids prior to 2 weeks of enrollment will be allowed if there is NO evidence of worsening symptoms or progression on screening brain scan. Patients on a stable dose of anticonvulsant therapy will be allowed
• Use of strong CYP1A2 inhibitors (e.g., ciprofloxacin at doses of more than 750 mg twice per day, abiraterone, quinidine, enoxacin, fluvoxamine. These agents may increase pirfenidone level in plasma)
• Previous history of cancer with active treatment within less than 1 year of enrollment. Exception: hormonal therapy for breast and prostate cancers
• Active auto-immune diseases ( including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjogren's syndrome, Guillain-Barré syndrome, autoimmune myelitis or multiple sclerosis) that requires treatment with systemic immunosuppressive medication (including, but not limited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrotic factor [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: * Has 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 * Has received mineralocorticoids (e.g., fludrocortisone), inhaled corticosteroids for chronic obstructive pulmonary disease (COPD) or asthma, or low-dose corticosteroids (equivalent to prednisone 10mg or less ) for orthostatic hypotension or adrenal insufficiency are eligible * Has prior auto-immune related hypothyroidism who are on thyroid-replacement hormone are eligible * Has dermatologic manifestations only (e.g., eczema, psoriasis, patients with psoriatic arthritis are excluded) – these patients are eligible for the study provided all of following conditions are met: controlled at baseline and requires only low-potency topical corticosteroids and no acute exacerbation within the last 2 weeks prior to enrollment
• Documented peritoneal metastatic disease on imaging studies (i.e. CT or PET)