All-Trans Retinoic Acid (ATRA) and Atezolizumab for the Treatment of Recurrent or Metastatic Non-Small Cell Lung Cancer

Inclusion Criteria

• Age >= 18 years
• Confirmed recurrent or metastatic non-small cell carcinoma of the lung of any histology for which there is no curative treatment option
• Measurable disease based on RECIST 1.1
• Patients must have received standard of care chemotherapy and/or immunotherapy. No limits to prior lines of therapy. Prior PD-1 and/or PD-L1 directed therapies are permitted
• Patients with adenocarcinoma and known actionable mutations with FDA-approved treatment options must have received all approved and standard of care treatment options (ie osimertinib for EGFR, alectinib for ALK, etc). Mutational testing is not required for patients with squamous cell non-small cell lung carcinoma
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
• Absolute neutrophil count (ANC) >= 1,500/mcL
• Hemoglobin >= 9 g/dL (Patients may be transfused to meet this criterion)
• Lymphocytes >= 500/mL
• Platelets >=100,000/mcL
• Serum creatinine =< 1.5 X upper limit of normal (ULN) OR measured or calculated creatinine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) >= 60 mL/min for subject with creatinine levels > 1.5 X institutional ULN
• Serum total bilirubin =< 1.5 X ULN OR direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 ULN. Patients with known Gilbert disease: serum bilirubin =< 3 x ULN
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X ULN OR =< 5 X ULN for subjects with liver metastases
• Albumin >= 2.5 mg/dL
• International normalized ratio (INR) or prothrombin time (PT) =< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants
• Activated partial thromboplastin time (aPTT) =< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants
• Anticipated life expectancy of >= 3 months
• Willing to comply with study procedures
• Female subject of childbearing potential should have a negative urine or serum pregnancy within 14 days prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
• For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods, and agreement to refrain from donating eggs, 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 or ATRA. Women must refrain from donating eggs during this same period. * A woman is considered to be of childbearing potential if she is postmenarchal, 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). The definition of childbearing potential may be adapted for alignment with local guidelines or requirements. * 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.
• For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm, for 5 months from last atezolizumab dose, as defined below * 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 ATRA 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.
• Be willing and able to understand and sign the written informed consent document
• Ability to swallow and retain oral medication
• Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection or chronic obstructive pulmonary disease exacerbation) are eligible for the study

Exclusion Criteria

• Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment
• 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 stable 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
• Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment
• Cirrhosis (Child-Pugh B or worse) or cirrhosis with history of hepatic encephalopathy or clinically meaningful ascites resulting from cirrhosis. Clinically meaningful ascites is defined as ascites from cirrhosis requiring diuretics or paracentesis
• Has symptomatic central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with asymptomatic CNS lesions will be eligible if considered appropriate by the treating physician. Subjects with previously treated brain metastases may participate provided they have had a stable neurological status for at least 2 weeks after completion of definitive therapy. Patients may be on corticosteroids (=< 10 mg of prednisone-equivalent) to control brain metastases if they have been on a stable dose for 2 weeks (14 days) prior to the start of study treatment and are clinically asymptomatic. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability
• Pregnancy or breastfeeding or intention of becoming pregnant during study treatment or within 5 months for atezolizumab after the final dose of study treatment. Women of childbearing potential must have a negative urine or serum pregnancy test result within 14 days prior to initiation of study treatment
• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject’s participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator or qualified designee
• Any patient who has experienced an unacceptable toxicity on prior checkpoint inhibitor therapy as detailed below: * >= Grade 3 adverse event (AE) related to checkpoint inhibitor. * Ongoing >= Grade 2 immune-related AE associated with checkpoint inhibitor with the exception of endocrine toxicities as detailed below ** CNS, ocular or cardiac AE of any grade related to checkpoint inhibitor ** NOTE: Patients with a prior or ongoing endocrine AE are permitted to enroll if they are stably maintained on appropriate replacement therapy and are asymptomatic
• History of migraines requiring treatment within 3 months of study entry
• 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) amendable to palliative radiotherapy should be treated prior enrollment. Patients should be recovered from the effects of radiation, i.e. recovered to ≤ grade 1 OR adequately recovered at the discretion of the treating physician. There is no required minimum recovery period
• Asymptomatic 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 or symptomatic hypercalcemia (ionized calcium > 1.5 mmol/L, calcium > 12 mg/dL or corrected serum calcium > ULN)
• 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
• Active tuberculosis
• 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
• 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 study
• History of malignancy other than lung cancer within 5 years prior to screening, with the exception of malignancies with a negligible risk of metastasis or death (e.g., 5-year OS rate > 90%), such as adequately treated carcinoma in situ of the cervix, non‑melanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, or stage I uterine or breast cancer
• 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
• Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment
• Prior allogeneic stem cell or solid organ transplantation
• Live, attenuated vaccines (e.g., FluMist) are prohibited within 4 weeks prior to initiation of study treatment, during treatment with atezolizumab, and for 5 months after the last dose of atezolizumab
• Current treatment with anti-viral therapy for Hepatitis B virus (HBV)
• Has had prior chemotherapy, immunotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1
• 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
• 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
• Known allergy or hypersensitivity to any component of ATRA