Atezolizumab and Cobimetinib in Treating Patients With Metastatic, Recurrent, or Refractory Non-small Cell Lung Cancer

Inclusion Criteria:

• Patients must have histologically or cytologically confirmed metastatic or recurrentnon-small cell lung cancer (any histology is permitted)

• Presence of a mutation in KRAS as detected by a Clinical Laboratory ImprovementAct (CLIA)-approved assay is required for patients enrolled in cohort 1;central validation is not required for enrollment

• Absence of a mutation in KRAS (KRAS wild type) is required for patientsenrolled in cohort 2; central validation is not required for enrollment butKRAS mutation status must be known, regardless of histology

• Patients must have primary resistance to anti-PD-1 or anti-PD-L1 therapy, given asmonotherapy or in combination with other agents; patients must have experiencedprogressive disease within 6 months (180 days) of initiating treatment with aPD-1/PD-L1 inhibitor

• Anti-PD-1 or anti-PD-L1 therapy does not need to be the most recent therapyprior to study enrollment

• Patients with a sensitizing alteration in EGFR, ALK or ROS1 are eligible providedthey have experienced disease progression or intolerance to treatment with anapproved EGFR, ALK or ROS1 inhibitor, respectively; patients who have receivedinvestigational inhibitors may be eligible following discussion with the studyprincipal investigator (PI)

• Patients must have disease amenable to core biopsy and be willing to undergo therequired research biopsies

• Patients must have measurable disease, defined as at least one lesion that can beaccurately measured in at least one dimension (longest diameter to be recorded fornon-nodal lesions and short axis for nodal lesions) as >= 20 mm (>= 2 cm) by chestx-ray or as >= 10 mm (>= 1 cm) with CT scan, MRI, or calipers by clinical exam

• Age >= 18 years

• Because no dosing or adverse event data are currently available on the use ofatezolizumab in combination with cobimetinib in patients < 18 years of age,children are excluded from this study, but will be eligible for futurepediatric trials

• Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

• Leukocytes >= 2,500/mcL

• Absolute neutrophil count >= 1,000/mcL

• Platelets >= 100,000/mcL

• Hemoglobin >= 8 g/dL

• Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (however,patients with known Gilbert disease who have serum bilirubin level =< 3 x upperlimit of normal [ULN] may be enrolled)

• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x ULN (AST and/or ALT =< 5 x ULN for patients with liver involvement)

• Alkaline phosphatase =< 2.5 x ULN (=< 5 x ULN for patients with documented liverinvolvement or bone metastases)

• Creatinine clearance >= 30 mL/min/1.73 m^2 by Cockcroft-Gault

• Institutional normalized ratio (INR) and partial thromboplastin time (aPTT) =< 1.5 xULN; (this applies only to patients who do not receive therapeutic anticoagulation;patients receiving therapeutic anticoagulation, such as low-molecular-weight heparinor warfarin, should be on a stable dose)

• Administration of atezolizumab or cobimetinib may have an adverse effect onpregnancy and poses a risk to the human fetus, including embryo-lethality; women ofchild-bearing potential and men must agree to use adequate contraception (hormonalor barrier method of birth control; abstinence) prior to study entry, for theduration of study participation, and for 5 months (150 days) after the last dose ofstudy agent; should a woman become pregnant or suspect she is pregnant while she orher partner is participating in this study, she should inform her treating physicianimmediately

• Ability to understand and the willingness to sign a written informed consentdocument

• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviraltherapy with undetectable viral load within 6 months are eligible for this trial

Exclusion Criteria:

• Patients who have not recovered from clinically significant adverse events (otherthan alopecia) due to prior anti-cancer therapy

• Treatment with any investigational agent within 4 weeks prior to cycle 1, day 1

• Treatment with systemic immunosuppressive medications (including, but not limitedto, prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, andanti-tumor necrosis factor [anti-TNF] agents) within 2 weeks prior to cycle 1, day 1

• Patients who have received acute, low dose, systemic immunosuppressantmedications (e.g., a one-time dose of dexamethasone for nausea) may be enrolled

• The use of inhaled corticosteroids and mineralocorticoids (e.g.,fludrocortisone) for patients with orthostatic hypotension or adrenocorticalinsufficiency is allowed

• Patients with symptomatic central nervous system (CNS) metastases are excluded

• Patients with asymptomatic untreated CNS disease may be enrolled, provided allof the following criteria are met:

• Evaluable or measurable disease outside the CNS

• No metastases to brain stem, midbrain, pons, medulla, cerebellum, orwithin 10 mm of the optic apparatus (optic nerves and chiasm)

• No history of intracranial hemorrhage or spinal cord hemorrhage

• No ongoing requirement for dexamethasone for CNS disease; patients on astable dose of anticonvulsants are permitted

• No neurosurgical resection or brain biopsy within 28 days prior to cycle 1, day 1

• Patients with asymptomatic treated CNS metastases may be enrolled, provided allthe criteria listed above are met as well as the following:

• Radiographic demonstration of improvement upon the completion ofCNS-directed therapy and no evidence of interim progression between thecompletion of CNS-directed therapy and the screening radiographic study

• No stereotactic radiation or whole-brain radiation within 28 days prior tocycle 1, day 1

• Screening CNS radiographic study >= 4 weeks from completion ofradiotherapy and >= 2 weeks from discontinuation of corticosteroids

• Has a known concurrent malignancy that is expected to require active treatmentwithin two years, or may interfere with the interpretation of the efficacy andsafety outcomes of this study in the opinion of the treating investigator;superficial bladder cancer, non-melanoma skin cancers, or low grade prostate cancernot requiring therapy should not exclude participation in this trial

• Known hypersensitivity to Chinese hamster ovary cell products or other recombinanthuman antibodies

• History of allergic reactions attributed to compounds of similar chemical orbiologic composition to atezolizumab or cobimetinib

• History of congenital long QT syndrome or corrected QT interval (QTc) by FridericiaFormula > 450 msec within 28 days of cycle 1, day 1

• Cardiac ejection fraction below institutional lower limit of normal (LLN) or below 50%, whichever is lower, as determined by echocardiogram or multigated acquisition (MUGA) scan within 4 weeks of cycle 1, day 1

• History of or evidence of retinal pathology on ophthalmologic examination that isconsidered a risk factor for neurosensory retinal detachment, central serouschorioretinopathy, retinal vein occlusion (RVO), or neovascular macular degeneration

• Any grade 3 or above hemorrhage or bleeding event within 4 weeks prior to initiationof study treatment

• History of stroke, reversible ischemic neurological defect, or transient ischemicattack within 6 months prior to initiation of study treatment

• Patients receiving any medications or substances that are strong or moderateinhibitors or inducers of CYP3A4 enzymes are ineligible; these include St. John'swort or hyperforin (potent CYP3A4 enzyme inducer) and grapefruit juice (potentcytochrome P450 CYP3A4 enzyme inhibitor); because the lists of these agents areconstantly changing, it is important to regularly consult medical reference textssuch as the Physicians' Desk Reference may also provide this information; as part ofthe enrollment/informed consent procedures, the patient will be counseled on therisk of interactions with other agents, and what to do if new medications need to beprescribed or if the patient is considering a new over-the-counter medicine orherbal product

• Known clinically significant liver disease, including active viral, alcoholic, orother hepatitis; cirrhosis; fatty liver; and inherited liver disease

• Patients with past or resolved hepatitis B infection (defined as having anegative hepatitis B surface antigen [HBsAg] test and a positive anti-HBc [antibody to hepatitis B core antigen] antibody test) are eligible

• Patients positive for hepatitis C virus (HCV) antibody are eligible only ifpolymerase chain reaction (PCR) is negative for HCV ribonucleic acid (RNA)

• History or risk of autoimmune disease, including, but not limited to, systemic lupuserythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosisassociated with antiphospholipid syndrome, autoimmune hemolytic anemia, Wegener'sgranulomatosis, Sjogren's syndrome, Bell's palsy, Guillain-Barre syndrome, multiplesclerosis, vasculitis, or glomerulonephritis

• Patients with a history of autoimmune hypothyroidism on a stable dose ofthyroid replacement hormone may be eligible

• Patients with controlled type 1 diabetes mellitus on a stable insulin regimenmay be eligible

• Patients with eczema, psoriasis, lichen simplex chronicus of vitiligo withdermatologic manifestations only (e.g., patients with psoriatic arthritis wouldbe excluded) are permitted provided that they meet the following conditions:

• Patients with psoriasis must have a baseline ophthalmologic exam to ruleout ocular manifestations

• Rash must cover less than 10% of body surface area (BSA)

• Disease is well controlled at baseline and only requiring low potencytopical steroids (e.g., hydrocortisone 2.5%, hydrocortisone butyrate 0.1%,flucinolone 0.01%, desonide 0.05%, aclometasone dipropionate 0.05%)

• No acute exacerbations of underlying condition within the last 12 months (not requiring psoralen plus ultraviolet A radiation [PUVA], methotrexate,retinoids, biologic agents, oral calcineurin inhibitors; high potency ororal steroids)

• History of idiopathic pulmonary fibrosis, pneumonitis (including drug induced),organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizingpneumonia, etc.), or evidence of active pneumonitis on screening chest computedtomography (CT) scan; history of radiation pneumonitis in the radiation field (fibrosis) is permitted

• Any significant active infection requiring treatment within 14 days prior to cycle 1, day 1

• Major surgical procedure within 28 days prior to cycle 1, day 1 or anticipation ofneed for a major surgical procedure during the course of the study

• Administration of a live, attenuated vaccine within 4 weeks before cycle 1, day 1 oranticipation that such a live, attenuated vaccine will be required during the studyand up to 5 months after the last dose of atezolizumab

• Influenza vaccination should be given during influenza season only (approximately October to March); patients must not receive live, attenuatedinfluenza vaccine within 4 weeks prior to cycle 1, day 1 or at any time duringthe study

• Uncontrolled pleural or pericardial effusion or ascites requiring recurrent drainageprocedures

• Uncontrolled intercurrent illness including, but not limited to, ongoing or activeinfection, active tuberculosis (TB), symptomatic congestive heart failure, unstableangina pectoris, cardiac arrhythmia, or psychiatric illness/social situations thatwould limit compliance with study requirements

• Pregnant women are excluded from this study because both atezolizumab andcobimetinib are expected to cause fetal harm if used during pregnancy; because thereis an unknown but potential risk for adverse events in nursing infants secondary totreatment of the mother with cobimetinib or atezolizumab, breastfeeding should bediscontinued if the mother is treated with either therapy; these potential risks mayalso apply to other agents used in this study

• Inability or unwillingness to swallow pills

• History of malabsorption syndrome or other condition that would interfere withenteral absorption