Atezolizumab and Cobimetinib in Treating Patients With Metastatic, Recurrent, or Refractory Non-small Cell Lung Cancer
Atezolizumab and Cobimetinib in Treating Patients With Metastatic, Recurrent, or Refractory Non-small Cell Lung Cancer
This phase II trial studies how well atezolizumab and cobimetinib work in treating patients
 with non-small cell lung cancer that has spread to other places in the body (metastatic), has
 come back (recurrent), or does not respond to treatment (refractory). Immunotherapy with
 monoclonal antibodies, such as atezolizumab, may help the body's immune system attack the
 cancer, and may interfere with the ability of tumor cells to grow and spread. Cobimetinib may
 stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving
 atezolizumab and cobimetinib may work better in treating patients with non-small cell lung
 cancer.
PRIMARY OBJECTIVE:

 I. To evaluate durable overall response rate with atezolizumab plus cobimetinib in patients
 with metastatic non-small cell lung cancer (NSCLC) resistant or refractory to prior PD-1 or
 PD-L1 therapy.

 SECONDARY OBJECTIVES:

 I. To evaluate the overall response rate of atezolizumab plus cobimetinib in patients with
 metastatic NSCLC resistant or refractory to prior PD-1 or PD-L1 therapy.

 II. To evaluate the progression-free survival (PFS) of atezolizumab plus cobimetinib in
 patients with metastatic NSCLC resistant or refractory to prior PD-1 or PD-L1 therapy.

 III. To evaluate the overall survival (OS) of atezolizumab plus cobimetinib in patients with
 metastatic NSCLC resistant or refractory to prior PD-1 or PD-L1 therapy.

 IV. To evaluate the duration of response (DOR) of atezolizumab plus cobimetinib in patients
 with metastatic NSCLC resistant or refractory to prior PD-1 or PD-L1 therapy.

 V. To evaluate the grade 3 and 4 toxicity rate in patients with metastatic NSCLC resistant or
 refractory to prior PD-1 or PD-L1 therapy when treated with atezolizumab plus cobimetinib.

 EXPLORATORY OBJECTIVES:

 I. To evaluate the consequences of treatment with atezolizumab plus cobimetinib on the tumor
 microenvironment in patients with metastatic NSCLC resistant or refractory to prior PD-1 or
 PD-L1 therapy.

 II. To correlate genomic characteristics including tumor mutation burden to response to
 therapy with atezolizumab plus cobimetinib in patients with metastatic NSCLC resistant or
 refractory to prior PD-1 or PD-L1 therapy.

 OUTLINE:

 Patients receive atezolizumab intravenously (IV) over 30-60 minutes on days 1, and
 cobimetinib orally (PO) once daily (QD) on days 1-21. Cycles repeat every 28 days in the
 absence of disease progression or unaccepted toxicity.

 After completion of study treatment, patients are followed up for 90 days.
Inclusion Criteria:

 -  Patients must have histologically or cytologically confirmed metastatic or recurrent
 non-small cell lung cancer; presence of a mutation in KRAS as detected by a Clinical
 Laboratory Improvement Act (CLIA)-approved assay is required for patients enrolled in
 cohort 1; central validation is not required for enrollment

 -  If, and only if, cohort 1 is positive (at least 1 out of up to 24 patients
 experience a confirmed durable response, lasting at least 6 months), then cohort
 2 will open; this can occur prior to full enrollment to 24 patients; absence of a
 mutation in KRAS (KRAS wild type) is required for patients enrolled in cohort 2;
 central validation is not required for enrollment

 -  Patients must have primary resistance to anti-PD-1 or anti-PD-L1 therapy, given as
 monotherapy or in combination with other agents; patients must experienced progressive
 disease within 6 months (180 days) of initiating treatment with a PD-1/PD-L1 inhibitor

 -  Patients with a sensitizing alteration in EGFR, ALK or ROS1 are eligible provided they
 have experienced disease progression or intolerance to treatment with an approved
 EGFR, ALK or ROS1 inhibitor, respectively; patients who have received investigational
 inhibitors may be eligible following discussion with the study principal investigator
 (PI)

 -  Patients must have disease amenable to core biopsy and be willing to undergo the
 required research biopsies

 -  Patients must have measurable disease, defined as at least one lesion that can be
 accurately measured in at least one dimension (longest diameter to be recorded for
 non-nodal lesions and short axis for nodal lesions) as >= 20 mm (>= 2 cm) by chest
 x-ray or as >= 10 mm (>= 1 cm) with computed tomography (CT) scan, magnetic resonance
 imaging (MRI), or calipers by clinical exam

 -  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 upper limit 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 liver
 involvement 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 x
 ULN; (this applies only to patients who do not receive therapeutic anticoagulation;
 patients receiving therapeutic anticoagulation, such as low-molecular-weight heparin
 or warfarin, should be on a stable dose)

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

 -  Ability to understand and the willingness to sign a written informed consent document

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

 Exclusion Criteria:

 -  Patients who have not recovered from clinically significant adverse events (other than
 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 limited to,
 prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor
 necrosis factor [anti-TNF] agents) within 2 weeks prior to cycle 1, day 1

 -  Patients who have received acute, low dose, systemic immunosuppressant
 medications (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 adrenocortical insufficiency is
 allowed

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

 -  Patients with asymptomatic untreated CNS disease may be enrolled, provided all of
 the following criteria are met:

 -  Evaluable or measurable disease outside the CNS

 -  No metastases to brain stem, midbrain, pons, medulla, cerebellum, or within
 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 a
 stable 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 all
 the criteria listed above are met as well as the following:

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

 -  No stereotactic radiation or whole-brain radiation within 28 days prior to
 cycle 1, day 1

 -  Screening CNS radiographic study >= 4 weeks from completion of radiotherapy
 and >= 2 weeks from discontinuation of corticosteroids

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

 -  Known hypersensitivity to Chinese hamster ovary cell products or other recombinant
 human antibodies

 -  History of allergic reactions attributed to compounds of similar chemical or biologic
 composition to atezolizumab or cobimetinib

 -  History of congenital long QT syndrome or corrected QT interval (QTc) > 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 is
 considered a risk factor for neurosensory retinal detachment, central serous
 chorioretinopathy, retinal vein occlusion (RVO), or neovascular macular degeneration

 -  Any grade 3 or above hemorrhage or bleeding event within 4 weeks prior to initiation
 of study treatment

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

 -  Patients receiving any medications or substances that are strong or moderate
 inhibitors or inducers of CYP3A4 enzymes are ineligible; these include St. John's wort
 or hyperforin (potent CYP3A4 enzyme inducer) and grapefruit juice (potent cytochrome
 P450 CYP3A4 enzyme inhibitor); because the lists of these agents are constantly
 changing, it is important to regularly consult medical reference texts such as the
 Physicians' Desk Reference may also provide this information; as part of the
 enrollment/informed consent procedures, the patient will be counseled on the risk of
 interactions with other agents, and what to do if new medications need to be
 prescribed or if the patient is considering a new over-the-counter medicine or herbal
 product

 -  Known clinically significant liver disease, including active viral, alcoholic, or
 other hepatitis; cirrhosis; fatty liver; and inherited liver disease

 -  Patients with past or resolved hepatitis B infection (defined as having a
 negative 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 if
 polymerase chain reaction (PCR) is negative for HCV ribonucleic acid (RNA)

 -  History or risk of autoimmune disease, including, but not limited to, systemic lupus
 erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis
 associated with antiphospholipid syndrome, autoimmune hemolytic anemia, Wegener's
 granulomatosis, Sjogren's syndrome, Bell's palsy, Guillain-Barre syndrome, multiple
 sclerosis, autoimmune thyroid disease, vasculitis, or glomerulonephritis

 -  Patients with a history of autoimmune hypothyroidism on a stable dose of thyroid
 replacement hormone may be eligible

 -  Patients with controlled type 1 diabetes mellitus on a stable insulin regimen may
 be eligible

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

 -  Patients with psoriasis must have a baseline ophthalmologic exam to rule out
 ocular manifestations

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

 -  Disease is well controlled at baseline and only requiring low potency
 topical 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 or
 oral steroids)

 -  History of idiopathic pulmonary fibrosis, pneumonitis (including drug induced),
 organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing
 pneumonia, etc.), or evidence of active pneumonitis on screening chest computed
 tomography (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 of
 need 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 or
 anticipation that such a live, attenuated vaccine will be required during the study
 and 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, attenuated influenza vaccine
 within 4 weeks prior to cycle 1, day 1 or at any time during the study

 -  Uncontrolled pleural or pericardial effusion or ascites requiring recurrent drainage
 procedures

 -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
 infection, active tuberculosis (TB), symptomatic congestive heart failure, unstable
 angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that
 would limit compliance with study requirements

 -  Pregnant women are excluded from this study because both atezolizumab and cobimetinib
 are expected to cause fetal harm if used during pregnancy; because there is an unknown
 but potential risk for adverse events in nursing infants secondary to treatment of the
 mother with cobimetinib or atezolizumab, breastfeeding should be discontinued if the
 mother is treated with either therapy; these potential risks may also apply to other
 agents used in this study

 -  Inability or unwillingness to swallow pills

 -  History of malabsorption syndrome or other condition that would interfere with enteral
 absorption