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

PRIMARY OBJECTIVES:

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 15 and
cobimetinib orally (PO) once daily (QD) on days 1-21. Courses 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 3 out of up to 24 patients
experience confirmed response) and at least one response is durable (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 have received anti-PD-1
or anti-PD-L1 therapy with a best response of progressive disease or stable disease
lasting =< 4 months; patients who achieved a partial response or a complete response
or stable disease lasting > 4 months are not eligible

- 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)

- 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

- Patients positive for human immunodeficiency virus (HIV) are allowed on study, but
HIV-positive patients must have:

- A stable regimen of highly active anti-retroviral therapy (HAART)

- No requirement for concurrent antibiotics or antifungal agents for the prevention
of opportunistic infections

- A CD4 count above 250 cells/mcL and an undetectable HIV viral load on standard
polymerase chain reaction (PCR)-based tests

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 2 weeks 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