Inclusion Criteria
- Written informed consent and HIPAA authorization for release of personal health
information. NOTE: HIPAA authorization may be included in the informed consent or
obtained separately.
- Age ≥ 18 years at the time of consent.
- Body weight > 30 kg. If body weight falls to 30 kg or below during the study, the
subject will be removed from study drugs.
- ECOG Performance Status of 0-1 within 7 days prior to registration.
- Life expectancy of ≥ 12 weeks.
- Histological or cytological evidence of stage IV Kras mutation positive non-squamous
NSCLC.
- Patients who have recurrence following treatment for earlier stages of NSCLC are
eligible provided the recurrence has not occurred within 12 months of completing prior
therapy.
- Patient's tumor must be known to be PD-L1 high (≥ 50%). SP-142 assay will not be
accepted. See Section 8.1 for additional information regarding this result.
- Measurable disease according to RECIST v1.1 criteria within 4 weeks of study
registration.
- Demonstrate adequate organ function as defined in the table below; all screening labs
to be obtained within 14 days prior to registration.
- Absolute Neutrophil Count (ANC) ≥ 1.5 K/mm3
- Hemoglobin (Hgb) ≥ 9.0 g/dL
- Platelets ≥ 75 k/mm3
- Calculated creatinine clearance ≥ 45 cc/min using the Cockcroft-Gault formula
- Bilirubin ≤ 1.5 × upper limit of normal (ULN) This will not apply to subjects
with clinical diagnosis of Gilbert's syndrome (persistent or recurrent
hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis
or hepatic pathology)
- Aspartate aminotransferase (AST) ≤ 2.5 × ULN, unless patients has liver
metastases in which case it must be ≤5 × ULN
- Alanine aminotransferase (ALT) ≤ 2.5 × ULN, unless patients has liver metastases
in which case it must be ≤5 × ULN
- Evidence of post-menopausal status or negative urine or serum pregnancy test for
female pre-menopausal patients. NOTE: Women will be considered post-menopausal if they
have been amenorrheic for 12 months without an alternative medical cause. See section
5.4 for age-specific requirements (<50 year old vs. ≥50 year old).
- Females of childbearing potential randomized to Arm A and males randomized to Arm A or
Arm B must be willing to abstain from heterosexual activity or agree to use a highly
effective method of contraception from the time of informed consent until 90 days
after treatment discontinuation. Females of childbearing potential randomized to Arm B
must be willing to abstain from heterosexual activity or agree to use a highly
effective method of contraception until 180 days after treatment discontinuation. See
section 5.4 for definition of childbearing potential.
- As determined by the enrolling physician or protocol designee, ability of the subject
to understand and comply with study procedures for the entire length of the study
Exclusion Criteria
- Patient must not have received any prior systemic therapy for stage IV NSCLC. Patients
must not have received prior anti-PD-1 or anti-PD-L1.
- Active infection including tuberculosis (clinical evaluation that includes clinical
history, physical examination and radiographic findings, and TB testing in line with
local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result),
hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies). Patients
with a past or resolved HBV infection (defined as the presence of hepatitis B core
antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for
hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative
for HCV RNA. Testing is not required at screening.
- Patients with history of non-infectious pneumonitis that required steroids or has
current pneumonitis. Has known history of Interstitial Lung Disease (ILD) or radiation
pneumonitis which required therapy with steroids.
- Active or prior documented autoimmune or inflammatory (including inflammatory bowel
disease [eg, colitis or Crohn's disease], diverticulitis, systemic lupus
erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with
polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc]) and
pneumonitis. The following are exceptions to this criterion:
- Diverticulosis
- Patients with vitiligo or alopecia
- Patients with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone
replacement
- Any chronic skin condition that does not require systemic therapy
- Patients without active disease in the last 5 years may be included but only
after consultation with the study sponsor investigator.
- Patients with celiac disease controlled by diet alone
- History of allogenic progenitor/stem cell or organ transplantation.
- History of immunodeficiency. Patient should not be on any immunosuppressive therapy or
steroids > prednisone 10mg/day or its equivalent on the day of the start of therapy.
- Patients with current or prior use of immune suppressive therapy within 7 days of
starting study therapy. Following exceptions are allowed
- Intranasal, local (eg. Intraarticular injections), inhaled or topical steroids
- Steroids to prevent hypersensitivity reactions, eg. IV contrast for CT scans
- Systemic steroids not to exceed 10mg of prednisone or its equivalent.
- Any concurrent chemotherapy, investigational product, biologic, or hormonal therapy
for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related
conditions (e.g., hormone replacement therapy) is acceptable.
- Patients who have received live attenuated vaccine within 30 days of the first dose of
study therapy. Patients should not receive live vaccines while on therapy and for 30
days after the last dose.
- Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the
mother is being treated on study).
- History of another primary malignancy except for
- Malignancy treated with curative intent and with no known active disease ≥2 years
before the first dose of IP and of low potential risk for recurrence. Patients
with elevated PSA (prostate specific antigen) as the only evidence of prostate
cancer may be considered for enrolment after discussion with the
sponsor-investigator.
- Adequately treated non-melanoma skin cancer or lentigo maligna without evidence
of disease
- Adequately treated carcinoma in situ without evidence of disease
- Patients with leptomeningeal carcinomatosis are not eligible. Patients with
symptomatic brain metastases are eligible only after receiving appropriate therapy,
are clinically stable and do not require steroids equivalent to 10 mg of prednisone
daily. Patients with asymptomatic brain metastases are eligible if the treating
physician determines that the brain metastases do not require immediate directed
therapy, they are clinically stable, and are not using steroids equivalent to >10mg of
prednisone day prior to trial treatment.
- Any unresolved toxicity from previous anticancer therapy Grade ≥2 except for alopecia,
vitiligo, and the laboratory values defined in the inclusion criteria.
- Patients with Grade ≥ 2 neuropathy will be evaluated on a case-by-case basis
after consultation with the sponsor-investigator.
- Patients with irreversible toxicity not reasonably expected to be exacerbated by
treatment with durvalumab may be included only after consultation with the
sponsor-investigator.
- Patients who have radiation therapy within 1 week prior to Day 1. Patients should have
recovered from any adverse events related to radiation therapy to ≤ grade 1 or
baseline. Patients must be considered stable to receive study therapy.
- Participation in another clinical study with an investigational product within 30 days
prior to study registration.
- Concurrent enrolment in another clinical study, unless it is an observational
(non-interventional) clinical study or during the follow-up period of an
interventional study.
- Major surgery as determined by the treating physician within 4 weeks of study
registration. Placement of a central access device (port) is not considered major
surgery.
- Uncontrolled intercurrent illness as determined by the treating physician, including
but not limited to, symptomatic congestive heart failure, uncontrolled hypertension,
unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious
chronic gastrointestinal conditions associated with diarrhea, or psychiatric
illness/social situations that would limit compliance with study requirement,
substantially increase risk of incurring AEs or compromise the ability of the patient
to give written informed consent.
- History or hypersensitivity reaction to carboplatin, cisplatin or other
platinum-containing compounds, pemetrexed, or durvalumab.
