This a phase III, Multi Centre, Open Label, Randomized, Study to Assess the Efficacy and
Safety of AZD9291 (80 mg, orally, once daily) in Combination with MEDI4736 (10 mg/kg (IV)
infusion q2w) versus AZD9291 Monotherapy (80 mg, orally, once daily) in patients with a
confirmed diagnosis of Epidermal Growth Factor Receptor (EGFR) T790M mutation positive
NSCLC, who have progressed following prior therapy with an approved Epidermal Growth Factor
Receptor Tyrosine Kinase Inhibitor (EGFR-TKI) agent. The randomization will be stratified by
previous lines of treatment (2nd or 3rd+) and ethnicity (Asian or Non-Asian). A mandatory
biopsy will be needed for central testing of T790M mutation status following confirmed
disease progression on the most recent treatment regimen. The primary objective of the study
is to assess the efficacy of AZD9291 in combination with MEDI4736 versus AZD9291 monotherapy
by assessment of Progression Free Survival (PFS) by investigators according to Response
Evaluation Criteria in Solid Tumours version 1.1 (RECIST 1.1).
Approximately 350 patients will be evaluated and will consist of 2 populations:
1. 2nd line: patients who have progressed following an approved first-line EGFR-TKI
treatment but who have not received further treatment.
2. 3rd line or higher: patients who have progressed following prior therapy with an
approved EGFR-TKI and an additional anti-cancer treatment. Patients may have also
received additional lines of treatment.
Inclusion Criteria:
- Aged at least 18 years. Japan patients aged at least 20 years.
- Locally advanced/metastatic NSCLC, not amenable to curative surgery or radiotherapy
- Confirmation from a previous archival sample that the tumour harbours an EGFR
mutation known to be associated with EGFR TKI sensitivity
- Radiological documentation of disease progression while on a previous continuous
treatment with an EGFR TKI. Additional other lines of therapy may have been given.
All patients must have documented radiological progression on the last treatment
administered prior to enrolling in the study.
- Patients must have central lab confirmation of tumour T790M status from a biopsy
taken after disease progression on the most recent treatment regimen. Only patients
with T790M+ will be included in the study
- At least one lesion, not previously irradiated and not chosen for biopsy during the
study screening period, that can be accurately measured at baseline as 10mm in the
longest diameter (except lymph nodes which must have short axis 15mm) with
computerised tomography (CT) or magnetic resonance imaging (MRI) which is suitable
for accurate repeated measurements
- World Health Organisation (WHO) performance status 0-1 with no deterioration over the
previous 2 weeks and a minimum life expectancy of 12 weeks
- Females of child-bearing potential using contraception; negative pregnancy test
Exclusion Criteria:
- Treatment with an EGFR-TKI within 5x half-life of study entry; any cytotoxic
chemotherapy, investigational agents or other anticancer drugs within 14 days of
study entry; current treatment with potent inhibitors/inducers of cytochrome P450 3A4
(CYP3A4); previous treatment with AZD9291 (or other agents specifically targeted
against EGFR T790M mutation positive NSCLC); Prior neo-adjuvant or adjuvant
chemotherapy treatment within 6 months of starting 1st EGFR TKI treatment; prior
exposure to immune-mediated therapy including, but not limited to, other anti
cytotoxic T-lymphocyte-associated antigen 4 (anti CTLA-4), anti- programmed cell
death 1 (anti-PD-1), anti- programmed cell death ligand 1 (anti-PD-L1), and
anti-programmed cell death ligand 2 (anti-PD-L2) antibodies, excluding therapeutic
anticancer vaccines; radiotherapy treatment to more than 30% of the bone marrow or
with a wide field of radiation within 4 weeks; major surgery within 4 weeks;
- Current or prior use of immunosuppressive medication within 14 days before the first
dose of MEDI4736 (excluding intranasal, inhaled, topical steroids, or local steroid
injections)
- Unresolved toxicities from prior therapy
- History of active primary immunodeficiency
- Unstable brain metastases or spinal cord compression
- Severe/uncontrolled systemic diseases, including uncontrolled hypertension, renal
transplant, bleeding diatheses or infection
- Cardiac disease
- Ophthalmological conditions
- Refractory nausea/vomiting, chronic gastrointestinal diseases or bowel resection
- Past history of interstitial lung disease (ILD), drug-induced ILD, radiation
pneumonitis which required steroid treatment, or any evidence of clinically active
interstitial lung disease.
- History of another primary malignancy
- Active or prior documented autoimmune or inflammatory disorders within the past 3
years prior to the start of treatment
- History of organ transplant that requires use of immunosuppressive medications
- Known history of tuberculosis
- Receipt of live, attenuated vaccine within 30 days prior to the first dose of
MEDI4736
- Inadequate bone marrow reserve or organ function
Minimum Eligible Age: 18 Years
Maximum Eligible Age: N/A
Eligible Gender: Both
ORR according to RECIST 1.1
DoR according to RECIST 1.1
DCR according to RECIST 1.1
Overall Survival
Tumour shrinkage according to RECIST 1.1
Number of subjects with Adverse Events as a measure of safety and tolerability of AZD9291 as a single agent and in combination with MEDI4736
European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 items (EORTC QLQ-C30) & EORTC QLQ - Lung Cancer 13 items (EORTC QLQ LC13) measuring patients general cancer symptoms and functioning