A Phase III, Multi-Centre, Open Label, Randomized Study to Assess the Efficacy and Safety of AZD9291 in Combination with MEDI4736 versus AZD9291 Monotherapy in patients with Locally Advanced or Metastatic Epidermal Growth Factor Receptor T790M mutation-positive Non-Small Cell Lung Cancer who have received Prior Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy

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 investigate the safety and tolerability profile of AZD9291 in combination with MEDI4736.

350 patients were originally planned to be evaluated across the two below populations. The recruitment was stopped due to new information on safety of the combination, received from another trial in similar patient population

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

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal.

All request will be evaluated as per the AZ disclosure commitment:

https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure

AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure

When a request has been approved AstraZeneca will provide access to the deidentified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure

The PI shall provide AstraZeneca with an opportunity to review/comment on drafts of any publication, review article or presentation (Publication) and shall afford AstraZeneca the opportunity to review the final draft of the Publication before its submission. The PI shall give AstraZeneca up to 45 days to respond with any proposed corrections and shall delete any confidential information before submission. If requested the PI shall delay submission for an additional period, not more than 60 days.