Non Small Cell Lung Cancer Trial of Durvalumab and Tremelimumab in Advanced Epidermal Growth Factor Receptor (EGFR) Mutant Disease.

Inclusion Criteria:

1. Adults, aged 18 years and older with histologically and/or cytologically confirmed non-squamous non-small cell lung cancer with EGFR mutation of Exon 19 deletion or Exon 21 L858R point mutation.

   * Patients with co-mutations are allowed as long as one of the mutation is either Exon 19 deletion or Exon 21 L858R point mutation
   * Patients with mixed histology must have non-squamous NSCLC as the predominant histology.
2. Disease that has progressed and either:

   (i) No evidence of EGFR T790M resistance mutation in both tissue re-biopsy and plasma after one-line of EGFR tyrosine kinase inhibitor therapy (TKI) OR (ii) T790M mutation (detected in tissue re-biopsy, plasma or both) and progression on 3rd generation EGFR TKI; patients are allowed to have one prior line of TKI therapy before 3rd generation TKI
3. Measurable disease according to RECIST 1.1
4. ECOG performance status of 0 or 1
5. Adequate bone marrow function as defined below (within 14 days prior to registration and with values within the ranges specified below):

   * Platelets equal to or greater than 100 x 109/L
   * Absolute neutrophil count (ANC) equal to or greater than 1.0 x 109/L (equal to or greater than 1000 per mm3)
   * Haemoglobin equal to or greater than 90 x g/L
6. Adequate liver function (within 14 days prior to registration and with values within the ranges specified below):

   * Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) equal to or less than 2.5 x institutional upper limit of normal (ULN). (or equal to or less than 5 x ULN if liver metastases are present)
   * Bilirubin equal to or less than 1.5 x ULN
7. Adequate renal function (within 14 days prior to registration):

   • Measured creatinine clearance greater than 40 mL/min or Calculated creatinine clearance greater than 40 mL/min by the Cockcroft-Gault formula or by 24-hour urine collection for determination of creatinine clearance
8. Provision of a pre-treatment tumour tissue sample from a biopsy taken within 42 days prior to enrolment (core biopsy preferred) to determine NSCLC histology and for translational research.
9. Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal patients.
10. Willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up.
11. Signed written informed consent (main study and optional biobanking).

Exclusion Criteria:

1. Prior chemotherapy or immunotherapy, including prior anti-PD-1/anti-PD-L1 or anti-CTLA-4 antibodies, for advanced NSCLC.

   * For recurrent, incurable disease, prior adjuvant chemotherapy or concurrent chemotherapy and radiotherapy with curative intent is allowed, but must have been completed more than 6 months ago, and must not have included treatment with an immune checkpoint inhibitor.
   * Prior EGFR-TKI (e.g. erlotinib, gefitinib, afatinib or osimertinib), including experimental TKI agents, within 8 days or approximately 5 x half-life, whichever is the longer, of the first dose of study treatment is allowed. (If sufficient washout time has not occurred due to schedule or PK properties, an alternative appropriate washout time based on known duration and time to reversibility of drug related adverse events could be agreed upon by contacting the ILLUMINATE Study Team).
2. Mixed histology with any small cell or squamous component.
3. Life expectancy of less than 3 months.
4. Current enrolment or participation in another clinical study with an investigational product during the last 12 months, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study must first be discussed with ILLUMINATE Study Team before study enrolment.
5. Any unresolved toxicity NCI CTCAE equal to or greater than Grade 2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria.

   * Patients with equal to or greater than Grade 2 neuropathy will be evaluated on a case-by-case basis after consultation with the ILLUMINATE Study Team.
   * Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab or tremelimumab may be included only after consultation with the ILLUMINATE Study Team.
6. Radiotherapy or major surgery (as defined by the local investigator) within 4 weeks of the first dose of study drug. Note: Local surgery on isolated lesions for palliative intent is acceptable.
7. History of pneumonitis or pulmonary fibrosis with clinically significant impairment of pulmonary function.
8. History of active primary immunodeficiency or allogeneic transplant.
9. Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease \[e.g., colitis or Crohn's disease\], diverticulitis (with the exception of diverticulosis), systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome \[granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc\]). The following are exceptions to this criterion:

   * Patients with vitiligo or alopecia
   * Patients with hypothyroidism (e.g., 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 physician
   * Patients with celiac disease controlled by diet alone
10. Concurrent illness, including severe infection that may jeopardise the ability of the patient to undergo the procedures outlined in this protocol with reasonable safety.
11. History of another primary malignancy except for

    * Malignancy treated with curative intent and with no known active disease equal to or greater than 5 years before the first dose of IP and of low potential risk for recurrence
    * Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
    * Adequately treated carcinoma insitu without evidence of disease.
12. Any history of leptomeningeal carcinomatosis, or untreated central nervous system metastases obtained during the screening period or identified prior to signing the PICF. Patients whose brain metastases have been treated may participate provided they show radiographic stability (defined as disease stability on imaging 4 weeks after commencing radiotherapy). Any neurologic symptoms that developed either as a result of the brain metastases or their treatment must have resolved or be stable either, without the use of steroids, or are stable on a steroid dose of equal to or less than 10mg/day of prednisone or its equivalent (and anti-epileptic drugs) for at least 14 days prior to the start of treatment.
13. 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.
14. Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab or tremelimumab. The following are exceptions to this criterion:

    * Intranasal, inhaled, topical steroids, or local steroid injections (e.g. intra articular injection)
    * Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent
    * Steroids as premedication for hypersensitivity reactions (e.g. CT scan premedication)
15. Live attenuated vaccine within 30 days prior to the first dose of study drug, whilst receiving study drug and up to 30 days after the last dose of study drug.
16. Serious medical or psychiatric conditions that might limit the ability of the patient to comply with the protocol.
17. Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ effective birth control from screening to 90 days after the last dose of durvalumab monotherapy or 180 days after the last dose of durvalumab plus tremelimumab combination therapy.
18. Known allergy or hypersensitivity to any of the study drugs or excipients.