Phase 2 Platform Study in Patients With Advanced Non-Small Lung Cancer Who Progressed on First-Line Osimertinib Therapy (ORCHARD)

Inclusion criteria applicable to all study treatment modules (Group A \& B) 1. NSCLC with the following features: 1. Locally advanced or metastatic disease (ie, advanced NSCLC) not amenable to curative surgery or radiotherapy at study entry. 2. Histologically or cytologically confirmed adenocarcinoma of the lung (patients with mixed histology are eligible if adenocarcinoma is the predominant histology) harboring EGFR mutation(s) known to be associated with EGFR TKI sensitivity at diagnosis. Any histologically identifiable component of neuroendocrine transformation to SCLC or large cell NEC is required for treatment under Module 7. 3. Received only one line of therapy, with single-agent osimertinib, for advanced NSCLC, with clinical benefit as judged by investigator discretion. (Note: a 'line' of therapy is defined as a daily anti-cancer treatment administered for \>14 days, or a single infusion of an intravenous anti-cancer treatment. For instance, patients who have had \<14 days of a first- or second- generation TKI prior to osimertinib, and stopped due to adverse events, would be eligible to enter this study, see also exclusion criteria 5). Patients previously treated adjuvantly or neo-adjuvantly are eligible per exclusion criterion 5. 4. Evidence of radiological disease progression on first-line monotherapy with osimertinib 80 mg po QD. 2. Suitable for a mandatory biopsy defined as having an accessible tumor; by whichever modality the site uses and, ideally, confirmed by the person who will perform the procedure; and a stable clinical condition that will allow the patient to tolerate the procedure. The biopsy should be performed within 60 days of the planned first dose of study treatment. 3. Patients must have measurable disease per RECIST 1.1, as defined by at least 1 lesion that can be accurately measured at baseline as ≥ 10 mm at the longest diameter (except lymph nodes which must have a short axis ≥ 15 mm) with computed tomography (CT) or magnetic resonance imaging (MRI), which is suitable for accurate repeated measurements. Previously irradiated lesions or a lesion in the field of radiation should not be used as measurable disease unless the lesion(s) has/have demonstrated unequivocal disease progression by RECIST 1.1. Target lesions should not be used for the baseline tumour biopsy, unless there are no other lesions suitable for biopsy and they fulfil requirements. 4. Adequate coagulation parameters, defined as: International Normalisation Ratio (INR) \< 1.5 × upper limit of normal (ULN) and activated partial thromboplastin time \< 1.5 × ULN unless patients are receiving therapeutic anti-coagulation which affects these parameters. \------------------------------------------------------------------------------------------- Exclusion Criteria applicable to all study treatment modules (Groups A/B): 1. Patients whose disease has progressed within the first 3 months of osimertinib treatment (refractory to osimertinib treatment). 2. Patients must not have experienced a toxicity(-ies) that led to permanent discontinuation or dose reduction of prior osimertinib. (a) Patients who had dose reductions in the past, but were receiving a full dose of osimertinib at the time of pre-screening should be discussed with the Study Physician. 3. Any unresolved toxicities from prior osimertinib treatment greater than CTCAE Grade 1 at the time of starting study treatment. 4. Patients should not have discontinued osimertinib \>60 days prior to the first dose of study treatment. 5. Inadequate bone marrow reserve or organ function as demonstrated by any of the following laboratory values: 1. Absolute neutrophil count \< 1.5 × 109/L. 2. Platelet count \< 100 × 109/L. 3. Haemoglobin \< 9 g/dL. 4. Alanine transaminase (ALT) \> 2.5 × ULN. 5. Aspartate aminotransferase (AST) \> 2.5 × ULN. 6. Total bilirubin (TBL) \> 1.5 × ULN, or \> 3 × ULN in the presence of documented Gilbert's Syndrome (unconjugated hyperbilirubinaemia). 6. Creatinine clearance (CrCl) \< 50 mL/min, calculated using Cockcroft-Gault equation (Cockcroft and Gault 1976) or 24-hour urine collection. For medical conditions where the Cockcroft-Gault equation is inappropriate or 24-hour urine collection is unfeasible, CrCl may be calculated differently following written approval from the Study Physician.