ORCHARD

Key outcome parameters

Primary endpoints:

• To assess the efficacy of each treatment by evaluation of objective response rate

Endpoint/variable:

• Endpoint based on Response Evaluation Criteria in Solid Tumours (RECIST 1.1); ORR

Secondary endpoints:

• To assess the efficacy of each treatment by evaluation of tumour response and overall survival
• To assess the pharmacokinetics (PK) of each treatment

Endpoints/variables:

• Endpoints based on Response Evaluation Criteria in Solid Tumours(RECIST 1.1)
  • Progression-free survival (PFS)
  • Duration of response (DoR)
  • Overall survival (OS)
• Plasma concentrations of therapeutic agents at selected time points

Note: Plasma concentrations may be measured only for specific agents at limited time points in each study treatment

Intervention

The study will be conducted in three groups (Groups A, B and C). Patient allocation to a study treatment within each group will be based on tumour molecular profile.

Biomarker positive patients will be allocated to a biomarker-matched study treatment in Group A, patients without a biomarker will be allocated to a study treatment in Group B, patients who are not eligible for either of these 2 groups will be allocated to Group C (observational; patients managed in accordance with local practice). Group C ensures that the best treatment choice for each patient is always possible, as certain treatments for specific molecular profiles may be available locally at a given site but not as a treatment within Groups A or B of ORCHARD.

Additionally, Group C allows for continued follow-up of these patients to assess their outcomes and contextualise the results from Groups A and B.

The structure of the protocol will follow a modular design. Study information applicable to all patients participating in this study will be described in the core protocol; each specific study treatment will be described in a separate module

Key inclusion criteria

• Ability to provide signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol
• Provision of signed and dated written informed consent prior to any study-specific procedures, sampling and analyses

Genetics sample stored for future genetic research (optional) For inclusion in the optional genetic research, study patients must provide informed consent for the genetics (Gx) sampling and analyses. If a patient declines to participate in the genetics research, there will be no penalty or loss of benefit to the patient. A patient who declines genetics research participation will not be
excluded from any other aspect of the main study.

• Female or male patients aged 18 years or over (Japan only- male or female patients aged 20 years or older) at the time of signing the ICF
• NSCLC with the following features:
  • Locally advanced or metastatic disease (ie, advanced NSCLC) not amenable to curative surgery or radiotherapy at study entry
  • Histologically or cytologically confirmed adenocarcinoma of the lung (patients with mixed histology are eligible if adenocarcinoma is the predominant histology) harbouring EGFR mutation(s) known to be associated with EGFR TKI sensitivity at diagnosis
  • Received only 1 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 AEs, would be eligible to enter this study, see also exclusion criteria). Patients previously treated adjuvantly or neo-adjuvantly are eligible per exclusion criteria.

• Evidence of radiological disease progression on first-line monotherapy with osimertinib 80 mg once daily
• Suitable for a mandatory biopsy defined as having an accessible tumour; 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 prior to the planned first dose of study treatment
• 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 (exceptlymph 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
• World Health Organisation (WHO) performance status 0 or 1 with no deterioration between screening and the first dose of study treatment
• A minimum life expectancy of 12 weeks
• Ability to swallow and retain oral medication and have adequate venous access
• Provision of archival tumour tissue for exploratory research (if such tissue/sample isavailable, its provision is mandatory)
• Ability and willingness to comply with the study and follow-up
• Adequate coagulation parameters, defined as:
  • International Normalisation Ratio (INR) <1.5 × ULN and activated partial thromboplastin time <1.5 × ULN unless patients are receiving therapeutic anti-coagulation which affects these parameters
• Patients with known tumour thrombus or deep vein thrombosis are eligible if clinically stable on low molecular weight heparin, factor Xa inhibitors or thrombin inhibitors for ≥2 weeks
• Willingness to adhere to the study treatment-specific contraception requirements (please refer to the module describing the patient’s study treatment)

Key exclusion criteria

• Patients whose disease has progressed within the first 3 months of osimertinib treatment (refractory to osimertinib treatment)
• Patients must not have experienced a toxicity(-ies) that led to permanent discontinuation or dose reduction of prior osimertinib
• Any unresolved toxicities from prior osimertinib treatment greater than CTCAE Grade 1 at the time of starting study treatment
• Patients should not have discontinued osimertinib >60 days prior to the first dose of study treatment
• Prior or concurrent treatment with any systemic anti-cancer therapy for locally advanced/metastatic NSCLC including chemotherapy, biologic therapy, immunotherapy, or any investigational drug with the following exceptions:
  • Prior adjuvant and neo-adjuvant therapy is permitted [chemotherapy, radiotherapy], if completed at least 12 months prior to diagnosis of advanced disease requiring 1st line osimertinib therapy
  • Limited systemic anti-cancer therapy for advanced/metastatic NSCLC may have been given PRIOR to osimertinib treatment as long as it does not fulfil the definition of a ‘line’ of therapy, as defined in inclusion criteria 4c above. The only systemic anticancer therapy permitted after progression on first-line osimertinib until C1/D1 is continued osimertinib treatment
  • Continued osimertinib use is permitted until Cycle 1 Day 1 of study treatment unless there is wash-out period stated in the study treatment protocol
  • Patients may receive treatment with bisphosphonates or receptor activator of nuclear factor kappa-Β ligand (RANKL) inhibitors for the treatment of bone metastases
  • Radiotherapy within the 28 days prior to the first dose of study treatment. Limited field radiotherapy for palliation is allowed up to 14 days prior to the first dose of study treatment. Patients who have not recovered from radiotherapy-related toxicity with or without the requirement of treatment (eg, steroids) will not be eligible
• Major surgery within the 28 days prior to the first dose of study treatment except:
  • After minor surgery, at least 7 postoperative days must elapse before study treatment is initiated
  • After placement of vascular access, this waiting period is not required
• Receipt of live attenuated vaccine within 30 days prior to the first dose of study treatment
• Treatment with warfarin/coumarin analogues within 7 days prior to the first dose of study treatment
• Diagnosis of small cell lung cancer (SCLC) or squamous cell carcinoma (SCC)Spinal cord compression, symptomatic and unstable brain metastases, except for those patients who have completed definitive therapy, are not on steroids, have a stable neurologic status for at least 2 weeks after completion of the definitive therapy and steroids
• Allogenic organ transplantation
• As judged by the investigator, any evidence of severe or uncontrolled systemic disease (eg, unstable or uncompensated respiratory, cardiac, renal, or hepatic disease, active bleeding diatheses) or evidence of any other significant clinical disorder or laboratory finding that makes it undesirable for the patient to participate in the study
• History of another primary malignancy except for:
  • Malignancy treated with curative intent and with no known active disease for at least 2 years before the first dose of study treatment and with low potential risk for recurrence
  • Adequately treated nonmelanoma skin cancer or lentigo maligna without evidence of disease
  • Adequately treated carcinoma in situ without evidence of disease
  • Localised non-invasive primary disease under surveillance
• Active infection, including infections with hepatitis B virus (HBV; verified by known positive HBV surface antigen [HBsAg] result), hepatitis C virus (HCV), or human immunodeficiency virus (HIV; verified by positive HIV-1 or HIV-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 testing positive for HCV antibody are eligible only if the polymerase chain reaction is negative for HCV RNA
• Pregnancy or breastfeeding in female patients
• Any of the following cardiac criteria:
  • Any clinically important abnormalities in rhythm, conduction, or morphology of resting ECG (eg, complete left bundle branch block, third degree heart block, second degree heart block, first degree heart block)
  • Unstable atrial fibrillation or unstable cardiac arrhythmia with a ventricular rate >100 bpm on an ECG at rest
  • Uncontrolled hypertension (blood pressure [BP] ≥150/95 mmHg despite optimal medical therapy)
  • Uncontrolled angina (Canadian Cardiovascular Society Grade II to Grade IV, despite medical therapy) or acute coronary syndrome within 6 months prior to screening
  • At risk for brain perfusion problems (eg, carotid stenosis) or stroke, or transient ischemic attack in the last 6 months prior to screening
  • Symptomatic heart failure (New York Heart Association [NYHA] Grade II to Grade IV)
  • Prior or current cardiomyopathy
  • Severe valvular heart disease
• Inadequate bone marrow reserve or organ function as demonstrated by any of the following laboratory values:
  • Absolute neutrophil count <1.5 × 109/L
  • Platelet count <100 × 109/L
  • Haemoglobin <9 g/dL
  • Alanine transaminase (ALT) >2.5 × the upper limit of normal (ULN)
  • Aspartate aminotransferase (AST) >2.5 × ULN
  • Total bilirubin (TBL) >1.5 × ULN, or >3 × ULN in the presence of documented Gilbert’s Syndrome (unconjugated hyperbilirubinaemia)
• Creatinine clearance (CrCl) <50 mL/min, calculated by Cockcroft-Gault equation
• Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site)
• Participation in another clinical interventional study
• Any medical, psychological, or social condition that would make it difficult for the patient to participate in the study and comply with the study procedures, restrictions and requirements
• Previous allogenic bone marrow transplant
• Non-leukocyte depleted whole blood transfusions within 120 days of the date of Gx sample collection