• Progression-free survival (PFS) [ Time Frame: Measured from first dose until progression. For each patient this is expected to be 6 months on average ]
  The time from first dose until the date of objective disease progression or death (by any cause in the absence of progression). Patients will be followed up every 6 weeks (±1 week) for the first 24 weeks and every 9 weeks thereafter until RECIST (Response Evaluation Criteria In Solid Tumours)1.1 defined disease progression or cessation of study treatment (if treating beyond progression).
• Duration of response (DoR) [ Time Frame: Measured from response until progression. For each patient this is expected to be 6 months on average ]
  The time from the date of first response until date of disease progression or death in the absence of disease progression. Patients will be followed up every 6 weeks (±1 week) for the first 24 weeks and every 9 weeks thereafter until RECIST 1.1 defined disease progression or cessation of study treatment (if treating beyond progression).
• Overall survival (OS) [ Time Frame: Measured from first dose until death or final cohort data cut-off. For each patient this is expected to be 20 months on average ]
  The time from the date of the first dose of study treatment until death due to any cause.
• Plasma concentrations of therapeutic agents [ Time Frame: Pre-dose and 1 hour post-dose blood samples on Day 1 of Cycles 1, 3 (Cycle 2 for durvalumab), 6 for all therapeutic agents and a sample at the 90-day safety follow up for durvalumab only. (One Cycle = 21 or 28 days, depending on treatment). ]
  Blood samples will be collected at various timepoints to evaluate the sparse pharmacokinetics of study therapeutic agents.
• Plasma concentrations of therapeutic agents [ Time Frame: Pre-dose and serial post-dose blood samples (1 hour, 2 hours, 4 hours, 6 hours, 8 hours) on Day 15 of Cycle 1 for alectinib and selpercatinib only. ]
  Blood samples will be collected at various timepoints to evaluate the serial pharmacokinetics of study therapeutic agents
• Incidence of Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) as characterized and graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event [CTCAE] v5 [ Time Frame: Continuously from first dose to end of safety follow up after study treatment discontinuation (approximately up to 21 Months) ]
  To evaluate safety and tolerability of each study treatment

• Progression-free survival (PFS) [ Time Frame: Measured from first dose until progression. For each patient this is expected to be 18 months on average ]
  The time from first dose until the date of objective disease progression or death (by any cause in the absence of progression). Patients will be followed up every 6 weeks (±1 week) for the first 24 weeks and every 9 weeks thereafter until RECIST (Response Evaluation Criteria In Solid Tumours)1.1 defined disease progression or cessation of study treatment (if treating beyond progression).
• Duration of response (DoR) [ Time Frame: Measured from response until progression. For each patient this is expected to be 15 months on average ]
  The time from the date of first response until date of disease progression or death in the absence of disease progression. Patients will be followed up every 6 weeks (±1 week) for the first 24 weeks and every 9 weeks thereafter until RECIST 1.1 defined disease progression or cessation of study treatment (if treating beyond progression).
• Overall survival (OS) [ Time Frame: Measured from first dose until death or final cohort data cut-off. For each patient this is expected to be 30 months on average ]
  The time from the date of the first dose of study treatment until death due to any cause.
• Plasma concentrations of therapeutic agents [ Time Frame: Pre-dose and 1 hour post-dose blood samples on Day 1 of Cycles 1, 3, 6 for all therapeutic agents and a sample at the 90-day safety follow up for durvalumab only. (One Cycle = 21 or 28 days, depending on treatment) ]
  Blood samples will be collected at various timepoints to evaluate the pharmacokinetics of study therapeutic agents.
• Incidence of Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) as characterized and graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event [CTCAE] v5 [ Time Frame: Continuously from first dose to end of safety follow up after study treatment discontinuation (approximately up to 21 Months) ]
  To evaluate safety and tolerability of each study treatment

This is an open-label, multicentre, multi-drug, biomarker-directed Phase 2 platform study in patients with advanced non-small cell lung cancer (NSCLC) harbouring an epidermal growth factor receptor (EGFR)-sensitizing mutation whose disease has progressed on first-line monotherapy with osimertinib.Treatment options for these patients are limited. Novel treatments for these patients are urgently required.

This study is modular in design, allowing evaluation of the efficacy, safety and tolerability of multiple study treatments.

• Drug: Osimertinib
  Osimertinib given orally at 80 mg once daily
  Other Name: TAGRISSO
• Drug: Savolitinib
  Savolitinib will be given orally at 300 mg or 600mg once daily
• Drug: Gefitinib
  Gefitinib given orally at 250 mg once daily
  Other Name: Iressa
• Drug: Necitumumab
  Necitumumab given IV at 800 mg on Day 1 and Day 8 of every 3-week cycle
  Other Name: Portrazza
• Drug: Durvalumab
  Durvalumab given IV at 1500 mg on Day 1 of every cycle
  Other Name: IMFINZI
• Drug: Carboplatin
  Carboplatin given IV on Day 1 of every 21-day cycle for up to 6 cycles
• Drug: Pemetrexed
  Pemetrexed given IV at 500 mg/m2 body BSA on Day 1 of every cycle
• Drug: Alectinib
  Alectinib given orally at 600mg twice daily and for Japanese patients at 300mg twice daily.
  Other Name: Alecensa
• Drug: Selpercatinib
  Selpercatinib given orally at 160mg twice daily
  Other Name: Loxo-292

• Experimental: Module 1: Osimertinib + Savolitinib
  The patients in this group will receive osimertinib taken in combination with savolitinib
  Interventions:

  • Drug: Osimertinib
  • Drug: Savolitinib
• Experimental: Module 2: Osimertinib + Gefitinib
  The patients in this group will receive osimertinib taken in combination with gefitinib
  Interventions:

  • Drug: Osimertinib
  • Drug: Gefitinib
• Experimental: Module 3: Osimertinib + Necitumumab
  The patients in this group will receive osimertinib taken in combination with necitumumab
  Interventions:

  • Drug: Osimertinib
  • Drug: Necitumumab
• Experimental: Module 4: Carboplatin + Pemetrexed + Durvalumab)
  The patients in this group will receive platinum-containing doublet (carboplatin + pemetrexed) taken in combination with durvalumab.
  Interventions:

  • Drug: Durvalumab
  • Drug: Carboplatin
  • Drug: Pemetrexed
• No Intervention: Observational Cohort: No study drug

  Patients in this group will not receive study treatment but receive further anticancer care (Standard of Care therapy or other experimental therapies) or supportive care, as clinically indicated, in accordance with local practice.

  With Group C, the aim is to understand the clinical course and/or outcome for the overall clinical population after progression on first-line monotherapy with osimertinib.

• Experimental: Module 5: Osimertinib + Alectinib
  The patients in this group will receive osimertinib taken in combination with alectinib
  Interventions:

  • Drug: Osimertinib
  • Drug: Alectinib
• Experimental: Module 6: Osimertinib + Selpercatinib
  The patients in this group will receive osimertinib taken in combination with selpercatinib
  Interventions:

  • Drug: Osimertinib
  • Drug: Selpercatinib

Inclusion criteria applicable to all study treatment modules (Groups A/B):

• Non-Small Cell Lung Cancer (NSCLC) with the following features:

  • Locally advanced or metastatic disease (i.e. advanced NSCLC) not amenable to curative surgery or radiotherapy at study entry.
  • Histologically or cytologically confirmed adenocarcinoma of the lung harbouring epidermal growth factor receptor (EGFR) mutation(s) known to be associated with tyrosine kinase inhibitors (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.
  • Evidence of radiological disease progression on first-line monotherapy with osimertinib 80mg once daily.
• Suitable for a mandatory biopsy defined as having an accessible tumour 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 Response Evaluation Criteria In Solid Tumours (RECIST) 1.1.
• 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 is available, 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 × upper limit of normal (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.

Exclusion Criteria applicable to all study treatment modules (Groups A/B):

• Patients whose disease has progressed within the first 3 months of osimertinib treatment
• Patients must not have experienced a toxicity(-ies) that led to permanent discontinuation or dose reduction of prior osimertinib or have any unresolved toxicities from prior osimertinib treatment greater than CTCAE (Common Terminology Criteria for Adverse Event) Grade 1 at the time of starting study treatment
• Patients must not have discontinued osimertinib >60 days prior to the first dose of study treatment
• Prior or concurrent treatment with any systemic anticancer therapy for locally advanced/metastatic NSCLC including chemotherapy, biologic therapy, immunotherapy, or any investigational drug (exceptions do apply)

• 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 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, hepatitis C virus, or human immunodeficiency virus (exceptions apply)
• Pregnancy or breastfeeding in female patients

• Any of the following cardiac criteria:

  • Any clinically important abnormalities in rhythm, conduction, or morphology of resting ECG
  • Unstable atrial fibrillation or unstable cardiac arrhythmia with a ventricular rate >100 bpm on an ECG at rest.
  • Uncontrolled hypertension
  • Uncontrolled angina or acute coronary syndrome within 6 months prior to screening.
  • At risk for brain perfusion problems or stroke, or transient ischemic attack in the last 6 months prior to screening
  • Symptomatic heart failure
  • Prior or current cardiomyopathy.
  • Severe valvular heart disease
• Inadequate bone marrow reserve or organ function
• Creatinine clearance <50 mL/min, calculated by Cockcroft-Gault equation