Neoadjuvant and Adjuvant Treatment in Resectable Non-small Cell Lung Cancer (NeoCOAST-2)

A Phase II, Open-label, Multicentre, Randomised Study of Neoadjuvant and Adjuvant Treatment in Patients With Resectable, Early-stage (II to IIIB) Non-small Cell Lung Cancer (NeoCOAST-2)

The study is intended to assess the safety and efficacy of perioperative treatment with Durvalumab in combination with Oleclumab, Monalizumab or AZD0171 and platinum doublet chemotherapy; or MEDI5752 in combination with platinum doublet chemotherapy or datopotamab deruxtecan (Dato-DXd) in combination with durvalumab and single agent platinum chemotherapy in participants with resectable, early-stage non-small cell lung cancer.

This is a open-label, multi-arms, multicentre, randomised study, eligible participants will be enrolled and randomised to one of the following treatment regimens. Arm 1: Participants will receive Oleclumab + durvalumab + platinum doublet chemotherapy as neoadjuvant treatment and Oleclumab + durvalumab as adjuvant treatment. Arm 2: Participants will receive Monalizumab + durvalumab + platinum doublet chemotherapy as neoadjuvant treatment and Monalizumab + durvalumab as adjuvant treatment. Arm 3: Participants will receive MEDI5752 + platinum doublet chemotherapy as neoadjuvant treatment and MEDI5752 as adjuvant treatment. Arm 4: Participants will receive Dato-DXd + durvalumab + single agent platinum chemotherapy as neoadjuvant treatment and durvalumab as adjuvant treatment. Arm 5: Participants will receive AZD0171 + durvalumab + platinum doublet chemotherapy as neoadjuvant treatment and AZD0171 + durvalumab as adjuvant treatment.

Lung Cancer, early-stage, Durvalumab, Oleclumab, Monalizumab, AZD0171, Datopotamab Deruxtecan, Neoadjuvant, Adjuvant, Chemotherapy, MEDI5752

Participants will receive Durvalumab + Oleclumab + platinum doublet chemotherapy as neoadjuvant treatment and Durvalumab + Oleclumab as adjuvant treatment. Participants will receive one of the following chemotherapy regimens, based on the tumour histology and Investigator's discretion, as part of their treatment regimen prior to surgery: Carboplatin/Paclitaxel Pemetrexed/Cisplatin Pemetrexed/Carboplatin

Participants will receive Durvalumab + Monalizumab + platinum doublet chemotherapy as neoadjuvant treatment and Durvalumab + Monalizumab as adjuvant treatment. Participants will receive one of the following chemotherapy regimens, based on the tumour histology and Investigator's discretion, as part of their treatment regimen prior to surgery: Carboplatin/Paclitaxel Pemetrexed/Cisplatin Pemetrexed/Carboplatin

Participants will receive MEDI5752 + platinum doublet chemotherapy as neoadjuvant treatment and MEDI5752 as adjuvant treatment. Participants will receive one of the following chemotherapy regimens, based on the tumour histology and Investigator's discretion, as part of their treatment regimen prior to surgery: Carboplatin/Paclitaxel Pemetrexed/Cisplatin Pemetrexed/Carboplatin

Participants will receive Dato-DXd + durvalumab + single agent platinum as neoadjuvant treatment and durvalumab as adjuvant treatment. Participants will receive one of the following chemotherapy regimens, based on physician choice of as part of their treatment regimen prior to surgery: Carboplatin or Cisplatin

Participants will receive AZD0171 + durvalumab + platinum doublet chemotherapy as neoadjuvant treatment and AZD0171 + durvalumab as adjuvant treatment. Participants will receive one of the following chemotherapy regimens, based on the tumour histology and Investigator's discretion, as part of their treatment regimen prior to surgery: Carboplatin/Paclitaxel Pemetrexed/Cisplatin Pemetrexed/Carboplatin

From randomization to up to 24 months after last dose of study interventions (Up to approximately 3 Years)

Inclusion Criteria: Newly diagnosed NSCLC patients with resectable disease (Stage IIA to Stage IIIB). WHO or Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Adequate organ and bone marrow function. Provision of tumour samples (newly acquired or archival tumour tissue [≤ 6 months old]) to confirm Programmed death-ligand 1 (PD-L1) status, epidermal growth factor receptor (EGFR), or anaplastic lymphoma kinase (ALK) status. Adequate pulmonary function. Exclusion Criteria: Participants with sensitising EGFR mutations or ALK translocations. History of allogeneic organ transplantation. Active or prior documented autoimmune or inflammatory disorders. Uncontrolled intercurrent illness, uncontrolled hypertension, unstable angina pectoris, uncontrolled cardiac arrhythmia, active bleeding diseases, serious chronic gastrointestinal conditions associated with diarrhoea, or psychiatric illness/social situations that would limit compliance with study requirement. History of another primary malignancy. Participants with small-cell lung cancer or mixed small-cell lung cancer. History of active primary immunodeficiency. History of non-infectious ILD/pneumonitis that required steroids, has current ILD/pneumonitis, or has suspected ILD/pneumonitis that cannot be ruled out by imaging at screening. Participants who have preoperative radiotherapy treatment as part of their care plan. Participants who require or may require pneumonectomy, segmentectomies, or wedge resections, as assessed by their surgeon at baseline, to obtain potentially curative resection of primary tumour. QTcF (QT interval corrected by Fridericia's formula) interval ≥ 470 ms. Any medical contraindication to treatment with chemotherapy as listed in the local labelling. Participants with moderate or severe cardiovascular disease. Any concurrent chemotherapy, investigational product, biologic, or hormonal therapy for cancer treatment. Receipt of live attenuated vaccine within 30 days prior to the first dose of study interventions. Prior exposure to approved or investigational immune-mediated therapy including, but not limited to, other anti-CTLA-4, anti-PD-1, anti-PD-L1, and anti-PD-L2 antibodies. Participants who received agents targeting the adenosine pathway, anti-NKG2A, anti-HLA-E agents, and anti-LIF agents are also excluded. Participants who have received previous treatment with a TROP2 targeting ADC or with another ADC containing a chemotherapy agent that inhibits TOP1 activity are also excluded. Current or prior use of immunosuppressive medication within 14 days before the first dose of study interventions. Active or uncontrolled infections including HBA, HBV, HCV, and HIV.

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the requests portal. All requests will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure. Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.

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 de-identified 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.