Phase III study to determine efficacy of durvalumab in stage II-III non-small cell lung cancer (NSCLC) after curative intent therapy. - MERMAID-2

Inclusion Criteria

• Informed consent
• 1. Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the ICFs and in the protocol.
• 2. Provision of signed and dated, written informed consent form prior to any mandatory study-specific procedures, sampling, and analyses.
• 3. Provision of signed and dated written optional genetic informed consent prior to collection of the optional sample for genetic analysis. This consent should be signed at the time of second screening. This optional sample and analyses are separate from the mandatory genetic testing consent included in ICF1.
• The following criteria must have been met at the time of surgery or at the time of the curative intent therapy (first screening):
• 4. Age ≥18 years at the time of screening (ICF1);
• 5. Male and/or female
• 6. Histologically confirmed NSCLC with resectable stage II-III disease who have undergone curative intent therapy (complete resection of the primary tumor ± neoadjuvant and/or adjuvant therapy) per SoC.
• Select stage IIIB (ie, T3N2 or T4N2) patients will be eligible, provided they are upstaged to T3N2 or T4N2 based on confirmed pathology after surgery. Patients who are staged as T3N2 or T4N2 prior to surgery are not eligible.
• 7. A contrast-enhanced CT/MRI scan of the chest and abdomen (including liver and adrenal glands) along with brain MRI (preferred) or brain CT with IV contrast must have been done for surgical planning prior to surgery. It is recommended that patients undergo combined FDG-PET (18F-Fluoro-deoxyglucose positron emission tomography) and CT scan (computerized tomography) within the 6 weeks prior to surgery in order to rule out detectable extrathoracic, extracranial metastasis and to assess for potential mediastinal lymph node involvement prior to surgery. If the positron emission tomography (PET) scan was not performed, or data from a PET is not available, patients may still be enrolled into the study provided appropriate imaging (CT/MRI) is performed prior to randomization.
• 8. Complete resection of the primary NSCLC is mandatory. Invasive (pre-operative or intra-operative) exploration of hilar and mediastinal lymph nodes must have been performed to confirm primary tumor nodal status (prior to or after surgery). Surgical resection of the primary NSCLC can occur by open thoracotomy or by video-assisted thoracic surgery (VATs) and resection can be achieved by segmentectomy, lobectomy, sleeve resection, bilobectomy or pneumonectomy. Patients undergoing wedge resection are not eligible for this study.
• Criteria for prior systemic chemotherapy/radiotherapy:
• 9. Patients should have completed (or be undergoing) curative intent therapy (surgery ± neoadjuvant and/or adjuvant therapy; adjuvant therapy can include PORT) with exceptions noted below:
• Patients who discontinue chemotherapy and/or PORT for toxicity prior to completion of all planned therapy are eligible.
• Patients who have not received any neoadjuvant and/or adjuvant chemotherapy, and meet all other eligibility criteria, may be eligible under the following circumstances:
• o All patients who are eligible for adjuvant chemotherapy MUST be offered adjuvant chemotherapy.
• o The patient has declined adjuvant chemotherapy, and in the opinion of the Investigator, this is the patient’s final decision after receiving appropriate information and adequate time to make the decision. The patient’s refusal of adjuvant chemotherapy must be documented.
• o If in the view of the Investigator, adjuvant chemotherapy is contraindicated due to an underlying intercurrent illness/laboratory abnormality, which is not considered reversible within a reasonable timeframe for the patient to be eligible for adjuvant therapy, which must be documented.
• Criteria assessed prior to and at the start of surveillance:
• 10. Confirmation of suitable biosamples for WES and central PD-L1 testing. Resected tumor tissue and whole blood samples must be provided to the diagnostic laboratory for WES of tumor and germline DNA, respectively as soon as possible following pathology confirmation. Samples must be sent no later than 1-2 weeks after completion of adjuvant therapy or 3-5 weeks after surgery (if no adjuvant therapy is given) for development of the Sponsor-approved personalized panel for MRD detection at a central reference laboratory. Germline sequencing of whole blood is mandatory. Resected tumor tissue must also be provided for PD-L1 testing at a
• central reference laboratory (see inclusion criteria 15).
• 11. Post-adjuvant therapy or post-surgery (if no adjuvant therapy is given) CT scan of the chest and abdomen (including liver and adrenal glands) and brain MRI [preferred] or brain CT with IV contrast should be available to confirm no evidence of metastasis. If scans were not performed post-curative intent therapy, additional scans must be done prior to start of surveillance.
• 12. Consents to be accessible for q6w±3d plasma sample collection for MRD evaluation and for q12w±1w CT scans during the 96-week surveillance period.
• 13. The plasma sample that marks the start of surveillance must be collected 8±1 weeks after completion of adjuvant therapy (if administered) or 12±1 weeks after surgery (where adjuvant therapy is not given).
• − A patient who is determined to be MRD- based on analysis of this plasma sample (ie, MRD- at the start of surveillance) may continue in surveillance provided all other eligibility criteria are met.
• − A patient who is determined to be MRD+ based on analysis of this plasma sample (ie, MRD+ at the start of surveillance) may be eligible for immediate randomization provided all other eligibility criteria are met.
• A patient who becomes MRD+ during surveillance is eligible to enter the second screening period and may be randomized in the study if all other eligibility criteria are met.
• Criteria for second screening prior to randomization to treatment:
• 14. CT scan of the chest and abdomen (including liver and adrenal glands) and brain MRI [preferred] or brain CT with IV contrast performed within the 28 days ± 7 days prior to randomization to confirm no evidence of RECIST 1.1-defined disease recurrence
• and/or metastasis.
• 15. Known tumor PD-L1 status determined at a central reference laboratory testing service using a validated Ventana SP263 PD-L1 immunohistochemistry (IHC) assay prior randomization. Patients with unknown PD-L1 status are not eligible for the study.
• 16. WHO/Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1.
• 17. Complete post-operative wound healing must have occurred prior to randomization; patients must have recovered from all acute, reversible toxic effects from prior treatments (excluding alopecia) that could potentially adversely impact further administration of durvalumab/placebo according to the Investigator’s judgment.
• 18. Must have recovered from all acute, reversible toxic effects from chemotherapy that could potentially adversely impact further administration of durvalumab or placebo according to the Investigator’s judgment
• 19. Adequate organ and marrow function as described in the protocol.
• 20. Must have a life expectancy of at least 12 weeks
• Weight
• 21. Body weight >30 kg
• Inclusion criteria assessed prior to entering the observation period
• 22. No evidence of RECIST 1.1-defined disease recurrence or metastasis confirmed by CT scan of the chest and abdomen (including liver and adrenal glands) and a brain MRI (preferred) or brain CT with IV contrast.
• 23. MRD- status, as determined by testing the last plasma sample collected during the 96-week surveillance period.