Phase III Study to Determine the Efficacy of Durvalumab in Combination With Chemotherapy in Completely Resected Stage II-III Non-small Cell Lung Cancer (NSCLC)

This is a Phase III, randomized, parallel-arm, placebo controlled, double blind, multicenter study assessing the efficacy and safety of durvalumab versus placebo following SoC chemotherapy in patients with completely resected stage II-III NSCLC who are MRD+ post surgery

Patients who have no evidence of disease recurrence confirmed by CT and/or MRI and are confirmed to meet all eligibility criteria will be randomized 1:1 to durvalumab + Standard of care (SoC) chemotherapy or placebo + Standard of care (SoC) chemotherapy arm.

The primary objective of this study is to assess the efficacy of durvalumab +SoC chemotherapy compared to placebo+ SoC chemotherapy as measured by DFS in all patients.

Eligibility Criteria:
Inclusion criteria:

Patients must be capable of giving signed informed consent, which includes a mandatory genetic informed consent and compliance with the requirements and restrictions listed in the informed consent forms (ICFs) and in this protocol. Provision of signed and dated, written ICFs must occur prior to any mandatory study-specific procedures, sampling, and analyses.

In addition to ICF1 and ICF2, patients will provide signed and dated written optional genetic informed consent prior to collection of a sample for optional genetic analysis at the time of second screening (Table 2). This is different from the genetic samples and testing covered by ICF1, which are mandatory for participation in this study.

Criteria and procedures initiated with the signing of ICF1

1. ICF1 must be signed and dated prior to any study procedures and prior to the planned surgical resection of the primary NSCLC, with the exceptions noted below. This consent will cover the study-specific first screening procedures outlined in Table 1.

   Exception: Patients will be permitted to sign ICF1 up to Week 3 (Day 21) postsurgery. Patients identified after Week 3 post-surgery but prior to Week 5 (Day 35) post-surgery may be allowed to sign ICF1 depending on the outcome of the discussion with the study physician. In these cases, a whole blood sample and resected tumor tissue must be collected and sent to the diagnostic lab as soon as possible after ICF1 is signed for development of the personalized panel. A plasma sample must still be collected at Week 3-5 (Day 21-35) post-surgery, even if creation of the personalized panel for MRD detection is delayed.

   Age
2. Age ≥18 years at the time of screening. Sex
3. Male and/or female. Type of patient and disease characteristics
4. Individuals who have diagnosis of histologically confirmed NSCLC (WHO 2015 classification) with resectable (stage II-III) disease (according to IASLC Staging Manual in Thoracic Oncology v8.0). Select (ie, T3N2 or T4N2) stage IIIB patients will be eligible, provided that they are upstaged to T3N2 or T4N2 based on confirmed pathology. Patients who are staged asT3N2 or T4N2 prior to surgery are not eligible.
5. A contrast-enhanced CT or MRI scan of the chest 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 (contrastenhanced or low-dose CT component) in order to rule out detectable extrathoracic, extracranial metastasis and to assess for potential mediastinal lymph node involvement prior to surgery. In the absence of pre-operative FDG-PET CT imaging, pre-operative contrast-enhanced CT imaging or MRI scan must cover liver and adrenal glands. If only CT is available, or FDG-PET reveals suspicious lymph node mediastinal involvement, it is recommended that invasive pre-operative mediastinal staging is performed according to the algorithm of the European Society of Thoracic Surgeons guidelines (algorithm to follow for primary mediastinal staging if only pre-operative CT is available \[De Leyn et al 2007\], algorithm to follow for primary mediastinal staging when PET-CT is available \[De Leyn et al 2014\]). It is preferred that imaging occurs within 6 weeks prior to surgery. Brain MRI (preferred) or brain CT with IV contrast is required for complete staging of the tumor.
6. Complete resection of the primary NSCLC is mandatory. The primary tumor must be deemed resectable by a multidisciplinary evaluation that must include a thoracic surgeon certified or trained according to local standards and who performs lung cancer surgery as a significant part of their practice. 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. Note: Patients undergoing segmentectomy must have tumors less than 2 cm in maximum diameter. Where a resection has been extended by means of a wedge resection of an adjacent lobe to ensure complete resection of a tumor at or crossing a fissure between lobes, this is acceptable if surgical margins are clear of disease. Where the resection of a second tumor nodule (eg, a T4 lesion) is undertaken by means of a wedge resection of a separate lobe, then the patient is not eligible.

   At a minimum, the following parameters should be met for a tumor to be declared completely resected:
   1. The surgeon performing the resection should remove all gross disease by the end of surgery. All surgical margins of resection must be macroscopically negative for tumor.
   2. Pathology and/or operative reports must include the examination of at least 2 different mediastinal lymph node (N2) levels, one of which is the subcarinal node-group (level 7) and the second of which is lobe-specific (defined below).

      Note: In the uncommon clinical situation where the surgeon thoroughly examines a mediastinal lymph node level and does not find any lymph nodes, that mediastinal lymph node level may be counted among the minimum 2 required levels. However, the surgeon must clearly document in the operative report or in a separate written statement that the lymph node level was explored and no lymph nodes were present. Normal appearing lymph nodes, if present, must be biopsied or removed. Exploration of nodes must clearly be documented in medical file if not recorded in operative report.

      Note: Lobe-specific lymph node stations are classified based on the location of the primary tumor as follows (based on IASLC 2009 lymph node map terminology \[Rusch et al 2009\]): Stations 2R and 4R for right upper lobe or middle lobe tumors, stations 4L, 5, and 6 for left upper lobe tumors, stations 8 and 9 for lower lobe tumors of both sides (Adachi et al 2017, Rami-Porta et al 2005).
   3. No extracapsular nodal extension of the tumor is observed in resected mediastinal N2 lymph nodes.

   Note: Extracapsular nodal extension in resected N1 nodes is permitted. Note: The highest mediastinal node resected can be positive for malignancy. Note: Carcinoma-in-situ can be present at the bronchial margin.
7. All patients who enrol in the study prior to surgery must have a pre-surgical plasma sample collected for MRD evaluation. Patients will not be excluded from randomization based on the results of analysing the pre-surgical plasma samples.

   The following criteria must be met prior to signing ICF2:
8. Confirmation of suitable samples of resected tumor tissue and whole blood for WES of tumor and germline DNA, respectively, and creation of Sponsor-approved personalized panel for MRD detection. Tumor tissue and whole blood samples must be provided to the diagnostic laboratory for development of the personalized panel as soon as possible.

   Germline sequencing of whole blood is mandatory. Note: If a patient's tumor has less than the requisite 50 tumor-specific variants, a panel cannot be built and the patient will no longer be able to participate in the study.
9. Established MRD status (MRD+ or MRD-) based on Sponsor-approved personalized assay of a plasma sample collected at Week 3-5 (Day 21-35) post-surgery.
10. 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.

    Criteria and procedures initiated with the signing of ICF2
11. Post-operative CT scan of the chest (including liver and adrenal glands) performed within 28 days + 7 days prior to randomization. If clinically indicated, additional scans (such as brain MRI \[preferred\] or brain CT with IV contrast) should be performed to confirm no evidence of metastasis.
12. ICF2 must be signed and dated after MRD status is determined and prior to initiation of any study-specific procedures, sampling, and analyses outlined in SoAs in Table 2 and Table 3. Randomization must occur within the 12 weeks (+ 7 days) following surgery.
13. WHO/Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
14. Complete postoperative 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 or chemotherapy according to the Investigator's judgment.
15. Eligible to tolerate 4 cycles of platinum-based adjuvant chemotherapy
16. Adequate organ and marrow function as described in the protocol. 17 Must have a life expectancy of at least 12 weeks Weight 18 Body weight \>30 kg

Exclusion criteria:

Diagnostic assessments

1. Post-operative imaging demonstrating unequivocal evidence of disease recurrence or tissue biopsy-proven disease recurrence. In the event of lymphadenopathy on imaging that would lead to exclusion, histopathological confirmation of lymph node metastasis should be obtained prior to excluding a patient from the study. If pathological confirmation of lymph-node metastasis is not technically feasible and imaging appearance are deemed unequivocal for relapse, the patient will be excluded.
2. EGFR-mutant and/or ALK-translocation-positive, as assessed either from a pre-surgical biopsy sample (preferred) or the resected tumor tissue (if biopsy was not evaluable or available). Any of the following scenarios are acceptable for this study:

   Where EGFR/ALK results are obtained from a pre-surgical tissue biopsy as part of standard local practice, the patient must be confirmed EGFR/ALK wild-type prior to enrolling in the study.

   Results obtained from testing the patient's primary tumor tissue during screening for another AstraZeneca study may be used in this study.

   Results from local testing of a pre-surgical biopsy. All local EGFR/ALK testing performed locally must be performed using a well-validated, local regulatory-approved test. EGFR/ALK may be tested centrally if local testing is unavailable. Patients will still be allowed to continue with first screening procedures while testing is ongoing but will not be able to continue into second screening if their tumor tests positive for EGFR mutations and/or ALK translocations.
3. Mixed small cell and NSCLC histology.
4. Require re-resection or are deemed to have unresectable NSCLC by a multidisciplinary evaluation that must include a thoracic surgeon who performs lung cancer surgery as a significant part of their practice.
5. Patients who are candidates to undergo only wedge resections. Medical conditions
6. History of allogeneic organ or bone marrow transplantation.
7. Non-leukocyte-depleted whole blood transfusion within 120 days of genetic sample collection. Note: This exclusion criterion only relates to whole blood and does not include other blood products (eg, packed red blood cells).
8. Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease \[eg, colitis or Crohn's disease\], diverticulitis \[with the exception of diverticulosis\], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome \[granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc\]). The following are exceptions to this criterion:

   * Patients with vitiligo or alopecia
   * Patients with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement
   * Any chronic skin condition that does not require systemic therapy
   * Patients without active disease in the last 5 years may be included but only after consultation with the Study Physician
   * Patients with celiac disease controlled by diet alone
9. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, uncontrolled cardiac arrhythmia, active ILD, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirements, substantially increase risk of incurring AEs, or compromise the ability of the patient to give written informed consent.
10. History of another primary malignancy, except for

    * Malignancy treated with curative intent and with no known active disease ≥5 years before the first dose of IP and of low potential risk for recurrence
    * Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
    * Adequately treated carcinoma-in-situ without evidence of disease
11. History of active primary immunodeficiency
12. Active infection, including tuberculosis (clinical evaluation that includes clinical history, physical examination, and radiographic findings, and tuberculosis testing in line with local practice), hepatitis B (HBV; known positive HBV surface antigen \[HBsAg\] result), hepatitis C (HCV), or human immunodeficiency virus infection (positive HIV 1/2 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 positive for HCV antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
13. Known allergy or hypersensitivity to any of the IPs or any of the IP excipients.
14. Any medical contraindication to treatment with platinum-based doublet chemotherapy as listed in the local labeling.

    Prior/concomitant therapy
15. Received any prior adjuvant therapy for NSCLC or any prior exposure to durvalumab.
16. Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (eg, hormone replacement therapy) is acceptable.
17. Radiotherapy treatment for NSCLC in the neoadjuvant setting. Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within 4 weeks of the first dose of IP.
18. Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note: Patients, if enrolled, should not receive live vaccine while receiving IP and up to 30 days after the last dose of IP.
19. Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of IP.
20. Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab/placebo. The following are exceptions to this criterion:

    * Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra-articular injection)
    * Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent
    * Steroids as premedication for hypersensitivity reactions (eg, CT scan premedication) Prior/concurrent clinical study experience
21. Participation in another clinical study with an IP administered since completion of surgery.
22. Previous IP assignment in the present study.
23. Concurrent enrollment in another clinical study, unless it is an observational (noninterventional) clinical study, or during the follow-up period of an interventional study.
24. Prior randomization or treatment in a previous durvalumab clinical study regardless of treatment group assignment.

    Other exclusions
25. Patients who are never-smokers; defined as no more than 100 cigarettes or its equivalent in his/her lifetime.
26. Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ effective birth control from screening to 90 days after the last dose of durvalumab/placebo.
27. Judgment by the Investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions, and requirements.