Study BO42777 is a Phase I-III, global, multicenter, multicohort study to evaluate the efficacy and safety of multiple therapies in patients with locally advanced, unresectable, Stage III NSCLC with eligible biomarker status. This population is based on the Version 8 of the American Joint Committee on Cancer/Union for International Cancer Control (AJCC/UICC) NSCLC staging system Patients with tumors harboring a cohort-eligible biomarker identified through one of the methods specified as follows will be screened for enrollment in the applicable cohort of this study

Cohort A1: The ALK-positive cohort will be evaluated using an open-label, two-arm, randomized study design in patients with ALK-positive (defined as an ALK rearrangement) locally advanced, unresectable, Stage III NSCLC, who have received prior SOC cCRT or sCRT, and have not had radiographic disease progression. Eligible patients will be randomized in a 1:1 ratio to receive either alectinib 600 mg orally (PO) BID with food in repeated 28-day cycles or 1500 mg durvalumab Q4W (administered by IV infusion on Day 1 of each 28-day cycle).

Cohort A2 en A3 dicht voor inclusie

Patients must meet the following criteria for entry in Cohort A1:

• Signed cohort-specific Informed Consent Form

• Age ≥ 18 years at time of signing cohort-specific Informed Consent Form

• Body weight ≥ 30 kg at screening

• Ability to comply with the study protocol

• Willingness and ability to use the electronic device(s) or application(s) for the electronic patient-reported outcome (PRO)

• Whole-body positron emission tomography/computed tomography scan (PET-CT) (from the base of skull to mid-thighs) for the purposes of staging, performed prior and within 42 days of the first dose of cCRT or sCRT

• Histologically or cytologically documented locally advanced, unresectable Stage III NSCLC of either squamous or non-squamous histology

• Staging should be based on Version 8 of the American Joint Committee on Cancer/Union for International Cancer Control NSCLC staging system (Amin et al. 2017).

• Patients with tumors of mixed NSCLC histology must be classified as having tumors that are of non-squamous or squamous histology on the basis of the major histologic component.

• Patients with T4 primary NSCLC with a separate nodule in a different ipsilateral lobe are not eligible.

• Patients with tumors of mixed histology containing both NSCLC and small-cell lung cancer are not eligible for enrollment in the study.

• Prior receipt of at least two prior cycles of platinum-based chemotherapy given concurrently with radiotherapy (cCRT); or at least two prior cycles of platinum-based chemotherapy given prior to radiotherapy (sCRT).

• One cycle is defined as 21 or 28 days

• cCRT or sCRT must be completed within 1 to 42 days prior to randomization in the study.

• cCRT is the preferred treatment of choice where clinically indicated and must be given in accordance with the National Comprehensive Cancer Network (2021) and/or the European Society of Medical Oncology guidelines (Postmus et al. 2017). If cCRT is not possible in the opinion of the investigator (e.g., comorbidities), sCRT is allowed.

• To ensure the best patient outcomes, sites are strongly encouraged to complete screening procedures within the first 14 days after the completion of cCRT or sCRT.

• The platinum-based chemotherapy regimen must contain one of the following agents: etoposide, a taxane (paclitaxel or docetaxel), pemetrexed, or vinorelbine.

• The final cycle of IV chemotherapy administration must end prior to or concurrently with the final dose of radiotherapy (RT) in the case of cCRT or prior to RT in the case of sCRT.

• Consolidation chemotherapy is not permitted, but administration of chemotherapy prior to concurrent CRT is acceptable (but not to exceed more than two cycles), in the case of cCRT.

• The RT component in the cCRT or sCRT must have been at a total dose of radiation of 60 (± 10%) Gy (54 Gy to 66 Gy) administered by intensity-modulated radiotherapy (preferred) or three dimension (3D)-conforming technique.

• Sites are encouraged to adhere to mean organ radiation dosing as follows:
  • The mean dose of radiation in the lung must be < 20 Gy and/or V20must be < 35%.
  • The mean dose of radiation in the esophagus must be < 34 Gy.
  • The mean dose of radiation in the heart must be V45 < 35% or V30< 30%.

• No disease progression during or following platinum-based cCRT or sCRT

• Life expectancy ≥ 12 weeks

• Confirmed availability of a representative formalin-fixed, paraffin-embedded(FFPE) tumor specimen (see details in Section 4.5.8.2)

• Tumor PD-L1 status (SP263 TC score or 22C3 tumor proportion score (TPS) < 1%vs. ≥ 1% vs. unknown) as determined:
  • At the Sponsor-designated central laboratory for the region using theVENTANA PD-L1 IHC SP263 assay,or
  • From previously obtained results from a local health authority approvedassay, either the VENTANA PD-L1 IHC SP263 assay (preferred) or the Dako PD-L1 IHC 22C3 pharmDx assay, if SP263 is not available

• Documented ALK fusion positivity by an eligible result from:

• Centralized multiplex molecular testing of tumor tissue at the Sponsor's designated central laboratory under Study BX43361

or
– Previously obtained local test results as ordered by a healthcare provider from a high-quality and appropriately validated ALK fusion test on tumor tissue performed in a Clinical Laboratory Improvement Amendments-certified or equivalent laboratory. Acceptable local test methods include the following:
– Next-generation sequencing; immunohistochemistry; fluorescence in situ hybridization; reverse transcription-polymerase chain reaction; NanoString.
– In the United States, an FDA-approved companion diagnostic (CDx) for ALK fusions is acceptable. In the European Economic Area, confirmation of Conformité Européenne mark will be required. In Mainland China, only National Medical Products Administration (NMPA)-approved tests for ALK fusions are acceptable.
– Identification of a specific gene fusion partner is required (exceptions: ALK immunohistochemistry and certain PCR tests for which the gene fusion partner is not pre-specified as part of the test design). The use of positional 5/3 imbalance probe gene expression is not acceptable.

• For patients enrolling based on results from a previous local test, the de-identified, full local test laboratory report documenting the study eligible biomarker must be submitted by the time of enrollment.
• Eastern Cooperative Oncology Group Performance Status of 0, 1, or 2
• Adequate hematologic and end-organ function, defined by the following laboratory test results, obtained within 14 days prior to initiation of study drug (i.e., Day 1 of Cycle 1):
  – ANC ≥ 1.5 * 10⁹/L (≥ 1500/µL) for patients of non-African descent or ≥ 1.3 * 10⁹/L (1300/µL) for patients of African descent, without granulocyte colony-stimulating factor support
  – Platelet count ≥ 100 * 10⁹/L (≥ 100,000/µL), without the need for transfusion
  – Hemoglobin ≥ 90 g/L (≥ 9.0 g/dL)

Patients may be transfused or receive erythropoietic treatment as per local SOC to meet this criterion.
– AST, ALT, and ALP ≤ 2.5 * upper limit of normal (ULN)
– Bilirubin ≤ 1.5 * ULN with the following exception:

Patients with known Gilbert disease: bilirubin level ≤ 3 * ULN

– Creatinine clearance (CrCl) ≥ 50 mL/min, calculated using the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of CrCl:

For males: CrCl (mL/min) = Weight (kg) * (140 - Age)
72 * serum creatinine (mg/dL)

Patients who meet any of following criteria will be excluded from entry in Cohort A1:

• Any history of previous NSCLC and/or any history of prior treatment for NSCLC (patients must be newly diagnosed with unresectable Stage III disease)

• Any evidence of Stage IV disease, including, but not limited to, the following:

• Pleural effusion

• Pericardial effusion

• Brain metastases

• History of intracranial hemorrhage or spinal cord hemorrhage

• Bone metastases

• Distant metastases

• malignant involvement (T4 disease):

• When pleural fluid is visible on both the CT scan and chest X-ray, a pleuracentesis is required to confirm that the pleural fluid is cytologically negative.

• Patients with exudative pleural effusions are excluded regardless of cytology.

• Patients with effusions that are minimal (i.e., not visible on chest X-ray) that are too small to safely tap are eligible.

• NSCLC known to have one or more of the following ALK point mutations, as identified by site local testing or Sponsor central testing: I1171X (where X is any other amino acid), V1180L, G1202R

• NSCLC known to have a known or likely oncogenic-driver mutation in the EGFR gene, as identified by site local testing or Sponsor central testing

• Impaired excretory function (e.g., hyperbilirubinemia), synthetic function, or other conditions of decompensated liver disease, such as coagulopathy, hepatic encephalopathy, hypoalbuminemia, ascites, and bleeding from esophageal varices
  or

• Active viral or active autoimmune, alcoholic, or other types of acute hepatitis

• Positive hepatitis B surface antigen (HBsAg) test at screening

• Participants with a previous hepatitis B virus (HBV) infection or resolved HBV infection (hepatitis B core antibody [HBcAb] positive, but negative HBsAg are eligible only if the HBV DNA test is negative.

• Patients known to be positive for hepatitis C virus (HCV) antibody (Ab) are excluded with the following exception:

• Patients who are HCV Ab positive but HCV RNA negative due to prior treatment or natural resolution are eligible.

• HIV infection, patients are excluded if they meet any of the following:

• CD4 + T-cell (CD4 +) counts ≤ 350 cells/µL

• On established antiretroviral therapy <4 weeks

• Have a detectable HIV viral load at screening

• Known active tuberculosis
  Cohort A1: Alectinib Compared with Durvalumab in Patients with ALK-Positive NSCLC after Concurrent or Sequential Chemoradiotherapy
  Alectinib, Entrectinib, and Pralsetinib—F. Hoffmann-La Roche Ltd 160/Protocol BO42777, Version 3

• Presence of clinically symptomatic interstitial lung disease or interstitial pneumonitis, including radiation pneumonitis (i.e., affecting activities of daily living or requiring therapeutic intervention)

• Grade ≥ 2 pneumonitis from prior cCRT or sCRT

• Symptomatic bradycardia

• Significant cardiovascular disease (such as New York Heart Association Class II or greater cardiac disease, myocardial infarction, or cerebrovascular accident) within 3 months prior to initiation of study treatment, unstable arrhythmia, or unstable angina

• Patients with known coronary artery disease, congestive heart failure not meeting the above criteria, or left ventricular ejection fraction < 50% must be on a stable medical regimen that is optimized in the opinion of the treating physician, in - Any gastrointestinal (GI) disorder that may affect absorption of oral medications, such as malabsorption syndrome or status post-major bowel resection

• Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug, may affect the interpretation of the results, or may render the patient at high risk from treatment complications

• Active or history of autoimmune disease or immune deficiency, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, or multiple sclerosis, with the following exceptions:

• Patients with a history of autoimmune-related hypothyroidism who are on thyroid-replacement hormone are eligible for the study.

• Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen are eligible for the study.

• Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for the study provided all of following conditions are met:

• Rash must cover < 10% of body surface area

• Disease is well controlled at baseline and requires only low-potency topical corticosteroids (equivalent of 10 mg/day prednisone orally)

• No occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high-potency or oral corticosteroids within the previous 12 months
  Cohort A1: Alectinib Compared with Durvalumab in Patients with ALK-Positive NSCLC after Concurrent or Sequential Chemoradiotherapy
  Alectinib, Entrectinib, and Pralsetinib—F. Hoffmann-La Roche Ltd 161/Protocol BO42777, Version 3

• Requirement for corticosteroid administration ≤ 10 mg/day oral prednisone or equivalent

• History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on the screening chest CT scan

• History of malignancy other than NSCLC within 5 years prior to screening, with the exception of malignancies with a negligible risk of metastasis or death (e.g., 5-year OS rate > 90%), such as adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized prostate cancer, ductal breast carcinoma in situ, or Stage I uterine cancer

• Any concurrent chemotherapy, immunotherapy, biologic, or hormonal therapy for cancer

• Note: Local treatment of isolated lesions, excluding target lesions, with palliative intent is acceptable (e.g., by local surgery or radiotherapy).

• Major surgical procedure, within 4 weeks prior to initiation of study treatment, or anticipation of need for a major surgical procedure during the study

• Severe infection within 4 weeks prior to initiation of study treatment, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia

• Treatment with systemic immunostimulatory agents (including, but not limited to, interferon and interleukin-2) within 4 weeks or 5 drug-elimination half-lives (whichever is longer) prior to initiation of study treatment

• Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study treatment, or anticipation of need for such a vaccine during study treatment or within 5 months after the final dose of study treatment

• Treatment with investigational therapy within 28 days prior to initiation of study treatment

• Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment

• Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection or chronic obstructive pulmonary disease exacerbation) are eligible for enrollment in the study.

• Treatment with systemic immunosuppressive medication (including, but not limited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor-alpha agents) within 2 weeks prior to initiation of study treatment, or anticipation of need for systemic immunosuppressive medication during study treatment, with the following exceptions:

• Patients who receive acute, low-dose systemic immunosuppressant medication or a one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of corticosteroids for a contrast allergy) are eligible for the study.

• Patients who receive mineralocorticoids (e.g., fludrocortisone), corticosteroids for chronic obstructive pulmonary disease or asthma, or low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible for enrollment in the study.

• Prior treatment with ALK inhibitors

• Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including anti-cytotoxic T lymphocyte-associated protein 4, anti-TIGIT, anti-PD-1, and anti-PD-L1 therapeutic antibodies

• Prior allogeneic stem cell or solid organ transplantation

• History of hypersensitivity to alectinib, durvalumab, or any of their excipients

• Any prior Grade ≥ 3 immune-mediated adverse event or any unresolved Grade > 1 immune-mediated adverse event while receiving any previous immunotherapy agent other than immune checkpoint blockade agents

• Any Grade > 2 unresolved toxicity from prior cCRT or sCRT

• Patients with an irreversible toxicity that is managed and is not expected to be exacerbated by study drug treatment may be included (e.g., hearing loss) at the discretion of the investigator, after consultation with the Medical Monitor.

• Concurrent enrollment in another clinical study, unless it is an observational (non-interventional) clinical study or the follow-up period of an interventional study

• Any condition that, in the opinion of the investigator, would interfere with the evaluation of the study drug or interpretation of patient safety or study results

• Inability to swallow oral study drug

• Known hereditary problems of galactose intolerance, a congenital lactase deficiency, or glucose-galactose malabsorption

• Pregnancy or breastfeeding, or intending to become pregnant during the study treatment or within 90 days after the final dose of alectinib or durvalumab

• Women of childbearing potential must have a negative serum pregnancy test result within 3 days prior to initiation of study drug