A Phase 3 study of belrestotug plus dostarlimab compared with placebo plus pembrolizumab in previously untreated PD L1 high NSCLC

Prior treatment

• Has known brain metastases meeting any of the following criteria: a. Symptomatic b. Untreated (NOTE: asymptomatic brain metastases are exclusionary if untreated) c. Actively progressing d. Any leptomeningeal disease (regardless of symptomatology, treatment status, or stability) NOTE: Participants with non leptomeningeal brain metastases who have received prior therapy for brain metastases and have radiographically stable CNS disease for at least 4 weeks (confirmed by 2 brain scans taken at least 4 weeks apart, with at least 1 scan collected after treatment of brain metastases) may participate, provided they are neurologically stable for at least 2 weeks following treatment for brain metastases (i.e., any neurologic symptoms that developed either as a result of the brain metastases or their treatment must have returned to baseline or resolved) and prior to the first dose of study intervention. Corticosteroids must be discontinued at least 3 days prior to the first dose of study intervention.
  • Has autoimmune disease or syndrome (current or history thereof) that required systemic treatment within the past 2 years. Replacement therapies (e.g., insulin, thyroxine, or physiologic doses of corticosteroids for treatment of adrenal or pituitary insufficiency) are not considered systemic treatments and are allowed. NOTE: Participants with controlled T1DM are eligible if the participant otherwise meets entry criteria.
  • Has received systemic steroid therapy within 3 days prior to the first dose of study intervention or is receiving any other form of immunosuppressive medication. Replacement therapy is not considered a form of systemic therapy. Note the following: a. Corticosteroid use is allowed as premedication for hypersensitivity reactions (e.g., IV contrast allergies/reactions). b. Use of topical, inhaled, or intranasal corticosteroids, local steroid injection, or steroid eye drops is allowed. c. Participants who receive daily steroid replacement therapy are an exception to this criterion. Daily prednisone at doses of ≤10 mg is an example of replacement therapy and are permitted in this study. Equivalent hydrocortisone doses are also permitted if administered as a replacement therapy.
• Has received any live vaccine within 30 days prior to first dose of study intervention. NOTE: mRNA and adenoviral-based COVID-19 vaccines are considered non-live. Study participants can be vaccinated against COVID-19 using vaccines authorized via the appropriate regulatory mechanisms (e.g., Emergency Use Authorization, Conditional Marketing Authorization, or Marketing Authorization Application). Refer to Protocol Section 6.9 and Appendix 5 (Section 10.5.1.4) for further information regarding COVID 19 vaccination recommendations and data to be collected in the eCRF.

Lab values

• Has NSCLC with a tumor that harbors any of the following molecular alterations: a. EGFR mutations that are sensitive to available targeted inhibitor therapy (including, but not limited to, deletions in exon 19, exon 20 insertion mutation, and exon 21 [L858R] substitution mutation). All participants with nonsquamous histology must have been tested for EGFR mutation status using a tissue-based test; use of an approved test is strongly encouraged. Participants with squamous histology do not need to be tested for EGFR mutation status. Participants with nonsquamous histology and unknown or indeterminate EGFR status are excluded. b. ALK translocations that are sensitive to available targeted inhibitor therapy. All participants with nonsquamous histology must have been tested for ALK fusion mutation status using a tissue-based test; use of an approved test is strongly encouraged. Participants with squamous histology do not need to be tested for ALK fusion mutation status. Participants with nonsquamous histology and unknown or indeterminate ALK status are excluded. c. Any other known genomic aberrations or oncogenic driver mutations for which an approved targeted therapy is available for first line treatment of locally advanced or metastatic NSCLC.
  • Has any history of idiopathic pulmonary fibrosis, organizing pneumonia, drug induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis.
  • Has advanced, symptomatic, or visceral spread and is considered to be at imminent risk of life-threatening complications (including, but not limited to, participants with massive uncontrolled effusions [e.g., pleural, pericardial, peritoneal]).
  • Has symptomatic ascites, pleural effusion, or pericardial effusion. A participant who is clinically stable following treatment of these conditions (including therapeutic thoracocentesis, paracentesis, or pericardiocentesis) is eligible if the participant otherwise meets entry criteria.
  • Has active inflammatory bowel disease, acute diverticulitis, intra-abdominal abscess, gastrointestinal obstruction, or peritoneal carcinomatosis.
  • Has a history or evidence of cardiac abnormalities within the 6 months prior to enrollment, including: a. Serious, uncontrolled cardiac arrhythmia or clinically significant ECG abnormalities including second degree (Type II) or third degree AV block. b. Cardiomyopathy, myocarditis, myocardial infarction, acute coronary syndromes (including angina pectoris), coronary angioplasty, stenting, or bypass grafting. c. Congestive heart failure (Class III or IV) as defined by the New York Heart Association functional classification system (Appendix 8) [NYHA, 1994]. d. Symptomatic pericarditis. NOTE: Participants with troponin and/or NT-proBNP/BNP values ≥2x ULN will require review by a cardiologist or locally appropriate specialist to identify underlying conditions that may meet exclusion criteria or that may require increased monitoring during study participation. In addition, cardiologist or locally appropriate specialist review should be considered for potentially significant ECG abnormalities such as AV block (except for first degree), new cardiac arrhythmias, or frequent PVCs. The sponsor is to be informed regarding these participants.
  • Has current unstable liver or biliary disease per investigator assessment defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, persistent jaundice, or cirrhosis. NOTE: Stable chronic liver disease (including Gilbert’s syndrome or asymptomatic gallstones) is acceptable if participant otherwise meets entry criteria.
  • Has any infectious diseases described below: a. A severe infection requiring IV antibiotics or requiring hospitalization for infection or complication of infection or severe pneumonia within 4 weeks prior to randomization. b. Active tuberculosis (i.e., history of exposure or history of positive tuberculosis test, plus presence of clinical symptoms or physical or radiographic findings). c. Has a known HIV infection AND meets at least 1 of the following criteria: i. Has documented evidence of plasma HIV-1 RNA ≥ 50 c/mL within 3 months prior to or at screening. In the 3 to 12 months prior to screening, plasma HIV-1 RNA levels consistently <50 c/mL are required for enrollment; if multiple instances of plasma HIV-1 RNA values ≥ 50 c/mL occurred in the 3 to 12 months prior to screening, the participant is not eligible for enrollment unless, per the investigator’s assessment, the elevations were neither persistent nor associated with antiretroviral resistance; OR ii. Has not had CD4 cell counts measured in the past 12 months (i.e., at least 2 separate measurements taken a minimum of 28 days apart, 1 of which must be conducted at screening); OR iii. Has had any CD4 cell count values ≤ 350 cells/mm3 in the past 12 months; OR iv. Has had 1 or more changes in their combination antiretroviral therapy regimen (except for switches as allowed per details provided in Protocol Appendix 9) or has received an antiretroviral therapy regimen that is inconsistent with locally recommended guidelines during the 3 months prior to screening; OR v. Has a history of HIV-associated non-Hodgkin lymphoma within 5 years prior to screening; OR vi. Has received treatment with an HIV 1 immunotherapeutic vaccine within 90 days of screening. NOTE: Participants with history of CDC Stage 3 disease (also known as AIDS defining disease [CDC, 2014]) are eligible (provided all other applicable criteria are met) if the AIDS-defining disease has been treated and cured or is stable for at least 3 months prior to screening. Cutaneous Karposi’s Sarcoma not requiring systemic therapy is not exclusionary.] d. Tests positive for HCV antibodies and HCV RNA. e. Untreated chronic hepatitis B or chronic HBV inactive carriers with HBV DNA >500 IU/mL (or >2500 copies/mL) at screening. NOTE: See Protocol Appendix 2 for additional information on management of participants with HBV, additional procedures, and dose modification guidelines in case of HBV reactivation.
  • Has a history of severe hypersensitivity to mAbs or to any of the excipients in the formulations of the components of the study interventions.
  • Has any serious and/or unstable pre-existing medical (aside from malignancy), psychiatric, or other condition that could, in the opinion of the investigator, interfere with the participant’s safety, obtaining informed consent, or compliance with the study procedures.
  • Is, at the time of signing the ICF, a regular user (including recreational use) of any illicit drugs or has a recent history (within the last year) of substance abuse (including alcohol) that, in the opinion of the investigator, would interfere with the evaluation of the study intervention or interpretation of safety.
  • Has had surgery within 4 weeks of the first dose of study intervention and has not recovered from AEs (i.e., has any ongoing surgery-related events equal or higher than Grade 1)/complications related to surgery or has received lung radiation therapy of >30 Gy within 6 months of the first dose of study intervention.
  • Is currently participating in or has participated in a study of an investigational therapy within 4 weeks prior to the first dose of study intervention.
  • Has a history of allogeneic tissue/stem cell transplant or solid organ transplant.
  • Has received prior therapy with any immune checkpoint inhibitors, including antibodies or drugs targeting PD-(L)1, CTLA-4, TIGIT, or other checkpoint pathways. NOTE: Participants may be enrolled if received neoadjuvant/adjuvant immunotherapy for resectable disease and at least 12 months has passed since last dose of prior immunotherapy to the diagnosis of locally advanced or metastatic disease and no permanent discontinuation of prior immunotherapy treatment due to toxicity.
  • Has never smoked, defined as smoking <100 tobacco cigarettes in a lifetime
  • Has an invasive malignancy or history of invasive malignancy other than the disease under study within the last 5 years, except as noted below: a. Participants may be enrolled in the study with a history of any other invasive malignancy for which the participant was definitively treated, from which the participant has been disease-free for at least 2 years, and which, in the opinion of the principal investigator and medical monitor, is not expected to affect the evaluation of the effects of the study intervention on the currently targeted malignancy. b. Participants with curatively treated basal cell carcinoma of the skin, superficial bladder cancer, squamous cell carcinoma of the skin, in situ cervical cancer, and/or in situ breast cancer may be enrolled in the study.

• Is capable of giving signed informed consent as described in Appendix 6 ( Protocol Section 10.6.3), which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.
• If of childbearing potential, female participants must be willing to use contraception. Contraceptive use by female participants should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. • A female participant is eligible to participate if she is not pregnant or breastfeeding, and 1 of the following conditions applies: o Is a WONCBP as defined in Protocol Appendix 1. Or o Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per year), as described in Appendix 1, during the Intervention Period and for at least 4 months after the last dose of study intervention. Female participant agrees not to donate eggs (ova, oocytes) for the purpose of reproduction during this timeframe. The investigator should evaluate the potential for contraceptive method failure (e.g., noncompliance, recently initiated) in relationship to the first dose of study intervention. o A WOCBP must not be pregnant; this will generally be confirmed via a negative highly sensitive serum pregnancy test within 7 days before the first dose of study intervention. In rare cases where it is suspected that hCG is elevated in the absence of pregnancy (e.g., due to a tumor producing hCG), an ultrasound must be performed to rule out pregnancy. • Additional requirements for pregnancy testing during and after study intervention administration are located in Section 8.3.8. • The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk of inclusion of a woman with an early undetected pregnancy.
• Is, at the time of signing the ICF, at least 18 years old or the legal age of consent in the jurisdiction in which the study is taking place.
• Has a histologically or cytologically confirmed diagnosis of 1 of the following: a. Locally advanced, unresectable NSCLC (not eligible for curative surgery and/or definitive radiotherapy with or without chemotherapy), or b. Metastatic NSCLC. NOTE: Squamous or nonsquamous histology is permitted. Mixed tumors will be categorized by the predominant cell type; if small cell or neuroendocrine elements are present, the participant is ineligible.
• Has not received prior systemic therapy for their locally advanced or metastatic NSCLC. NOTE: Completion of treatment with cytotoxic chemotherapy and/or radiation as part of neoadjuvant/adjuvant therapy is allowed if therapy was completed at least 6 months prior to the diagnosis of locally advanced or metastatic disease. Prior treatment with neoadjuvant/adjuvant immunotherapy for resectable disease is permitted if at least 12 months have passed since the last dose of immunotherapy prior to the diagnosis of locally advanced or metastatic disease and no permanent discontinuation of prior immunotherapy treatment due to toxicity.
• Provides a tumor tissue sample obtained at the time of or after the initial diagnosis of locally advanced or metastatic NSCLC. Although a fresh tumor tissue sample obtained during screening is preferred, an archival tumor specimen (collected within 2 years prior to screening*) is acceptable. Tumor tissue must be from a site not previously irradiated. Biopsies obtained prior to the administration of any systemic therapy administered for the treatment of a participant’s tumor (such as neoadjuvant/adjuvant therapy) are not acceptable. Needle or excisional biopsies or resected tissue is required. Cytological specimens such as fine needle aspirates, bone marrow samples, or cell blocks are not acceptable, nor are bone specimens. *NOTE: If multiple specimens are available, the most recent archival tumor specimen should be submitted.
• Has a PD-L1-high (TC ≥ 50%) tumor as determined by the PD-L1 CDx Assay at a central laboratory.
• Has measurable disease (at least 1 target lesion) based on RECIST 1.1, as determined by the investigator. Measurable lesions that have been previously irradiated and have been shown to be progressing following irradiation may be considered as target lesions. NOTE: It is preferable not to have a lymph node as a singular target lesion.
• Has an ECOG PS score of 0 or 1
• Has adequate organ function: System Laboratory Values Hematologic ANC ≥1.5x109/L Hemoglobin ≥9 g/dL Platelets ≥100x109/L Hepatic Total bilirubin ≤1.5x ULN For participants with Gilbert’s Syndrome (only if direct bilirubin ≤35%) ≤3.0x ULN ALT and AST ≤2.5x ULN For participants with liver metastases ≤5x ULN Renal eGFRa ≥30 mL/min Abbreviations: ALT = alanine aminotransferase; ANC = Absolute neutrophil count; AST = aspartate aminotransferase; eGFR = estimated glomerular filtration rate; ULN = upper limit of normal. eGFR to be calculated as individualized eGFR using the CKD-EPI + Mosteller formulas (Protocol Appendix 4).