BMS-986489 (Atigotatug + Nivolumab) vs Durvalumab in Limited-stage Small-cell Lung Cancer (TIGOS-LS)

This is an open-label, randomized study of BMS-986489 (atigotatug + nivolumab fixed-dose combination) vs durvalumab as consolidation therapy following chemoradiotherapy in participants with limited-stage (LS)-small-cell lung cancer (SCLC). Participants will receive concurrent chemotherapy and radiotherapy according to standard guidelines for treatment of LS-SCLC without progressive disease prior to randomization. Eligible participants will be randomly assigned to receive either BMS-986489 (atigotatug + nivolumab as a fixed-dose combination; Arm A) or durvalumab (Arm B) as consolidation therapy. Atigotatug is a first-in-class, fully human IgG1 antibody being developed for the treatment of SCLC. Atigotatug specifically binds to fuc-GM1 on the tumor cell. Nivolumab is a monoclonal anti-PD-1 antibody. Combining atigotatug with another immunotherapy may provide enhanced antitumor effects.

Inclusion criteria

• At least 18 years-of-age at the time of signature of the Informed Consent Form (ICF)
• Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1 (Appendix A)
• Histologically or cytologically confirmed pulmonary SCLC, evaluable by RECIST v1.1
• Limited-stage (LS) disease as determined by positron emission tomography (PET) scan prior to initiation of chemotherapy and radiation therapy
• Completed concurrent chemotherapy and radiotherapy for LS-SCLC without progression per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 (computed tomography [CT] scan chest/abdomen/pelvis; Appendix B) within 42 days before date of randomization and first dose of study treatment

• Chemotherapy should consist of a platinum and IV etoposide. Participants who received at least 3 cycles of chemotherapy will be eligible to participate.
• Radiotherapy should be administered per institutional guidelines
• Prophylactic cranial irradiation (PCI) may be delivered at the discretion of the Investigator and institutional guidelines. PCI, if applicable, must be conducted after the end of chemoradiotherapy and completed between 14 and 42 days before date of randomization and first dose of study treatment.
• Adequate hematologic and organ function
• Willingness to abide by protocol defined contraceptive requirements for the duration of the study.

Exclusion criteria

• Small-cell cancer not pulmonary in origin
• Large cell neuroendocrine carcinoma
• ES-SCLC
• Mixed SCLC and NSCLC histologic features; diagnosis of NSCLC; or EGFR-activating, mutation-positive NSCLC that has transformed to SCLC
• History of severe hypersensitivity reaction to monoclonal antibodies
• Known hypersensitivity to any excipients of atigotatug, nivolumab, or durvalumab
• Grade ≥2 peripheral neuropathy by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.0
• Active, prior, or suspected autoimmune disease, including autoimmune neurologic disorders such as paraneoplastic syndrome involving the CNS, peripheral sensory/motor nerves, or neuromuscular junction. Exceptions to this criterion include:

• Type 1 diabetes mellitus
• Hypothyroidism requiring only hormone replacement
• Skin disorders not requiring systemic treatment
• Autoimmune conditions not expected to recur during the study
• Diseases or conditions requiring chronic systemic corticosteroids (>10 mg daily prednisone or equivalent) or other immunosuppressive therapy within 14 days of starting study treatment. Limited-course (<2 weeks' duration) oral steroids (10 mg prednisone or equivalent) are permitted. Bronchodilators, inhaled or topical steroids, and adrenal replacement steroid doses >10 mg daily prednisone equivalent are permitted in the absence of active autoimmune disease.
• History of solid organ or bone marrow transplantation
• History of Grade ≥2 pneumonitis (excepting resolved infective pneumonitis)
• Any of the following cardiac criteria, currently or within the last 3 months:

• Any clinically important abnormalities (as assessed by the Investigator) in rhythm, conduction, or morphology of resting electrocardiograms (ECGs), e.g., complete left bundle branch block, third-degree heart block, atrial fibrillation not rate controlled. Certain conditions may be considered through discussion with the Medical Monitor.
• Congestive heart failure (New York Heart Association [NYHA] > Grade 2) or classified as Class 3 or 4 by the NYHA Functional Classification (Appendix D)
• Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, uncontrolled hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years-of-age, or any concomitant medication known to prolong the QT interval (Appendix E). Certain conditions may be considered through discussion with the Medical Monitor.
• Participants with a left ventricular ejection fraction <55% or the lower limit of normal of the institutional standard
• Uncontrolled hypertension, defined as systolic blood pressure >150 mmHg or diastolic blood pressure >90 mmHg despite optimal medical management
• Active coronary artery disease, including unstable or newly diagnosed angina
• Myocardial infarction
• History of clinically significant arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or Torsade de Pointes)
• History or current diagnosis of myocarditis
• As judged by the Investigator, participants with serious or uncontrolled medical disorders
• Presence of other active invasive cancers. Participants with a previously treated malignancy will be eligible to participate if treatment of that malignancy was completed at least 2 years before date of screening and the participants has no evidence of disease. Exceptions to this criterion include appropriately treated basal cell carcinoma of the skin; in situ carcinoma of uterine cervix; localized prostate cancer that has been definitively treated; or other local tumors considered cured by local treatment.
• Received sequential chemotherapy and radiotherapy as a definitive treatment for LS-SCLC
• Treatment with any of the following:

• Any systemic anticancer chemotherapy, small molecule, biologic, or hormonal agent from a previous treatment regimen or clinical study within 21 days or 5 half-lives (whichever is longer) prior to the first dose of study treatment
• Wide-field radiotherapy (including therapeutic radioisotopes such as strontium-89) administered ≤28 days or limited field radiation for palliation ≤7 days prior to starting study treatment or has not recovered from side effects of such therapy
• Prior systemic treatment for LS-SCLC, with the exception of chemoradiotherapy and PCI
• Prior treatment with an anti-PD-1, anti-PD-L1, anti-programmed cell death ligand 2 (anti-PD-L2), anti-CD137, anti-cytotoxic T-lymphocyte associated protein 4 (anti-CTLA-4) antibody, or any other antibody or drug specifically targeting T-cell costimulation or checkpoint pathways
• Prior treatment with fuc-GM-1 vaccine or targeted agent or similar vaccine targeting ganglioside antigens
• Current treatment with immunosuppressive medications
• Live attenuated vaccine within 100 days before first dose of study treatment
• Major surgery (excluding placement of vascular access) within 4 weeks of date of screening
• With the exception of alopecia, any unresolved toxicities from prior therapy greater than CTCAE Grade 1 at the time of starting study treatment. Note: Participants with chronic Grade 2 toxicities who are asymptomatic or adequately managed with stable medication may be eligible with approval by the Medical Monitor or Principal Investigator.
• Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol and/or follow-up procedures outlined in the protocol