A Study to Learn About the Study Medicine Called Ponsegromab in Adults With Lung Cancer-Associated Significant Weight Loss

The primary purpose of this Phase 1b, double-blind, sponsor-open, randomized, 2-arm study to investigate the effect of study medicine (ponsegromab) compared to placebo (an injection that looks like the study medicine but does not contain the active medicine) on skeletal muscle mass, blood and urine-based assessments and physical function in adults with locally advanced, unresectable, Stage III non-small cell lung cancer and cachexia, who have completed chemoradiotherapy and are starting on consolidation therapy with an immune checkpoint inhibitor (durvalumab). The study will also assess the safety, tolerability, PK, PD, and immunogenicity of ponsegromab.

Participants will not know which treatment group they are assigned. Participants in this study will equally receive either the study medicine (ponsegromab) or placebo by shots under the skin every four weeks. Participants will take part in this study for about 8 months. During this time participants will visit the study clinic once a month. Participants in this study may also be eligible to join an extra 1-year open-label extension period where everyone is administered ponsegromab.

Key Inclusion Criteria:

• Signed Informed Consent
• Documented histological or cytologic diagnosis of NSCLC with each of the following:

• locally advanced, unresectable, stage III disease (according to the 9th edition of the Union for International Cancer Control and American Joint Committee on Cancer lung cancer TNM staging system); and
• measurable disease at time of screening (assessment per RECIST v1.1); and
• must have completed platinum-based chemotherapy concurrent with radiation therapy, within 7 to 42 days prior to the randomization; and
• no evidence of progression of disease following definitive, platinum-based, concurrent chemoradiation therapy; and
• must be due to receive consolidation immunotherapy with durvalumab for up to 12 months, with the first dose of blinded study intervention to coincide with the first dose of durvalumab +/- 7 days; and
• absence of actional genomic mutations (eg, EGFR, ALK).
• Cachexia defined by Fearon criteria:

• BMI <20 kg/m2 and involuntary weight loss of >2% within 6 months prior to screening; or
• Involuntary weight loss of >5% over the past 6 months prior to screening irrespective of BMI
• Participant has been evaluated and determined that available anticachexic treatments have either been administered with no positive effect or the participant is not suitable for these treatments.
• Participants who are assessed by the investigator to have an ECOG PS ≤1.

Key Exclusion Criteria:

• Current active reversible causes of decreased food intake, as determined by the investigator. These causes may include, but are not limited to:

• NCI CTCAE Grade 3 or 4 oral mucositis
• Mechanical obstructions interfering with the participant's ability to eat
• Receiving tube feedings or parenteral nutrition (either total or partial) at the time of screening or randomization.
• Any prior or current clinical diagnosis of heart failure, irrespective of left ventricular ejection fraction or New York Heart Association classification.
• Cachexia caused by reasons other than NSCLC, as determined by the investigator (eg, severe COPD).
• Mixed small cell and non-small cell lung cancer histology.
• Undergoing major surgery within 4 weeks prior to randomization or planned major surgical procedures during the study.
• History of immune-related adverse event(s) in setting of immunotherapy that required treatment with systemic corticosteroids.
• Chronic use of systemic corticosteroid.
• History of any secondary malignancy in the last 2 years, except for adequately treated basal cell or squamous cell skin cancer or carcinoma in situ.
• Symptomatic brain metastasis or leptomeningeal disease.
• Any Grade ≥3 pulmonary disease unrelated to underlying malignancy including, but not limited to:

• Severe asthma requiring systemic corticosteroids within 30 days prior to first dose of study intervention or not well controlled with low-dose inhaled corticosteroids/long-acting beta-2 agonists.
• Severe chronic obstructive pulmonary disease requiring supplemental oxygen or systemic corticosteroids.
• Clinically severe and/or Grade 4 pulmonary emboli within 3 months of the first dose of study intervention. Pulmonary emboli in main or lobar pulmonary arteries are also excluded.
• Any autoimmune or inflammatory disorders with significant pulmonary parenchymal involvement at time of screening (ie, rheumatoid arthritis, Sjögren's syndrome, sarcoidosis, etc).
• Renal disease requiring dialysis or eGFR <30 mL/min/1.73 m².
• History of severe liver disease or cirrhosis, unrelated to metastatic cancer. LFT abnormalities at the time of screening; confirmed by a single repeat test if deemed necessary: AST or ALT level ≥ 3 x ULN (>5 x ULN if liver involvement by the tumor), alkaline phosphatase > 3 x ULN (>5 x ULN if liver involvement by the tumor and/or in case of bone metastases), or total bilirubin level ≥ 1.5 x ULN (For Gilbert's syndrome, direct bilirubin > ULN is exclusionary).
• Left ventricular ejection fraction <50% on screening echocardiogram (or MUGA scan).