Reduced-dose Carboplatin-doublet-chemotherapy + Cemiplimab vs Cemiplimab Monotherapy in Treatment Naive Older and Frail Patients With Metastatic NSCLC With PD-L1 <50%

This randomized, open-label, phase II clinical trial evaluates the efficacy, safety, and overall treatment utility of reduced-dose platinum-doublet chemotherapy (rdCT) in combination with cemiplimab (cemi) versus cemiplimab monotherapy in older and/or frail patients with stage III/IV non-small cell lung cancer (NSCLC) and PD-L1 expression <50%. The study specifically addresses a major evidence gap for a vulnerable patient population often underrepresented in registrational trials.

Cemiplimab in combination with full-dose carboplatin-based doublet chemotherapy is a Swissmedic-approved first-line treatment for advanced NSCLC, based on data from EMPOWER-Lung 03. However, full-dose chemotherapy regimens (e.g., carboplatin AUC 5 + pemetrexed, paclitaxel, or gemcitabine) are frequently associated with prohibitive toxicity in elderly and/or frail patients. Over half of all newly diagnosed mNSCLC cases occur in individuals aged 70 or older, many of whom present with frailty or multimorbidity. While atezolizumab monotherapy has shown a survival benefit over single-agent chemotherapy in older, treatment-ineligible patients (IPSOS trial), overall outcomes remain suboptimal.

In clinical practice, rdCT regimens are commonly used in this patient population, despite limited prospective evidence. The present study uses the G8 screening tool-a validated geriatric assessment instrument-to identify patients at risk for increased treatment toxicity and to support treatment adaptation.

Objectives The primary objective is to compare overall survival (OS) between rdCT + cemiplimab and cemiplimab monotherapy. Secondary objectives include comparison of progression-free survival (PFS), objective response rate (ORR), adverse events (AE), health-related quality of life (HRQoL), and overall treatment utility (OTU).

Design and Interventions This is a multicenter, randomized, open-label, parallel-group study enrolling approximately 156 patients (78 per arm) across ~17 sites in Switzerland. Eligible patients are ≥70 years old, have a G8 score ≤14 or are deemed unsuitable for full-dose chemotherapy, and have advanced or metastatic NSCLC without actionable genomic alterations and PD-L1 <50%.

Patients are randomized to one of two arms:

• Experimental Arm: rdCT + cemiplimab
• Control Arm: cemiplimab monotherapy Patients who progress and are deemed suitable may cross over to receive rdCT + cemiplimab.

Cemiplimab maintenance continues until disease progression, unacceptable toxicity, or a maximum of 2 years. Treatment beyond progression is permitted in cases of oligoprogression amenable to local therapy.

Assessments Radiologic response assessments (CT ± CNS imaging) are performed every 6 weeks until week 12, then every 9 weeks until week 30, and every 12 weeks thereafter. HRQoL is assessed using NFLSI-17 and QLQ-ELD14 at baseline, every 6 weeks to week 12, every 9 weeks to week 30, and every 24 weeks thereafter.

Overall Treatment Utility (OTU) is assessed at the same intervals and incorporates:

• Radiological and clinical disease progression
• Toxicity profile and serious adverse events
• Patient-reported treatment acceptability Geriatric-specific assessments (hand-grip strength and timed up-and-go) are performed at baseline, week 12, week 30, and every 24 weeks.

Statistical Considerations With 128 OS events, the study is powered (80%) to detect an increase in median OS from 10.3 months (based on IPSOS trial) to 16 months in the experimental arm (one-sided alpha = 0.05). Sample size: 156 patients (allowing 5% attrition).

Time-to-event outcomes will be analyzed using Kaplan-Meier methods with log-rank tests and Cox proportional hazards models. Response rates and adverse events will be compared using Fisher's exact or chi-square tests. Continuous variables (e.g., HRQoL scores) will be analyzed using Wilcoxon rank-sum or linear regression (mixed models as appropriate).

Quality Assurance and Data Integrity

Although not formally a registry, the trial employs registry-like quality control elements:

• Data validation: Real-time data entry into electronic case report forms (eCRFs) with predefined logic and range checks.
• Source Data Verification (SDV): Conducted to ensure data accuracy and completeness via comparison with medical records and source documents.
• Standard Operating Procedures: SOPs are implemented, which cover all trial operations-site initiation, data collection, patient assessments, safety reporting, and amendment handling.
• Monitoring and auditing: Central and on-site monitoring according to a risk-based monitoring plan. Sites may be audited for compliance with ICH-GCP.
• Missing data management: Missing values due to dropout, nonresponse, or data inconsistency will be handled using pre-specified strategies, including sensitivity analyses.

Conclusion This trial responds to the pressing need for evidence-based, tolerable, and effective treatment strategies for older and/or frail patients with advanced NSCLC. By leveraging geriatric screening tools and integrating real-world adaptations such as reduced-dose chemotherapy, this study aims to optimize oncologic outcomes while preserving quality of life and functional status. Findings will inform clinical decision-making for a frequently excluded patient group in oncology research.