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First-line cemiplimab (anti-programmed cell death-1 (PD-1)) monotherapy has previously shown significant improvement in overall survival (OS) and progression-free survival (PFS) versus chemotherapy in patients with advanced non-small cell lung cancer (aNSCLC) and PD-ligand 1 (PD-L1) expression ≥50%. EMPOWER-Lung 3 ( NCT03409614 ), a double-blind, placebo-controlled, phase 3 study, examined cemiplimab plus platinum-doublet chemotherapy as first-line treatment for aNSCLC, irrespective of PD-L1 expression or histology. In this study, 466 patients with stage III/IV aNSCLC without EGFR , ALK or ROS1 genomic tumor aberrations were randomized (2:1) to receive cemiplimab 350 mg ( n  = 312) or placebo ( n  = 154) every 3 weeks for up to 108 weeks in combination with four cycles of platinum-doublet chemotherapy (followed by pemetrexed maintenance as indicated). In total, 57.1% (266/466 patients) had non-squamous NSCLC, and 85.2% (397/466 patients) had stage IV disease. The primary endpoint was OS. The trial was stopped early per recommendation of the independent data monitoring committee, based on meeting preset OS efficacy criteria: median OS was 21.9 months (95% confidence interval (CI), 15.5–not evaluable) with cemiplimab plus chemotherapy versus 13.0 months (95% CI, 11.9–16.1) with placebo plus chemotherapy (hazard ratio (HR) = 0.71; 95% CI, 0.53–0.93; P  = 0.014). Grade ≥3 adverse events occurred with cemiplimab plus chemotherapy (43.6%, 136/312 patients) and placebo plus chemotherapy (31.4%, 48/153 patients). Cemiplimab is only the second anti-PD-1/PD-L1 agent to show efficacy in aNSCLC as both monotherapy and in combination with chemotherapy for both squamous and non-squamous histologies. Results from EMPOWER-Lung 3 demonstrate increased overall survival with cemiplimab plus platinum-doublet chemotherapy compared to cemiplimab as first-line treatment in patients with advanced non-small cell lung cancer, irrespective of PD-L1 expression.

Cemiplimab provided significant survival benefit to patients with advanced non-small-cell lung cancer with PD-L1 tumour expression of at least 50% and no actionable biomarkers at 1-year follow-up. In this exploratory analysis, we provide outcomes after 35 months' follow-up and the effect of adding chemotherapy to cemiplimab at the time of disease progression. EMPOWER-Lung 1 was a multicentre, open-label, randomised, phase 3 trial. We enrolled patients (aged ≥18 years) with histologically confirmed squamous or non-squamous advanced non-small-cell lung cancer with PD-L1 tumour expression of 50% or more. We randomly assigned (1:1) patients to intravenous cemiplimab 350 mg every 3 weeks for up to 108 weeks, or until disease progression, or investigator's choice of chemotherapy. Central randomisation scheme generated by an interactive web response system governed the randomisation process that was stratified by histology and geographical region. Primary endpoints were overall survival and progression free survival, as assessed by a blinded independent central review (BICR) per Response Evaluation Criteria in Solid Tumours version 1.1. Patients with disease progression on cemiplimab could continue cemiplimab with the addition of up to four cycles of chemotherapy. We assessed response in these patients by BICR against a new baseline, defined as the last scan before chemotherapy initiation. The primary endpoints were assessed in all randomly assigned participants (ie, intention-to-treat population) and in those with a PD-L1 expression of at least 50%. We assessed adverse events in all patients who received at least one dose of their assigned treatment. This trial is registered with ClinicalTrials.gov, NCT03088540. Between May 29, 2017, and March 4, 2020, we recruited 712 patients (607 [85%] were male and 105 [15%] were female). We randomly assigned 357 (50%) to cemiplimab and 355 (50%) to chemotherapy. 284 (50%) patients assigned to cemiplimab and 281 (50%) assigned to chemotherapy had verified PD-L1 expression of at least 50%. At 35 months' follow-up, among those with a verified PD-L1 expression of at least 50% median overall survival in the cemiplimab group was 26·1 months (95% CI 22·1–31·8; 149 [52%] of 284 died) versus 13·3 months (10·5–16·2; 188 [67%] of 281 died) in the chemotherapy group (hazard ratio [HR] 0·57, 95% CI 0·46–0·71; p<0·0001), median progression-free survival was 8·1 months (95% CI 6·2–8·8; 214 events occurred) in the cemiplimab group versus 5·3 months (4·3–6·1; 236 events occurred) in the chemotherapy group (HR 0·51, 95% CI 0·42–0·62; p<0·0001). Continued cemiplimab plus chemotherapy as second-line therapy (n=64) resulted in a median progression-free survival of 6·6 months (6·1–9·3) and overall survival of 15·1 months (11·3–18·7). The most common grade 3–4 treatment-emergent adverse events were anaemia (15 [4%] of 356 patients in the cemiplimab group vs 60 [17%] of 343 in the control group), neutropenia (three [1%] vs 35 [10%]), and pneumonia (18 [5%] vs 13 [4%]). Treatment-related deaths occurred in ten (3%) of 356 patients treated with cemiplimab (due to autoimmune myocarditis, cardiac failure, cardio-respiratory arrest, cardiopulmonary failure, septic shock, tumour hyperprogression, nephritis, respiratory failure, [n=1 each] and general disorders or unknown [n=2]) and in seven (2%) of 343 patients treated with chemotherapy (due to pneumonia and pulmonary embolism [n=2 each], and cardiac arrest, lung abscess, and myocardial infarction [n=1 each]). The safety profile of cemiplimab at 35 months, and of continued cemiplimab plus chemotherapy, was generally consistent with that previously observed for these treatments, with no new safety signals At 35 months' follow-up, the survival benefit of cemiplimab for patients with advanced non-small-cell lung cancer was at least as pronounced as at 1 year, affirming its use as first-line monotherapy for this population. Adding chemotherapy to cemiplimab at progression might provide a new second-line treatment for patients with advanced non-small-cell lung cancer. Regeneron Pharmaceuticals and Sanofi.

BackgroundImmune checkpoint inhibitors (ICIs) are now standard of care for advanced hepatocellular carcinoma (HCC). Early-stage HCC is potentially curable through surgical resection, though recurrence is seen in up to 70%, with an ~55% disease-free survival (DFS) at 2 years with surveillance. Neoadjuvant immunotherapy induces tumor necrosis and may reduce the risk of local and distal recurrences. Addition of stereotactic body radiation therapy (SBRT) before anti-PD1 augmented abscopal responses to ICI in preclinical studies.MethodsIn this Phase 2 open-label trial (NCT03916627), participants with resectable HCC received 2 doses of neoadjuvant cemiplimab 350 mg IV every 3 weeks before surgical resection and 8 cycles of adjuvant cemiplimab. Participants in cohort B2 received additional low-dose SBRT (8 Gy × 3 fractions) immediately before neoadjuvant cemiplimab. The primary endpoint was significant tumor necrosis (STN; >70% necrosis). Secondary endpoints included DFS and incidence of adverse events (AEs). ctDNA (by the Signatera assay) was evaluated as a correlate of response and DFS. As of July 31, 2025 (data cut-off; last patient on study ~24 months [first treatment August 7, 2023]), median follow-up was 41 months (IQR 32-58 months) post-resection.ResultsFrom August 2019 to August 2023, 41 participants received neoadjuvant cemiplimab and 20 patients also received SBRT. Thirty-six completed planned surgery, with one patient experiencing a delay to surgery (defined as surgery >28 days following the end of neoadjuvant immunotherapy). Five did not undergo resection due to subsequent determination of unresectable diseases (n=3) or comorbidity (n=2). Thirty-three received adjuvant cemiplimab (median exposure 23.7 weeks). For patients who underwent resection, rates of tumor necrosis and 1- and 2-year DFS are shown in table 1. Immune-related grade 3/4 adverse events occurred in 4, including grade 3 rash maculo-papular (n=1), hepatitis (n=1), and grade 3 pneumonitis (n=2). ctDNA kinetics in the neoadjuvant period and the prognostic value of minimal residual disease by ctDNA will be included in the full presentation.ConclusionsNeoadjuvant immunotherapy with cemiplimab with or without low-dose SBRT in patients with resectable HCC is potentially feasible with a generally acceptable safety profile consistent with the established profile of cemiplimab. Two-year DFS with neoadjuvant therapy may be favorable compared to historic controls. A larger study is needed to validate the benefits of neoadjuvant immunotherapy and the potential contribution of SBRT to survival outcomes.Trial RegistrationClinicaltrials.gov NCT03916627Ethics ApprovalThe study was approved by BRANY IRB, approval number 19-06-061-05.Abstract 1308 Table 1Disease-free survival for patients with resected tumors treated with and without SBRT.CTN, complete tumor necrosis (100% tumor necrosis); DFS, disease-free survival; IV, intravenous; Q3W, every 3 weeks; SBRT, stereotactic body radiation therapy; STN, significant tumor necrosis (> 70% tumor necrosis).