Cemiplimab Displays Survival Benefits Over Chemotherapy in First-Line Advanced PD-L1–High NSCLC With Brain Metastases

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Frontline treatment with the PD-1 inhibitor cemiplimab-rwlc (Libtayo) led to improvements in progression-free survival (PFS) and overall survival (OS) vs chemotherapy in patients with advanced non–small cell lung cancer (NSCLC) with brain metastases and a confirmed PD-L1 expression of at least 50%, according to data from an exploratory subgroup analysis of the phase 3 EMPOWER-Lung 1 trial (NCT03088540) published in Cancer.1

At a median follow-up of 55.7 months, patients with brain metastases who received cemiplimab (n = 34) achieved a median OS of 52.4 months (95% CI, 20.6-not evaluable [NE]) compared with 20.7 months (95% CI, 9.1-29.5) among those treated with chemotherapy (n = 35;HR, 0.40; 95% CI, 0.21-0.75; P = .0031). The estimated 12-month OS rates were 84.7% (95% CI, 67.1%-93.3%) and 59.6% (95% CI, 41.5%-73.8%), respectively.

The median PFS among patients with brain metastases who received cemiplimab and chemotherapy was 12.5 months (95% CI, 6.1-33.5) and 5.3 months (95% CI, 2.2-6.5), respectively (HR, 0.33; 95% CI, 0.18-0.61; P = .0002). The estimated 12-month PFS rates were 55.1% (95% CI, 36.8%-70.0%) and 6.4% (95% CI, 1.2%-18.5%), respectively. The median brain metastasis PFS was 20.6 months (95% CI, 16.3-NE) vs 9.1 months (95% CI, 5.1-20.7), respectively (HR, 0.35; 95% CI, 0.18-0.66; P = .0008).

“In patients with advanced NSCLC with PD-L1 [expression] of at least 50%, first-line cemiplimab monotherapy improved survival and patient-reported outcomes [PROs] over chemotherapy for those who received prior radiotherapy for symptomatic brain metastases,” the study authors wrote.

In February 2021, the FDA approved cemiplimab monotherapy for the frontline treatment of patients with advanced NSCLC with a PD-L1 expression level of at least 50% as determined by an FDA-approved test and no EGFR, ALK, or ROS1 aberrations.2 Prior data from EMPOWER-Lung 1 supported the regulatory decision.

Data from the 5-year follow-up of EMPOWER-Lung 1 demonstrated that patients with a PD-L1 expression level of at least 50% who received cemiplimab (n = 284) experienced a median OS of 26.1 months (95% CI, 22.1-31.9) compared with 13.3 months (95% CI, 10.5-16.2) in the chemotherapy arm (n = 281; HR, 0.59; 95% CI, 0.48-0.72; P < .0001).3 The median PFS was 8.1 months (95% CI, 6.2-8.8) and 5.3 months (95% CI, 4.3-6.1), respectively (HR, 0.50; 95% CI, 0.41-0.61; P < .0001).

EMPOWER-Lung 1 Study Design and Subgroup Analysis Methods

EMPOWER-Lung 1 was an open-label, global study that enrolled patients with squamous or nonsquamous stage IIIB or IIIC NSCLC who were not candidates for treatment with concurrent chemoradiation, or those with treatment-naive stage IV disease.1,3 Eligible patients needed to be at least 18 years old, have a PD-L1 expression level of at least 50%, have an ECOG performance status of 0 or 1, have a life expectancy of at least 3 months, and have adequate organ and bone marrow function.3

Following enrollment, patients were randomly assigned 1:1 to receive 350 mg of intravenous cemiplimab every 3 weeks for 108 weeks or investigator’s choice of platinum-based doublet chemotherapy for 4 to 6 cycles. Crossover from the chemotherapy to the cemiplimab arm was permitted in the event of disease progression verified by a blinded independent review committee.1

The coprimary end points were OS and PFS.3 Objective response rate (ORR) represented the study’s key secondary end point. Additional secondary end points included duration of response (DOR), PROs, and safety and tolerability.

The exploratory analysis included patients with a PD-L1 expression level of at least 50% in the intention-to-treat population.1 For patients with treated symptomatic brain metastases which had neurologically returned to baseline for at least 2 weeks prior to random assignment, radiologic confirmation of response or stability of brain metastases following treatment was not necessary for inclusion in the study.

Patients with brain metastases at baseline in the cemiplimab and chemotherapy arms were a median age of 60.0 years (range, 45.0-76.0) and 62.0 years (range, 48.0-77.0), respectively. Most patients in both groups were males (97.1% vs 82.9%), had an ECOG performance status of 1 (70.6% vs 82.9%), were past smokers (79.4% vs 65.7%), and had nonsquamous histology (85.3% vs 74.3%). Metastatic sites consisted of the lung (52.9% vs 74.3%), liver (11.8% vs 14.3%), bone (11.8% vs 20.0%), adrenal glands (26.5% vs 17.1%), intrathoracic lymph nodes (70.6% vs 80.0%), or other lymph nodes (17.6% vs 11.4%). The median durations of treatment were 55.5 weeks (range, 5.4-132.7) and 17.9 weeks (range, 3.0-82.7), respectively.

Patients without brain metastases at baseline had a median age of 64.0 years (range, 31.0-79.0) in the cemiplimab arm (n = 250) and 64.0 years (range, 40.0-84.0) in the chemotherapy arm (n = 246). Most patients in both groups were males (86.4% vs 82.1%), had an ECOG performance status of 1 (73.2% vs 71.5%), were past smokers (60.4% vs 67.5%), and had nonsquamous histology (52.8% vs 54.1%). Metastatic sites consisted of the lung (68.8% vs 67.1%), liver (18.4% vs 16.3%), bone (24.0% vs 26.8%), adrenal glands (19.6% vs 19.1%), intrathoracic lymph nodes (70.0% vs 67.5%), or other lymph nodes (23.2% vs 22.0%). The median durations of treatment were 36.0 weeks (range, 0.3-136.0) and 18.0 weeks (range, 0.6-141.1), respectively.

Further Efficacy Data and Safety Findings

Additional findings from the exploratory analysis demonstrated that patients without brain metastases in the cemiplimab arm experienced a median OS of 24.3 (95% CI, 21.1-30.6) compared with 12.5 months (95% CI, 10.1-14.8) in the chemotherapy arm (HR, 0.63; 95% CI, 0.50-0.78; P < .0001). The estimated 12-month OS rates were 68.3% (95% CI, 62.0%-73.9%) and 51.4% (95% CI, 44.5%-57.8%), respectively.

The median PFS among patients without brain metastases was 6.5 months (95% CI, 5.2-8.5) in the cemiplimab arm vs 5.2 months (95% CI, 4.3-6.1) in the chemotherapy arm (HR, 0.55; 95% CI, 0.44-0.67; P < .0001). The estimated 12-month PFS rates were 39.8% (95% CI, 33.6%-45.9%) and 7.3% (95% CI, 4.2%-11.6%), respectively. The median brain metastasis PFS was 22.7 months (95% CI, 17.7-26.2) in the investigational arm compared with 10.3 months (95% CI, 8.8-12.5) in the control arm (HR, 0.50; 95% CI, 0.40-0.62; P < .0001).

Among patients with brain metastases, the ORR was 55.9% (95% CI, 37.9%-72.8%) in the cemiplimab arm, including an 11.8% complete response (CR) rate, compared with 11.4% (95% CI, 3.2%-26.7%) in the chemotherapy arm (OR, 9.3; 95% CI, 2.6-32.7; P = .0002). The estimated median DOR was 50.3 months (95% CI, 14.7-NE) and 12.5 months (95% CI, 4.4-NE), respectively.

Patients without brain metastases who received cemiplimab achieved an ORR of 45.2% (95% CI, 38.9%-51.6%) vs 22.0% (95% CI, 16.9%-27.7%) in the chemotherapy arm (OR, 2.9; 95% CI, 2.0-4.3; P < .0001). The respective CR rates were 8.0% and 1.6%. The estimated median DOR was 22.8 months (95% CI, 16.6-33.0) and 5.1 months (95% CI, 4.3-6.4), respectively.

In terms of safety, any-grade treatment-emergent adverse effects (TEAEs) were reported in 97.1% of both patients with brain metastases who received cemiplimab or chemotherapy. Serious TEAEs occurred in 26.5% and 37.1% of patients, respectively. The most common any-grade TEAEs in the cemiplimab arm included anemia (26.5%), fatigue (20.6%), back pain (17.6%), decreased appetite (17.6%), and pruritus (17.6%). Common any-grade TEAEs in the chemotherapy arm included anemia (54.3%), nausea (25.7%), and decreased appetite (22.9%).

Notably, there was a statistically significant difference in overall change from baseline between the cemiplimab and chemotherapy arms among patients with brain metastases in terms of the QLQ-C30 global health status/quality of life scale in favor of the investigational arm (difference in least-squares [LS] means, 9.35; 95% CI, 2.24-16.45; P = .0110). There was also a significant change from baseline in favor of the cemiplimab in terms of the role functioning (difference in LS means, 8.59; 95% CI, 0.16-17.01; P = .0459) and emotional functioning (difference in LS means, 7.27; 95% CI, 1.86-12.69; P = .0095) scales.

“In conclusion, this study showed that first-line cemiplimab monotherapy improved clinical outcomes, including DOR and PROs, vs chemotherapy in patients with advanced NSCLC with [a] PD-L1 [expression level] of at least 50% and symptomatic radiotherapy-treated brain metastases at baseline,” the study authors wrote. “Thus, first-line cemiplimab monotherapy represents a suitable treatment option for this subgroup of patients.”

References

1. Kilickap S, Özgüroğlu M, Sezer A, et al. Cemiplimab monotherapy as first-line treatment of patients with brain metastases from advanced non-small cell lung cancer with programmed cell death-ligand 1 ≥50. Cancer. 2025;131(10):e35864. doi:10.1002/cncr.35864
2. FDA approves cemiplimab-rwlc for non-small cell lung cancer with high PD-L1 expression. FDA. February 22, 2021. Accessed May 14, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-cemiplimab-rwlc-non-small-cell-lung-cancer-high-pd-l1-expression
3. Kilickap S, Baramidze A, Sezer A, et al. Cemiplimab monotherapy for first-line treatment of patients with advanced NSCLC with PD-L1 expression of 50% or higher: five-year outcomes of EMPOWER-Lung 1. J Thorac Oncol. Published online March 18, 2025. doi:10.1016/j.jtho.2025.03.033