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February 18, 2021 - Single-agent cemiplimab has been found to result in a significant improvement in overall survival and progression-free survival versus chemotherapy in patients with advanced non–small cell lung cancer who had a PD-L1 expression of at least 50%.
Single-agent cemiplimab (Libtayo) has been found to result in a significant improvement in overall survival (OS) and progression-free survival (PFS) versus chemotherapy in patients with advanced non–small cell lung cancer (NSCLC) who had a PD-L1 expression of at least 50%, according to data from the phase 3 EMPOWER-Lung 1 (NCT033088540) published in the Lancet.1
Among the 563 patients with PD-L1 expression of at least 50%, the median OS had not yet been reached (95% CI, 17.9–not evaluable) with cemiplimab versus 14.2 months (95% CI, 11.2-17.5) with chemotherapy (hazard ratio [HR], 0.57; 95% CI, 0.42-0.77; P = .0002). Moreover, the estimated OS rates at 24 months in the investigative and control arms were 50% and 27%, respectively.
Cemiplimab was also found to reduce the risk of disease progression or death by 46% compared with chemotherapy (HR, 0.54; 95% CI, 0.43-0.68; P <.0001). The median PFS with cemiplimab was 8.2 months (95% CI, 6.1-8.8) versus 5.7 months (95% CI, 4.5-6.2) with chemotherapy. The estimated PFS rates at 12 months in the investigative and control arms were 21% and 7%, respectively.
Notably, the survival benefit associated with cemiplimab was observed across all subgroups analyzed, except for OS in female patients.
Additionally, an objective response per independent review committee was reported in 39% of patients (n = 111/283; 95% CI, 34%-45%) who received cemiplimab versus 20% (n = 57/280; 95% CI, 16%-26%) of those given chemotherapy. The median duration of response (DOR) in the investigative and control arms was 16.7 months (95% CI, 12.5-22.8) and 6.0 months (95% CI, 4.3-6.5), respectively.
“The results of EMPOWER-Lung 1 showed a clinically meaningful and statistically significant improvement in OS and PFS with first-line cemiplimab monotherapy over platinum-doublet chemotherapy in patients with advanced NSCLC with PD-L1 of at least 50% despite a high crossover rate and broadened inclusion criteria,” Ahmet Sezer, MD, professor in the Department of Medical Oncology, of Baskent University, and colleagues, wrote in the paper.
For the multicenter, open-label, global, phase 3 trial, investigators set out to examine single-agent cemiplimab versus investigator’s choice of platinum-doublet chemotherapy in the frontline treatment of patients with advanced NSCLC whose tumors have a PD-L1 expression of at least 50%.
To be eligible for enrollment, patients had to be 18 years of age, have histologically or cytologically confirmed stage IIIB or IIIC or stage IV squamous or nonsquamous NSCLC with PD-L1 expression of at least 50%, an ECOG performance status of 0-1, acceptable organ and bone marrow function, and at least 1 measurable lesion per RECIST v1.1 criteria.
If patients had never smoked; had active or untreated brain metastases; had tumors positive for EGFR mutations, ALK translocations, or ROS1 fusions; active, known, or suspected autoimmune disease that required systemic treatment during the prior 2 years; or uncontrolled infection with hepatitis B or C or human immunodeficiency virus, they were excluded.
Patients were stratified based on histology (squamous vs nonsquamous) and geographical region (Europe, Asia, or the rest of the world). Those on the investigative arm (n = 356) received 350 mg of intravenous cemiplimab over 30 minutes every 3 weeks, while those on the control arm (n = 354) received investigator’s choice of platinum-based chemotherapy for 4 or 6 cycles.
The primary end points were OS and PFS, and secondary end points included objective response rate (ORR), DOR, health-related quality of life (HRQoL), and safety with cemiplimab compared with chemotherapy. Moreover, investigators examined the pharmacokinetics and immunogenicity of cemiplimab and conducted exposure–response analyses.
As of the data cutoff, 3662 patients across 188 sites spanning 24 countries were screened for enrollment on the trial. A total of 710 patients from 138 clinics spanning 24 countries met the eligibility criteria. Seventy-four percent (n = 150/203) of patients who progressed on chemotherapy received cemiplimab as a crossover treatment, while 32% (n = 50/158) of patients who progressed on cemiplimab received extended treatment with the addition of chemotherapy.
Additionally, 563 patients comprised the PD-L1 of at least 50% population. The median age in this population was 63.5 years and 46.5% were aged 65 years or older. The majority, or 85.5%, of patients were male, from Europe (76.5%), and had an ECOG performance status of 1 (73%). Sixty-five percent of patients were past smokers, 57% had nonsquamous histology, and 12% had brain metastases.
In the PD-L1 of at least 50% population, the overall median duration of follow-up was 10.8 months for cemiplimab and 10.9 months for chemotherapy. Forty six-percent of patients were still receiving cemiplimab and 16% of patients were still receiving chemotherapy.
The intent-to-treat (ITT) population (n = 710) was comprised of the 563 patients with a PD-L1 of at least 50% plus 56 patients who definitively had a PD-L1 expression of less than 50%. The over median duration of follow-up with cemiplimab and chemotherapy was 13.1 months each.
Here, cemiplimab also demonstrated an improvement in OS compared with chemotherapy, at 22.1 months (95% CI, 17.7–not evaluable) and 14.3 months (95% CI, 11.7-19.2), respectively (HR, 0.68; 95% CI, 0.53-0.87; P = .0022). Cemiplimab also improved PFS over chemotherapy, at a median of 6.2 months (95% CI, 4.5-8.3) versus 5.6 months (95% CI, 4.5-6.1), respectively (HR, 0.59; 95% CI, 0.49-0.72; P <.0001).
Another sensitivity analysis was requested by the FDA to evaluate the efficacy of cemiplimab in a population that excluded those with known PD-L1 expression of less than 50% (n = 654); this population was comprised of 563 patients with a PD-L1 of at least 50% and 91 patients for whom PD-L1 expression could not be determined. Similar HRs for OS and PFS were observed, at 0.65 (95% CI, 0.50-0.85) and 0.58 (95% CI, 0.47-0.70), respectively.
The survival benefits demonstrated with cemiplimab in the ITT population were observed across all subgroups assessed, with the exception of OS in participants who were enrolled in Asia (n = 77). Tumor response also proved to be consistent with what had been seen in the population of patients with a PD-L1 expression of at least 50%. Moreover, meaningful improvements in HRQoL were observed with cemiplimab but not with chemotherapy.
Results from an exploratory analysis of PD-L1 expression proportions demonstrated that PD-L1 proportions correlate with depth of changes in tumor measurement and incremental improvements in OS, PFS, and ORR.
“Patients who were treated with cemiplimab who had a PD-L1 less than 50% or unknown did not do as well as patients with PD-L1 of at least 50%,” the authors wrote. “However, they did broadly as well as chemotherapy-treated patients.”
Regarding safety, 28% of 355 patients who received cemiplimab experienced grade 3/4 treatment-emergent adverse effects (TEAEs), with pneumonia (5%) being the most frequently reported, followed by anemia (3%), and hyponatremia (3%). Grade 3/4 TEAEs were observed in 39% of those who received chemotherapy, with anemia reported in 16% of patients, neutropenia presenting in 10%, and thrombocytopenia occurring in 8%.
Twenty-three patients who received cemiplimab experienced TEAEs that resulted in treatment discontinuation versus 14 patients who were given chemotherapy. Serious toxicities were reported in 28% and 27% of those on the investigative and control arms, respectively; 11% and 15%, respectively were determined to be related to treatment.
Treatment-related toxicities were reported in 57% of those given cemiplimab versus 89% of those given chemotherapy; grade 3/4 effects were reported in 12% and 37% of patients, respectively. The most frequently reported treatment-related toxicities that were grade 3 or 4 in severity included increased aspartate aminotransferase (1%) and pneumonia (1%) in the investigative arm and anemia (15%) and neutropenia (10%) in the control arm.
Ten percent of patients on the cemiplimab arm died compared with 9% of those on the chemotherapy arm.