FDA Grants Priority Review to Frontline Cemiplimab for PD-L1-High Advanced or Metastatic NSCLC

The FDA has accepted the supplemental Biologics License Application (sBLA) for cemiplimab-rwlc (Libtayo) and granted it Priority Review for the frontline treatment of patients with locally advanced or metastatic non–small cell lung cancer (NSCLC) with ≥50% PD-L1 expression.¹ The Prescription Drug User Fee Act target action date for this potential approval is set to February 28, 2021.

The sBLA for cemiplimab as treatment of this patient population was supported by findings from the phase 3 EMPOWER-Lung1 clinical trial of cemiplimab versus chemotherapy in patients with advanced or metastatic PD-L1–positive NSCLC, for which topline results were recently presented during the European Society of Medical Oncology (ESMO) Virtual Annual Congress 2020.²

In the intention-to-treat (ITT) population of the study, 710 patients were included and 88 of those patients were identified as having a PD-L1 expression of ≥ 50%, as identified by the PD-L1 IHC 22C3 pharmDx kit. All patients in the study were evaluated for the coprimary end points of overall survival (OS) and progression-free survival (PFS). The secondary end points assessed were objective response rate (ORR), duration of response (DOR), health-related quality of life (HRQoL), and safety.

The ITT population had a median OS of 22.1 months (95% CI, 17.7 to not evaluable [NE]) in the cemiplimab arm versus 14.3 months (95% CI, 11.7-19.2) in the chemotherapy arm (HR, 0.68; 95% CI, 0.53-0.87; P = .0022). At 12 months, the OS rate in this population was 70.3% (95% CI, 64.4%-75.4%) with cemiplimab compared with 55.7% (95% CI, 49.2%-61.7%) with chemotherapy. The 24-month OS rate was 48.6% (95% CI, 39.2%-57.3%) in the cemiplimab arm versus 29.7% (95% CI, 18.8%-41.4%) in the chemotherapy arm.

Also, in the overall ITT population, the median PFS was 6.2 months (95% CI, 4.5-8.3) with cemiplimab compared with 5.6 months (95% CI, 4.5-6.1) with chemotherapy (HR, 0.59; 95% CI, 0.49-0.72; P = .0001). Treatment with cemiplimab showed a 12-month PFS rate of 37.8% (95% CI, 31.9%-43.6%) with cemiplimab compared with 7.2% (95% CI, 4.3%-11.25) with chemotherapy. The 18-month PFS rate was 28.0% (95% CI, 21.7%-34.7%) with cemiplimab versus only 3.9% (95% CI, 1.8%-7.5%) with chemotherapy.

Among the group of patients with high PD-L1 expression, the median OS was not reached (95% CI, 17.9-NE) in the cemiplimab arm compared with 14.2 months (95% CI, 11.2-17.5) in the chemotherapy arm (HR, 0.57; 95% CI, 0.42-0.77; P = .0002). At the 12-month mark, the OS rate in the cemiplimab arm was 72.4% (95% CI, 65.6%-78.1%) versus 53.9% (95% CI, 46.2-61.1) in the chemotherapy arm. At 24 months, the OS rate was 50.4% (95% CI, 36.4%-62.9%) in the cemiplimab arm compared with 27.1% (95% CI, 13.7%-42.5%) in the chemotherapy arm.

The median PFS observed in the high PD-L1 expression group was 8.2 months (95% CI, 6.1-8.8) with cemiplimab versus 5.7 months (95% CI, 4.5-6.2) with chemotherapy (HR, 0.53; 95% CI, 0.43-0.68; P = .0001). Cemiplimab achieved a 12-month PFS rate of 40.7% (95% CI, 33.7%-47.5%) compared with the 7.1% (95% CI, 3.6%-12.1%) observed with chemotherapy. At 18 months, the PFS rate was 27.8% (95% CI, 19.4%-36.7%) in the cemiplimab arm and NE in the chemotherapy arm.

The OS and PFS benefits observed with cemiplimab over chemotherapy in the overall and high PD-L1 populations were carried across the subgroup populations assessed in the study.

In terms of the study’s secondary end points, the ORR in patients with and without PD-L1 expression ≥50% favored the cemiplimab arm, however, the high PD-L1 expression group had higher response rates. The overall ITT population achieved an ORR of 36.5% (95% CI, 31.5%-41.8%) with cemiplimab compared with only 20.6% (95% CI, 16.5%-25.2%) with chemotherapy (P <.0001). Notably, 3.1% of the responses observed in the cemiplimab arm were complete responses (CRs) compared with only 0.8% of the chemotherapy group. The median DOR in this population was 21.0 months (95% CI, 14.9-NE) in the cemiplimab arm versus 6.0 months (95% CI, 4.3-6.4) in the chemotherapy arm.

Patients with high PD-L1 expression had an ORR of 39.2% (95% CI, 33.5%-45.2%) with cemiplimab versus 20.4% (95% CI, 15.8%-25.6%) with chemotherapy (P <.0001). With cemiplimab, the CR rate was 2.1% compared with 1.1% in the chemotherapy arm. The median DOR in the high PD-L1 group was 16.7 months (95% CI, 12.5-22.8) with cemiplimab compared with 6.0 months (95% CI, 4.3-6.5) in the chemotherapy arm.

Cemiplimab therapy led to improved HRQoL scores in patients, defined as a ≥10-point increase from outcomes assessed at baseline. In comparison, chemotherapy led to a ≥10-point deterioration of HRQoL in patients.

The safety analysis of EMPOWER-Lung1 supported the positive benefit-risk profile of cemiplimab. Treatment-emergent adverse events (TEAEs) were observed in 88.2% of the study population with 37.2% being grade 3 to 5 in severity. TEAEs led to treatment discontinuation in 6.5% of the population and death in 9.6%. Immune-related AEs were also observed in the study (17.5%), leading to discontinuation in 2.5% of patients, and death in 0.3%.

The most common TEAEs of any-grade observed in the study were anemia (14.6%), decreased appetite (11.8%), fatigue (10.1%), pneumonia (9.3%), and constipation (7.6%).

EMPOWER-Lung1 is an open-label, randomized, multicenter trial for which analyses are ongoing. In addition to the FDA, the European Medicines Agency is also reviewing the study data while considering cemiplimab for approval as treatment of advanced NSCLC with ≥50% PD-L1 expression. A decision is expected in the second quarter of 2021.

Cemiplimab is a monoclonal antibody which targetes the immune checkpoint receptor PD-1 on T cells. Studies of this agent are ongoing across multiple tumor types, including cutaneous squamous cell carcinoma and advanced basal cell carcinoma.

_References:

_{1. FDA accepts for Priority Review Libtayo® (cemiplimab-rwlc) for advanced non-small cell lung cancer with pd-l1 expression of ≥50%. News release. Regeneron Pharmaceuticals. October 29, 2020. Accessed October 29, 2020. https://bit.ly/3ejDSg1​}

_{2. Sezer A, Kilickap S, Gumus M, et al. EMPOWER-Lung 1: Phase 3 first-line (1L) cemiplimab monotherapy vs platinum-doublet chemotherapy (Chemo) in advanced non-small cell lung cancer (NSCLC) with programmed cell death-ligand 1 (PD-L1) ≥50%. 2020 European Society for Medical Oncology Virtual Congress; September 19-21, 2020. Abstract LBA52.}