FDA Accepts sBLA for Cemiplimab Plus Chemo in Frontline Advanced NSCLC

The FDA has accepted for review a supplemental biologics license application (sBLA) for cemiplimab-rwlc (Libtayo) in combination with chemotherapy in the frontline treatment of patients with advanced non–small cell lung cancer (NSCLC).¹

The application is supported by findings from the phase 3 EMPOWER-Lung 3 trial (NCT03409614), which showed that the combination significantly improved overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and duration of response (DOR) compared with chemotherapy alone in this patient population.²

The trial enrolled treatment-naïve patients with advanced NSCLC, nonsquamous and squamous histology, stage IIIB/C and IV disease, and an ECOG performance status of 0 or 1. Patients could have any PD-L1 expression, and those with treated, clinically stable central nervous system metastases were permitted. Patients could not have tumors that harbored EGFR, ALK, or ROS1 mutations.

A total of 466 participants were randomized 2:1 to receive cemiplimab at 350 mg every 3 weeks with investigator’s choice of platinum-doublet chemotherapy every 3 weeks for 4 cycles (n = 312) or placebo every 3 weeks plus investigator’s choice of platinum-doublet chemotherapy given on the same schedule (n = 154). Treatment was administered until disease progression or up to 108 weeks.

Patients were stratified based on PD-L1 expression (less than 1% vs 1% to 49% vs 50% or higher) and histology (nonsquamous vs squamous).

The primary end point of the trial was OS, and key secondary end points comprised PFS and ORR. Additional secondary end points included DOR, best overall response, safety, and patient-reported outcomes.

The median age among the 466 participants was 63.0 years (range, 25-84), and 40.3% were aged 65 years or older. Moreover, 83.9% were male. Regarding histology, 57.1% had nonsquamous disease and 42.9% had squamous disease. Additionally, 29.8% of patients had a PD-L1 expression of less than 1%, 37.6% had an expression in the range of 1% and 49%, and 32.6% had an expression of 50% or higher.

Most patients (84.3%) had an ECOG performance status of 1, and 6.7% of patients had brain metastases. Moreover, 85.2% had metastatic disease at the time of screening, and 14.8% had locally advanced disease. Approximately half of patients (53.2%) were current smokers.

All 312 patients on the cemiplimab arm received treatment, and 108 were still receiving treatment at the data cutoff date of June 14, 2021. In the control arm, 153 of 154 patients received treatment and only 15 were still receiving treatment at data cutoff. In the cemiplimab/chemotherapy arm, 204 patients discontinued treatment because of disease progression (n = 137), death (n = 24), toxicity (n = 14), patient decision (n = 13), withdrawn consent (n = 8), physician decision (n = 4), and loss to follow-up (n = 1).

Data from the trial, which were presented during the 2021 ESMO Congress, showed that the median OS with the addition of cemiplimab was 21.9 months (95% CI, 15.5–not evaluable [NE]) vs 13.0 months (95% CI, 11.9-16.1) with chemotherapy alone (HR, 0.71; 95% CI, 0.53-0.93; P = .014). The 12-month OS rates in the investigative and control arms were 65.7% (95% CI, 59.9%-70.9%) and 56.1% (95% CI, 47.5%-63.8%), respectively.

The median PFS with the combination was 8.2 months (95% CI, 6.4-9.3) vs 5.0 months (95% CI, 4.3-6.2) with chemotherapy alone (HR, 0.56; 95% CI, 0.44-0.70; P < .0001). The 12-month PFS rates in the cemiplimab and control arms were 38.1% (95% CI, 32.4%-43.8%) and 16.4% (95% CI, 10.5%-23.4%), respectively.

The combination also elicited an ORR of 43.3% (95% CI, 37.7%-49.0%) vs 22.7% (95% CI, 16.4%-30.2%) with chemotherapy alone (odds ratio, 2.68; 95% CI, 1.72-4.19; P < .0001). Among those who responded to cemiplimab plus chemotherapy, 40.7% achieved a partial response and 2.6% experienced a complete response; these rates were 22.7% and 0%, respectively, in the chemotherapy-alone arm.

Moreover, the median DOR in the investigative arm was 15.6 months (95% CI, 12.4–NE) vs 7.3 months (95% CI, 4.3-12.6) in the control arm.

A delay in the time to definitive clinically meaningful deterioration in Global Health Score (GHS)/Quality of Life (QoL) was observed with cemiplimab plus chemotherapy vs chemotherapy alone (HR, 0.78; 95% CI, 0.51-1.19; P = .248), as well as pain symptoms (HR, 0.39; 95% CI, 0.26-0.60; P < .0001). Moreover, an improvement in overall change from baseline in GHS/QoL (0.61; 95% CI, -2.23 to 3.45; P = .673) and pain symptoms (-4.98; 95% CI, -8.36 to -1.60; P = .004) was also noted in the investigative arm vs the control arms.

The combination of cemiplimab and chemotherapy was noted to have an acceptable benefit-risk profile. Any-grade treatment-emergent adverse effects (TEAEs) occurred in 96% of patients on the cemiplimab arm vs 94% of those on the control arm; grade 3 to 5 TEAEs were reported in 4% and 3% of patients, respectively. Any-grade TEAEs resulted in treatment discontinuation in 5% of those in the investigative arm and 3% of those in the control arm; grade 3 to 5 TEAEs resulting in discontinuation occurred in 4% and 3% of patients, respectively.

Any-grade treatment-related AEs (TRAEs) were experienced by 88% of those in the cemiplimab arm vs 84% of those in the control arm; these effects were grade 3 to 5 in 29% and 18% of patients, respectively. Any-grade TRAEs led to discontinuation in 3% and 1% of patients, respectively; grade 3 to 5 TRAEs resulted in discontinuation in 2% vs 1% of patients, respectively.

The most common grade 3 to 5 TEAEs reported in the cemiplimab (n = 312) and control (n = 153) arms included anemia (10% vs 7%, respectively), decreased appetite (1% vs 0%), fatigue (2% vs 1%), thrombocytopenia (3% vs 1%), neutropenia (6% vs 6%), hyperglycemia (2% vs 0%), increased alanine aminotransferase (2% vs 2%), arthralgia (1% vs 0%), increased aspartate aminotransferase (0% vs 2%), dyspnea (2% vs 1%), asthenia (2% vs 1%), decreased weight (1% vs 0%), diarrhea (1% vs 0%), and hypoalbuminemia (1% vs 0%).

The target action date for the sBLA has been set to September 19, 2022.

References

1. FDA accept for review Libtayo (cemiplimab-rwlc) in combination with chemotherapy for first-line treatment of advanced NSCLC. News release. Regeneron Pharmaceuticals, Inc.; January 19, 2022. Accessed January 19, 2022. https://bit.ly/32cfSJQ
2. Gogishvili M, Melkadze T, Makharadze T, et al. EMPOWER-Lung 3: cemiplimab in combination with platinum-doublet chemotherapy (chemo) for first-line (1L) treatment of advanced non-small cell lung cancer (NSCLC). Ann Oncol. 2021;32(suppl 5):S1283-S1346. doi:10.1016/annonc/annonc741