Cemiplimab Demonstrates Frontline Potential in Advanced PD-L1+ NSCLC

Cemiplimab-rwlc (Libtayo) monotherapy led to a significant improvement in overall survival (OS) and progression-free survival (PFS) versus platinum-doublet chemotherapy as first-line treatment in patients with advanced non–small cell lung cancer (NSCLC) with PD-L1 expression on at least 50% of their tumor cells, according to findings from the second preplanned interim analysis of the phase 3 EMPOWER-Lung 1 trial that were presented during the 2020 ESMO Virtual Congress.

At a median follow-up of approximately 10 months in the PD-L1 ≥50% intention-to-treat (ITT) population, the median OS was not reached (95% CI, 17.9–not estimable [NE]) in the cemiplimab arm versus 14.2 months (95% CI, 11.2-17.5) in the chemotherapy arm (HR, 0.57; 95% CI, 0.42-0.77; P = .0002). This translated to a 43% reduction in the risk of death with the PD-1 inhibitor.

The median PFS was 8.2 months (95% CI, 6.1-8.8) in the cemiplimab arm versus 5.7 months (95% CI, 4.5-6.2) in the chemotherapy arm, translating to a 46% reduction in the risk of progression or death with cemiplimab (HR, 0.54; 95% CI, 0.43-0.68; P < .0001).

“The EMPOWER-Lung 1 study met its primary and secondary end points,” said Ahmet Sezer, MD, lead study author and professor in the Department of Medical Oncology at Başkent University, in Ankara, Turkey, in a virtual presentation of the data. “Taken together, our data provide the rationale for cemiplimab as a new first-line monotherapy option for patients with advanced NSCLC with PD-L1 expression ≥50%.”

For patients with advanced NSCLC with PD-L1 expression ≥50% and without targetable mutations, PD-1/PD-L1 inhibitors alone or in combination with chemotherapy are preferred treatment options. However, selecting the most effective treatment with minimal toxicity remains a challenge. Additional treatment options with survival benefits and optimization of chemotherapy-free regimens are needed for patients with PD-L1 ≥50%.

Cemiplimab is a high-affinity, highly potent, human PD-1 inhibitor approved for the treatment of patients with advanced cutaneous squamous cell carcinoma. In phase 1 and 2 studies, cemiplimab demonstrated antitumor activity with a safety profile similar to that described for other PD-1 inhibitors in other advanced solid tumors, including NSCLC.

In EMPOWER-Lung 1, eligible patients had treatment-naïve advanced NSCLC, PD-L1 ≥50%, no EGFR, ALK, or ROS1 mutations, and an ECOG performance status of 0 or 1. Patients with treated, clinically stable central nervous system metastases and controlled hepatitis B or C, or HIV were allowed on study.

Patients in the ITT population were randomized 1:1 to 350 mg of intravenous cemiplimab monotherapy every 3 weeks (n = 356) or 4 to 6 cycles of investigator’s choice chemotherapy (n = 354). Patients in the cemiplimab arm were treated until progressive disease or up to 108 weeks. Upon progressive disease, patients in the cemiplimab arm had the option of continuing cemiplimab plus 4 cycles of chemotherapy, and patients in the chemotherapy arm had the option of crossing over to the cemiplimab arm.

OS and PFS served as primary end points of the study. Secondary end points included objective response rate (ORR), duration of response (DOR), health-related quality of life (HRQoL), and safety.

All patients were subject to PD-L1 testing with the 22C3 pharDx assay. Patients who underwent testing prior to August 2018 (n = 235) were retested for PD-L1 expression ≥50%, per protocol, and grouped among those who had been tested after August 2018 (n = 475). A total of 563 patients with PD-L1 expression ≥50% comprised the PD-L1 ≥50% ITT population, wherein 283 received cemiplimab and 280 received chemotherapy.

Baseline characteristics were well balanced between arms in the ITT and PD-L1 ≥50% ITT populations. In the ITT population, 11.7% of patients had brain metastases at baseline, and 16.2% of patients had locally advanced disease, both populations which have been historically underrepresented in clinical trials of first-line PD-1/PD-L1 inhibitors, said Sezer.

Additional analysis from the PD-L1 ≥50% ITT population showed that the 12-month OS rate was 72.4% (95% CI, 65.6%-78.1%) in the cemiplimab arm versus 53.9% (95% CI, 46.2%-61.1%) in the chemotherapy arm. The 24-month OS rates were 50.4% (95% CI, 36.4%-62.9%) and 27.1% (95% CI, 13.7%-42.5%), respectively.

The 12-month PFS rate was 40.7% (95% CI, 33.7%-47.5%) in cemiplimab arm versus 7.1% (95% CI, 3.6%-12.1%) in the chemotherapy arm. The 18-month PFS rates were 27.8% (95% CI, 19.4%-36.7%) and NE, respectively.

At a median follow-up of 13.1 months in the ITT population, the median OS was 22.1 months (95% CI, 17.7–not estimable [NE]) with cemiplimab versus 14.3 months (95% CI, 11.7-19.2) with chemotherapy (HR, 0.68; 95% CI, 0.53-0.87; P = .0022).

The 12-month OS rate was 70.3% (95% CI, 64.4%-75.4%) in cemiplimab arm versus 55.7% (95% CI, 49.2%-61.7%) in the chemotherapy arm. The 24-month OS rates were 48.6% (95% CI, 39.2%-57.3%) and 29.7% (95% CI, 18.8%-41.4%), respectively.

The median PFS was 6.2 months (95% CI, 4.5-8.3) in the cemiplimab arm versus 5.6 months (95% CI, 4.5-6.1) in the chemotherapy arm (HR, 0.59; 95% CI, 0.49-0.72; P < .0001).

The 12-month PFS rate was 37.8% (95% CI, 31.9%-43.6%) in the cemiplimab arm versus 7.2% (95% CI, 4.3%-11.2%) in the chemotherapy arm. The 18-month PFS rates were 28.0% (95% CI, 21.7%-34.7%) and 3.9% (95% CI, 1.8%-7.5%), respectively.

“In both [the PD-L1 ≥50% ITT and ITT] populations, the PFS curves separate at approximately 6 months and remain well separated,” said Sezer.

All subgroups derived OS and PFS benefit from cemiplimab, with the exception of Asian patients (HR, 1.34; 95% CI, 0.52-3.42). However, the number of events in this subgroup is too small to draw a definitive conclusion from, said Sezer.

In the PD-L1 ≥50% ITT population, the ORR was 39.2% (95% CI, 33.5%-45.2%) in cemiplimab arm versus 20.4% (95% CI, 15.8%-25.6%) in the chemotherapy arm (P < .0001). The median DOR was 16.7 months (range, 12.5-22.8) in the cemiplimab arm versus 6.0 months (range, 4.3-6.5) in the chemotherapy arm.

In the ITT population, the ORR was 36.5% (95% CI, 31.5%-41.8%) in the cemiplimab arm versus 20.6% (95% CI, 16.5%-25.2%) in chemotherapy arm (P < .0001). The median DOR was 21.0 months (range, 14.9-NE) in the cemiplimab arm versus 6.0 months (range, 4.3-6.4) in the chemotherapy arm.

In the PD-L1 ≥50% ITT and ITT populations, patients in the cemiplimab and chemotherapy arms both had a median time to response of 2.1 months.

Investigators also evaluated the delta in target tumor volume and ORR with baseline PD-L1 levels and found that higher PD-L1 expression correlated with improved responses to cemiplimab but not chemotherapy. In patients with PD-L1 expression ≥90%, >60% to <90%, ≥50% to ≤60%, and 50% or unknown in the cemiplimab and chemotherapy arms, these rates were 45.9% vs 18.1%, 39.3% vs 20.0%, 32.3% vs 22.9%, and 26.0% vs 21.6%, respectively.

The PFS and OS curves favored cemiplimab, regardless of PD-L1 expression level. Moreover, higher PD-L1 expression was associated with improved PFS and OS to cemiplimab but not chemotherapy.

Regarding HRQoL, patients in the cemiplimab arm experienced a clinically meaningful improvement in Global Health Status/HRQoL, which was defined as at least a 10-point increase from baseline.

Among 355 patients who received cemiplimab, 139 remain on treatment and 6 completed treatment. A total of 210 patients discontinued treatment due to progressive disease (n = 133), death (n = 29), adverse effects (AEs; n = 23), patient decision (n = 9), withdrawn consent (n = 8), physician decision (n = 5), and lost follow-up (n = 3).

Among 342 patients who received chemotherapy, 45 remain on treatment and 149 completed treatment. A total of 148 patients discontinued treatment due to progressive disease (n = 84), death (n = 25), AEs (n = 14), patient decision (n = 7), withdrawn consent (n = 9), physician decision (n = 5), and lost follow-up (n = 4).

The majority of patients who progressed on chemotherapy (n = 150; 73.9%) received cemiplimab as a crossover treatment. Additionally, 31.6% of patients who progressed on cemiplimab (n = 50) received extended cemiplimab treatment with the addition of chemotherapy.

The median duration of treatment with cemiplimab was 27.3 months (range, 0.3-115.0) versus 17.7 months (range, 0.6-86.7) with chemotherapy.

Grade 3 or greater treatment-emergent AEs (TEAEs) occurred in 37.2% of patients in the cemiplimab arm versus 48.5% in the chemotherapy arm. Grade 3 or greater treatment-related AEs (TRAEs) occurred in 14.1% of patients in the cemiplimab arm versus 39.2% in the chemotherapy arm. Fatal TEAEs and TRAEs were comparable in both arms, at approximately 9.0% and 2.0%, respectively. 

Grade 3 or greater AEs that occurred in the cemiplimab and chemotherapy arms, respectively, included anemia (3.4% vs 16.4%), decreased appetite (0.6% vs 0.3%), fatigue (1.1% vs 1.5%), pneumonia (4.8% vs 5.6%), nausea (0% vs 1.2%), vomiting (0% vs 1.2%), thrombocytopenia (0% vs 8.2%), neutropenia (0.6% vs 10.2%), decreased platelet count (0% vs 3.5%), alopecia (0% vs 0.6%), peripheral neuropathy (0.3% vs 0.3%), and decreased neutrophil count (0.3% vs 5.3%).

“The safety profile of cemiplimab was consistent with the previously reported profile for cemiplimab and other PD-1/PD-L1 inhibitors in NSCLC and other tumor types,” said Sezer “Despite substantially longer exposure to cemiplimab, the safety profile of cemiplimab appeared to be better than chemotherapy.”

Reference:

Sezer A, Kilickap S, Gümüş 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%. Presented at: 2020 ESMO Virtual Congress; September 19-21, 2020; Virtual. Abstract LBA52.