PD-L1 expression determines the level of clinical benefit derived from first-line cemiplimab in patients with advanced non-small cell lung cancer

The phase III EMPOWER-Lung 1 study previously demonstrated superior anti-tumour activity of cemiplimab compared to chemotherapy in advanced non-small cell lung cancer (NSCLC). A post-hoc analysis of this study, reported at WCLC 2020, indicates that the clinical benefit derived from cemiplimab is closely linked to the level of PD-L1 expression.

Introduction

PD-1 blockade, with or without chemotherapy, has become the standard of care in the frontline treatment of advanced non-small cell lung cancers (NSCLC) that do not harbour oncogenic driver mutations. The phase III EMPOWER-Lung 1 study previously established the anti-tumour activity of the anti-PD1 antibody cemiplimab and showed a superior overall (OS) and progression-free survival (PFS), as well as a higher objective response rate (ORR) and a longer duration of response (DoR), compared to chemotherapy, in treatment-naïve, advanced NSCLC. In a subsequent presentation on this study (at ESMO 2020) it was shown that patients with ≥50% PD-L1 expression who received cemiplimab had better survival outcomes. the clinical significance of PD-L1 expression above 50% remains unclear.

The trial randomised (1:1) 710 patients who had a PD-L1 expression ≥50% to receive either cemiplimab (350 mg every 3 weeks) or 4-6 cycles of platinum doublet chemotherapy. Upon disease progression, continuation of cemiplimab was permitted and crossover was allowed. In this post-hoc analysis, the clinical benefits of cemiplimab, compared to chemotherapy, were assessed by PD-L1 tertiles in a randomised sub-group cohort (N= 475) with ≥50% PD-L1 expression, assessed via 22C3 assay.

Greatest objective response rate observed in PD-L1 ≥90

In the cemiplimab arm (N= 238), 33.6%, 31.9% and 34.5% of patients had PD-L1 expression ≥90%, >60 to <90% and ≥50 to ≤60%, respectively. Corresponding levels of expression in the chemotherapy arm (N=237) were 34.2%, 30.4% and 35.4%, respectively. In this analysis, PD-1 expression tertiles were positively correlated with incremental OS, PFS and ORR benefits, compared to chemotherapy, with the greatest ORR difference observed in the PD-L1 ≥90% subgroup (PD-L1 ≥90% OS: NR vs. 13.3 months, HR[95%CI]: 0.54[0.27-1.10]; PFS: 12.7 vs. 6.1 months, HR[95%CI]: 0.33[0.19-0.58]; ORR: 38.8% vs. 14.8%), (PD-L1 >60% to <90% OS: NR vs. 14.2 months, HR[95%CI]: 0.49[0.26-0.92]; PFS: 6.2 vs. 4.3 months, HR[95%CI]: 0.57[0.38-0.85]; ORR: 39.5% vs. 16.7%), (PD-L1 ≥50% to ≤60% OS: NR vs. 11.7 months, HR[95%CI]: 0.74[0.44-1.24]; PFS: 4.3 vs. 6.0 months, HR[95%CI]: 0.89[0.61-1.29]; ORR: 28.0% vs. 21.4%). PD-L1 expression levels were also correlated with tumour size reduction in patients who received cemiplimab, with the greatest reduction observed in patients with ≥90% PD-L1 expression.

The most common ≥grade 3 adverse events (AEs) with cemiplimab compared to chemotherapy were anaemia (3.4% vs. 16.4%), decreased appetite (0.6% vs. 0.3%), fatigue (1.1% vs. 1.5%) and pneumonia (4.8% vs. 5.6%). Haematological AEs were more common with chemotherapy and the safety profile observed with cemiplimab was comparable to previous safety findings.    

Conclusion

Overall, the results of the EMPOWER-Lung 1 study show that cemiplimab monotherapy is superior to chemotherapy in advanced NSCLC patients, and that the benefit derived from this therapy is incrementally associated with PD-L1 expression. The findings of this post-hoc analysis support the use of PD-L1 expression as a patient identifier tool to select patients who might derive the most benefit from cemiplimab monotherapy.

Reference

Kilickap S et al,. EMPOWER-Lung 1: Clinical benefits of first-line (1L) cemiplimab monotherapy by PD-L1 expression levels in patients with advanced NSCLC. Presented at WCLC 2020. Abstract OA01.03.