McGahan, L. (2019): Pembrolizumab (Keytruda®) as first-line therapy for PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (NSCLC). DSD: Horizon Scanning in Oncology 91.
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Non-small cell lung cancer (NSCLC) arises when epithelial cells lining the bronchial tubes undergo aberrant cell growth due to up-regulation of programmed death (PD-1) ligands, thereby affording evasion of immune surveillance. Pembrolizumab, a monoclonal antibody, is an immune checkpoint inhibitor. By blocking PD-1 from binding its ligands, programmed death ligand (PD-L1) and programmed death 2 (PD-L2), pembrolizumab restores T-cell activation, enabling effective detection and destruction of tumour cells.
KEYNOTE-042, an ongoing, randomised, open-label, phase III trial compared the efficacy and safety of pembrolizumab (200 mg IV; every three weeks up to 35 cycles) versus platinum-based chemotherapy (carboplatin + paclitaxel or pemetrexed; up to six cycles) as first-line therapy for 1,274 patients with PD-L1-expressing metastatic NSCLC. Pembrolizumab increased overall survival (OS) by 7.8 months, 4.7 months, and 4.6 months for patients with PD-L1 tumour proportion scores (TPS) ≥50%, ≥20%, and ≥1%, respectively. The OS benefit of pembrolizumab over chemotherapy was demonstrated across three TPS populations; PD-L1 TPS ≥50% derived the greatest benefit (n=599 PD-L1 TPS ≥50%, HR 0.69, 95% CI 0.56–0.85 p=0.0003; n=818 PD-L1 TPS ≥20%, HR 0.77, 95% CI 0.64–0.92, p < 0.0020; n=1,274 PD-L1 TPS ≥1%, HR 0.81, 95% CI 0.71–0.93, p < 0.0018). An exploratory analysis found no OS benefit for those with PD-L1 TPS 1–49% (n=675, 13.4 months versus 12.1 months; HR 0.92, 95% CI 0.77–1.11, no statistically significant difference). No statistically significant differences in progression-free survival (PFS) or overall response rate (ORR) were noted between groups in any PD-L1 TPS population. Pneumonitis (8%) was the most frequently reported adverse event (AE) of grade ≥3 in severity. Common immune-mediated AEs occurring in pembrolizumab patients included hypothyroidism (12%), hyperthyroidism (6%), skin reactions (2%), colitis (1%) and hepatitis (1%).
Overall, first-line pembrolizumab monotherapy increases OS for patients with PD-L1-expressing metastatic NSCLC. Comprising 46.6% of the ITT population, the greatest OS benefit of pembrolizumab over chemotherapy was observed in patients with PD-L1 TPS ≥50%. No statistically significant difference in OS was noted between groups for those with PD-L1 TPS 1–49%; and no statistically significant differences in PFS or ORR were noted in any PD-L1 TPS population. Data regarding quality of life (QoL) and CNS activity are needed to ensure patients derive a clinically relevant benefit over time despite manageable toxicity. Further biomarkers are needed to ensure the appropriate patient selection and facilitate comparison with other immune checkpoint inhibitors. In the absence of direct comparison trials, physicians may need to discuss whether adding pembrolizumab to chemotherapy would provide greater individual efficacy than chemotherapy alone, especially for PD-L1 TPS 1–49% patients.
|Item Type:||DSD: Horizon Scanning in Oncology|
|Keywords:||Pembrolizumab, Keytruda, non-small cell lung cancer (NSCLC), metastatic, monoclonal antibody, first-line therapy, KEYNOTE-042|
|Subjects:||WB Practice of medicine > WB 300-962 Therapeutics|
QZ Pathology > QZ 200-380 Neoplasms.Cysts
WF Respiratory system
QV Pharmacology, toxicology, pharmacy > QV 60-370 Pharmacology
|Series Name:||DSD: Horizon Scanning in Oncology 91|
|Deposited on:||28 Oct 2019 14:12|
|Last Modified:||28 Oct 2019 14:12|
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