First-line pembrolizumab plus chemotherapy prolongs survival in advanced non-small cell lung cancer with a high PD-L1 expression

Based on results of the phase III KEYNOTE-024 study, pembrolizumab is set to become the new standard first-line therapy for patients with advanced non-small cell lung cancer (NSCLC), expressing high levels of PD-L1. In this study including patients with a PD-L1 expression in at least 50% of tumor cells, pembrolizumab significantly improved the progression-free survival (PFS) as compared to chemotherapy. Moreover, the overall survival (OS) was also significantly better, with 70% of the pembrolizumab treated patients still alive after 12 months as compared to 54% in the chemotherapy-treated population.¹ In a second study investigating a PD-L1 inhibitor in the first-line treatment of advanced NSCLC (CheckMate 026 trial), researchers failed to show a PFS advantage for nivolumab over chemotherapy in patients with a PD-L1 expression in at least 5% of the tumor cells.²

Pembrolizumab is a PD-1 targeting antibody that is approved for the second-line treatment of patients with advanced NSCLC, expressing PD-L1 in their tumor cells. In KEYNOTE-024, a total of 305 untreated patients with advanced NSCLC and a PD-L1 tumor proportion score (TPS) of at least 50% (i.e. expressing PD-L1 in at least 50% of tumor cells) were randomly assigned to a treatment with pembrolizumab (200mg Q3W for 35 cycles), or 4 to 6 cycles of investigator’s choice of platinum-based doublet chemotherapy (cisplatin + pemetrexed, carboplatin or cisplatin + gemcitabine, carboplatin plus paclitaxel), with optional pemetrexed maintenance for non-squamous NSCLC patients. Patients with activating mutations in EGFR, ALK or ROS were not eligible for the trial.

After a median follow-up of 11.2 months, 48% of patients remained on treatment in the pembrolizumab arm as compared to 10% in the chemotherapy arm. In total, 44% of patients in the chemotherapy arm used the option to cross over to pembrolizumab. Patients in the pembrolizumab arm had a median PFS that was more than 4 months longer than patients in the chemotherapy arm (median PFS: 10.4 versus. 6.0 months; HR[95%CI]: 0.50[0.37-0.68], p< 0.001). After 12 months, 48% of patients on pembrolizumab was free of progression as compared to 15% of patients treated with chemotherapy. This PFS benefit also translated into a significant OS advantage for pembrolizumab. After 12 months, 70% of the patients in the pembrolizumab arm was still alive, while this was only the case for 54% in the chemotherapy treated population (median OS not reached in both arms, HR[95%CI]: 0.60[0.41-0.89]; p= 0.005). This OS benefit is even more remarkable taking into account the significant cross-over in this trial (50% cross-over: 44% in study, 6% to other anti-PD1/PD-L1 therapy).¹

Interestingly, also the incidence of grade 3/4 adverse events was lower with pembrolizumab than with chemotherapy: 26% versus. 51%. In total 11 patients (7%) discontinued pembrolizumab due to treatment-related AEs as compared to 16 (11%) in the chemotherapy arm.¹

In summary, pembrolizumab reduced the risk of disease progression by 50% as compared to chemotherapy. Moreover, the risk of dying was also reduced by 40%, despite 50% of cross-over in this trial. Based on these findings, pembrolizumab is likely to become the new standard first-line therapy for patients with advanced NSCLC with high PD-L1 expression, who do not harbor activating oncogenic driver mutations.

A second study investigating a PD-L1 checkpoint inhibitor in the first-line treatment of advanced NSCLC (CheckMate 026) failed to show a PFS advantage of nivolumab over chemotherapy. The big difference with KEYNOTE-024 and this trial is that the inclusion criteria for PD-L1 expression were far less stringent in CheckMate 026. In fact, CheckMate 026 included patients with a PD-L1 TPS of at least 1% as compared to 50% for KEYNOTE-024. Among the 423 patients with a TPS of at least 5% included in CheckMate 026, the median PFS was 4.1 months with nivolumab as compared to 5.9 months with chemotherapy (HR[95%CI]: 1.15[0.91-1.45]; p=0.25).² The OS was 14.4 months with nivolumab as compared to 13.2 months with chemotherapy. (HR[95%CI]: 1.02[0.80-1.30]). With respect to safety, no new toxicity signals were reported with nivolumab and it was less toxic than chemotherapy.

Commenting on CheckMate 026, prof. Johan Vansteenkiste (UZ Leuven) stated that the most probable reason for a lack of PFS advantage is the broad range of patients that was included in this trial, with a PD-L1 threshold of only 1% or more. The standard first-line treatment with platinum-doublet chemotherapy in this setting gives a median PFS of approximately 6 months. In order to improve this with a PD-1 inhibitor, a more stringent PD-L1 threshold is probably needed.

References

1. Reck M, Rodriguez-Abreu D, Robinson A et al. KEYNOTE-024: pembrolizumab (pembro) vs platinum-based chemotherapy (chemo) as first-line therapy for advanced NSCLC with a PD-L1 tumor proportion score (TPS) ≥50%. Presented at ESMO 2016; Abstract LBA8_PR.
2. Socinski M, Creelan B, Horn L et al. CheckMate 026: A phase 3 trial of nivolumab vs investigator’s choice (IC) of platinum-based doublet chemotherapy (PT-DC) as first-line therapy for stage IV/Recurrent programmed death ligand 1 (PD-L1)-positive NSCLC. Presented at ESMO 2016; Abstract LBA7_PR.