Pembrolizumab immunotherapy in the 1st-line NSCLC

In the open-label Phase II KEYNOTE-021 study, the addition of pembrolizumab to carboplatin and pemetrexed in patients with non-squamous NSCLC (N=123) improved the overall response rate (ORR) to 55% from 29% with the doublet alone (P=0.0032). An improvement regardless of PD-L1 expression. The median progression-free survival (PFS) was 13.0 months with the addition of pembrolizumab vs 8.9 months for the pemetrexed/carboplatin doublet (HR=0.53, P=0.0205, 95% CI, 0.31-0.91). Patients in the pembrolizumab arm continued to receive the immunotherapy up to 24 months. After a median 10.6 months follow-up, 88% of patients in the experimental-arm remained alive and progression-free compared to 78% of patients receiving the doublet.

The multi-centre, double-blind, Phase III KEYNOTE-189 trial confirmed the early results of the KEYNOTE-021 study. In the KEYNOTE-189 study, 616 EGFR- or ALK-negative non-squamous NSCLC patients were randomised 2:1 to receive frontline pembrolizumab or placebo in combination with pemetrexed and a platinum salt. The co-primary endpoints of improved overall survival (OS) and PFS were met and published in the New England Journal of Medicine in April 2018.

Single-agent pembrolizumab

At a median follow-up of 25.2 months in the open-label KEYNOTE-024 study, pembrolizumab more than doubled median OS compared to platinum-based chemotherapy in 154 NSCLC patients with a PD-L1 expression ≥50% and negative EGFR- or ALK-status. Single-agent pembrolizumab led to a 30.2 months OS vs 14.2 months with chemotherapy (HR=0.63, P=0.002; 95% CI, 0.47-0.86) despite the crossover of 82 patients from the chemotherapy-arm to the pembrolizumab-arm. The 24-month OS-rate favoured pembrolizumab vs platinum doublet: 51.5% vs 34.5% respectively and the ORR was 45.5% in the pembrolizumab-arm compared to 29.8% in the chemotherapy-arm.

Common pembrolizumab-related side effects.

Durvalumab for maintenance after frontline chemoradiotherapy in NSCLC

The phase III PACIFIC trial (N=709) randomised patients 2:1 to either receive durvalumab or placebo after chemoradiotherapy. Durvalumab-maintenance therapy was associated with improved median PFS, 16.8 months in the durvalumab-group vs 5.6 months in the placebo group (HR=0.52, P<0.0001; 95% CI, 0.42-0.65). The 12-month and 18-month PFS-rates both favoured the immunotherapy: 55.9% (durvalumab) vs 35.3% (placebo) and 44.2% (durvalumab) vs 27.0% (placebo) respectively, and was irrespective of PD-L1 expression before chemoradiotherapy. Durvalumab treatment was associated with a higher ORR of 28.4% vs 16.0% with placebo. Patients with a response to the immune-checkpoint inhibitor had durable, ongoing responses of 72.8% at both 12 and 18 months. In the placebo-arm, the 12- and 18-month ORRs were 56.1% and 46.8%, respectively.

Common durvalumab-related side effects.