Pembrolizumab Sustains Efficacy at 5 Years in First-Line, PD-L1+, Advanced NSCLC


Findings from the 5-year follow-up analysis of the phase 3 KEYNOTE-042 study continue to support frontline pembrolizumab as standard of care for PD-L1-positive, locally advanced/metastatic non–small cell lung cancer (NSCLC).

A version of this article was originally published on Targeted Oncology. This version has been lightly edited.

A study published in the Journal of Clinical Oncology found that first-line immunotherapy with pembrolizumab (Keytruda) demonstrated a long-term overall survival (OS) benefit and durable responses compared with chemotherapy in patients with PD-L1-positive, locally advanced/metastatic non–small cell lung cancer (NSCLC) without EGFR/ALK alterations.

The efficacy of pembrolizumab was shown regardless of patients’ PD-L1 tumor proportion scores. These findings solidify the role of pembrolizumab as standard-of care for patients with previously untreated PD-L1-positive, advanced or metastatic NSCLC, according to investigators of the phase 3 KEYNOTE-042 study (NCT02220894), led by Gilberto de Castro Jr, MD, PhD of the Instituto do Cancer do Estado de Sao Paulo.

KEYNOTE-042 was a randomized, open-label, phase 3 study that compared pembrolizumab to the platinum-based chemotherapy combination of carboplatin, paclitaxel, and pemetrexed. Patients in the experimental arm of the study received pembrolizumab 200 mg intravenously (IV) on day 1 of each 21-day cycle for up to 35 rounds. In the comparator arm, patients received IV carboplatin at a minimum dose of 900 mg on day 1 of every 21-day cycles, along with IV paclitaxel 200 mg/m2, pemetrexed 500 mg/m2 of day 1, every 3 weeks.

Patients in the study were evaluated for the primary end point of OS by tumor proportion score (TPS). The secondary end points were progression-free survival (PFS) by TPS, objective response rate (ORR) by TPS, the number of patients with a minimum of 1 adverse event (AE), and the number of patients who discontinued study treatment because of an AE.

Results reported were from 1274 patients from the intent-to-treat (ITT) population. Outcomes appeared better in patients with a higher TPS (at least 50%) compared with a lower TPS of at least 20% or at least 1%.

Of the 299 patients with a TPS of at least 50%, the median TPS was 20.0 months (95% CI, 15.9-24.2 months) with pembrolizumab compared with 12.2 months (95% CI, 10.4-14.6 months) with chemotherapy (HR, 0.68; 95% CI, 0.57-0.81). At 5 years, the OS rate observed in the pembrolizumab arm among patients with high TPS was 21.9% (95% CI, 17.3%-26.9%) vs 9.8% (95% CI, 6.6%-13.7%) in the chemotherapy arm.

The median PFS observed in patients with a TPS of at least 50% was 6.5 months (95% CI, 5.9-8.6 months) with pembrolizumab compared with 6.5 months (95% CI, 6.2-7.6 months) with chemotherapy (HR, 0.86; 95% CI, 0.72-1.02). The 5-year PFS rate in the pembrolizumab arm vs the chemotherapy arm in the PD-L1 TPS of 50% or higher group was 9.2% (95% CI, (5.9%-13.4%) vs 2.1% (95% CI, 0.7%-5.0%), respectively.

In terms of tumor response among patients with a PD-L1 TPS of at least 50%, the ORR was 39.1% (95% CI, 33.6%-44.9%) in the pembrolizumab arm compared with 32.3% (95% CI, 27.1%-37.9%) with chemotherapy.

Patients with a PD-L1 TPS of 20% or higher also had favorable survival and response outcomes to treatment with pembrolizumab. The median OS observed in the pembrolizumab arm was 18.0 months (95% CI, 15.5-21.5 months) compared with 13.0 months (95% CI, 11.6-15.3 months) with chemotherapy (HR, 0.75; 95% CI, 0.64-0.87). The 5-year OS rate was 19.4% (95% CI, 15.6%-23.4%) with pembrolizumab vs 10.1% (95% CI, 7.2%-13.5%) in the chemotherapy arm. In terms of PFS, the median was 6.2 months (95% CI, 5.4-7.8 months) with pembrolizumab treatment compared with 6.9 months (95% CI, 6.3-8.2 months) with chemotherapy (HR, 0.94; 95% CI, 0.81-1.09). At the 5-year mark, the PFS rates in the pembrolizumab arm vs the chemotherapy arm were 7.8% (95% CI, 5.2%-11.1%) compared with 1.6% (95% CI, 0.5%-3.9%), respectively.

Patients in the PD-L1 TPS at least 20% population treated with pembrolizumab achieved an ORR of 33.2% (28.6%-37.9%) vs 29.1% (95% CI, 24.8%-33.8%) in the chemotherapy arm.

In the PD-L1 TPS ≥ 1 group, patients had a median OS of 16.4 months (95% CI, 14.0-19.6 months) with pembrolizumab vs 12.1 months (95% CI, 11.3-13.3 months) with chemotherapy (HR, 0.79; 95% CI, 0.70-0.89). At 5 years, the OS rate observed in patients treated with pembrolizumab was 16.6% (95% CI, 13.7%-19.6%) compared with 8.5% (95% CI, 6.4%-11.0%) with chemotherapy. Median PFS in this group was 5.6 months (95% CI, 4.3-6.2 months) in the pembrolizumab arm vs 6.8 months (95% CI, 6.4-7.9 months) in the chemotherapy arm (HR, 1.03; 95% CI, 0.91-1.16) with a 5-year PFS rate of 6.9% (95% CI, 4.9%-9.4%) vs 1.2% (95% CI, 0.5%-2.7%).

The ORR observed with pembrolizumab in the PD-L1 TPS ≥ 1 group was 27.3% (95% CI, 23.9%-31.0%) compared with 26.7% (95% CI, 23.3%-30.3%) in the chemotherapy arm.

Median duration of response was similar in each PD-L1 TPS group and was longer for patients treated with pembrolizumab compared with those who received chemotherapy. Time to response was also similar across the PD-L1 TPS groups.

For safety, treatment-related AEs (TRAEs) occurred in ≥ 10 of patients in either treatment arm. Specifically, 63.8% of the pembrolizumab arm experienced TRAEs compared with 90.2% of the chemotherapy arm. The most common TRAEs observed in the pembrolizumab arm vs the chemotherapy arm included hypothyroidism (10.8% v 0.3%), fatigue (8.0% v 16.7%), decreased appetite (6.3% v 17.6%), and anemia (5.5% v 38.0%). No patient died as a result of TRAEs.

Immune-mediated AEs and infusion reactions were seen in 27.5% of patients in the pembrolizumab arm compared with 7.6% of the chemotherapy arm. Finally, exposure-adjusted TRAEs and immune-mediated AEs occurred in 61.8% of the pembrolizumab arm.

Overall, the safety profile of pembrolizumab was manageable and no new safety signals were observed, according to de Castro et al.


de Castro G, Kudaba I, Wu Y, et al. Five-year outcomes with pembrolizumab versus chemotherapy as first-line therapy in patients with non–small-cell lung cancer and programmed death ligand-1 tumor proportion score ≥ 1% in the KEYNOTE-042 study. J Clin Oncol. 2023;41(11):1986-1991. doi:10.1200/JCO.21.02885

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