Pembrolizumab Maintains Efficacy After 5 Years in First-Line, PD-L1+, Advanced NSCLC

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First-line pembrolizumab (Keytruda) demonstrated a sustained ability to produce 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.¹

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 of ≥ 50% compared with a lower TPS of either ≥ 20 or ≥ 1.

Of the 299 patients with a TPS of ≥ 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 a TPS ≥ 50% 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 ≥ 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 ≥ 50% 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 ≥ 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 ≥ 20% 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 ≥ 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.

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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.

_REFERENCE:

_{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}