First-line treatment with pembrolizumab (Keytruda) has demonstrated long-term survival benefits and durable responses in patients with PD-L1-positive, locally advanced or metastatic non-small cell lung cancer (NSCLC) without EGFR/ALK alterations, surpassing the efficacy of chemotherapy. These findings, derived from the Phase III study (NCT02220894) led by Dr. Gilberto de Castro Jr. of the Instituto do Câncer do Estado de São Paulo, established pembrolizumab as the standard of care for previously untreated patients with PD-L1-positive advanced or metastatic NSCLC.
The study compared pembrolizumab with a platinum-based chemotherapy combination of carboplatin, paclitaxel, and pemetrexed. Patients in the experimental arm received pembrolizumab intravenously (200 mg) on day 1 of each 21-day cycle for up to 35 cycles. In the comparator arm, patients received intravenous carboplatin (at least 900 mg) on day 1 of every 21-day cycle, along with intravenous paclitaxel (200 mg/m2) and pemetrexed (500 mg/m2) on day 1 of every 3 weeks.
The primary endpoint of overall survival (OS) was evaluated based on the tumor proportion score (TPS) of patients, while secondary endpoints included progression-free survival (PFS), objective response rate (ORR), adverse events (AEs), and treatment discontinuation due to AEs.
The reported results are based on an intent-to-treat (ITT) population of 1274 patients. Patients with a higher TPS (≥ 50%) experienced superior outcomes compared to those with lower TPS (≥ 20 or ≥ 1).
Among the 299 patients with a TPS ≥ 50%, pembrolizumab demonstrated a median OS of 20.0 months (95% CI, 15.9-24.2 months) compared to 12.2 months (95% CI, 10.4-14.6 months) with chemotherapy (HR, 0.68; 95% CI, 0.57-0.81). At the 5-year mark, the OS rate for patients in the pembrolizumab group with a TPS ≥ 50% was 21.9% (95% CI, 17.3%-26.9%), while it was 9.8% (95% CI, 6.6%-13.7%) in the chemotherapy group.
The median PFS in patients with a TPS ≥ 50% was 6.5 months (95% CI, 5.9-8.6 months) for pembrolizumab and 6.5 months (95% CI, 6.2-7.6 months) for chemotherapy (HR, 0.86; 95% CI, 0.72-1.02). The 5-year PFS rate for patients with a TPS ≥ 50% was 9.2% (95% CI, 5.9%-13.4%) in the pembrolizumab arm, whereas it was 2.1% (95% CI, 0.7%-5.0%) in the chemotherapy arm.
In a study conducted by de Castro et al., promising results were observed in the treatment of patients with a PD-L1 TPS (tumor proportion score) ≥ 20% using pembrolizumab compared to chemotherapy. The study found that patients treated with pembrolizumab achieved an overall response rate (ORR) of 33.2% (28.6%-37.9%), while the ORR in the chemotherapy arm was 29.1% (95% CI, 24.8%-33.8%).
Furthermore, in the PD-L1 TPS ≥ 1 group, patients treated with pembrolizumab had a median overall survival (OS) of 16.4 months (95% CI, 14.0-19.6 months) compared to 12.1 months (95% CI, 11.3-13.3 months) with chemotherapy. The hazard ratio (HR) for OS was 0.79 (95% CI, 0.70-0.89), indicating a significant improvement with pembrolizumab. At the 5-year mark, the OS rate for pembrolizumab-treated patients was 16.6% (95% CI, 13.7%-19.6%) compared to 8.5% (95% CI, 6.4%-11.0%) for chemotherapy. In terms of progression-free survival (PFS), the median PFS was 5.6 months (95% CI, 4.3-6.2 months) for pembrolizumab and 6.8 months (95% CI, 6.4-7.9 months) for chemotherapy (HR, 1.03; 95% CI, 0.91-1.16), with a 5-year PFS rate of 6.9% (95% CI, 4.9%-9.4%) and 1.2% (95% CI, 0.5%-2.7%), respectively.
The ORR in the PD-L1 TPS ≥ 1 group was 27.3% (95% CI, 23.9%-31.0%) for pembrolizumab and 26.7% (95% CI, 23.3%-30.3%) for chemotherapy, showing comparable efficacy between the two treatment approaches.
Regarding safety, treatment-related adverse events (TRAEs) occurred in ≥ 10% of patients in either treatment arm. Specifically, 63.8% of patients in the pembrolizumab arm experienced TRAEs compared to 90.2% in the chemotherapy arm. The most common TRAEs observed in the pembrolizumab arm were hypothyroidism (10.8% vs. 0.3% in the chemotherapy arm), fatigue (8.0% vs. 16.7%), decreased appetite (6.3% vs. 17.6%), and anemia (5.5% vs. 38.0%). Importantly, no treatment-related deaths occurred.
Immune-mediated adverse events (AEs) and infusion reactions were seen in 27.5% of patients in the pembrolizumab arm compared to 7.6% in the chemotherapy arm. Overall, pembrolizumab demonstrated a manageable safety profile, with no new safety concerns reported.
In summary, the study conducted by de Castro et al. highlighted the efficacy of pembrolizumab in the treatment of patients with PD-L1 TPS ≥ 20%, showing improved ORR, OS, and PFS compared to chemotherapy. The safety profile of pembrolizumab was generally acceptable, and manageable.
