Longer survival with first-line pembrolizumab compared to platinum-based chemotherapy in patients with NSCLC and a PD-L1 tumour proportion score of 1% or more

In KEYNOTE-024, pembrolizumab significantly improved the progression-free (PFS) and overall survival (OS) compared to chemotherapy as first-line therapy for metastatic non-small-cell lung cancer (NSCLC) without targetable alterations and a PD-L1 tumour proportion score (TPS) of 50% or more. Data from the KEYNOTE-042, presented in the plenary session of ASCO 2018, indicate that pembrolizumab also prolongs the survival of advanced, or metastatic NSCLC with lower levels of PD-L1 expression. In fact, patients with advanced NSCLC and a TPS of 1% or more, first treated with pembrolizumab lived a median of 4-8 months longer than those who received chemotherapy. Moreover, severe side effects occurred in fewer patients receiving pembrolizumab than in those treated with chemotherapy (18% vs. 41%). As such, these data indicate that pembrolizumab is a viable first-line treatment option for a much larger group of patients than previously thought.

In KEYNOTE-042, 1,274 patients with locally advanced or metastatic NSCLC were randomized to receive either pembrolizumab (200 mg Q3W), or investigator’s choice of chemotherapy (≤6 cycles of paclitaxel + carboplatin or pemetrexed + carboplatin with optional pemetrexed maintenance [non-squamous only]). The randomisation was stratified by region (east Asia vs. non-east Asia), ECOG performance status (0 vs. 1), histology (squamous vs. non-squamous), and TPS (≥50% vs. 1-49%). For the analysis, researchers explored treatment benefits in three patient groups according to the TPS: at least 50% (N= 599), at least 20% (N= 818) and at least 1% (N= 1,274).

After a median follow-up of 12.8 months, patients treated with pembrolizumab had a statistically longer median OS than patients in the chemotherapy arm, regardless of PD-L1 expression in the tumour. Among patients with a TPS ≥1%, the median OS with pembrolizumab was 16.7 months. This was 4.6 months longer than the 12.1 months seen with chemotherapy (HR[95%CI]: 0.81[0.71-0.93]; p= 0.0018). At two years, 39.3% of patients in the pembrolizumab arm were still alive as compared to 28% in the chemotherapy cohort. The survival benefit with pembrolizumab grew with an increasing TPS. In fact, patients with a TPS ≥20% had a median OS of 17.7 months with pembrolizumab vs. 13 months with chemotherapy (HR[95%CI]: 0.77[0.64-0.92]; p= 0.0020). Patients with the highest TPS (≥50%) had a median OS of 20 months with pembrolizumab as compared to 12.2 months with chemotherapy (HR[95%CI]: 0.69[0.56-0.85]; p= 0.0003). The objective response rate (ORR) with pembrolizumab increased as well with a higher TPS from 27.3% in the ≥1% cohort to 33.4% and 39.5% in patients with a TPS of ≥20% and ≥50, respectively (ORR with chemotherapy in these three populations were 26.5%, 28.9% and 32,0%, respectively). The responses seen with pembrolizumab in this trial also proved to be much more durable than the responses obtained with chemotherapy. In the entire study population (TPS ≥1%), the median duration of response was 20.2 months with pembrolizumab as compared to 8.3 months with chemotherapy.

Also with respect to safety, pembrolizumab outperformed chemotherapy. The incidence of grade 3-5 adverse events was only 17.8% in the pembrolizumab treated patients, while this was 41% in the chemotherapy arm. The treatment discontinuation due to adverse events was similar in both arms at approximately 9%. Grade 3-5 immune mediated adverse events were reported in 8% of the pembrolizumab treated patients (vs. 1.5% with chemotherapy), with one fatal case of pneumonitis.

In summary, pembrolizumab significantly improved the OS compared to platinum-based chemotherapy as first-line therapy for advanced/metastatic NSCLC with PD-L1 TPS ≥50%, ≥20%, and ≥1%. The magnitude of the pembrolizumab benefit increased with higher levels of PD-L1 expression. This is consistent with previous studies of pembrolizumab monotherapy in metastatic NSCLC. Given the overall efficacy and safety profile, pembrolizumab monotherapy is a standard-of-care first-line therapy for PD-L1–expressing, locally advanced or metastatic, squamous or non-squamous NSCLC without sensitizing EGFR mutations or an ALK translocation. It is not yet clear whether pembrolizumab combined with chemotherapy is better than pembrolizumab alone in patients who express PD-L1, as there has not yet been a head-to-head comparison trial of the two approaches. On-going research is exploring the use of pembrolizumab after surgery (adjuvant) and combinations of immunotherapy with bevacizumab-containing combination regimens as part of initial therapy for NSCLC.

Reference

Lopes G, Wu Y-L, Kudaba I, et al. Pembrolizumab (pembro) versus platinum-based chemotherapy (chemo) as first-line therapy for advanced/metastatic NSCLC with a PD-L1 tumor proportion score (TPS) ≥ 1%: Open-label, phase 3 KEYNOTE-042 study. Presented at ASCO 2018; Abstract LBA4.