The anti-PD-1-antibodies pembrolizumab and nivolumab have been shown to be active in lung cancer. Pembrolizumab is a high-affinity, humanised, monoclonal IgG4κ antibody against PD-1 that prevents the interaction of the receptor with PD-L1 and PD-L2.
The KEYNOTE-001 trial demonstrated significant anti-tumour activity of pembrolizumab in advanced NSCLC, with improved outcomes in terms of PD-L1 Tumor Proportion Scores (TPS) ≥ 50 % . The TPS reflects the expression of PD-L1 on the tumour. The ≥ 50 % cut-off was determined using independent training and validation datasets from KEYNOTE-001.
Pembrolizumab is approved in the US for treatment of patients with advanced, PD-L1–positive NSCLC that has progressed after platinum-containing chemotherapy and appropriate TKI therapy for EGFR or ALK genomic aberrations.
Additional data are provided by the randomised phase II/III KEYNOTE-010 trial, which included patients with PD-L1-positive advanced NSCLC and disease progression after at least one line of chemotherapy . Two doses of pembrolizumab (2 mg/kg every 3 weeks, or 10 mg/kg every 3 weeks, for 24 months) were compared with docetaxel (75 mg/m2 every 3 weeks, per local guidelines). Patients had to be PD-L1 positive. A TPS of ≥ 1 % was one of the inclusion criteria, and PD-L1 status was a stratification factor (i.e., TPS ≥ 50 % vs. 1 %–49 %). The following endpoints were assessed separately for the TPS ≥ 50 % and TPS ≥ 1 % groups: PFS and OS (co-primary), objective response rate (ORR), duration of response, and safety (secondary).
The screening included 2,699 patients, 1,475 of whom were PD-L1 positive with TPS ≥ 1 %. Initially, both archival biopsies and new tissue samples were allowed for the tumour analysis, although after an amendment, new tumour samples had to be used unless the risk of a biopsy was considered too high. Overall, 456 out of 1,034 randomised patients participated in the trial based on archival samples. Approximately 20 % in each arm had squamous-cell carcinoma. EGFR mutations were found in 8 %, 9 % and 8 % of patients treated with pembrolizumab 2 mg/kg, 10 mg/kg, and docetaxel, respectively. The analysis revealed a PD-L1 TPS of ≥ 50 % and 1 %–49 % in approximately 40 % and 60 % of the patients, respectively, across the treatment arms. Twenty percent to 30 % of the patients received the study treatment as third line or later lines.
Outcome improvements in patients with TPS ≥ 1 %
In the TPS ≥ 50 % group, pembrolizumab treatment at both doses gave rise to highly significant OS benefits compared to docetaxel chemotherapy (HR, 0.54, 0.50 with 2 mg/kg, 10 mg/kg, respectively; p = 0.0002, p < 0.0001, respectively). The median survival rates obtained with pembrolizumab were nearly doubled compared to docetaxel. The results for the TPS ≥ 1 % group were of particular interest, as these represented the majority of the patients. Again, the two pembrolizumab doses showed similar activities (Figure), with the mortality risk reduced by 29 % and 39 %, respectively, compared to docetaxel (p = 0.0008, p < 0.0001, respectively). The OS benefit emerged early on. All of the subgroups (i.e., sex, age, ECOG performance status, tumour sampling [archival vs. new], histology, EGFR status) benefited from the pembrolizumab treatment. This advantage of pembrolizumab also applied to both of the TPS groups (≥ 50 % vs. 1 %–49 %), which is relevant for treatment decisions.
For PFS, the analysis also favoured pembrolizumab treatment to a significant extent in both of the TPS groups. For the TPS ≥ 50 % group, the HRs were 0.59 for both pembrolizumab doses compared to docetaxel (p = 0.0001, p < 0.0001, respectively). For the TPS ≥ 1 % group, the HRs were 0.88 and 0.79, respectively (p = 0.07, p = 0.004, respectively). The response rates were highly significantly improved in the TPS ≥ 50 % group (30 %, 29 % vs. 8 %; p < 0.0001 for both comparisons), as well as in the TPS ≥ 1 % group (18 % for both pembrolizumab doses vs. 9 % for docetaxel; p = 0.0005, p = 0.0002, respectively). Also, the duration of these responses was considerably longer with both pembrolizumab doses than with docetaxel, irrespective of TPS.