Results of the KEYNOTE-042 study – the largest clinical trial of the immunotherapy drug pembrolizumab as a standalone therapy, have demonstrated pembrolizumab to be more effective in most patients with the most common form of lung cancer, in comparison to the current standard-of-care, namely, chemotherapy.
The findings of this randomized, Phase III trial were presented in the plenary session of ASCO 2018, having been chosen as one of four studies (out of more than 5800 abstracts) ‘deemed to have the greatest potential impact on patient care’. Investigators discovered that advanced NSCLC patients with a PD-L1 expression of ≥1% and first treated with pembrolizumab immunotherapy lived a median of 4-8 months longer compared with patients who received chemotherapy. Furthermore, investigators found that fewer patients who were treated with pembrolizumab experienced severe side effects in comparison to patients on chemotherapy (18 vs 41%).
In the Merck-funded, KEYNOTE-042 study, 1274 patients were randomly assigned to receive chemotherapy or pembrolizumab. The patients had locally advanced or metastatic NSCLC and the chemotherapy regimen was paclitaxel plus carboplatin, or pemetrexed plus carboplatin. Squamous and non-squamous cancers were included in the trial, and cancers with genetic changes treatable with targeted therapies were excluded.
PD-L1 is often used to predict response to immune checkpoint inhibitors, and in general, tumors with a higher expression of PD-L1 respond more effectively to these treatments. However, some studies have demonstrated that such immunotherapies were even effective against tumors with little or no detectable PD-L1. Treatment benefits were examined in three patient groups: 1) patients with a tumor PD-L1 expression score of at least 50%, 2) patients with a tumor PD-L1 expression score of at least 20%, and c) patients with a tumor PD-L1 expression score of at least 1%.
The median follow-up time was 12.8 months, and results demonstrated that, regardless of the extent of PD-L1 expression in the tumor, overall survival was longer in patients treated with pembrolizumab in comparison to those treated with chemotherapy. In the PD-L1 50% or more group, overall survival was 20 months with pembrolizumab and 12.2 months with chemotherapy; in the PD-L1 20% or more group, overall survival was 17.7 months with pembrolizumab and 13 months with chemotherapy; and in the PD-L1 1% or more group, overall survival was 16.7 months with pembrolizumab and 12.1 months with chemotherapy.
Pembrolizumab was approved by the FDA for ‘initial treatment of NSCLC with high PD-L1 expression (score of at least 50%)’, and this approval was based on results of an earlier and smaller clinical trial – KEYNOTE-024. At present, pembrolizumab is the only immunotherapy approved for the initial treatment of lung cancer and is approved for use as a standalone treatment, as well as in combination with chemotherapy.
Gilberto Lopes, the lead study author explained, “A large number of patients with lung cancer now have a new treatment option with better efficacy and few side effects than standard chemotherapy. Our study shows that pembrolizumab provides more benefit than chemotherapy for two-thirds of all people with the most common type of lung cancer.”
This research doesn’t end here. There are certainly further avenues that will need to be explored, for example, to define specific patient groups that will benefit from pembrolizumab, as currently, the three groupings used in the KEYNOTE-042 study are not specific enough. Additionally, no head-to-head comparison trials have yet been carried out to look at whether combination of pembrolizumab and chemotherapy is better than pembrolizumab alone, in PD-L1-expressing patients. Other research in the area of pembrolizumab use after adjuvant surgery, and other possible treatment combinations for initial NSCLC therapy are ongoing.