Pembrolizumab monotherapy for non-small cell lung cancer (NSCLC): can patient stratification be improved in the UK Tayside population? A retrospective cohort study.

OBJECTIVE: Pembrolizumab is a programmed cell death protein-1 (PD-1) inhibitor used to treat advanced patients with non-small cell lung cancer (NSCLC) with a programmed cell death ligand-1 (PD-L1) tumour proportion score (TPS) ≥50. Further sub-division of TPS-based stratification has not been evaluated in the UK, although smoking-induced tumour mutational burden and the immunogenic effects of prior radiotherapy are suggested to improve response. AIMS: To investigate if PD-L1 TPS ≥80%, smoking status or radiotherapy before or within 2 months of treatment influenced progression-free survival (PFS) in patients with NSCLC treated with pembrolizumab monotherapy. METHODS: PD-L1 TPS, smoking status and radiotherapy exposure were compared in patients with NSCLC in National Health Service (NHS) Tayside (n=100) treated with pembrolizumab monotherapy between 1 November 2017 and 18 February 2022. Survival estimates were compared using log-rank analysis, and Cox proportional hazards analysis was used to investigate the influence of potential confounding factors, including tumour stage and performance status. RESULTS: PFS was not significantly different (log-rank HR=0.330, p=0.566) comparing patients with PD-L1 TPS 50-79% and PD-L1 TPS ≥80%. Smokers had significantly improved PFS (log-rank HR=4.867, p=0.027), while patients receiving radiotherapy had significantly decreased PFS (log-rank HR=6.649, p=0.012). A Cox regression model confirmed that both radiotherapy (p=0.022) and performance status (p=0.009) were independent negative predictors of PFS. CONCLUSIONS: More rigorous PD-L1 TPS stratification did not influence survival outcomes. Smoking history improved PFS, although it was not an independent response predictor, while radiotherapy and performance status independently influenced clinical response. We suggest that further stratification of PD-L1 TPS is not warranted, while performance status and radiotherapy treatment may be additional clinically useful biomarkers of response to pembrolizumab in patients with NSCLC.

Unravelling the biology of human papillomavirus (HPV) related tumours to enhance their radiosensitivity.

HPV infection is associated with most squamous cell carcinomas (SCC) of the uterine cervix and many head and neck SCC. While recent understanding of the mechanisms of HPV-induced carcinogenesis has lead to the development of prophylactic vaccines, the principal modality of treatment is radiotherapy and despite concurrent chemotherapy, outcomes remain suboptimal. Improving the radiotherapeutic index thus remains an important challenge as well as defining predictive assays for treatment outcome of HPV-related tumours. Therefore elucidating the influence of the HPV virus on tumour radiosensitivity is of major interest due to the prevalence of HPV-related tumours worldwide and due to evidence that head and neck HPV-tumours have markedly different clinical outcomes compared to non-HPV-related tumours. This difference may allow for different treatment strategies to be developed. The present review aims to summarize the current understanding of radiosensitivity and HPV-related tumour biology in order to subsequently develop new approaches to enhance the therapeutic index. This review also emphasizes the relevance of E6 and E7 oncoproteins to tumour cell response to radiotherapy suggesting that specific targeted approaches such as concomitant modulation of additional pathways using targeted therapies should offer new therapeutic avenues.