Survival and response outcomes in patients with recurrent/metastatic head and neck cancer treated with opioids and statins: an exploratory pilot study

Anti-PD-1 immune checkpoint blockade (ICB) is a common first-line treatment for patients with recurrent/metastatic head and neck cancer (HNC), but many patients fail to respond. There is a growing interest in the impact of concomitant medications on responses to ICB, with studies in other tumor types showing poor responses in patients taking opioid pain medications and modest improvements in response to ICB in patients taking statins for hyperlipidemia. Our previous preclinical and retrospective clinical data suggest that use of specific statin drugs is associated with increased responses to ICB in HNC, and emerging studies suggest that opioids may have the opposite effect. In this retrospective cohort study, pharmacy records were searched for patients with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) treated at our institution with pembrolizumab or nivolumab from 2015 to 2022. We recorded whether patients were taking opioid pain medications upon initiation of ICB or later during ICB therapy. Response to ICB was determined by reviewing routine surveillance imaging. A total of 158 patients met inclusion criteria; 102 were taking opioids, and 44 were taking statins. There was no difference in objective response rate (ORR) based on opioid use at the start of immunotherapy (P=0.74). There was also no significant difference in progression-free survival (PFS; P=0.14), though patients not taking opioids had superior overall survival (OS; median OS 20.67 versus 13.5 months in opioid users, P=0.002). Interestingly, use of both drugs together was associated with improved ORR odds ratio (OR) =2.8, and use of opioids without statins was associated with worse ORR (OR =0.34), though these results did not reach statistical significance (P=0.06). Patients taking both statins and opioids had superior PFS versus patients taking either drug class alone (P=0.02). Our data suggest a complex relationship between statins and opioids in HNSCC patients treated with ICB. Larger, prospective clinical studies are needed to verify these results, and preclinical studies are needed to determine how opioids and statins impact T-cell function and other aspects of the tumor microenvironment.