Statin-Specific Effects May Influence Immunotherapy Outcomes in Patients With Head and Neck Squamous Cell Carcinoma

Clinical Summary: 

• Design/Population: This large retrospective database study evaluated approximately 22,000 patients with mucosal head and neck squamous cell carcinoma treated with pembrolizumab or nivolumab to assess the association between concurrent statin use and overall survival. 
• Key Outcomes: Overall statin use was associated with a modest increase in mortality risk after adjustment, although residual confounding may have contributed to this finding. Statin specific-analysis showed differing associations, with rosuvastatin associated with a lower risk of death while atorvastatin showed a modestly unfavorable association.
• Clinical Relevance: These hypothesis-generating findings suggest that individual statins may have distinct associations with outcomes during immune checkpoint inhibitor therapy and support prospective investigation rather than considering statins as a single therapeutic class. 

Allen Khudaverdyan, MD, NYU Grossman School of Medicine, New York, New York, discusses results from a large retrospective analysis evaluating the association between concurrent statin use and overall survival in patients with head and neck squamous cell carcinoma treated with immune checkpoint inhibitors. 

The analysis identified differing survival associations among individual statin agents, with rosuvastatin associated with a lower risk of death despite no favorable association for statins overall. Dr Khudaverdyan discusses how different statin agents may warrant more nuanced investigation and emphasizes the need for prospective studies to determine whether these associations translate into clinically meaningful effects. 

Transcript: 

Hello, my name is Alan Khudaverdyan, I'm a medical student at the NYU Grossman School of Medicine. I'm a fourth year student applying into otolaryngology head and neck surgery. I've had an interest in head and neck cancer, specifically understanding resistance and adjuncts to therapies that we have in the case of resistant metastatic disease.

The project today that I'm talking about is entitled “Concurrent statin use and overall survival in immune checkpoint inhibitor-treated head and neck squamous cell carcinoma." This study was a large, retrospective database study. We used the Epic Cosmos database, the largest in the US, about 300 million patients, so we could be adequately powered. 

We ended up with about 22,000 patients who had mucosal head and neck cancer who had received either pembrolizumab or nivolumab. We defined our exposure as a couple of statin medication orders about a year before starting immunotherapy until about 6 months of immunotherapy, and then measured their overall survival from first dose until about 5 years. We used a time to event model, a Cox regression model, which we sequentially adjusted for various factors that might influence survival. 

Being an AMAR study, it comes with plenty of limitations as to the data itself and the database and how data is collected. We try and account for that as much as we can in a retrospective sense, but ultimately this is hypothesis generating work that we hope will motivate prospective work, especially randomized clinical trials.

Statin users overall are a different population than the average cancer population. They're older, they're sicker– it makes sense. The statin indications are cardiovascular disease, diabetes, dyslipidemia. At baseline, we expected that they're going to be sicker and that this will likely affect their mortality if we're just looking at overall survival. And that's what we see when we look at the unadjusted Kaplan-Meier survival curve. Statin users overall have worse survival starting pretty early on in a year up until 5 years. 

However, when we start sequentially adjusting for the various factors that might impact survival, demographics, the indications and the comorbidities of the patients, the cancers, the treatments, metabolic factors, etc, we find that demographics have a reduction in the hazard or improve the overall survival for statin users. 

When we sequentially adjust for cardiovascular mortality, we attenuate to that survival difference closer to a null between statin users and other cancer ICI patients. When we adjust for cancer treatment, like the use of chemotherapy, radiation or their stage of disease, we end up finding that it doesn't make a difference in the actual hazard ratio, likely because these patients are receiving similar cancer treatments– there's no real difference in how they're treated.

The overall effect of the statin use between these 2 patients ends up being slightly negative, very modestly about 1.08 hazard ratio. We think this is likely due to some residual confounding and limitations of using the database and adjusting retrospectively. There's likely something there maybe we're not catching, although it is also a possibility that is a real effect. 

The interesting part of the study comes when we look at the individual statin agents. The statin drug that had the largest response, the largest larger ratio of response, was rosuvastatin. When we look at our own data at the individual statin medications, which we can do because we have such a large population, we found that atorvastatin, the most common statin, a lipophilic statin, has a slightly negative effect, which dominates the classical effect. But when we look at rosuvastatin, a hydrophilic agent, they actually have a slightly reduced hazard of death and their hazard is about 0.87.

 We find that statin medications on themselves, depending on the specific type, may have different effects in terms of the cancer mortality. This sort of motivates a more nuanced understanding of the individual effects of each statin. We often think of them interchangeably in the literature, just use of any statin because we think of their broad level classical effects, but different statins have different tissue penetrants and understanding that difference or understanding the nuance there I think will be helpful in the prospective studies.

In conclusion, we found that although the class level effect of the statins in a large population on immunotherapy patients was slightly worse, likely due to underlying comorbidity and disease, the class level, the statin specific effects, show that rosuvastatin actual has a positive effect, which is kind of opposite what we expect. I think it's an interesting result and one that we are hopefully going to see maybe in the perspective studies.

Source: 

Khudaverdyan A, Jabban S, Morales EG, et al. Concurrent statin use and overall survival in immune checkpoint inhibitor‐treated mucosal head and neck squamous cell carcinoma: A multi‐institutional real‐world analysis. Head Neck. Published online: July 17, 2026. doi: 10.1002/hed.70398