Highlights
Neoadjuvant immune checkpoint inhibition (ICI) is an emerging paradigm in the management of resectable mucosal head and neck squamous cell carcinoma (HNSCC). This systematic review and meta-analysis highlights several critical insights into the relationship between pathologic response and clinical outcomes:
- Partial Pathologic Response (PPR), defined as 50% or less residual viable tumor, is significantly associated with improved disease-free survival (DFS) (HR, 0.53; 95% CI, 0.28-0.97).
- Major Pathologic Response (MPR), defined as 10% or less residual viable tumor, demonstrates an even stronger association with improved DFS (HR, 0.34; 95% CI, 0.12-0.93).
- While pathologic response is a strong surrogate for DFS up to two years, it has not yet shown a statistically significant association with overall survival (OS) in the current cohort of trials.
- The results provide robust evidence supporting the use of pathologic response as a primary or secondary endpoint in future neoadjuvant immunotherapy clinical trials.
Background: The Challenge of Resectable Mucosal HNSCC
Mucosal head and neck squamous cell carcinoma (HNSCC) represents a significant global health burden, often requiring aggressive multi-modal therapy including surgery, radiation, and chemotherapy. Despite these interventions, recurrence rates remain high, and the functional morbidity of treatment can be profound. In recent years, the success of immune checkpoint inhibitors (ICI) in the recurrent and metastatic setting has prompted their movement into the neoadjuvant (pre-surgical) space.
The biological rationale for neoadjuvant ICI is compelling: by treating the tumor while it is still in situ, clinicians can potentially prime the immune system against a broader array of tumor-specific antigens, leading to a more robust and durable anti-tumor response. However, a major hurdle in drug development is the long duration required to observe survival outcomes. Consequently, there is an urgent need for surrogate endpoints that can predict long-term survival shortly after surgery. Pathologic response—the quantitative assessment of residual tumor in the surgical specimen—has emerged as a leading candidate.
Study Design and Methodology
This systematic review and meta-analysis, conducted by Mastrolonardo et al., sought to clarify whether pathologic treatment response is a meaningful surrogate for survival. The researchers performed an exhaustive search of databases including PubMed, OVID Medline, and Embase through May 31, 2025.
The inclusion criteria focused on peer-reviewed, English-language studies investigating neoadjuvant ICI in adults with mucosal HNSCC. To be included, studies had to provide both pathologic response data and survival data (OS or DFS). Data extraction was performed by three blinded reviewers following PRISMA guidelines. The primary outcomes measured were the hazard ratios (HRs) for the association of pathologic treatment response with DFS and OS. Statistical synthesis was performed using a random-effects model, and heterogeneity was assessed via the I2 index.
Key Findings: Does Pathologic Response Translate to Survival?
The meta-analysis ultimately included 11 trials involving 451 patients, with 368 patients providing sufficient data for the quantitative analysis. The included studies were diverse, spanning seven cohort studies, two randomized clinical trials, and two retrospective cohort studies, each utilizing varying neoadjuvant ICI regimens.
Association with Disease-Free Survival (DFS)
The pooled analysis revealed a clear and statistically significant correlation between pathologic response and DFS. Patients achieving a Partial Pathologic Response (PPR), characterized by having 50% or less residual viable tumor in the primary tumor and lymph nodes, had a nearly 50% reduction in the risk of disease recurrence or death (HR, 0.53; 95% CI, 0.28-0.97). The heterogeneity for this finding was remarkably low (I2 = 2.1%).
The effect was even more pronounced for those achieving a Major Pathologic Response (MPR), defined as 10% or less residual viable tumor. These patients experienced a 66% reduction in the risk of recurrence or death compared to those who did not achieve MPR (HR, 0.34; 95% CI, 0.12-0.93), with no observed heterogeneity (I2 = 0.0%).
Association with Overall Survival (OS)
Interestingly, the study did not find a statistically significant association between pathologic response (either PPR or MPR) and overall survival. Several factors may contribute to this discrepancy. First, the follow-up period in many phase 2 trials is relatively short, and OS typically requires a longer duration to mature than DFS. Second, the availability of effective salvage therapies following recurrence may decouple DFS from OS in this patient population.
Expert Commentary and Clinical Implications
The findings of this meta-analysis are pivotal for the design of future HNSCC trials. The identification of PPR and MPR as surrogates for DFS allows for earlier signals of efficacy in drug development. From a clinical perspective, these results suggest that a patient’s pathologic response to neoadjuvant ICI provides valuable prognostic information that could potentially guide adjuvant treatment decisions.
However, the lack of an OS benefit remains a point of discussion. While DFS is a meaningful clinical endpoint, particularly in head and neck cancer where recurrence often leads to significant morbidity, OS remains the gold standard. Clinicians must exercise caution and avoid equating a pathologic response with a guaranteed cure, though it is clearly a positive prognostic marker.
The biological plausibility of these findings is strong. A pathologic response indicates that the ICI successfully activated the immune system to recognize and eliminate tumor cells. This systemic priming is likely what provides the protection against micrometastatic disease, thereby extending the disease-free interval.
Limitations and Future Directions
Despite the high quality of the included studies (9 of 11 were at low risk of bias), limitations exist. The trials used different ICI agents and combinations, and the definitions of pathologic response were not perfectly uniform across all studies. Furthermore, the total sample size of 368 patients, while substantial for this specific field, still limits the power to detect smaller effects on overall survival.
Future research should focus on validating these surrogate endpoints in larger, phase 3 randomized controlled trials. Additionally, identifying biomarkers (such as PD-L1 expression or tumor mutational burden) that predict which patients are most likely to achieve an MPR will be essential for personalizing neoadjuvant therapy.
Conclusion
This meta-analysis provides the most comprehensive evidence to date that pathologic response—specifically PPR and MPR—is a valid surrogate for disease-free survival in patients with resectable mucosal HNSCC receiving neoadjuvant immunotherapy. While the association with overall survival remains unproven, the DFS benefit is clear and clinically significant. These findings support the continued integration of pathologic response assessment into clinical trial design and suggest its utility in prognosticating outcomes for patients in the clinical setting.
References
Mastrolonardo EV, De Ravin E, Kaki PC, et al. Pathologic Response and Survival After Neoadjuvant Immunotherapy for Resectable Mucosal HNSCC: A Systematic Review and Meta-Analysis. JAMA Otolaryngol Head Neck Surg. 2025; Published online December 18, 2024. doi:10.1001/jamaoto.2025.4573.
