Pathologic Response After Neoadjuvant Immunotherapy Correlates With Disease-Free Survival in Head and Neck Cancer

Key Clinical Takeaways: 

• Partial (≤50% residual viable tumor) and major (≤10% residual viable tumor) pathologic responses after neoadjuvant immune checkpoint inhibition were significantly associated with improved disease-free survival in mucosal head and neck squamous cell carcinoma.
•  Neither partial nor major pathologic response was associated with an improvement in overall survival, highlighting limitations of pathologic response as a universal surrogate end point.
• These findings support the use of pathologic treatment response as a surrogate for disease-free survival, but not overall survival, in neoadjuvant immunotherapy trials for resectable head and neck cancer.

Eric Mastrolonardo, MD, Thomas Jefferson University, Philadelphia, Pennsylvania, discusses findings from a systematic review and meta-analysis evaluating whether pathologic treatment response after neoadjuvant immune checkpoint inhibition is associated with survival outcomes in resectable mucosal head and neck squamous cell carcinoma. 

Across 11 trials, partial and major pathologic responses were significantly associated with improved disease-free survival, though not overall survival. These results inform ongoing efforts to validate pathologic response as a meaningful surrogate end point in neoadjuvant immunotherapy trials.

Transcript:

Hi everyone, my name is Eric Mastrolonardo and I’m an otolaryngology resident at Thomas Jefferson University in Philadelphia, Pennsylvania. Today, I’ll be taking the time to talk about a paper that we recently published in JAMA Otolaryngology and is titled Pathologic response and survival after neoadjuvant immunotherapy for resectable mucosal head and neck squamous cell carcinoma– we performed a systematic review and meta-analysis. 

Numerous phase 2 trials have evaluated the efficacy of neoadjuvant immunotherapy for mucosal head and neck squamous cell carcinoma using some degree of pathologic response, meaning how much tumor was essentially destroyed by the neoadjuvant treatment, as a primary or secondary end point. However, whether pathologic response is a meaningful surrogate end point for survival has yet to be determined. The central question that this study addresses is whether achieving a pathologic response after neoadjuvant immunotherapy is associated with improved disease-free or overall survival. 

We performed a systematic review and meta-analysis in accordance with PRISMA guidelines for studies from 2000 to 2025. We looked at adult patients with mucosal head and neck squamous cell carcinoma who were treated with neoadjuvant immunotherapy where both pathologic response and survival data were available. We assessed pathologic response using the following categories: partial pathologic response means that less than 50% of the tumor was still viable, major pathologic response is defined as less than 10% residual viable tumor, a pathologic complete response (pCR) is defined as 0% viable tumor after treatment.

In total, there were about 1,900 studies that met the initial search criteria. Seventy-eight qualified for full-text assessment, and ultimately 11 were included in the study. These 11 studies included a total of 451 patients, with 368 included in the pooled analysis. Most of the studies were phase 1/2 clinical trials with a mix of prospective randomized and retrospective designs and included a variety of neoadjuvant immunotherapy regimens.

For the pooled analysis looking at partial pathologic response, again, less than 50% residual viable tumor, there were 6 studies that evaluated this end point. The pooled analysis showed that achieving an overall partial pathologic response, meaning assessment of both the primary tumor and lymph nodes, was significantly associated with improved disease-free survival, with a hazard ratio of 0.53 and a 95% confidence interval between 0.29 and 0.97 compared with those who did not achieve a partial pathologic response. 

Looking at major pathologic response, 8 studies evaluated this outcome, and achieving an overall major pathologic response was associated with improved disease-free survival, with a hazard ratio of 0.34 and a 95% confidence interval between 0.12 and 0.93. 

There were insufficient events to perform a reliable pooled analysis for pathologic complete response, which was interesting because patients who achieved a pCR often had limited or even 0 recurrences or deaths during the study period. Neither partial nor major pathologic response showed a statistically significant association with overall survival. Confidence intervals for this analysis were wide, reflecting limited power to make a meaningful interpretation of the data. In terms of important considerations and limitations, the available data for this study were limited to phase 2 trials at best, which lacked power for robust analysis and randomization. The included studies also demonstrated notable heterogeneity regarding the type of neoadjuvant treatment, the presence or absence of adjuvant treatment, and study design.

In summary, this meta-analysis investigated the association between pathologic treatment response and overall and disease-free survival after neoadjuvant immunotherapy for mucosal head and neck squamous cell carcinoma. It demonstrated that achieving a partial pathologic response, defined as less than 50% residual viable tumor after treatment, or a major pathologic response, defined as less than 10% residual viable tumor, was associated with improved disease-free survival.

This study provides data to support the use of pathologic tumor response as a potential surrogate endpoint for disease-free survival in clinical trials using neoadjuvant immunotherapy in mucosal head and neck squamous cell carcinoma, although further investigation is required.

Source: 

Mastrolonardo EV, De Ravin E, Kaki PC, et al. Pathologic response and survival after neoadjuvant immunotherapy for resectable mucosal HNSCC. JAMA Otolaryngol Head Neck Surg. Published online: December 18, 2025. doi: 10.1001/jamaoto.2025.457