Neoadjuvant Immunotherapy and Chemoimmunotherapy Regimens in Head and Neck Cancer: A Systematic Review and Meta-Analysis

Here is an expanded summary of Baratz et al., “Neoadjuvant Immunotherapy and Chemoimmunotherapy Regimens in Head and Neck Cancer: A Systematic Review and Meta-Analysis,” published online in JAMA Otolaryngology–Head & Neck Surgery on March 12, 2026. 

Why this paper matters

Neoadjuvant immunotherapy in resectable HNSCC has been attractive because it may treat micrometastatic disease early, exploit the intact tumor-immune microenvironment before surgery, and potentially improve pathologic response without delaying definitive treatment. What has been unclear is whether immunotherapy alone or chemoimmunotherapy is more effective. This meta-analysis addresses that question by pooling the available prospective data in resectable, treatment-naive HNSCC. 

Objective

The investigators aimed to:

Summarize the efficacy of neoadjuvant chemoimmunotherapy in HNSCC. Compare outcomes of chemoimmunotherapy vs immunotherapy alone before definitive surgery in locoregionally advanced resectable HNSCC. 

Methods

This was a librarian-led systematic review and meta-analysis performed according to PRISMA methodology. The authors searched MEDLINE, EMBASE, Cochrane Central, Cochrane Database of Systematic Reviews, and Scopus from database inception through October 2024. They included prospective interventional trials in resectable, treatment-naive HNSCC that had completed accrual and reported pathologic response and/or RECIST response data. 

Two investigators independently performed study screening and extraction. The main outcomes were:

Major pathologic response (MPR) Complete pathologic response (CPR) Complete radiographic response (CR) by RECIST 1.1

Secondary outcomes included:

1-year overall survival Toxicity

The pooled analysis used a binary random-effects model, with heterogeneity reported as I². 

Study population

The meta-analysis included 23 studies with a total of 751 patients. Of these:

357 patients (47%) received chemoimmunotherapy 102 patients (14%) received dual-agent immunotherapy 292 patients (39%) received single-agent immunotherapy 

The pooled cohort was predominantly male (77%) with an age range of 27 to 87 years. 

Main findings

1) Pathologic response strongly favored chemoimmunotherapy

The most important finding was the marked gradient in pathologic response across regimens.

Pooled MPR + CPR rates were:

66% for chemoimmunotherapy 95% CI 58%–73% 18% for dual-agent immunotherapy 95% CI 6%–29% 6% for single-agent immunotherapy 95% CI 3%–9% 

This is the key take-home point: adding chemotherapy to immunotherapy was associated with substantially higher pathologic response rates than immunotherapy alone.

Clinically, this matters because in head and neck cancer, pathologic response has increasingly been explored as an early signal of antitumor activity and a possible surrogate for longer-term benefit, although it is not yet a fully validated surrogate for survival in this setting. That distinction is important when interpreting these results. The paper shows better tumor kill in the surgical specimen, but it does not yet prove that patients live longer because of the neoadjuvant regimen. That is why the authors call for phase 3 trials. 

2) Short-term survival looked promising across groups, but differences were not definitive

Across the included studies, 1-year overall survival ranged:

88% to 96% with single-agent immunotherapy 88% to 96% with dual-agent immunotherapy 88% to 100% with chemoimmunotherapy 

These ranges suggest that all three strategies can be delivered with good short-term outcomes in selected patients. However, because these were mainly early-phase, non-comparative studies with heterogeneous populations and follow-up, the survival data should be viewed as hypothesis-generating, not practice-defining. 

3) Toxicity was higher than dual immunotherapy, but not prohibitive

Among studies reporting adverse events, grade 3–5 adverse events occurred in:

29% of patients receiving single-agent immunotherapy 3% with dual-agent immunotherapy 17% with chemoimmunotherapy 

These numbers need cautious interpretation because toxicity reporting was not uniform across studies, and the denominators were limited to reporting studies rather than all pooled patients. Still, the overall message is that chemoimmunotherapy increased efficacy while maintaining an acceptable, though not trivial, toxicity burden in selected surgical candidates. 

Authors’ conclusion

The authors concluded that neoadjuvant chemoimmunotherapy was associated with higher pathologic and radiographic response rates than immunotherapy alone in locoregionally advanced resectable HNSCC, and that these findings support the need for head-to-head phase 3 trials. 

How to interpret this as a head and neck oncologic surgeon

Strengths

This study has several strengths:

It focuses specifically on resectable, treatment-naive HNSCC, which is the clinically relevant population for neoadjuvant decision-making. It includes only prospective interventional studies. It separates single-agent, dual-agent, and chemoimmunotherapy approaches rather than lumping all neoadjuvant immunotherapy together. It uses outcomes surgeons and multidisciplinary teams care about: pathologic response, radiographic response, survival, and toxicity. 

Important limitations

The paper is very useful, but it does not settle the question of standard of care.

The biggest limitations are:

Most included studies were phase 1/2, small, and often single-arm. There was likely substantial clinical heterogeneity: primary site, stage, PD-L1 status, regimen, number of cycles, and adjuvant treatment strategies. The outcome driving the signal is primarily pathologic response, not mature event-free survival or overall survival. Cross-trial comparisons may exaggerate differences because these were not randomized head-to-head comparisons. Toxicity and imaging response reporting were not fully standardized. 

So the paper supports promise, not final proof.

Practical clinical implications

For a practicing surgeon, this meta-analysis suggests that chemoimmunotherapy is currently the most active neoadjuvant immune-based strategy in resectable HNSCC, at least if the endpoint is pathologic response. If a center is considering neoadjuvant treatment within a trial or highly selected multidisciplinary framework, the data support prioritizing chemoimmunotherapy over immunotherapy alone when the goal is maximizing preoperative tumor regression. 

At the same time, these data do not mean every resectable oral cavity, larynx, or oropharynx patient should routinely receive neoadjuvant chemoimmunotherapy outside a protocol. The field is moving quickly, and the editorial accompanying this paper emphasizes that these results arrive in the context of KEYNOTE-689, the first phase 3 randomized study to establish perioperative immunotherapy as a standard-of-care option in locally advanced resectable HNSCC, while also warning that enthusiasm should be balanced with caution as these strategies enter broader practice. 

Bottom line

This meta-analysis is one of the clearest pooled signals so far that in resectable locoregionally advanced HNSCC, neoadjuvant chemoimmunotherapy produces substantially higher pathologic response rates than immunotherapy alone. The benefit signal is strong for tumor response, short-term survival appears encouraging, and toxicity seems manageable in selected patients. But the evidence base is still dominated by early-phase studies, so phase 3 randomized data remain essential before universal adoption.