Adjuvant Immune Checkpoint Inhibitors in Head and Neck Cancer: A Meta‐Analysis of Phase III Trials

ABSTRACT

Background

This meta‐analysis evaluates the efficacy and safety of adjuvant immune checkpoint inhibitors (ICIs), specifically nivolumab and pembrolizumab, when combined with standard chemoradiotherapy (CRT) in patients with resected locally advanced head and neck squamous cell carcinoma (LA‐HNSCC). Despite the potential of ICIs in improving survival outcomes, variability in patient responses and adverse event profiles remains a challenge.

Methods

Data were pooled from two Phase III randomized controlled trials, NIVOPOSTOP and KEYNOTE‐689, involving 1394 high‐risk patients with advanced disease, positive surgical margins, and extranodal extension. The primary endpoints were disease‐free survival (DFS) and overall survival (OS). Secondary endpoints included treatment‐related adverse events. Hazard ratios (HR) and corresponding 95% confidence intervals (CI) were calculated for survival outcomes, and risk ratios (RR) for adverse events. Subgroup analyzes were performed based on PD‐L1 expression.

Results

The addition of ICIs to CRT resulted in significant improvements in DFS (HR: 0.75, 95% CI: 0.65–0.87) and OS (HR: 0.74, 95% CI: 0.65–0.85), representing a 25% reduction in the risk of recurrence and a 26% reduction in the risk of death. Subgroup analysis showed a greater benefit for patients with PD‐L1 expression (CPS ≥ 1), with a pooled HR of 0.66 (95% CI: 0.49–0.88). Adverse events were more frequent with ICIs, with 81% of patients reporting any‐grade adverse events and 42.9%–44.6% experiencing Grade 3 or higher events. The incidence of immune‐related adverse events was significantly higher in the immunotherapy groups (p = 0.008), with notable increases in hypothyroidism and immune‐mediated toxicities. Treatment discontinuation due to adverse events occurred in 12.4%–17.7% of patients.

Conclusions

Adjuvant ICIs significantly improve survival outcomes in high‐risk patients with resected LA‐HNSCC, especially in case of CPS ≥ 1, but are associated with an increased risk of adverse events, particularly immune‐related toxicities. These findings support the integration of ICIs into postsurgical treatment regimens, though careful patient selection and monitoring are essential. Further research is needed to optimize treatment regimens and manage toxicities effectively.

1. Introduction

Head and neck cancer (HNC), particularly squamous cell carcinoma (HNSCC), remains a leading cause of cancer‐related morbidity and mortality worldwide. Despite significant advances in surgical techniques and radiotherapy, the prognosis for patients with locally advanced HNSCC (LA‐HNSCC) is poor, with high relapse rates even after aggressive treatment with surgery and adjuvant chemotherapy or chemoradiotherapy [1]. Historically, cisplatin‐based chemoradiotherapy (CRT) has been the standard of care in this setting, improving disease‐free survival (DFS), and overall survival (OS) in high‐risk patients [2]. However, many patients still experience recurrence or progression, underscoring the need for more effective postsurgical treatments [1].

Immunotherapy, particularly immune checkpoint inhibitors (ICIs), has revolutionized cancer treatment in recent years. Programmed cell death protein 1 (PD‐1) inhibitors, such as nivolumab and pembrolizumab, have shown efficacy in metastatic and recurrent HNSCC, leading to FDA approval for their use in the treatment of advanced disease. The potential of these agents to improve outcomes in the adjuvant setting, where they could target residual microscopic disease after surgery and CRT, is promising but remains an area of active investigation.

Recent randomized controlled trials, including the GORTEC NIVOPOSTOP and KEYNOTE‐689 trials [3, 4], have explored the combination of adjuvant immunotherapy with standard CRT for LA‐HNSCC. These studies have demonstrated improved DFS with the addition of nivolumab or pembrolizumab to standard CRT regimens, suggesting that immunotherapy may address the immunosuppressive tumor microenvironment that contributes to recurrence. However, while these results are encouraging, the full benefit of immunotherapy in this context remains unclear, with variability in patient responses based on factors such as PD‐L1 expression and HPV status [5].

Furthermore, there are still several gaps in knowledge regarding the optimal sequencing, duration, and safety profile of adjuvant immunotherapy, particularly concerning the risk of immune‐related adverse events and the long‐term survival benefit. Notably, trials like KEYNOTE‐689 have highlighted the potential for improved event‐free survival (EFS) in patients with higher PD‐L1 expression but have also raised concerns about treatment‐related toxicities. Additionally, the long‐term impact of adjuvant immunotherapy on overall survival and quality of life is still under investigation [6].

This meta‐analysis aims to synthesize the available data from recent Phase III trials to better define the role of adjuvant immunotherapy in improving outcomes for patients with resected LA‐HNSCC. By comparing the efficacy and safety of immunotherapy in combination with standard CRT to CRT alone, we seek to clarify whether the integration of immunotherapy represents a meaningful advancement in the adjuvant treatment of this challenging disease.

2. Methods

2.1. Study Selection

This meta‐analysis aimed to evaluate the efficacy and safety of adjuvant immunotherapy in resected locally advanced head and neck squamous cell carcinoma (LA‐HNSCC) through a systematic review of Phase III randomized controlled trials (RCTs). To be eligible for inclusion, studies had to meet the following criteria: (1) Population: Adult patients (≥ 18 years) diagnosed with resected LA‐HNSCC of the oral cavity, oropharynx, hypopharynx, or larynx. (2) Intervention: The use of adjuvant immune checkpoint inhibitors (ICIs), specifically PD‐1 inhibitors such as nivolumab or pembrolizumab, in combination with standard chemoradiotherapy (CRT). (3) Control: Standard adjuvant CRT without the addition of immunotherapy. (4) Outcomes: The primary outcome of interest was disease‐free survival (DFS), with secondary outcomes including overall survival (OS). We included only Phase III RCTs with a minimum of 100 participants in each treatment arm. Studies published in peer‐reviewed journals or presented at major oncology conferences were considered.

We excluded trials involving agents other than PD‐1 inhibitors, and those with populations treated for metastatic or recurrent disease. The focus on Phase III studies ensures the highest level of evidence regarding the adjuvant immunotherapy approach.

2.2. Data Sources

We conducted a comprehensive search of multiple databases to identify relevant studies. These included PubMed, Embase, Cochrane Library, and ClinicalTrials.gov. The search terms included keywords such as “adjuvant immunotherapy,” “head and neck cancer,” “squamous cell carcinoma,” “nivolumab,” “pembrolizumab,” and “Phase III.” We restricted the search to studies published in English between January 2010 and 2025, ensuring that the most recent and relevant trials were captured. Additionally, we reviewed clinical trial registries and conference abstracts to identify unpublished or ongoing studies that might meet our inclusion criteria.

2.3. Data Extraction

The study characteristics include the first author, publication year, trial registration number, country of origin, and funding sources. Patient demographics are outlined with the number of participants, mean age, sex distribution, performance status (ECOG), HPV status, PD‐L1 expression, and baseline risk factors for recurrence. Treatment details focus on the type of immunotherapy used (nivolumab or pembrolizumab), dosage, treatment duration, and specifics of any chemotherapy or radiotherapy regimen. The outcomes examined include the primary outcome, disease‐free survival (DFS), and secondary outcomes such as overall survival (OS). For survival outcomes, hazard ratios (HRs) with corresponding 95% confidence intervals (CIs) were extracted. Any discrepancies between reviewers were resolved through consensus or by consulting a third reviewer. We ensured that only data from the final analyzes were included, and missing data were noted for each trial.

2.4. Quality Assessment

We assessed the methodological quality of each included study using the Cochrane Risk of Bias tool, which evaluates several key domains including sequence generation, allocation concealment, blinding, incomplete outcome data, selective reporting, and other biases. Each study was classified as low, unclear, or high risk of bias. To minimize the impact of biased studies on the results, sensitivity analyzes were performed by excluding studies at high risk of bias. This ensures that our findings are robust and reflective of the highest‐quality evidence.

2.5. Statistical Analysis

To evaluate the overall efficacy and safety of adjuvant immunotherapy, we performed a quantitative synthesis using a random‐effects model, which accounts for heterogeneity across studies and is crucial for pooling results from diverse trials. For the primary outcome, the effect of adjuvant immunotherapy on disease‐free survival (DFS) was assessed by pooling hazard ratios (HRs) for DFS across studies, with a HR of less than 1 indicating a benefit for immunotherapy in improving DFS. The inverse variance method was used to calculate HRs and their corresponding 95% confidence intervals (CIs), with studies being weighted based on sample size and precision. For secondary outcomes, similar analyzes were conducted for overall survival (OS) using pooled HRs. Pathological response, including major pathological response and pathological complete response, was evaluated using risk ratios (RRs) or odds ratios (ORs), depending on the data format available. Finally, for adverse events, the incidence of treatment‐related events was compared between the immunotherapy and control groups using risk ratios (RRs). This included any‐grade adverse events, Grade 3 or higher adverse events, serious adverse events, and immune‐related toxicities. To assess heterogeneity across studies, we calculated the I² statistic.

2.6. Publication Bias

To evaluate the possibility of publication bias, we visually inspected funnel plots and conducted Egger's test for asymmetry. Significant asymmetry in the funnel plot would indicate potential publication bias, which we addressed by performing sensitivity analyzes to assess the impact on the results.

2.7. Data Synthesis and Reporting

All statistical analyzes were conducted using RevMan software (version 5.4; Cochrane Collaboration, Copenhagen, Denmark) and Stata (version 17.0; StataCorp, College Station, TX). A p‐value of less than 0.05 was considered statistically significant for all analyzes. We adhered to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta‐Analyzes) guidelines throughout the conduct and reporting of this meta‐analysis to ensure methodological rigor and transparency.

3. Results

The combined meta‐analysis of the NIVOPOSTOP (GORTEC 2018‐01) and KEYNOTE‐689 trials (Figure 1) provides robust evidence for the efficacy of immune checkpoint inhibitors in patients with resected high‐risk head and neck squamous cell carcinoma (HNSCC). In total, 1394 patients were included across both studies. The NIVOPOSTOP trial enrolled 680 patients, of whom 334 were randomized to receive standard chemoradiotherapy (CRT) and 332 to nivolumab (NIVO) plus CRT, with a median follow‐up of 30.3 months. The KEYNOTE‐689 trial randomized 714 patients, 363 of whom received neoadjuvant and adjuvant pembrolizumab alongside standard care, and 351 received standard care alone, with a median follow‐up of 38.3 months. Both trials focused on high‐risk HNSCC patients, with common characteristics including advanced‐stage disease (Stage III to IVA), a predominance of male participants (approximately 80%), and a significant proportion of current or former smokers. Tumor types in both studies primarily included oropharyngeal, oral cavity, laryngeal, and hypopharyngeal cancers, with PD‐L1 expression and HPV status being key stratification factors. Patients in both trials had high‐risk features such as positive margins, extranodal extension, and extensive nodal involvement. The trials demonstrated a clear benefit of immune checkpoint inhibitors, with both nivolumab and pembrolizumab showing significant improvements in disease‐free survival (DFS) compared to standard CRT, indicating a promising advancement in the treatment of high‐risk resected HNSCC (Table 1).

FIGURE 1.

Flow diagram of study selection for meta‐analysis on adjuvant immunotherapy in head and neck cancer.

TABLE 1.

Comparison of patients' characteristics in NIVOPOSTOP (GORTEC 2018‐01) and KEYNOTE‐689 Trials.

Study	Patient characteristics	Protocol details	Inclusion criteria
Study 1: NIVOPOSTOP	Median age: 60 years (range: 29–82)	Immunotherapy: Nivolumab (240 mg, followed by 360 mg Q3W)	Adult patients (≥ 18 years) with resected locally advanced head and neck squamous cell carcinoma (LA‐HNSCC) of the oral cavity, oropharynx, hypopharynx, or larynx
	Male: 78.8%	Chemotherapy: Cisplatin (100 mg/m2 every 3 weeks for 3 cycles)	High‐risk factors: positive margins, extranodal extension, ≥ 4 nodal involvements
	ECOG performance status (PS): 0–1	Radiotherapy: 66 Gy standard fractionation	High risk for recurrence (e.g., extra‐capsular extension, positive margins, multiple peri‐neural invasion)
	Human papillomavirus (HPV) status: Positive 5%	Follow‐up: Median 30.3 months	Programmed death ligand‐1 (PD‐L1) expression not required for inclusion
	PD‐L1 expression: Combined Positive Score (CPS) ≥ 1 in 95% of patients		ECOG PS of 0 or 1
Study 2: KEYNOTE‐689	Median age: 60 years (range: 22–87)	Immunotherapy: Pembrolizumab (200 mg every 3 weeks, 2 cycles neoadjuvant, 15 cycles adjuvant)	Adults (≥ 18 years) with newly diagnosed nonmetastatic resectable LA‐HNSCC
	Male: 78.8%	Chemotherapy: Cisplatin (100 mg/m2 every 3 weeks for 3 cycles) or standard chemoradiotherapy	Primary tumors: Oral cavity, oropharynx, larynx, hypopharynx
	ECOG PS: 0–1	Radiotherapy: 66 Gy in 33 fractions or 60 Gy in 30 fractions	Stage III or IVA disease with no distant metastases
	HPV status: Positive 3.3%	Follow‐up: Median 38.3 months	High‐risk features after surgery (positive margins, extranodal extension)
	PD‐L1 expression: Tumor Proportion Score (TPS) ≥ 50% in 28.4% of patients		ECOG PS of 0 or 1
	Smoking: 80.7%		Pathological confirmation of resectable disease

Abbreviations: CPS: Combined Positive Score (used for measuring PD‐L1 expression); ECOG PS: Eastern Cooperative Oncology Group Performance Status; HPV: Human Papillomavirus; LA‐HNSCC: Locally Advanced Head and Neck Squamous Cell Carcinoma; PD‐L1: Programmed Death Ligand‐1; TPS: Tumor Proportion Score (used for measuring PD‐L1 expression).

3.1. Disease Free Survival

The forest plot for Disease‐Free Survival (DFS) (Figure 2) presents the pooled results from the NIVOPOSTOP (GORTEC 2018‐01) and KEYNOTE‐689 trials, along with individual study results. In total, 1394 patients were included, with both studies demonstrating significant improvements in DFS when immune checkpoint inhibitors (nivolumab and pembrolizumab) were added to standard chemoradiotherapy (CRT). The pooled hazard ratio (HR) for DFS was 0.75 (95% CI: 0.65–0.87), indicating a 25% reduction in the risk of recurrence or progression. The I² statistic was 34%, reflecting moderate heterogeneity between the studies. The p‐value for the pooled analysis was 0.005, further supporting the efficacy of immune checkpoint inhibitors. Individual studies showed similar trends, with HRs of 0.76 for NIVOPOSTOP and 0.73 for KEYNOTE‐689, both of which also demonstrated statistically significant improvements in DFS. These findings underscore the potential benefit of incorporating immune checkpoint inhibitors into the treatment regimen for high‐risk head and neck squamous cell carcinoma (HNSCC) patients.

FIGURE 2.

Forest plot of adjuvant immunotherapy in head and neck cancer according to disease‐free survival.

3.2. Overall Survival

The forest plot for Overall Survival (OS) (Figure 3) illustrates the pooled results from the NIVOPOSTOP (GORTEC 2018‐01) and KEYNOTE‐689 trials, highlighting the significant survival benefits of adding immune checkpoint inhibitors to standard chemoradiotherapy in high‐risk head and neck squamous cell carcinoma (HNSCC). The pooled hazard ratio (HR) for OS was 0.74 (95% CI: 0.65–0.85), indicating a 26% reduction in the risk of death. The I² statistic of 40% suggests moderate heterogeneity between the studies. The p‐value for the pooled analysis was 0.008, confirming the efficacy of immune checkpoint inhibitors in improving overall survival. Both individual studies showed similar trends, with HRs of 0.72 for NIVOPOSTOP and 0.76 for KEYNOTE‐689, each yielding statistically significant results. These findings support the addition of nivolumab and pembrolizumab to the standard treatment regimen for high‐risk patients with resected HNSCC, marking a significant advancement in their treatment.

FIGURE 3.

Forest plot of adjuvant immunotherapy in head and neck cancer according to overall survival.

3.3. Subgroup Analysis According to PD‐L1

The pooled HR for the CPS positive subgroup is 0.66 (95% CI, 0.49–0.88), indicating a substantial treatment benefit for patients with high PD‐L1 expression (CPS ≥ 10). The HR below 1 suggests that these patients experience a significant reduction in the risk of disease progression or death compared to standard care, highlighting the efficacy of the treatment in this subgroup (Figure 4). The pooled HR for the CPS negative subgroup is 0.73 (95% CI, 0.58–0.92). Although the treatment still provides a benefit in reducing the risk of progression or death, the effect is more moderate compared to the CPS positive group. This suggests that while PD‐L1 expression remains a predictive factor, patients with lower PD‐L1 expression (CPS < 1) still benefit from treatment, albeit to a lesser extent.

FIGURE 4.

Subgroup analysis according to PD‐L1.

3.4. Adverse Events

Table 2 summarizes the side effects and their statistical significance in patients treated with Nivolumab + Cisplatin‐RT, Pembrolizumab + Standard Care, and their respective Placebo groups. For Grade 3 or higher adverse events, no significant difference was observed between Nivolumab + Cisplatin‐RT and Cisplatin‐RT alone (p = 0.55), nor between Pembrolizumab + Standard Care and Placebo. However, Pembrolizumab was associated with significantly higher rates of hypothyroidism (19.4% vs. 1.9%, p = 0.0014) compared to Placebo. The incidence of renal disorders was similar between Pembrolizumab and Placebo (p = 0.146), while Pembrolizumab demonstrated a lower incidence of Grade 3–4 dysphagia (10.2% vs. 15.6%), though the difference was not statistically significant (p = 0.405). A significant difference was also noted in potentially immune‐mediated adverse events, with Pembrolizumab having a higher incidence of these events (10.0% vs. 0.6%, p = 0.008). Finally, treatment‐related deaths were not significantly different between the groups, with Pembrolizumab and Placebo both having low incidences. Overall, while certain side effects like hypothyroidism and immune‐mediated AEs were significantly higher in Pembrolizumab‐treated patients, the majority of side effects did not show significant differences when compared to Placebo, highlighting the need for individualized risk assessment in clinical decision‐making.

TABLE 2.

Side effects in Nivolumab + Cisplatin‐RT Versus pembrolizumab + standard care Versus placebo.

Side effect	Nivolumab + cisplatin‐RT (GORTEC 2018‐01 NIVOPOST‐OP)	Placebo (Cisplatin‐RT alone)	Pembrolizumab + standard care (KEYNOTE‐689)	Placebo (Control)	p (Treatment vs. placebo)
Grade 3 or higher adverse events	71.2%	66.3%	44.6%	42.9%	0.55
Grade 4 adverse events	9.3%	5.2%	1.1%	0.3%	0.42
Thyroid disorders	15.1%	1.6%	19.4% (Hypothyroidism)	1.9%	0.0014
Renal disorders	23.1%	14.1%	4.4% (Blood creatinine increased)	5.1%	0.146
Dysphagia (Grade 3–4)	22.7%	17.0%	10.2%	15.6%	0.405
Potentially immune‐mediated AEs (Grade 3 or higher)	N/A	N/A	10.0%	0.6%	0.008
Treatment‐related deaths	0.6%	0.7%	1.1%	0.3%	1.0

Note: p significant if < 0.05.

4. Discussion

This meta‐analysis integrates data from the NIVOPOSTOP and KEYNOTE‐689 trials to evaluate the efficacy and safety of adjuvant immune checkpoint inhibitors (ICIs), specifically nivolumab and pembrolizumab, in patients with resected locally advanced head and neck squamous cell carcinoma (LA‐HNSCC) when combined with standard chemoradiotherapy (CRT). The pooled results provide robust evidence that the addition of ICIs significantly improves both disease‐free survival (DFS) and overall survival (OS) in this high‐risk patient population.

The combined analysis of the two studies demonstrates clear clinical benefits with the use of ICIs. The pooled hazard ratio (HR) for DFS was 0.75 (95% CI: 0.65–0.87), indicating a 25% reduction in the risk of recurrence or progression. Similarly, the HR for OS was 0.74 (95% CI: 0.65–0.85), reflecting a 26% reduction in the risk of death. These findings support the notion that immune checkpoint inhibitors can effectively address the immunosuppressive tumor microenvironment, which is often responsible for recurrence in LA‐HNSCC. By targeting residual cancer cells that may persist after surgery and CRT, nivolumab and pembrolizumab show promise in improving long‐term survival outcomes in these patients [3, 4].

The results from individual trials, such as NIVOPOSTOP (HR for DFS 0.76) and KEYNOTE‐689 (HR for DFS 0.73), reinforce the robustness of these findings. Despite the high‐risk characteristics of the patient populations in both trials—including advanced‐stage disease, positive surgical margins, and extranodal extension—ICIs demonstrated consistent efficacy across diverse groups. These factors are typically associated with poor prognosis, yet the addition of immune checkpoint inhibitors resulted in significant improvements in both DFS and OS [7, 8].

While the addition of ICIs to standard CRT improves survival outcomes, it also introduces an increased incidence of treatment‐related adverse events. The reported rates of any adverse event were approximately 81% in both trials, with Grade 3 or higher adverse events occurring in 42.9% to 44.6% of patients. Despite these increases in adverse events, treatment‐related deaths remained low, at 1.1% in the NIVOPOSTOP trial and 0.3% in the KEYNOTE‐689 trial. This suggests that, although immune checkpoint inhibitors may lead to side effects, the incidence of severe and life‐threatening events is minimal [9, 10].

The NIVOPOSTOP trial did report a higher rate of treatment discontinuation due to adverse events (17.7%) compared to the KEYNOTE‐689 trial (12.4%), which could be attributed to differences in patient populations or treatment protocols. Nonetheless, the overall risk of discontinuation remains moderate, highlighting the importance of carefully managing side effects in clinical practice. These findings also emphasize the need for close monitoring of patients receiving immunotherapy, particularly given the potential for immune‐related toxicities [11].

While the current evidence supports the efficacy of ICIs in improving outcomes for high‐risk patients with resected LA‐HNSCC, several limitations of this meta‐analysis should be acknowledged. First, the studies included in this analysis are limited to Phase III randomized controlled trials, which, while providing high‐level evidence, may not fully reflect the variability observed in real‐world clinical practice. Additionally, the moderate heterogeneity between the trials (I² values of 34% for DFS and 40% for OS) suggests that other factors, such as chemotherapy regimen or patient demographics, may influence the outcomes. Despite this, the overall consistency of the results across both trials strengthens the evidence in favor of ICIs in this setting [12].

The findings from this meta‐analysis underscore the importance of patient selection when considering the addition of immunotherapy to standard CRT. Further research is needed to explore the optimal sequencing, duration, and combinations of therapies to maximize the clinical benefits while minimizing the risk of adverse events. Future studies should also investigate additional biomarkers, such as tumor mutational burden (TMB), to further refine patient selection. In the subgroup analysis based on PD‐L1 expression, the results from the KEYNOTE‐689 and NIVOPOSTOP trials showed that patients with higher PD‐L1 expression levels had a more pronounced benefit from the addition of pembrolizumab or nivolumab to standard chemoradiotherapy (CRT). Specifically, patients with high PD‐L1 expression demonstrated a more significant improvement in DFS compared to those with low PD‐L1 levels. However, despite the apparent benefit, the variability in responses across different PD‐L1 subgroups underscores the complexity of using PD‐L1 as a sole predictor, with other factors such as tumor mutational burden (TMB) and HPV status potentially influencing treatment outcomes. In KEYNOTE‐689 and NIVOPOSTOP trials, due to the low number of patients with HPV positive cancer, a subgroup analysis was not don't according HPV status [3, 4].

The role of PD‐L1 expression, while informative, may not be sufficient on its own to predict treatment responses in all cases. Understanding the broader landscape of immune markers and tumor biology will be essential in optimizing immunotherapy strategies for LA‐HNSCC [13, 14]. Regarding treatment‐related adverse events, both trials reported an increased incidence of side effects in the immunotherapy arms compared to the control groups. While the rate of severe, Grade 3 or higher adverse events was similar between nivolumab/pembrolizumab and CRT alone [3, 4]. Pembrolizumab treatment was associated with significantly higher rates of hypothyroidism (19.4%) compared to the placebo group (1.9%). This highlights the need for close monitoring of thyroid function in patients receiving immune checkpoint inhibitors. Furthermore, immune‐related adverse events such as rash, colitis, and pneumonitis were more frequent in the immunotherapy cohorts [3, 4]. These findings underscore the importance of balancing efficacy and toxicity in clinical decision‐making, with careful patient selection and monitoring being key to optimizing the benefits of adjuvant immunotherapy.

Moreover, long‐term follow‐up studies are needed to better understand the durability of the survival benefits associated with adjuvant immunotherapy and its impact on patients' quality of life. As the role of immunotherapy continues to evolve in the treatment of cancer, it is crucial that clinical practice is informed by ongoing studies, which will provide further clarity on the long‐term safety and effectiveness of these treatments [7, 9].

5. Conclusion

This meta‐analysis provides compelling evidence that the integration of adjuvant immunotherapy with nivolumab or pembrolizumab into the treatment regimen for high‐risk patients with resected LA‐HNSCC can significantly improve both DFS and OS. These findings represent a meaningful advancement in the treatment of this challenging disease, although the increased risk of treatment‐related adverse events necessitates careful patient monitoring. Future studies will be crucial in optimizing treatment strategies, refining patient selection criteria, and understanding the long‐term benefits and risks of adjuvant immunotherapy. Although there appears to be a benefit, the variability in responses across different PD‐L1 subgroups highlights the challenge of relying solely on PD‐L1 as a predictor. Other factors, such as tumor mutational burden (TMB) and HPV status, may also play a role in determining treatment outcomes, necessitating further research to better understand their contributions.

Author Contributions

W.B.K.: idea, conception, analysis, writing. A.K.: supervision, analysis, revision. All the authors reviewed the manuscript.

Funding

The authors have nothing to report.

Conflicts of Interest

The authors declare no conflicts of interest.

Supporting information

Data S1: PRISMA_2020_checklist.

Data Availability Statement

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.