Reduced Recurrence Rate with Nivolumab Combination After Head and Neck Cancer Surgery, but Discrepancies in Independent Evaluation Spark Debate
Background
Head and neck squamous cell carcinoma is a representative cancer type with a high incidence rate worldwide. For patients with locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN) who have progressed beyond the early stage, the standard post-surgical treatment typically involves a combination of cisplatin-based chemotherapy and radiation therapy. However, despite this treatment, approximately half of the patients experience recurrence within two years. Due to the poor prognosis of recurrent patients, reducing recurrence rates through adjuvant therapy has long been a significant challenge.
Over the past two decades, numerous studies have attempted to develop new combination therapies that could surpass the efficacy of standard treatment in this high-risk patient group, but with limited success. In recent years, immune checkpoint inhibitors have shown promising results in various solid tumors, prompting research into their integration into head and neck cancer treatment. The NIVOPOST-OP clinical trial, which evaluated the recurrence-prevention efficacy of combining the immune checkpoint inhibitor nivolumab with standard treatment, was initiated in response to these expectations.
Key Findings
The NIVOPOST-OP phase III clinical trial, led by GORTEC, was conducted in high-risk LA-SCCHN patients who had undergone surgery. Patients were randomly assigned to either a group receiving standard cisplatin-based chemoradiotherapy alone or a group receiving nivolumab in combination. The primary endpoint of the trial was investigator-assessed disease-free survival (DFS).
The evaluation results showed that the nivolumab combination group reduced the risk of disease recurrence or death by 24% compared to the control group. The hazard ratio (HR) was 0.76 (95% confidence interval [CI] 0.60–0.98), with a p-value of 0.034. The 3-year DFS rate was 63.1% in the nivolumab combination group, which was 10.6 percentage points higher than the 52.5% in the control group. The consistent therapeutic benefit observed regardless of PD-L1 expression in tumor cells was also a positive finding.
However, a significant issue arose during detailed analysis. The blinded independent central review (BICR), conducted to ensure the objectivity of the trial, yielded results that contradicted the investigator assessments. According to BICR, the HR for the nivolumab combination group was 0.89 (95% CI 0.69–1.14), which did not meet statistical significance. This means the treatment's efficacy could not be confirmed under independent evaluation criteria. The discrepancy in results based on evaluation methods highlights the need for cautious interpretation of the data.
Implications and Outlook
The NIVOPOST-OP clinical trial achieved a clinical success in reducing recurrence rates, but there remain challenges to be addressed before it can lead to guideline revisions. A commentary in The Lancet raised two additional concerns beyond the evaluation method discrepancy.
First, the effect of suppressing distant metastasis recurrence was not confirmed. While the nivolumab combination therapy controlled local recurrence, it did not prevent distant metastasis. The authors of the commentary suggest that patients may have already had undetected microscopic local recurrence lesions before receiving post-surgical radiation therapy. This implies that the results may reflect the control of early local recurrence through nivolumab treatment, rather than the prevention of recurrence itself.
Second, the monitoring schedule for patients was not transparently disclosed. There was no clear information on whether patients strictly adhered to follow-up schedules or how missing data from regular check-ups were statistically accounted for. This could have led to an imbalance in the timing of recurrence diagnoses between the two groups. For future adjuvant therapy guidelines to be established, the impact of missing data on the results must be thoroughly investigated.
The NIVOPOST-OP investigators1 should be congratulated for their foresight in anticipating the biologically plausible benefits of integrating immunotherapy into the curative-intent treatment setting for head and neck cancer, alongside the KEYNOTE-689 results.2 The trial can be said to have met its primary endpoint, since investigator-assessed disease-free survival was statistically significantly greater when nivolumab was administered (hazard ratio [HR] 0·76, 95% CI 0·60–0·98; p=0·034).1 However, three considerations warrant reflection in our view.
The findings of this study are expected to serve as an important reference for making adjuvant therapy prescription decisions in clinical practice. In particular, for high-risk locally advanced patients who are classified as having a high risk of recurrence after surgery, the environment is now in place to consider nivolumab combination therapy as an active option following standard chemoradiotherapy. For example, patients with multiple lymph node metastases or those with residual cancer cells at the surgical margin and a high risk of recurrence are the primary targets. Healthcare providers can now design treatment scenarios to proactively administer nivolumab adjuvant therapy to these patients in order to slow the progression of local recurrence. However, since the independent evaluation committee's analysis showed a lack of statistical significance, healthcare providers must carefully assess each patient's clinical characteristics and the risk of adverse reactions before making a decision on administration.