SUMMARY: The American Cancer Society estimates that 59,660 new cases of cancer involving the oral cavity and pharynx will be diagnosed in the US in 2025 and 12,770 will die of the disease. The head and neck region includes the oral cavity, oropharynx, hypopharynx and larynx. Squamous Cell Carcinoma (SCC) of the Head and Neck accounts for about 3-5% of all cancers in the United States. Common risk factors include tobacco and alcohol use and Human PapillomaVirus (HPV) infection. Even though tobacco has long been associated with head and neck cancer development, cannabis has similar carcinogens.
The Standard of Care for patients with Stage III–IVA Head and Neck Squamous Cell Carcinoma (HNSCC) has remained largely static for nearly 2 decades: surgery followed by risk-adapted adjuvant radiotherapy, with or without concurrent Cisplatin based chemotherapy. Despite refinements in technique and supportive care, relapse rates remain high, particularly among patients with adverse pathological features such as extranodal extension and positive margins.
The treatment paradigm for Head and Neck cancer has been rapidly evolving with the recognition and better understanding of immune evasion and the role of immune checkpoints or gate keepers in suppressing antitumor immunity. Blocking the immune checkpoints unleashes the T cells, resulting in T cell proliferation, activation, and a therapeutic response. Checkpoint inhibitors administered in a neoadjuvant setting activates both the priming phase of immunity within tumor tissue, and the effector phase within the tumor microenvironment. It has been shown that neoadjuvant immunotherapy expands more T-cell clones than adjuvant treatment. Preclinical models have also demonstrated that both radiation therapy and Cisplatin chemotherapy increase the PD-L1 expression on the tumor, suggesting that combining radiotherapy with anti-PD-1 therapy could improve the outcomes.
Phase 3 NIVOPOSTOP trial (GORTEC 2018-01) provides compelling evidence that integrating immunotherapy into the adjuvant setting may finally shift this long-standing treatment landscape. Nivolumab (OPDIVO®) is a fully human, immunoglobulin G4 monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2. Blocking the Immune checkpoint proteins unleashes the T cells, resulting in T cell proliferation, activation and a therapeutic response.
Study Design and Patient Population
NIVOPOSTOP (NCT03576417) was an international, randomized, open-label Phase 3 study that enrolled 680 patients with completely resected LA-SCCHN (Locally Advanced Squamous Cell Carcinoma of the Head and Neck), which included the oral cavity, oropharynx, hypopharynx, and larynx. Eligible patients were less than 75 years old, with ECOG performance status 0-1, and exhibited high-risk features for recurrence, including extracapsular nodal extension, positive surgical margins, involvement of 4 or more lymph nodes, or extensive perineural invasion. PD-L1 expression was not required for study eligibility. Majority of patients had disease of the oral cavity (58%), about 50% were current smokers, most patients had Stage IVA or IVB disease (83%), and slightly more than one-half of patients (56%) had a PD-L1 Combined Positive Score less than 20. Patients were first stratified by HPV status and enrolling center before being randomly assigned to receive standard CRT or standard CRT plus nivolumab.
Patients were randomized 1:1 to receive:
- Control Arm (SOC CRT): 66 Gy radiotherapy with three cycles of Cisplatin 100 mg/m² Q3W (N=334).
- Experimental Arm (NIVO + CRT): One lead-in dose of Nivolumab 240 mg, followed by CRT plus Nivolumab 360 mg Q3W for three cycles, followed by six cycles of Nivolumab 480 mg Q4W for maintenance (N=332).
Both treatment groups were well balanced. The Primary endpoint was Disease Free Survival (DFS). Key Secondary endpoints include Overall Survival (OS) and Safety.
Primary Endpoint Met: Significant Improvement in Disease-Free Survival
At a median follow-up of 30.3 months, the trial met its Primary endpoint. Among the 666 patients included in the Disease-Free Survival (DFS) analysis (ITT population), the addition of adjuvant Nivolumab significantly reduced the risk of disease recurrence or death compared with CRT alone (HR 0.76; 95% CI, 0.60–0.98; P = 0.034).
Three-year DFS rates were 63.1% with NIVO + CRT (95% CI, 57.0–68.7) and 52.5% with CRT alone (95% CI, 46.2–58.4). This represents a 24% relative reduction in recurrence risk with Nivolumab. Importantly, this benefit was observed across all PD-L1 expression levels, supporting the use of this strategy in an unselected population.
Safety Profile: Manageable Toxicity with Increased Grade 3–4 Events
While the addition of Nivolumab was associated with an increase in grade 3-4 adverse events, particularly within the first 100 days post-CRT (13.1% vs. 5.6%), no increase in treatment-related mortality was seen (0.6% vs. 0.7%). Late grade ≥3 toxicities occurring beyond 9 months were rare in both groups and did not exceed grade 3. The overall safety profile was considered acceptable and consistent with known immune-related toxicities.
Locoregional Control Improved with Nivolumab
One of the most noteworthy findings was a significant reduction in locoregional recurrences. At 3 years, locoregional failure occurred in 13% of patients in the NIVO + CRT arm versus 20% in the CRT-only arm (HR 0.63; 95% CI, 0.42–0.94). Interestingly, unlike perioperative immunotherapy regimens such as KEYNOTE-689 that predominantly reduced distant failures, NIVOPOSTOP’s benefit was concentrated in locoregional disease control, suggesting a synergistic effect between radiotherapy and immune checkpoint inhibition.
Survival Data Pending but Trending Favorably
Although Overall Survival (OS) data remain immature, early trends favor the Nivolumab arm. At the time of reporting, 74% of patients receiving NIVO + CRT remained alive at 3 years, compared to 68% in the CRT-alone group. The final OS analysis is planned upon reaching 283 events (currently at 158).
Clinical Context and Expert Perspectives
The NIVOPOSTOP findings stand in sharp contrast to prior trials like KEYNOTE-412 and JAVELIN Head and Neck 100, which failed to show benefit from concurrent immune checkpoint inhibitor with CRT in unselected populations. Notably, the timing and sequencing of immunotherapy in NIVOPOSTOP, administered in the postoperative setting and continued as maintenance may have circumvented the immunosuppressive milieu of CRT and allowed more robust immune priming. The researchers emphasized the clinical need among the ~40–45% of LA-SCCHN patients who relapse after surgery and CRT.
Conclusion
NIVOPOSTOP represents the first successful Phase 3 trial to demonstrate a Disease-Free Survival advantage with the addition of immunotherapy to adjuvant CRT in high-risk, resected LA-SCCHN. With a favorable balance of efficacy and manageable toxicity, this regimen is poised to reshape clinical practice, marking a long-overdue advancement in the postoperative management of head and neck cancer.
NIVOPOSTOP (GORTEC 2018-01): A phase III randomized trial of adjuvant nivolumab added to radio-chemotherapy in patients with resected head and neck squamous cell carcinoma at high risk of relapse. Bourhis J, Auperin A, Borel C, et al. J Clin Oncol 43, 2025 (suppl 17; abstr LBA2).
