A phase 2/3 randomized clinical trial published in The Lancet Oncology on November 14, 2024 compared radiotherapy with durvalumab versus cetuximab for patients with locoregionally advanced head and neck squamous cell carcinoma (HNSCC) who had contraindications to cisplatin. The open-label, multicenter study was conducted at 89 academic and community medical centers in North America and funded by the US National Cancer Institute and AstraZeneca.
The trial aimed to assess whether radiotherapy with concurrent and adjuvant durvalumab would improve outcomes compared to radiotherapy with cetuximab in this patient population. A total of 186 patients were randomized in a 2:1 ratio to receive either durvalumab (123 patients) or cetuximab (63 patients) along with intensity-modulated radiotherapy.
Eligible patients were 18 years or older with American Joint Committee on Cancer 8th edition stage III-IVB p16-negative HNSCC or unfavorable stage I-III p16-positive oropharyngeal or unknown primary carcinoma. Importantly, all patients had contraindications to cisplatin, including ECOG performance status 2, renal or hearing impairment, peripheral neuropathy, age ≥70 years with moderate/severe comorbidity, or age <70 years with severe comorbidity.
The study population had a median age of 72 years, with 84% male patients. Nearly half (47%) had p16-positive oropharyngeal or unknown primary disease. The most common contraindications to cisplatin were hearing loss (49%), renal insufficiency (28%), and peripheral neuropathy (21%).
At the prespecified interim analysis, the trial was stopped early for futility. The final phase 2 results with extended follow-up (median 2.3 years) showed no benefit for durvalumab over cetuximab. The 2-year progression-free survival was 50.6% in the durvalumab group versus 63.7% in the cetuximab group (hazard ratio 1.33, 95% CI 0.84-2.12, p=0.89). Overall survival results were similar, with 2-year rates of 69.3% for durvalumab and 77.5% for cetuximab.
Interestingly, the 2-year progression-free survival of 63.7% in the cetuximab arm was higher than previously reported in similar trials of cisplatin-ineligible patients. This may be partly attributed to the novel criteria used to define cisplatin ineligibility, which incorporated validated instruments to assess comorbidities and vulnerability.
Adverse events were generally similar between the two groups. The most common grade 3-4 adverse events were dysphagia (22% with durvalumab vs 30% with cetuximab), lymphopenia (28% vs 33%), and oral mucositis (11% vs 18%). Treatment-related deaths occurred in 3% of durvalumab patients and 2% of cetuximab patients.
The study had some limitations, including early closure which limited the ability to robustly analyze treatment effects in subgroups. The authors could not rule out potential benefits of durvalumab in patients with high PD-L1 expression or determine if p16 status influences checkpoint inhibitor effectiveness in this population.
The investigators concluded that durvalumab did not improve outcomes compared to cetuximab when combined with radiotherapy in patients with HNSCC contraindicated for cisplatin. These findings align with other recent trials showing lack of benefit for immune checkpoint inhibitors over cetuximab in the cisplatin-ineligible HNSCC population.
The results have important clinical implications, supporting cetuximab with radiotherapy as a standard treatment option for patients with locoregionally advanced HNSCC who have contraindications to cisplatin. The higher than expected progression-free survival in the cetuximab arm may alleviate some prior concerns about its effectiveness in older adults with comorbidities.
This trial also introduces novel criteria for defining cisplatin ineligibility based on validated instruments, which could help standardize patient selection in future studies. The findings suggest that alternative radiosensitizing strategies are still needed for this challenging patient population.
While checkpoint inhibition showed initial promise, it does not appear to be an effective overall strategy for cisplatin-ineligible HNSCC patients receiving definitive radiotherapy. However, further investigation may be warranted in specific subgroups, such as patients with high PD-L1 expression or p16-positive disease.
In conclusion, this important negative trial provides valuable insights to guide treatment selection and future research directions for patients with locoregionally advanced HNSCC who cannot receive standard cisplatin-based chemoradiotherapy. It reinforces the role of cetuximab plus radiotherapy as a standard approach while highlighting the ongoing need for more effective therapies in this setting.
References
Mell LK, Torres-Saavedra PA, Wong SJ, et al. Radiotherapy with cetuximab or durvalumab for locoregionally advanced head and neck cancer in patients with a contraindication to cisplatin (NRG-HN004): an open-label, multicentre, parallel-group, randomised, phase 2/3 trial. Lancet Oncol. 2024;25(12):1576-1588. doi:10.1016/S1470-2045(24)00507-2
