Nivolumab/TMC-I Reduces Risk of Death in Platinum-Sensitive HNSCC

Findings from a phase 3 trial (CTRI/2024/01/061661) shared at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting demonstrated that combining triple-oral metronomic chemotherapy and ultra-low-dose nivolumab (Opdivo; TMC-I) significantly reduced the risk of death among patients with platinum-sensitive recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) who received first-line palliative treatment.

The median OS was 10.32 months with the TMC-I regimen vs 6.21 months with paclitaxel-carboplatin (PC; HR, 0.57; 95% CI, 0.44-0.73; P < .0001). The survival benefit deepened over time: the 6-month OS rate was 69.21% with TMC-I versus 52.29% with PC, and the 1-year OS rate was 46.37% with TMC-I vs 23.24% with PC.

TMC-I also demonstrated a 53% lower risk of disease progression or death compared with PC. Median PFS was 5.5 months with TMC-I versus 2.7 months with PC (HR, 0.47; 95% CI, 0.37-0.58; P < .001). The 1-year PFS rate was 26.1% with TMC-I versus 4.7% with PC.

TMC-I doubled the ORR compared with PC. Among evaluable patients, the ORR was 53.4% with TMC-I (n = 95/178) versus 24.1% with PC (n = 42/174), an absolute difference of 29.3 percentage points (odds ratio, 3.64; 95% CI, 2.23-5.94; P < 0.001). Disease control was also substantially higher with TMC-I at 74.7% versus 44.3% with PC (odds ratio, 3.78; 95% CI, 2.23-6.41; P < .001).

The median duration of response (DOR) was 11.0 months with TMC-I versus 3.6 months with PC (HR, 0.32; 95% CI, 0.19-0.53; P < .001). The 1-year DOR rate was 44.5% with TMC-I versus 11.6% with PC.

“Although effective treatments such as immunotherapy and cetuximab exist for patients with advanced head and neck cancer, they remain inaccessible to most patients due to cost and toxicity. This study demonstrates that a low-cost, well-tolerated regimen can significantly improve survival, making it highly relevant for global oncology practices,” said lead study author Minit Jalan Shah, MBBS, MD, of the Tata Memorial Centre in Mumbai, India.

Safety

The rate of grade 3 or higher TRAEs was lower with TMC-I at 37.1% compared with 47.5% with PC. Immune checkpoint inhibitor (ICI)-related adverse events were uncommon with the ultra-low-dose nivolumab component of the TMC-I regimen. Any-grade ICI-related adverse events occurred in only 3.5% of patients, and grade 3 or higher ICI-related events were observed in 1.5% (3/199).

Study Design and Patient Characteristics

The TMC-I trial is an open-label, multicenter, phase 3 study conducted at Tata Memorial Centre in Mumbai, India. Patients in the PC arm (n = 211) received intravenous paclitaxel 175 mg/m² with intravenous carboplatin AUC-6 once every 21 days. Patients in the TMC-I arm (n = 211) received tablet methotrexate 9 mg/m² once weekly, tablet erlotinib 150 mg orally once daily, capsule celecoxib 200 mg orally twice daily, and injection nivolumab 20 mg—all cycled once every 21 days. Platinum-sensitive disease was defined as recurrence ≥6 months after prior platinum-based chemotherapy. The primary endpoint was OS (non-inferiority), with secondary endpoints including OS superiority, PFS, ORR, DOR, safety, and quality of life.

Baseline characteristics were well-balanced between arms. The overall population (N = 422) had a median age of 49.5 years (IQR, 42-58) and was predominantly male (85.5%) and younger than 60 years (79.6%). A history of tobacco use in any form was present in 87.2% of patients, with oral tobacco consumption being the most common form (78.9%). ECOG performance status was 2 in 30.6% of patients. The primary tumor site was the oral cavity in 76.3% of patients, reflecting the tobacco-predominant epidemiology of HNSCC in India. Approximately 25.6% of patients had M1 disease, and 50.5% had received prior anticancer therapy, most commonly radiotherapy (42.7%) and surgery (39.6%).

Cost and Global Access Implications

The investigators reported that standard chemo-immunotherapy for HNSCC costs approximately $12,000 per year, and cetuximab-based regimens cost approximately $30,000 per year. By contrast, the TMC-I regimen costs approximately $2,700 per year.

“This study is important in that it represents a potential therapy option for patients in resource-limited parts of the world, including India, where the research was conducted. The median overall survival was improved in the triple oral metronomic chemotherapy combined with ultra-low-dose immunotherapy arm when compared with chemotherapy. However, the comparator regimen would not be a standard first-line option in the US, and the overall survival is lower than what we observe with standard first-line US agents,” said Glenn J. Hanna, MD, director of the Center for Cancer Therapeutic Innovation at Dana-Farber Cancer Institute and an ASCO Expert in head and neck cancers.

Reference

1. Shah MJ, on behalf of all co-authors and the Solid Tumor Unit 2 investigators at Tata Memorial Centre. Ultra-low-dose immunotherapy plus oral metronomic chemotherapy versus paclitaxel-carboplatin in platinum-sensitive recurrent or metastatic head and neck squamous cell carcinoma: a randomized phase III trial. Presented at: 2026 American Society of Clinical Oncology Annual Meeting; May 29-June 2, 2026; Chicago, IL.
2. American Society of Clinical Oncology. Ultra-low-dose immuno combo shows benefit in head and neck cancer. ASCO Press Center. Published May 31, 2026. Accessed May 30, 2026. https://ac.asco.org/about-asco/press-center/ultra-low-dose-immuno-combo-head-and-neck