Triple-oral metronomic chemotherapy combined with ultra-low-dose nivolumab (Opdivo; full regimen: TMC-I) reduced the risk of death by 43% compared with paclitaxel plus carboplatin in patients with platinum-sensitive recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) receiving first-line palliative treatment, according to data from a phase 3 trial (CTRI/2024/01/061661) presented in a press briefing at the
Patients in the TMC-I arm (n = 211) achieved a median overall survival (OS_ of 10.32 months vs 6.21 months with paclitaxel-carboplatin (n = 211; HR, 0.57; 95% CI, 0.44-0.73; P < .0001). The 1-year OS rate was 46.37% with TMC-I vs 23.24% with paclitaxel-carboplatin.
Full data from the phase 3 study will be presented on Sunday, May 31, 2026, during ASCO 2026.
The open-label, multicenter, noninferiority phase 3 study enrolled adults with platinum-sensitive advanced HNSCC who were receiving treatment with palliative intent. Patients were required to have an ECOG performance status of 0 to 2 and normal organ function.
The 422 patients were randomly assigned between February 2024 and December 2025; stratification factors included primary tumor site (oral vs other), prior chemotherapy (yes vs no), age (<60 vs ≥60 years), and gender.
Patients enrolled in arm A received at paclitaxel 175 mg/m² plus carboplatin at area under the curve 6 once every 21 days. Those in arm B received the TMC-I regimen, comprising methotrexate at 9 mg/m² once weekly, erlotinib (Tarceva) 150 mg orally once daily, celecoxib (Celebrex) at 200 mg orally twice daily, and nivolumab at 20 mg intravenously, all cycled once every 21 days.
The primary end point was OS assessed sequentially for noninferiority and superiority. Secondary end points included progression-free survival (PFS), objective response rate (ORR), duration of response (DOR), safety, and quality of life (QOL).
Baseline characteristics were well balanced between the 2 study arms. In the overall study population ( n = 422), the median age was 49.5 years (interquartile range, 42-58), 79.6% of patients were younger than 60, and 85.5% were male. The primary tumor site was the oral cavity in 76.3% of patients, and 25.6% had M1 disease. Approximately 50% had received prior treatment, and 87.2% had any history of tobacco exposure.
The trial was conducted at Tata Memorial Centre in Mumbai, India, where access to standard immune checkpoint inhibitors remains severely limited, with fewer than 3% of eligible patients in India able to receive checkpoint inhibitor–based therapy due to cost and infrastructure barriers, per investigators’ background data cited in the presentation.
TMC-I improved outcomes across all prespecified secondary efficacy end points. The median PFS was 5.5 months with TMC-I vs 2.7 months with paclitaxel/carboplatin (HR, 0.47; 95% CI, 0.37-0.58; P < .001), representing a 53% reduction in the risk of progression or death. The 1-year PFS rate was 26.1% with TMC-I compared with 4.7% with paclitaxel/carboplatin.
The ORR was 53.4% with TMC-I (n = 178) vs 24.1% with paclitaxel/carboplatin (n = 174; odds ratio [OR], 3.64; 95% CI, 2.23–5.94; P < .001). Disease control was achieved in 74.7% of patients receiving TMC-I vs 44.3% receiving paclitaxel/carboplatin (OR, 3.78; 95% CI, 2.23–6.41; P < .001). Among responders, the median DOR was 11.0 months with TMC-I vs 3.6 months with paclitaxel/carboplatin (HR, 0.32; 95% CI, 0.19–0.53; P < .001); the 1-year DOR rate was 44.5% vs 11.6%, respectively.
All patients in both arms experienced at least one treatment-related adverse effect (TRAEs) of any grade. Grade 3 or higher TRAEs occurred in 37.1% of patients receiving TMC-I (n = 202) vs 47.5% of those receiving paclitaxel/carboplatin (n = 198). Checkpoint inhibitor-related AEs were infrequent with the ultra-low-dose nivolumab approach: any-grade checkpoint inhibitor–related AEs occurred in 3.5% of TMC-I–treated patients, and grade 3 or higher related AEs in 1.5% (3 of 199).
QOL assessments showed no meaningful difference between arms at any timepoint, with global health status, role functioning, and social functioning maintained throughout treatment. Minor between-arm differences in pain medication use (P = .009) and nutritional supplement use (P = .007) were observed without impact on overall QOL scores.
Investigators noted that the annual cost of TMC-I is approximately $2,700, compared with approximately $12,000 for standard chemo-immunotherapy regimens and approximately $30,000 for cetuximab-based therapy. This is a disparity the authors identified as central to the regimen’s potential scalability in low- and middle-income countries where HNSCC burden is disproportionately high.
Interest in novel first-line regimens for recurrent/metastatic HNSCC has continued ahead of the 2026 ASCO Annual Meeting. A recent analysis published this month showed
