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.

Abstract

LBA6007 Background: Standard first-line therapy for recurrent or metastatic head and neck squamous cell carcinoma (R/M-HNSCC) includes platinum-based chemotherapy (PBC) combined with pembrolizumab or cetuximab; however, these regimens remain inaccessible for many patients globally, particularly in resource-limited settings. Triple oral metronomic chemotherapy combined with ultra-low-dose immunotherapy (TMC-I) has demonstrated promising activity and tolerability in earlier studies. We conducted a randomized phase III trial comparing TMC-I with PBC (paclitaxel and carboplatin) in patients with R/M-HNSCC receiving first-line palliative therapy. Methods: In this open-label, multicenter, phase III trial conducted at two centers, 422 patients with R/M-HNSCC were randomized (1:1) to receive paclitaxel 175 mg/m² plus carboplatin AUC 6 every 3 weeks (Arm-A) or TMC-I (oral methotrexate 9 mg/m² weekly, celecoxib 200 mg twice daily, erlotinib 150 mg daily, and nivolumab 20 mg IV every 3 weeks) (Arm-B). Treatment continued until disease progression or unacceptable toxicity. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), safety, and quality of life (QoL). The planned sample size of 422 patients (211 per arm) provided 80% power with a two-sided α of 0.05. The trial was registered with the Clinical Trials Registry–India (CTRI/2024/01/061661). Results: The median age was 49.5 years (IQR 42–58), 85.5% were male, 78.9% had oral tobacco use, 76.3% had oral cavity primaries, 25.6% had metastatic disease, and 30.6% had ECOG performance status 2. After a median follow-up of 10.8 months (95% CI 8.1–13.6) in Arm-A and 11.9 months (95% CI 10.3–13.4) in Arm-B, the primary endpoint of OS was significantly improved with TMC-I compared with PBC. Twelve-month OS was 46% versus 23%, and six-month OS was 69% versus 52% (p < 0.001). Median OS was 10.3 versus 6.2 months (HR 0.565, 95% CI 0.439–0.728; p < 0.001). Median PFS was 5.5 versus 2.7 months (HR 0.465, 95% CI 0.371–0.582; p < 0.001). ORR was higher with TMC-I than with PBC (53.4% vs 24.1%; p < 0.001), with fewer grade ≥3 adverse events (34.1% vs 46.4%; p = 0.010). No treatment-related deaths were observed, and patient-reported QoL was preserved with TMC-I. Conclusion: TMC-I significantly improved survival outcomes and response rates while reducing severe toxicity and preserving QoL compared with PBC. At approximately USD 230 per month, TMC-I represents a promising and cost-effective first-line treatment option for patients with R/M-HNSCC. Clinical trial information: CTRI/2024/01/061661.