Iparomlimab and tuvonralimab (QL1706) combined definitive chemoradiotherapy in patients with locally advanced esophageal squamous cell carcinoma (QL1706-IIT-02): a single arm, phase 2 trial
Mené sur 20 patients atteints d'un carcinome épidermoïde de l'oesophage localement avancé et inopérable, cet essai de phase II évalue l'efficacité, du point de vue de la survie sans progression, et la toxicité du QL1706 (un anticorps monoclonal bispécifique ciblant PD-1 et CTLA-4, composé d’iparomlimab et de tuvonralimab) en combinaison avec une chimioradiothérapie
Background: Definitive chemoradiotherapy is the standard treatment for inoperable locally advanced esophageal squamous cell carcinoma (ESCC). However, the prognosis for these patients remains poor. This study aimed to evaluate iparomlimab and tuvonralimab (QL1706), a novel PD-1/CTLA-4 dual inhibitor, combined with definitive chemoradiotherapy in patients with unresectable stage III-IVA ESCC.
Methods: This single-arm, open-label phase 2 trial was conducted at a single center in China between August 2022 and September 2023. 39 patients with unresectable stage III-IVA ESCC were included. QL1706 is composed of iparomlimab (anti-PD-1 IgG4) and tuvonralimab (anti-CTLA-4 IgG1) in a fixed 2:1 ratio. Patients received radiotherapy (50.4 Gy/28 in fractions on 5 days per week), concurrent chemotherapy (paclitaxel 135 mg/m2 d1+ cisplatin 25 mg/m2 d1–3, q3w, 2 cycles), and QL1706 (5 mg/kg q3w for up to 1 year [total of 18 cycles]). The primary endpoint was progression-free survival (PFS). This study is registered with ClinicalTrials.gov (NCT05490719).
Findings: 20 patients (51.3%) completed the full cycles of QL-1706. Reasons for the premature cessation of QL1706 were disease progression (n = 7), COVID-19 infection (n = 2), pneumonia (n = 2), allergic reaction (n = 2), patient refusal (n = 4), rash (n = 1), and esophageal hemorrhage (n = 1). With a median follow-up of 21.1 months, the median progression-free survival (PFS) was 14.8 (95% CI: 11.2–NA) months. The median overall survival (OS) was immature. The 1-year PFS and OS rates were 58.6% (95% CI: 44.9–76.4) and 84.6% (95% CI: 74.0–96.7). The objective response rate and median duration of response were 84.6% (95% CI: 69.5–94.1) and 12.7 months (95% CI: 8.9–NA). Exploratory biomarker analyses identified several potential predictive biomarkers: 1) immunochemistry staining revealed that PD-L1 combined positive score ≥1 correlated with prolonged PFS (HR 0.37, p = 0.036); 2) Whole-exome sequencing detected high tumor mutation burden associated with better PFS (HR 0.24, p = 0.0066), while the mutated group (TNRC18/CAMSAP3/CARMIL2/ZFHX4 gene alterations) correlated with poor PFS (HR 6.40, p = 0.0002) and OS (HR 6.45, p = 0.0020); and 3) Olink plasma proteomics identified baseline levels of TWEAK and FASLG were both positively associated with PFS and OS (p < 0.05 for all). Grade ≥3 adverse events occurred in 89.7% (35/39) of the patients, predominantly lymphopenia (31/39, 79.5%).
Interpretation: QL1706 combined with chemoradiotherapy demonstrated potential antitumor activity and manageable toxicity, supporting further investigation.
eClinicalMedicine , article en libre accès, 2026