Cadonilimab in combination with chemotherapy versus chemotherapy alone in patients with immunotherapy-refractory recurrent or metastatic nasopharyngeal carcinoma: A multicenter, randomized, phase III trial the CONQUEST trial).

6033 Background: Chemotherapy combined with immune checkpoint inhibitors (ICIs) is the standard first-line treatment for recurrent or metastatic nasopharyngeal carcinoma (R/M NPC); however, resistance is common. In the post-ICI setting, prospective trials have demonstrated limited efficacy, with objective response rates (ORRs) ranging from 4.2% to 34.3%. A prior phase II study of nab-paclitaxel, cisplatin, and capecitabine (TPC) plus cadonilimab demonstrated a promising ORR of 68% in ICI-refractory patients, providing the rationale for this phase III trial comparing TPC plus cadonilimab versus TPC alone in this population. Methods: In this randomized, multicenter, phase III trial, patients were assigned (1:1) to receive TPC plus cadonilimab or TPC alone. TPC consisted of nab-paclitaxel 200 mg/m² d1, cisplatin 60 mg/m² d1, and capecitabine 1000 mg/m² BID d1–14 (Q3W). In the experimental arm, cadonilimab (10 mg/kg d1) was added. Maintenance with capecitabine plus cadonilimab (experimental) or capecitabine alone (control) continued until disease progression, unacceptable toxicity, or 2 years. The primary endpoint was progression-free survival (PFS), defined as the time from randomization to disease progression or death from any cause. Secondary endpoints included overall survival (OS), ORR (defined as the best overall response), and safety. Results: A total of 84 patients were randomized (n=42/arm) at three hospitals. Baseline prior therapies were balanced ( P =0.533): 35 (83.3%) patients in the experimental arm and 37 (88.1%) in the control arm had received 1-3 prior lines of therapy, while 7 (16.7%) and 5 (11.9%) had received >3 prior lines, respectively. After a median follow-up of 10.2 months, PFS was significantly prolonged in the experimental arm versus the control arm (8.9 months [95% CI 6.3-11.4] vs. 5.1 months [95% CI 3.2-6.9]; HR 0.47, 95% CI 0.28-0.80; P =0.004). The ORR was 61.9% in the experimental arm versus 52.4% in the control arm, showing no statistically significant difference ( P =0.378). Median OS was not reached. All patients experienced adverse events (AEs). Grade 3-4 AEs occurred in 19 (45.2%) patients in the experimental arm versus 23 (54.8%) in the control arm ( P =0.383). The most common Grade 3-4 AEs were anemia (31.0% vs. 21.4%), neutropenia (21.4% vs. 21.4%), and leukopenia (16.7% vs. 14.3%). Immune-related AEs (irAEs) were more frequent in the experimental arm (34 [82.9%] vs. 25 [58.1%]; P =0.013); however, no Grade 3-4 irAEs were observed in either arm. Conclusions: TPC chemotherapy combined with cadonilimab demonstrated a statistically significant improvement in PFS compared with TPC alone in heavily pretreated, ICI-refractory R/M NPC patients, with a manageable safety profile (NCT06664983). Clinical trial information: NCT06664983 .