Cadonilimab plus axitinib demonstrated an ORR of 51.6% and manageable safety in frontline advanced nccRCC.
The PD-1/CTLA-4 bispecific antibody cadonilimab (AK104) plus axitinib (Inlyta) produced promising antitumor activity with a manageable safety profile for the first-line treatment of patients with advanced non–clear cell renal cell carcinoma (nccRCC), according to data from a phase 1b/2 study (NCT05808608) presented during the
In the phase 2 cohort (n = 31), the objective response rate (ORR) was 51.6% and the disease control rate (DCR) was 96.8%. The median progression-free survival (PFS) was 14.2 months (95% CI, 11.2-not reached [NR]), with a 12-month PFS rate of 61.2%. No dose-limiting toxicities (DLTs) were observed in the phase 1b dose-escalation portion, and 10 mg/kg every 3 weeks was established as the recommended phase 2 dose (RP2D) of cadonilimab. The median overall survival (OS) was NR (95% CI, NR-NR), and no deaths were attributed to treatment-related adverse effects (TRAEs).
"This is the first phase 1b/2 trial to evaluate the use of [a] PD-1/CTLA-4 bispecific antibody in combination with axitinib for the treatment of advanced nccRCC,” presenting author Junru Chen, MD, PhD, of the Department of Urology at West China Hospital of Sichuan University, in Chengdu, China, stated during the presentation.
The study enrolled patients with histologically confirmed, locally advanced or metastatic nccRCC, who received no prior systemic therapy and had an ECOG performance status 0 to 2.1,2
Phase 1b utilized a 3+3 dose-escalation design evaluating cadonilimab at 10 mg/kg or 15 mg/kg every 3 weeks in combination with axitinib at 5 mg twice daily. Phase 2 examined cadonilimab at the RP2D of 10 mg/kg every 3 weeks plus axitinib 5 mg twice daily.
The primary end points in phase 1b were safety and determining the RP2D of cadonilimab; the primary end point in phase 2 was ORR per RECIST 1.1 criteria. Secondary end points included PFS, DCR, duration of response (DOR), OS, and safety. Pharmacokinetics, biomarker analyses from tumor tissue and peripheral blood, and functional MRI were evaluated as exploratory end points. The data cutoff was March 1, 2026.
In the full analysis set (FAS; n = 37), the median age was 41.0 years (IQR, 35.0-53.0). Most patients were male (54%), had intermediate-risk disease per IMDC criteria (78%), and had metachronous metastatic disease (65%). By histopathology after genetic testing, the most common subtypes were FH-dRCC (43%) and TFE3-rearranged RCC (tRCC; 24%). The PD-L1 combined positive score (CPS) was at least 1 in 51% of patients. Common metastatic sites included lymph nodes (46%), bone (27%), liver (24%), and lung (16%).
In phase 1b, no DLTs were observed at either the 10-mg/kg (n = 3) or 15-mg/kg (n = 3) dose levels during the 21-day evaluation period. In the full 37-patient safety population, any-grade TRAEs occurred in 100% of patients and grade 3 or higher TRAEs were reported in 59.5%. The most frequent any-grade TRAEs included hypertriglyceridemia (81.1%), increased aspartate aminotransferase (AST) levels (75.7%), proteinuria (75.7%), increased alanine aminotransferase (ALT) levels (70.3%), diarrhea (59.5%), vomiting (32.4%), and hypertension (27.0%). Grade 3 or higher TRAEs included increased ALT levels (32.4%), increased AST levels (21.6%), diarrhea (10.8%), and hypertension (10.8%). Treatment interruption due to an adverse effect occurred in 64.9% of patients; treatment discontinuation due to a TRAE occurred in 2.7% (axitinib only); cadonilimab was not permanently discontinued due to a TRAE in any patient; and no patient discontinued both drugs due to a TRAE. No deaths were attributed to treatment.
In the phase 2 cohort, the median time to response was 3.5 months (range, 2.7-9.5); median DOR was 17.5 months (95% CI, 11.2-NR), with 61.1% of responders remaining in response at 12 months. Nineteen patients remained on treatment at the data cutoff. In the FAS, the median PFS was 19.2 months (95% CI, 13.9-NR) with a 12-month PFS rate of 64.8%. The 12-month OS rate was 91.8%; median OS was NR (95% CI, NR-NR).
ORR varied meaningfully across histologic subgroups: FH-dRCC had the highest response rate at 81.8% (n = 9 of 11), followed by SMARCB1-dRCC at 50.0% (n = 1 of 2), chRCC at 50.0% (n = 1 of 2), TFE3-rRCC at 37.5% (n = 3 of 8), TFEB-altered RCC at 33.3% (n = 1 of 3), and unclassified RCC at 33.3% (n = 1 of 3); no responses were observed in the 2 collecting duct carcinoma patients. Among clinical subgroups, the presence of liver metastasis was associated with a notably high ORR of 87.5% (n = 7 of 8). In the PFS analysis, synchronous metastatic disease was associated with shorter median PFS (11.2 months vs 20.3 months for metachronous disease), and patients with a PD-L1 CPS of at least 1 trended toward longer median PFS compared with those with a PD-L1 CPS of less than 1 (NR vs 11.2 months).
“Longer follow-up and biomarker analyses are still ongoing,” Chen stated in his conclusion.
Disclosures: Chen had no relevant financial relationships to disclose.
