Neoadjuvant toripalimab combined with axitinib in patients with locally advanced clear cell renal cell carcinoma: a single-arm, phase II trial

Abstract

Background: A combination of axitinib and immune checkpoint inhibitors (ICIs) demonstrated promising efficacy in the treatment of advanced renal cell carcinoma (RCC). This study aims to prospectively evaluate the safety, efficacy, and biomarkers of neoadjuvant toripalimab plus axitinib in non-metastatic clear cell RCC.

Methods: This is a single-institution, single-arm phase II clinical trial. Patients with non-metastatic biopsy-proven clear cell RCC (T2-T3N0-1M0) are enrolled. Patients will receive axitinib 5 mg twice daily combined with toripalimab 240 mg every 3 weeks (three cycles) for up to 12 weeks. Patients then will receive partial (PN) or radical nephrectomy (RN) after neoadjuvant therapy. The primary endpoint is objective response rate (ORR). Secondary endpoints include disease-free survival, safety, and perioperative complication rate. Predictive biomarkers are involved in exploratory analysis.

Results: A total of 20 patients were enrolled in the study, with 19 of them undergoing surgery. One patient declined surgery. The primary endpoint ORR was 45%. The posterior distribution of πORR had a mean of 0.44 (95% credible intervals: 0.24-0.64), meeting the predefined primary endpoint with an ORR of 32%. Tumor shrinkage was observed in 95% of patients prior to nephrectomy. Furthermore, four patients achieved a pathological complete response. Grade ≥3 adverse events occurred in 25% of patients, including hypertension, hyperglycemia, glutamic pyruvic transaminase/glutamic oxaloacetic transaminase (ALT/AST) increase, and proteinuria. Postoperatively, one grade 4a and eight grade 1-2 complications were noted. In comparison to patients with stable disease, responders exhibited significant differences in immune factors such as Arginase 1(ARG1), Melanoma antigen (MAGEs), Dendritic Cell (DC), TNF Superfamily Member 13 (TNFSF13), Apelin Receptor (APLNR), and C-C Motif Chemokine Ligand 3 Like 1 (CCL3-L1). The limitation of this trial was the small sample size.

Conclusion: Neoadjuvant toripalimab combined with axitinib shows encouraging activity and acceptable toxicity in locally advanced clear cell RCC and warrants further study.

Trial registration number: clinicaltrials.gov, NCT04118855.

Keywords: Immune Checkpoint Inhibitors; Renal Cell Carcinoma.

Figure 1

Trial design and profile. (A) Study schema. (B) Trial profile. Twice a day.

Figure 2

Treatment response. (A) Spider plot of tumor response evaluated by radiological imaging. (B) Waterfall plot of tumor response. (C) The change between clinical T stage and pathological T stage.

Figure 3

Treatment follow-up. (A) Swimmer plot. (B) Disease-free survival.

Figure 4

(A and B) MRI and pathological alterations in patients before and after axitinib plus toripalimab administration. (A) Example of highly immune infiltrated tumor; (B) example of minimally infiltrated tumor. ADC: apparent diffusion coefficient. (C) Baseline biomarkers correlated with response to treatment analyzed by NanoString IO 360. The volcano plot displays differential gene expression at baseline. (D). Relative fraction of tumor-infiltrating lymphocytes. Each row represents an immune cell subpopulation estimated by multiplexed immunofluorescence, including the density of PD1+ cells, PD1+CD8+ cells, PD-L1+ cells, PD-L1+CK+ cells, CD3+ cells, CD4+ cells, CD8+ cells, CD20+ cells, CD56+ cells, FOXP3+ cells, CD68+CD163- macrophage cells M1, CD68+CD163+ macrophage cells M2. The relative infiltrations of each lymphocyte subpopulations were normalized into a z-score. (E). Comparison of density levels of tumor-infiltrating PD1+ cells, PD1+CD8+ cells, PD-L1+ cells, PD-L1+CK+ cells between partial response (PR) and SD patients. *, p<0.05. (F). Comparison of density levels of tumor-infiltrating CD3+ cells, CD4+ cells, CD8+ cells, CD20+ cells, CD56+ cells, FOXP3+ cells, M1 macrophages, and M2 macrophages between PR and SD patients. No significant differences were found. (G). Representative multiplexed immunofluorescence images showing the simultaneous staining of panel 1 (left): DAPI (blue), CD8+ (red), PD-1+ (green), PD-L1+ (yellow), and CK (gray). Panel 2 (right): DAPI (blue), CD3+ (red), CD4+ (green), FOXP3+ (yellow), CD20+ (orange), and CK (gray) in PR (up) and SD (bottom) patients. Scale bar: 20 µm.