Combination neoadjuvant therapy with toripalimab and axitinib for renal cell carcinoma with inferior vena cava thrombus: Insights from the NEOTAX study

SUMMARY The NEOTAX trial is a phase 2, open-label, single-arm study conducted at a single center in China between March 2020 and October 2023. It evaluated the efficacy and safety of toripalimab-based neoadjuvant therapy, a PD-1 inhibitor, with axitinib, a vascular endothelial growth factor receptor-tyrosine kinase inhibitor (TKI), in patients with clear cell renal cell carcinoma (ccRCC) and inferior vena cava tumor thrombus (IVC-TT). Patients received toripalimab 240 mg intravenously every 3 weeks (up to 4 cycles), in combination with axitinib 5 mg orally twice daily. The primary endpoint was the down-staging rate of the IVC-TT level, evaluated after 12 weeks of neoadjuvant therapy and immediately prior to surgery. The secondary endpoints included changes in thrombus length, overall tumor response according to the RECIST criteria, surgical approach modifications, progression-free survival (PFS), safety, and biomarker analyses. Twenty-five patients with Mayo levels II–IV IVC-TT were enrolled. The median age of the 25 patients was 58 years (76% male). Clinical stages included T3b (56%), T3c (36%), and T4 (8%). Lymph node metastasis was present in 40% of patients and 25% had distant metastasis. The median tumor thrombus length was 9.5 cm. EFFICACY OUTCOMES Down-staging: 44% of patients experienced a reduction in Mayo level, with no patients showing disease progression in thrombus level Tumor thrombus length: The median reduction in thrombus length was 2.3 cm (range: −7.1–1.1 cm) Overall tumor response: According to the RECIST criteria, 40% achieved a partial response and 60% had stable disease Surgical strategy modifications: 61.9% had changes in surgical approach from the initial plan. The median PFS was 25.3 months (median follow-up duration of 23.3 months), with 1-year and 2-year PFS rates of 89.1% and 54.8%. All patients had treatment-related adverse events (TRAEs), mostly Grade 1 or 2. Grade 3 TRAEs occurred in 28% of patients, including hypertension and proteinuria. No grade 4/5 TRAEs reported. Among patients categorized using RECIST (n = 15), biopsy samples from nonresponders (n = 6) showed increased T-cytotoxic cell infiltration, primarily PD-1 positive. In contrast, responders showed lower levels of T-helper cells, with regulatory T-cell subtypes remaining unchanged. Surgical samples from nonresponders revealed increased CD8+ T cells expressing GZMK and CXCR4. COMMENTS While surgical resection remains the cornerstone of treatment, neoadjuvant therapies like immune checkpoint inhibitors and TKIs have shown promise in down-staging ccRCC tumors, potentially facilitating less invasive surgery and improving outcomes. The NEOTAX study[1] assessed the combination of toripalimab and axitinib in ccRCC, leading to down-staging of the IVC-TT in 44% of patients. It permitted surgical plan modifications in over 60% of cases, suggesting systemic therapy before surgery may reduce complexity and morbidity. The median PFS of 25.3 months and a 1-year PFS rate of 89.1% are notable for this high-risk population and compare favorably to historical outcomes of similar cohorts treated with upfront surgery alone. These findings align with prior successes in metastatic RCC, where immune checkpoint inhibitors and TKIs, such as pembrolizumab plus axitinib (KEYNOTE-426 trial),[2] nivolumab plus cabozantinib (CheckMate 9ER),[3] demonstrated improved survival outcomes. However, NEOTAX is among the first studies to apply this combinatorial strategy in the neoadjuvant setting specifically for RCC with IVC-TT, thereby expanding the potential utility of immunotherapy beyond advanced disease stages. When benchmarked against prior neoadjuvant approaches, such as the axitinib monotherapy trial by Karam et al.,[4] which demonstrated a 35% down-staging rate and a median thrombus reduction of 1.5 cm, and the retrospective sunitinib study by Cost et al.,[5] which reported a 25% down-staging rate,[5] NEOTAX showed superior efficacy with a 44% down-staging rate and a median thrombus reduction of 2.3 cm. Moreover, NEOTAX uniquely reported a median PFS of 25.3 months, a key outcome absent in the above-mentioned studies. NEOTAX offers valuable prospective data in this complex clinical setting. The study’s limitations include a single-arm design, no control group, small sample size, single-center study, and a short follow-up period. The biomarker analyses were exploratory and limited in scope, highlighting the need for predictive markers to identify responders to neoadjuvant immune-targeted therapy. Despite a favorable safety profile with no grade 4/5 adverse events, 28% of patients experienced Grade 3 toxicities, which is not negligible, especially in the preoperative period. This necessitates careful patient selection and close monitoring. Thus, the NEOTAX trial should be a foundation for future multicenter randomized controlled trials with broader RCC subtypes, larger cohorts, longer follow-up, further exploring surgical outcomes, quality of life, and biomarker-guided therapy. Financial support and sponsorship: Nil. Conflicts of interest: There are no conflicts of interest.