The neoadjuvant combination of avelumab (Bavencio) and axitinib (Inlyta) resulted in a partial response (PR) rate of 30% in patients with localized renal-cell carcinoma (RCC) at high risk for relapse after nephrectomy, according to results from the phase 2 NeoAvAx clinical trial.
Of the 40 total patients in the study, 12 (30%) experienced a PR in their primary tumor, and 10 of these 12 patients (83%) were free of disease at the study cutoff. The median disease-free survival (DFS) has not yet been reached.
The data, presented at the 2022 American Society of Clinical Oncology Genitourinary Cancers Symposium, support the continued evaluation of this neoadjuvant combination, said lead investigator Axel Bex, MD, PhD, Professor, Urology, The Netherlands Cancer Institute, Antoni van Leeuwenhoekziekenhuis, Amsterdam.
“This is the first neoadjuvant trial reporting results from a combination of an immune checkpoint inhibitor and VEGFR-tyrosine kinase inhibitor [TKI] for locally advanced, high-risk RCC,” he said. “The DFS data are encouraging, supporting further evaluation, although currently there are no randomized neoadjuvant versus adjuvant [immune checkpoint inhibitor] trials or neoadjuvant versus adjuvant [immune checkpoint inhibitor]/VEGFR-TKI combination.”
The combination of avelumab and axitinib is currently approved by the FDA for first-line treatment of patients with advanced RCC.
NeoAvAx was an open-label, single-arm study in which 40 patients with high-risk, nonmetastatic, clear-cell RCC were treated with 12 weeks of axitinib 5 mg twice daily (escalated to 10 mg if tolerated) and avelumab 10 mg/kg for 6 cycles every 2 weeks, followed by complete surgical resection. The primary end point of the trial was a PR in the primary tumor ≥25%.
The median patient age was 63 years, with a male-to-female ratio of 70% to 30%. Baseline clinical TNM staging was T1b-T2b in 10%, T3a in 60%, T3b in 10%, and T4 in 20%. Biopsy grades were G1-2 in 67.5%, G3-4 27.5%, and Gx in 5%. A total of 17 (42.5%) patients were clinically node-positive. The baseline tumor diameter was 10.3 cm.
The median primary tumor downsizing was 20%. At a median follow-up of 23.5 months, 13 (32%) patients had a recurrence and 3 died of their disease. The median overall survival and median DFS had not yet been reached. No patients had progression of their primary tumor.
No new safety signals emerged with the neoadjuvant regimen compared with previous reports for axitinib and avelumab, and there were no treatment-related surgical delays. Surgical adverse events (AEs) were as expected in a patient population with locally advanced RCC. “All serious AEs were attributable to either prolonged hospitalization or readmission,” said Dr Bex.
The majority of the AEs were grade 1 or 2, most often hypertension, infusion-related reactions, and fatigue. Grade 3 AEs occurred in 6 patients (1 case each of hypertension, infusion-related reaction, fatigue, nausea, hand-foot syndrome, and elevated levels of liver function enzymes). No grade 4 or 5 AEs were observed.
Biomarker analysis on sequential tissue was an exploratory end point. “Patients with recurrence had lower CD8+ densities after treatment compared with patients without recurrence,” said Dr Bex. “Spatial transcriptomics of posttreatment primary tumor tissue revealed focal intratumoral differences in immune signatures and we are currently investigating this further to see whether this may be one of the reasons why these patients have recurrence.”
Discussant Daniel Geynisman, MD, Associate Professor, Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, PA, said that the objective with neoadjuvant therapy in this setting is to downstage tumors to facilitate resection, spare nephrons, and prevent relapse.
Neoadjuvant TKIs lead to approximately a 30% PR rate and are tolerable and safe for 8 to 16 weeks presurgery. Neoadjuvant single-agent immune-oncology (IO) therapy leads to primarily stable disease per RECIST criteria with mild tumor reduction; the effect on long-term immunologic memory is unknown. Therefore, the combination “makes great sense to try [in this setting],” Dr Geynisman said. “A short course of preoperative IO/TKI therapy is generally safe and does not delay surgery.”
“I will feel more comfortable continuing to use IO/TKI therapy in the neoadjuvant setting in highly select patients,” he said. “These are patients with a solitary kidney where you’re trying to go to a partial nephrectomy and spare nephrons [in addition to] unresectable disease that you’re trying to make resectable, or potentially lymph node-positive disease, although this is not a standard of care and best done on trial.”