Importance Renal cell carcinoma (RCC) with inferior vena cava (IVC) tumor thrombus is associated with substantial perioperative risk and frequent recurrence despite nephrectomy and thrombectomy. No established neoadjuvant local therapy exists for this high-risk population. Objective To evaluate the feasibility, safety, clinical outcomes, and exploratory biomarker effects of neoadjuvant stereotactic ablative radiotherapy (SABR) targeting IVC tumor thrombus before nephrectomy and thrombectomy. Design, Setting, and Participants This single-center prospective phase 2 nonrandomized clinical trial enrolled patients with newly diagnosed RCC and Mayo level II to IV IVC tumor thrombus eligible for neoadjuvant SABR and definitive surgery from July 2015 to January 2024. Data were analyzed from August 2025 to August 2026. Intervention Neoadjuvant SABR to the radiographically defined IVC tumor thrombus, delivered as 40 Gy in 5 fractions or 36 Gy in 3 fractions, followed by radical nephrectomy and IVC thrombectomy. Main Outcomes and Measures The primary end point was 1-year recurrence-free survival (RFS) compared with a prespecified historical surgery-alone benchmark of 55.7%. Secondary outcomes included 90-day perioperative morbidity and mortality, adverse events, pulmonary embolism, overall survival, and cancer-specific survival. Exploratory analyses included Ki-67 immunohistochemistry and tumor-informed circulating tumor DNA. Results Of 23 patients who received neoadjuvant SABR, 22 completed surgery, and 21 were included in the primary RFS analysis. Of 21 included patients, 12 (57%) were male, and the median (IQR) age was 62.5 (54.0-73.2) years. A total of 19 patients had clear-cell RCC; all tumors were grade 3 or 4, and 3 patients had metastatic disease at enrollment. At a median (range) follow-up of 108.6 (2.0-127.2) months, 1-year RFS was 71.4% (80% CI, 56.6-82.0; 95% CI, 47.2-86.0), meeting the prespecified phase 2 screening criterion based on comparison with the historical surgery-alone benchmark of 55.7% ( P = .09). One-year overall survival was 95.2% (80% CI, 83.9-98.7; 95% CI, 70.7-99.3) and cancer-specific survival was 95.2% (80% CI, 83.9-98.7; 95% CI, 70.7-99.3). No 90-day perioperative mortality occurred; 4 grade 4 treatment-attributed events occurred, but no grade 4/5 radiation-attributed toxic effects occurred. Ki-67 expression was reduced in patients with irradiated tumor thrombus compared with nonirradiated controls. Tumor-informed circulating tumor DNA was detected in all patients with available plasma and declined after treatment. Conclusions and Relevance In this nonrandomized clinical trial, neoadjuvant SABR before nephrectomy and IVC thrombectomy appeared feasible with an acceptable safety profile. RFS met the prespecified phase 2 screening criterion but remains exploratory and warrants further evaluation. Trial Registration ClinicalTrials.gov Identifier: NCT02473536
Importance Neoadjuvant nivolumab plus ipilimumab in localized deficient mismatch repair/microsatellite instability–high gastric or gastroesophageal junction (GEJ) adenocarcinoma was evaluated in the NEONIPIGA study. The primary end point of pathological complete response (pCR) was previously reported. Objective To report long-term follow-up results and secondary end points, including event-free survival (EFS) and overall survival (OS), of the NEONIPIGA study. Design, Setting, and Participants The NEONIPIGA study is a French, multicenter, single-arm, phase 2 nonrandomized clinical trial that included patients with histologically proven cT2-T4NXM0 deficient mismatch repair/microsatellite instability–high GEJ adenocarcinoma who were eligible for surgery. Patients were enrolled between October 23, 2019, and June 4, 2021, and the database was locked on November 13, 2025. Intervention Neoadjuvant nivolumab, 240 mg, every 2 weeks for 6 cycles plus ipilimumab, 1 mg/kg, every 6 weeks for 2 cycles, followed by surgery 5 weeks after the last nivolumab dose, and adjuvant nivolumab, 480 mg, every 4 weeks for 9 cycles. Main Outcomes and Measures EFS and OS. Results A total of 32 patients (median [range] age, 65 [40-80] years; 8 [28%] female and 21 [72%] were male) were included: 16 (50%) with gastric cancer and 16 (50%) with GEJ cancer. Three patients did not undergo surgery (1 with metastatic disease and 2 who refused). Twenty-seven patients (84%) completed neoadjuvant therapy and 14 (44%) received all treatment as planned. Neoadjuvant and adjuvant therapy-related grade 3/4 adverse events occurred in 6 (19%) and 4 patients (17%), respectively. Median follow-up was 48.3 months (95% CI, 44.8-52.0 months). Among the 32 patients in the intention-to-treat population, 4-year OS was 84.1% (95% CI, 65.8%-93.0%). In the 31 patients eligible for surgery, 4-year EFS was 83.5% (95% CI, 64.8%-92.8%). One patient relapsed with cerebral metastases. Six deaths occurred: 2 related to gastric cancer or treatment (1 patient had postoperative complications and 1 cerebral metastases) and 4 unrelated. All patients who did not undergo surgery achieved a clinical complete response after immune checkpoint inhibitor therapy. One patient subsequently died of causes unrelated to their cancer. Overall, 17 of 29 patients (59%) achieved pCR on surgical specimen. Safety was previously reported, and no additional late toxic effects were observed. Conclusions and Relevance In this phase 2 nonrandomized clinical trial, the immunotherapy regimen evaluated was associated with sustained long-term survival, but no clear evidence of improved survival over outcomes reported in other studies evaluating surgery alone in this patient population was observed. The high pCR rates and durable responses observed may provide useful information for designing future clinical studies, including randomized trials investigating organ-preserving strategies. Trial Registration ClinicalTrials.gov Identifier: NCT04006262
This Viewpoint evaluates the present relevance of Response Evaluation Criteria in Solid Tumors (RECIST) as cancer therapeutics have evolved beyond cytotoxic chemotherapy in assessing treatment outcomes.
