{"entity":{"id":"io-rechallenge-caution-rcc","kind":"pairing","name":"Caution: PD-1 rechallenge after progression on immunotherapy (RCC)","aka":[],"tldr":"Restarting immunotherapy alongside a targeted pill after immunotherapy has already failed adds side effects and no benefit.","summary":"This caution pairing concerns restarting an immune checkpoint inhibitor together with an anti-angiogenic tyrosine kinase inhibitor in renal cell carcinoma after the disease has already progressed on immunotherapy. Two phase 3 trials tested it and both were negative: CONTACT-03 compared atezolizumab plus cabozantinib with cabozantinib alone, and TiNivo-2 compared nivolumab plus tivozanib with tivozanib alone. The explanation is that acquired resistance to PD-1 blockade is not overcome by adding a VEGF-directed TKI, and the apparent activity of IO-TKI after IO in earlier single-arm studies reflected the TKI. After progression on immunotherapy, single-agent cabozantinib, tivozanib or axitinib, or belzutifan, is standard, and immunotherapy rechallenge is reserved for clinical trials.","asOf":"2026-09-07","links":[{"label":"ClinicalTrials.gov NCT04338269: CONTACT-03","url":"https://clinicaltrials.gov/study/NCT04338269"},{"label":"ClinicalTrials.gov NCT04987203: TiNivo-2","url":"https://clinicaltrials.gov/study/NCT04987203"}],"tags":[],"related":[],"cancers":["rcc"],"sections":[],"technologies":[],"targets":[],"drugs":["atezolizumab","cabozantinib","tivozanib","nivolumab"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["contact-03","tinivo-2"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"a":"checkpoint-inhibitor","b":"antiangiogenic","rationale":"Acquired resistance to PD-1 blockade is not overcome by adding a VEGF-TKI; the apparent activity of IO-TKI after IO in single-arm studies reflected the TKI.","evidence":"Two negative phase 3 trials.","pairingType":"caution"},"route":"/pairings/io-rechallenge-caution-rcc/","neighbours":{"cancer":[{"id":"rcc","kind":"cancer","name":"Renal cell carcinoma","route":"/cancers/rcc/"}],"drug":[{"id":"atezolizumab","kind":"drug","name":"Atezolizumab","route":"/drugs/atezolizumab/"},{"id":"cabozantinib","kind":"drug","name":"Cabozantinib","route":"/drugs/cabozantinib/"},{"id":"nivolumab","kind":"drug","name":"Nivolumab","route":"/drugs/nivolumab/"},{"id":"tivozanib","kind":"drug","name":"Tivozanib","route":"/drugs/tivozanib/"}],"trial":[{"id":"contact-03","kind":"trial","name":"CONTACT-03","route":"/trials/contact-03/"},{"id":"tinivo-2","kind":"trial","name":"TiNivo-2","route":"/trials/tinivo-2/"}],"technology":[{"id":"antiangiogenic","kind":"technology","name":"Anti-angiogenic therapy","route":"/technologies/antiangiogenic/"},{"id":"checkpoint-inhibitor","kind":"technology","name":"Immune checkpoint inhibitors","route":"/technologies/checkpoint-inhibitor/"}]}}