# Caution: PD-1 rechallenge after progression on immunotherapy (RCC)

Source: https://onco.cc/pairings/io-rechallenge-caution-rcc/  
OnCo record `io-rechallenge-caution-rcc` (Pairing). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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.

## Fields

- Kind: Pairing
- Last checked: 2026-09-07
- Pairs: Immune checkpoint inhibitors + Anti-angiogenic therapy
- Type: caution
- 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.

## Sources

- ClinicalTrials.gov NCT04338269: CONTACT-03: https://clinicaltrials.gov/study/NCT04338269
- ClinicalTrials.gov NCT04987203: TiNivo-2: https://clinicaltrials.gov/study/NCT04987203

## Connected records

- cancers: [Renal cell carcinoma](https://onco.cc/cancers/rcc/)
- drugs: [Atezolizumab](https://onco.cc/drugs/atezolizumab/), [Cabozantinib](https://onco.cc/drugs/cabozantinib/), [Nivolumab](https://onco.cc/drugs/nivolumab/), [Tivozanib](https://onco.cc/drugs/tivozanib/)
- trials: [CONTACT-03](https://onco.cc/trials/contact-03/), [TiNivo-2](https://onco.cc/trials/tinivo-2/)
- technologies: [Anti-angiogenic therapy](https://onco.cc/technologies/antiangiogenic/), [Immune checkpoint inhibitors](https://onco.cc/technologies/checkpoint-inhibitor/)

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