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Immunotherapy Salvage in mRCC Pretreated with Immunotherapy - Beyond the Abstract

One of the concepts discussed in our review of first-line immunotherapy combinations in renal cell carcinoma (RCC) was a potential strategy involving immune checkpoint inhibitor (ICI) rechallenge following previous exposure to ICI in metastatic RCC (mRCC) in an earlier setting. This topic was the focus of a recent presentation in mRCC at ASCO GU 2022.1 HCRN GU16-260 was a phase II study of nivolumab and salvage nivolumab + ipilimumab in treatment-naïve patients with advanced clear cell RCC (ccRCC). Here, eligible patients with treatment-naïve mccRCC received nivolumab induction 40 mg IV q2 wk x 6 doses followed by 360mg IV q3 wk x 4 doses followed by 480 mg q4 wk until progressive disease (PD), toxicity, or completion of 96 wks of treatment (Part A). Patients with PD prior to, or stable disease (SD) at 48 wks were eligible to receive salvage nivo (3mg/kg)/ipi (1 mg/kg) q3 wk x 4 doses followed by q4 wk nivo maintenance for up to 48 wks (Part B). With a median follow-up of 26.9 mos, 123 pts with ccRCC were enrolled with 76 (62%) having IMDC intermediate-risk disease 12 (10%) poor-risk disease, and 22 (18%) having a component of sarcomatoid histology. In Part A, RECIST defined ORR was 34.1% (95% CI 25.8-43.2%), CR 6.5%, and PR 27.6% for all subjects in the monotherapy nivolumab arm, while there was a 36.4% ORR (all PRs) for those with sarcomatoid RCC receiving monotherapy nivolumab. PD-L1 positivity was prognostic for improved response and 1-year PFS rate to nivolumab induction. However, in the salvage nivolumab/ipilimumab cohort (Part B), only 4/35 patients achieved an ORR.


The findings of HCRN GU16-260 are consistent with those of earlier studies OMNIVORE2 and TITAN-RCC3 whereby salvage nivolumab and ipilimumab in non-responders to nivolumab induction in mRCC generally have a low PR/CR conversion, and at best, the bulk of the efficacy assessments result in SD for salvage nivolumab and ipilimumab in this setting. However, the HCRN GU16-260 study does present two important findings. Firstly, nivolumab monotherapy has encouraging activity for those with sarcomatoid histology and may be an alternative option for those patients where there are concerns for tolerability to an ICI-based combination. Secondly, it reinforces the idea that the best upfront option in mRCC is likely an ICI-based combination such as nivolumab and ipilimumab. This is a topic we covered in our review as well where in order to achieve durable responses and the best chance for a prolonged overall survival benefit, it is likely imperative to combine all the best agents upfront (i.e., VEGF-TKI + ICI or ICI + ICI) rather than a sequential or salvage approach.

Lastly, in our review, we did cover results from a phase Ib/II Study 111/KEYNOTE-146 study whereby salvage Lenvatinib + pembrolizumab did appear to produce promising response rates even in those with mRCC pretreated with ICI (ORR at 24 weeks as high as 55.8%). We also highlight that the phase III PDIGREE trial is exploring a response-adapted treatment approach in first-line mccRCC where those treated with nivo/ipi will be stratified into different treatment arms including cabozantinib +/- nivolumab depending on response at 3 months. The success of ICI rechallenge is likely dependent on mechanism of action of the pairing of ICI with VEGF-TKI rather than ICI + ICI as in nivolumab + ipilimumab, based on the evidence to date. This concept is an ever-important one to study as ICI-based first-line combinations in mRCC are widely established as standards in mRCC in this setting.

Written by: Jun Gong, Division of Hematology and Oncology, Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA

References:

  1. Atkins MB, et al. "Phase II study of nivolumab and salvage nivolumab + ipilimumab in treatment-naïve patients (pts) with advanced clear cell renal cell (HCRN GU16-260-Cohort A): Final report." J Clin Oncol. 2022;40(suppl 6):288)
  2. McKay R, McGregor B, Xie W. et al. "Optimized Management of Nivolumab and Ipilimumab in Advanced Renal Cell Carcinoma: A Response-Based Phase II Study (OMNIVORE)." J Clin Oncol. 2020 Dec 20;38(36):4240-4248. doi: 10.1200/JCO.20.02295.
  3. Grimm MO, Esteban E, Barthélémy P, et al. "Efficacy of nivolumab/ipilimumab in patients with initial or late progression with nivolumab: Updated analysis of a tailored approach in advanced renal cell carcinoma (TITAN-RCC)." Journal of Clinical Oncology 2021 39:15_suppl, 4576-4576.

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