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Background <p>We aimed to investigate the exposure-response (E/R) relationship for ipilimumab and nivolumab in metastatic clear cell renal cell carcinoma (m-ccRCC) patients from the randomised phase 2 BIONIKK trial (EudraCT 2016-003099-28).</p> Methods <p>This study included patients treated with either single-agent nivolumab (Nivo monotherapy group, <i>n</i> = 39) or nivolumab plus ipilimumab (Ipi/Nivo group, <i>n</i> = 71). Trough plasma concentrations (<i>C</i><sub>min</sub>) were assayed at week 6 after treatment start. Cox proportional hazard and logistic regression models were used to investigate the E/R relationship between <i>C</i><sub>min</sub> and clinical outcomes.</p> Results <p>Low nivolumab <i>C</i><sub>min</sub> (&lt;median) was not identified as an independent risk factor for progression in either the Nivo monotherapy group (HR 2.03, 95% CI [0.93–4.44]; <i>p</i> = 0.076) or the Ipi/Nivo group (HR 1.06, 95% CI [0.63–1.79]; <i>p</i> = 0.83). Interestingly, low ipilimumab <i>C</i><sub>min</sub> (&lt;4.9 µg/mL) was independently associated with worse PFS in the Ipi/Nivo group (HR 1.77, 95% CI [1.03–3.05]; <i>p</i> = 0.040). In both groups, neither nivolumab <i>C</i><sub>min</sub> nor ipilimumab <i>C</i><sub>min</sub> was associated with the risk of death or grade ≥ 3 TRAEs occurrence.</p> Conclusions <p>This study suggests an E-R relationship for the efficacy of ipilimumab in m-ccRCC patients treated in combination with nivolumab. Prospective validation of our efficacy threshold in larger cohorts or phase 3 trials is essential prior to the implementation of a pharmacokinetically guided strategy.</p>

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Exposure-response relationship of nivolumab and ipilimumab in patients with metastatic renal cell carcinoma from the randomised phase 2 BIONIKK study

  • 期刊论文

  • 发表日期：

    2026年2月6日

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  • Benoit Blanchet,
  • Alicja Puszkiel,
  • Anne Jouinot,
  • Mostefa Bennamoun,
  • Denis Maillet,
  • Delphine Borchiellini,
  • Brigitte Laguerre,
  • Diane Pannier,
  • Marine Gross-Goupil,
  • Christine Chevreau,
  • Philippe Barthélémy,
  • Christophe Tournigand,
  • Elodie Coquan,
  • Gwenaelle Gravis,
  • Eve Lepicard,
  • Wolf Herman Fridman,
  • Catherine Sautes-Fridman,
  • Stéphane Oudard,
  • Cheng-Ming Sun,
  • Yann-Alexandre Vano

摘要

Background

We aimed to investigate the exposure-response (E/R) relationship for ipilimumab and nivolumab in metastatic clear cell renal cell carcinoma (m-ccRCC) patients from the randomised phase 2 BIONIKK trial (EudraCT 2016-003099-28).

Methods

This study included patients treated with either single-agent nivolumab (Nivo monotherapy group, n = 39) or nivolumab plus ipilimumab (Ipi/Nivo group, n = 71). Trough plasma concentrations (Cmin) were assayed at week 6 after treatment start. Cox proportional hazard and logistic regression models were used to investigate the E/R relationship between Cmin and clinical outcomes.

Results

Low nivolumab Cmin (<median) was not identified as an independent risk factor for progression in either the Nivo monotherapy group (HR 2.03, 95% CI [0.93–4.44]; p = 0.076) or the Ipi/Nivo group (HR 1.06, 95% CI [0.63–1.79]; p = 0.83). Interestingly, low ipilimumab Cmin (<4.9 µg/mL) was independently associated with worse PFS in the Ipi/Nivo group (HR 1.77, 95% CI [1.03–3.05]; p = 0.040). In both groups, neither nivolumab Cmin nor ipilimumab Cmin was associated with the risk of death or grade ≥ 3 TRAEs occurrence.

Conclusions

This study suggests an E-R relationship for the efficacy of ipilimumab in m-ccRCC patients treated in combination with nivolumab. Prospective validation of our efficacy threshold in larger cohorts or phase 3 trials is essential prior to the implementation of a pharmacokinetically guided strategy.