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Optimal Treatment Duration in Metastatic Renal Cell Carcinoma Patients Responding to Immune Checkpoint Inhibitors: Should We Treat Beyond Two Years? - Beyond the Abstract

Immune checkpoint inhibitors (ICPIs) have fundamentally changed the therapeutic landscape of metastatic renal cell carcinoma (mRCC). Unlike pivotal trials in melanoma and non-small cell lung cancer, where ICPI therapy was capped at two years, treatment with nivolumab monotherapy or ipilimumab/nivolumab in mRCC has traditionally continued indefinitely, often until progression or unacceptable toxicity.1,2 This practice raises an important clinical question: is prolonged ICPI exposure truly necessary in patients with durable responses, or can we safely stop treatment around two years?

In our multicenter Belgian retrospective study of 95 patients achieving a partial or complete response to nivolumab or ipilimumab/nivolumab after a treatment of at least 21 months (without treatment-limiting toxicity), we observed that elective ICPI discontinuation between 21 and 25 months did not compromise long-term outcomes. Using a causal inference approach (artificial censoring along with inverse probability of censoring weighting) to minimize biases inherent to retrospective analyses, we found no significant increase in progression risk (adjusted HR 1.08, 95% CI: 0.64-1.84, p = 0.766) when therapy was stopped around two years compared to continuing beyond that point. In particular, 5-year progression-free survival would only be 6.2% (95% CI: -26.7 to 39.1) lower in absolute terms, translating to an estimated number needed to treat of 17 in favor of continuing ICPI treatment, while potentially saving, on average, 26.4 months (95% CI: 23.1-29.6) of additional therapy per patient.

These findings highlight several key considerations:

  • The “legacy effect” of ICPIs: durable tumor control may persist long after treatment cessation, reducing the need for indefinite therapy.
  • Patient quality of life: discontinuing treatment spares patients ongoing hospital visits and the cumulative toxicity burden of long-term therapy.
  • Healthcare impact: avoiding unnecessary years of expensive therapy alleviates strain on oncology day clinics and reduces costs for healthcare systems.
  • Clinical decision-making: while patients with stable disease remain a challenging group, those achieving partial or complete appear candidates for treatment discontinuation around two years.
In addition, our study addresses why even seemingly simple clinical questions - such as whether to continue or stop treatment at two years - require specific statistical approaches when answered using observational data.

Our study adds to a growing body of evidence across tumor types suggesting that shorter ICPI courses may be sufficient once durable responses are achieved.3-7 Nevertheless, caution is warranted. The number of patients who discontinued around two years was modest, and residual bias as well as subtle survival differences could not be entirely excluded. While subgroup analyses did not reveal any subgroups that significantly benefited from treatment continuation, these analyses may have been underpowered. Prospective, randomized de-escalation trials, therefore, remain essential to confirm these findings.8

For now, our results support the concept that in responding to mRCC patients, continuing ICPIs indefinitely may not be necessary, and elective discontinuation around two years can be considered without clear detriment to outcomes. This opens the door to a more patient-centered approach to immunotherapy in mRCC.

Written by:

  • Alexander Decruyenaere, Department of Medical Oncology, Ghent University Hospital, Ghent, Belgium
  • Benoit Beuselinck, General Medical Oncology, University Hospital Leuven, Leuven, Belgium
References:

  1. Regan MM, Jegede OA, Mantia CM, Powles T, Werner L, Motzer RJ, et al. Treatment-free survival after immune checkpoint inhibitor therapy versus targeted therapy for advanced renal cell carcinoma: 42-month results of the CheckMate 214 Trial. Clin Cancer Res. 2021;27(24):6687-95.
  2. Tzeng A, Tzeng TH, Ornstein MC. Treatment-free survival after discontinuation of immune checkpoint inhibitors in metastatic renal cell carcinoma: a systematic review and meta-analysis. J Immunother Cancer. 2021;9(10):1-11.
  3. Waterhouse DM, Garon EB, Chandler J, McCleod M, Hussein M, Jotte R, et al. Continuous versus 1-year fixed-duration nivolumab in previously treated advanced non-small-cell lung cancer: CheckMate 153. J Clin Oncol. 2020;38(33):3863-73.
  4. Kim H, Kim DW, Kim M, Lee Y, Ahn HK, Cho JH, et al. Long-term outcomes in patients with advanced and/or metastatic non-small cell lung cancer who completed 2 years of immune checkpoint inhibitors or achieved a durable response after discontinuation without disease progression: multicenter, real-world data (KCSG LU20-11). Cancer. 2022;128(4):778-87.
  5. Sun L, Bleiberg B, Hwang WT, Marmarelis ME, Langer CJ, Singh A, et al. Association between duration of immunotherapy and overall survival in advanced non-small cell lung cancer. JAMA Oncol. 2023;9(8):1075-82.
  6. Jansen YJL, Rozeman EA, Mason R, Goldinger SM, Geukes Foppen MH, Hoejberg L, et al. Discontinuation of anti-PD-1 antibody therapy in the absence of disease progression or treatment limiting toxicity: clinical outcomes in advanced melanoma. Ann Oncol. 2019;30(7):1154-61.
  7. Ito K, Kita Y, Yokomizo A, Miki J, Yoshio Y, Matsumoto H, et al. Discontinuation of pembrolizumab for advanced urothelial carcinoma without disease progression: nationwide cohort study. Cancer Med. 2023;12(3):2325-32.
  8. Ghorani E, Quartagno M, Blackhall F, Gilbert DC, O’Brien M, Ottensmeier C, et al. REFINE-Lung implements a novel multi-arm randomised trial design to address possible immunotherapy overtreatment. Lancet Oncol. 2023;24(5):e219-e227.
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