Progression-free Survival after Second Line of Therapy for Metastatic Clear Cell Renal Cell Carcinoma in Patients Treated with First-line Immunotherapy Combinations - Beyond the Abstract

Contemporary immuno-oncology (IO) and tyrosine kinase inhibitor (TKI)-based therapies have revolutionized the clinical management of metastatic clear cell renal cell carcinoma (ccRCC). Ipilimumab with nivolumab (IO/IO), as well as several combinations of vascular endothelial growth factor receptor (VEGFR)-targeting TKIs with IO agents (TKI/IO) are approved by the US Food and Drug Administration (FDA) for use in the first-line setting.1 Additionally, VEGFR TKIs are widely employed in the second-line setting for metastatic ccRCC.1 Deciding between first-line IO/IO or TKI/IO approaches represents a key clinical decision in the management of ccRCC; however, these approaches have not been directly compared, and physicians currently rely on a constellation of clinical factors to guide recommendation of one approach over the other.2 Furthermore, it is unknown whether patients who do not respond to first-line IO/IO can salvage long-term survival by receiving a TKI in the second-line setting.

Thanks to these modern regimens, expected patient survival upon initiation of therapy for metastatic ccRCC approaches 55 months or more,3,4 and multiple efficacious options are available to patients in the first- and second-line setting. However, in the phase III clinical trials leading to their FDA approval, IO/IO and TKI/IO combinations were compared with sunitinib monotherapy rather than with other contemporary IO-based regimens, and not all of the studies were universally designed to prospectively assess outcomes on subsequent therapies.5-9 The impact of initial therapy on second-line and long-term outcomes is therefore poorly understood. Consequently, in addition to the challenge of selecting IO/IO versus TKI/IO for first-line therapy, rising challenges in the field include optimal therapeutic sequencing and identification of clinical trial endpoints that are feasible to obtain and reflective of real-world, long-term patient outcomes.

Progression-free survival after second line of therapy (PFS-2) is an endpoint that incorporates outcomes on two consecutive lines of therapy, and has been shown to be a superior surrogate for overall survival compared with progression-free survival (PFS) or objective response rate (ORR).10 PFS-2 is a particularly useful endpoint in RCC as it may better reflect the increasing overall survival seen in patients with newly diagnosed metastatic disease, and can be used to compare outcomes for different therapeutic sequences.

We performed a retrospective comparison of PFS-2 in 173 patients with metastatic ccRCC who were treated at a single institution (Memorial Sloan Kettering Cancer Center) with first-line IO/IO versus TKI/IO. Patients with ccRCC who initiated treatment with a contemporary IO-based combination between 1/1/2014 - 12/31/2020 were eligible for inclusion, and PFS-2 was defined as time from start of first-line therapy to second objective disease progression or death from any cause; patients were otherwise censored at the time of last scan prior to the 12/31/2020 data cutoff date. Propensity score for receipt of treatment was calculated based on predictors including IMDC or MSKCC risk category, presence of sarcomatoid features, age, sex, and other baseline clinical factors, and adjusted restricted mean survival time (RMST) was reported for PFS-2. The RMST model was favored over the Cox proportional hazards model for adjusted survival estimates because the data violated the proportional hazards assumption.

After adjusting for propensity score, RMST for PFS-2 was 33 months for the TKI/IO group versus 30 months for the IO/IO group (difference 2.6 months; 95% CI: -2.6, 7.9; p=0.3). We concluded that our findings do not support a change in the current utilization practices for IO/IO and TKI/IO treatment strategies, whereby a multifactorial clinical stratification approach is used to guide treatment recommendations for individual patients.

Nevertheless, first-line therapeutic selection strategies can and should be improved. In this real-world cohort whose outcomes represent the results of regimen selection via clinical stratification, over 25% of patients experienced primary progression of disease as their best response to first-line therapy. Continued efforts towards identifying predictive biomarkers for response to IO/IO or TKI/IO therapies are therefore essential.

Written by: Kelly N. Fitzgerald and Chung-Han Lee, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York


  1. Network, N. C. C. Kidney Cancer, <> (2022).
  2. Fitzgerald, K. N. & Lee, C.-H. Personalizing First-Line Management of Metastatic Renal Cell Carcinoma: Leveraging Current and Novel Therapeutic Options. Journal of the National Comprehensive Cancer Network 1, 1-9 (2022).
  3. Motzer, R. J. et al. Conditional survival and long-term efficacy with nivolumab plus ipilimumab versus sunitinib in patients with advanced renal cell carcinoma. Cancer 128, 2085-2097, doi: (2022).
  4. Bersanelli, M., Buti, S. & Rizzo, M. The need for new algorithms of treatment sequencing in clear-cell metastatic renal cell carcinoma. Expert Review of Anticancer Therapy 21, 401-412, doi:10.1080/14737140.2021.1861941 (2021).
  5. Motzer, R. J. et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. New England Journal of Medicine (2018).
  6. Motzer, R. J. et al. Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. New England Journal of Medicine 380, 1103-1115 (2019).
  7. Rini, B. I. et al. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. New England Journal of Medicine 380, 1116-1127 (2019).
  8. Choueiri, T. K. et al. Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma. New England Journal of Medicine 384, 829-841 (2021).
  9. Motzer, R. et al. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. New England Journal of Medicine 384, 1289-1300 (2021).
  10. Woodford, R. G. et al. The validity of progressionā€free survival 2 as a surrogate trial end point for overall survival. Cancer 128, 1449-1457 (2022).
Read the Abstract