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A Syngeneic Mouse Model of Metastatic Renal Cell Carcinoma for Quantitative and Longitudinal Assessment of Preclinical Therapies
Published on: April 12, 2017
Comparative and Critical Analysis of Immune-based Combinations for First-line Treatment of Metastatic Renal Cell
Tomer Meirson1, Luciano Mutti2, Daniel A Goldstein3
1Davidoff Cancer Center, Rabin Medical Center-Beilinson Hospital, Petah Tikva, Israel; Rabin Medical Center-Beilinson Hospital, Samueli Integrative Cancer Pioneering Institute, Petah Tikva, Israel; Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
Introduction:
The 4 immuno-combinations currently approved in first-line metastatic renal cell carcinoma were not compared in head-to-head randomized controlled trials (RCTs). We compared the efficacy, statistical robustness, and censoring patterns of 4 phase 3 RCTs investigating these combinations versus sunitinib.
Patients And Methods:
Patient-level data on progression-free survival (PFS) and overall survival (OS) were extracted from the latest available updates of these studies (CheckMate-214, nivolumab + ipilimumab; CheckMate-9ER, nivolumab + cabozantinib; KEYNOTE-426, pembrolizumab + axitinib; CLEAR, pembrolizumab + lenvatinib). Censoring patterns were assessed using reverse Kaplan-Meier analyses. the restricted-mean survival time difference (RMST-D) was calculated. The survival-inferred fragility index (SIFI) for significant results was determined by reassigning the longest survivors from intervention to control until significance was lost.
Results:
The 58-month RMST-D for OS ranged from 3.5 (CLEAR) to 5.1 months (CheckMate-9ER) across the four trials. All studies showed significant control arm censoring in PFS. Before adjusting for censoring, the RMST-D for OS for the complete follow-up was statistically significant for all evaluated studies; after adjustment, only CLEAR lost OS benefit. The highest calculated SIFI for OS was in CheckMate-214 (2.2%).
Conclusions:
Nivolumab-based combinations and pembrolizumab + axitinib had more robust OS results compared to pembrolizumab + lenvatinib. While exploratory, this analysis provides a critical framework for contextualizing evidence where head-to-head data are lacking.
Insights
Four first-line metastatic renal cell carcinoma immuno-combinations were compared using statistical robustness and censoring patterns. Nivolumab-based combinations and pembrolizumab plus axitinib showed more robust overall survival results than pembrolizumab plus lenvatinib.
Area of Science:
- Oncology
- Clinical Trials
- Immunotherapy
Background:
- Four immuno-combinations are approved for first-line metastatic renal cell carcinoma (mRCC).
- No head-to-head randomized controlled trials (RCTs) directly compare these combinations.
- This study analyzes efficacy, statistical robustness, and censoring patterns of four pivotal phase 3 RCTs against sunitinib.
Purpose of the Study:
- To compare the efficacy and statistical robustness of four first-line mRCC immuno-combinations.
- To assess the impact of censoring patterns on survival outcomes.
- To provide a framework for evidence contextualization in the absence of head-to-head data.
Main Methods:
- Patient-level data on progression-free survival (PFS) and overall survival (OS) were extracted from four phase 3 RCTs.
- Censoring patterns were evaluated using reverse Kaplan-Meier analyses.
- Restricted-mean survival time difference (RMST-D) and survival-inferred fragility index (SIFI) were calculated to assess robustness.
Main Results:
- The 58-month RMST-D for OS varied across trials, from 3.5 months (CLEAR) to 5.1 months (CheckMate-9ER).
- All studies exhibited significant control arm censoring for PFS.
- After adjusting for censoring, only the CLEAR trial lost its statistically significant OS benefit; CheckMate-214 showed the highest SIFI for OS (2.2%).
Conclusions:
- Nivolumab-based combinations and pembrolizumab plus axitinib demonstrated more robust OS results compared to pembrolizumab plus lenvatinib.
- This exploratory analysis offers a critical method for evaluating evidence when direct comparative data are unavailable.
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