2. UroToday Home
  3. Recent Abstracts
  4. Urologic Oncology
  5. Renal Cancer

Immunotherapy Combinations in Favourable Risk Score Metastatic Renal Cell Carcinoma, an Individual Patients Data Metanalysis - Beyond the Abstract

The introduction of immune-checkpoint inhibitors (ICIs) overturned the treatment of metastatic renal cell carcinoma (mRCC). While the benefit of ICI-based combination (both dual immunotherapy or ICI plus a tyrosine kinase inhibitor (TKI) compared to sunitinib is undeniable for International Metastatic RCC Database Consortium (IMDC) intermediate and poor risk patients, for favorable-risk patients, it’s still debated, and the scientific community asks if there is still a space for TKI monotherapy in this specific setting.1

In effect, the biology of IMDC favorable risk patients is often led by angiogenesis, making TKI monotherapy a viable comparator. The phase III trials concerning mRCC showed less significant advantage in terms of survival of ICI combinations compared to sunitinib in this group of patients.

To answer this question, we performed a reconstructed individual patient's data meta-analysis of 1088 favorable-risk patients from the pivotal phase III clinical trials: JAVELIN Renal 101, KEYNOTE-426, CheckMate 214, CheckMate 9ER, and CLEAR.

To obtain individual patients' data, we reconstructed them from the Kaplan-Meier curves. We used the IPDfromKM workflow (URL: https://biostatistics.mdanderson.org/shiyapps/IPDfromKM/). This workflow enables us to obtain individual patients' raw data from the published Kaplan Meier curves.1

Once obtained raw data we were able to compare indirectly the different experimental arm (assuming that the enrolled population was similar in every clinical trial: mRCC with IMDC favorable-risk score); to enhance the strength of our results, we compared the sunitinib arms among each trial to confirm that there weren’t statistically significant differences in terms of outcomes in standard of care arm among all the included clinical trials. Then we compared every ICI-based combination to a sunitinib curve of merged IPD from the five clinical trials. Fig 1.


Figure 1. Flow diagram of methods used to obtain individual patients' data (IPD) from the clinical trials.

The aim of the meta-analysis was to determine if the combinations improved outcomes compared to sunitinib and which combination performed better.

The key finding of the analysis in terms of progression-free survival is that Pembrolizumab -Lenvatinib regimen emerged as the better combination with a statistically significant advantage over sunitinib (HR 0.53). (Figure 2)

PFS_Analysis.png
Figure 2: PFS Analysis

On the other hand, none of the ICI-based combinations showed a statistically significant benefit versus sunitinib in terms of overall survival (Figure 3), even if there were benefit trends, even if non-significant from ICI-based combinations.


Figure 3: KM OS analysis

Data from our meta-analysis support the evidence that when approaching favorable-risk mRCC, it’s crucial to study the clinical features of every patient, and there is no single answer that works for everyone.

Probably there is a major benefit in using ICI-based combination in patients with a higher disease burden, while the monoTKI option can be viable for the Very Favorable risk patients (IMDC favorable risk characteristic and:2

  • Primary diagnosis to systemic therapy ≥3 years
  • Absence of brain, liver, or bone metastases
  • Karnofsky Performance Status of 90–100%.
In conclusion, among the limits of this approach, we have to consider that none of the included trials were specifically designed for IMDC favorable-risk patients, as all were conducted in broader untreated mRCC populations. Secondly, the duration of follow-up varied widely across trials, with the CheckMate-214 study’s extended follow-up (108 months) potentially influencing results. Additionally, the favorable-risk populations in the included studies may be heterogeneous in prognostic terms, as data on the proportion of very favorable-risk patients were unavailable. Lastly, because we used reconstructed IPD, it was not possible to adjust for patient-level covariates such as age, sex, and comorbidities.

Written by: Mattia Alberto Di Civita,1,2 Daniele Marinelli,1 Valerio Marco Michetti,3 Adele Artemi,2,4 Andrea Ballario,2,5 Andrea Torchia,6 Laura Pappalardo,2,4 Martina Pecoraro,2 Iolanda Speranza,5 Alessandro Sciarra,7 Valeria Panebianco,2 Michela Roberto,5 Daniele Santini,4,5,8

  1. Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy.
  2. Department of Radiological Sciences, Oncology and Pathology, Sapienza University of Rome, Rome, Italy.
  3. Sapienza University of Rome, Rome, Italy.
  4. Division of Medical Oncology B, Policlinico Umberto I, Department of Hematology, Oncology, and Dermatology, Sapienza University of Rome, Rome, Italy.
  5. Division of Medical Oncology A, Policlinico Umberto I, Department of Hematology, Oncology, and Dermatology, Sapienza University of Rome, Rome, Italy.
  6. Clinical and Molecular Medicine, Sapienza University of Rome, Rome, Italy.
  7. Department of Urology, Policlinico Umberto I, Sapienza University of Rome, Rome, Italy.
  8. Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy.
References:

  1. Liu, N., Zhou, Y. & Lee, J.J. IPDfromKM: reconstruct individual patient data from published Kaplan-Meier survival curves. BMC Med Res Methodol 21, 111 (2021). https://doi.org/10.1186/s12874-021-01308-8
  2. Martin Zarba et al. Systemic treatments in favorable and very favorable risk metastatic renal cell carcinoma (mRCC): Real world evidence from the International mRCC Database Consortium (IMDC).. J Clin Oncol 42, 4514-4514(2024) DOI:10.1200/JCO.2024.42.16_suppl.4514
Read the Abstract