Impact of site of metastatic involvement on IMDC classification in metastatic renal cell carcinoma patients treated with immunotherapy.
Authors: Fernandez-Mañas Laia , Ortiz Irene , Pozas Javier , Beland Chloe , Larkin James , Moll-Febrer Alba , González-Aguado Laura , Sanz Beltran Judit , Anguera Georgia , Navarro Nil , Rodriguez-Vida Alejo , Rubio Novella Silvia , Sierra Marina , Carrasco Alicia , Sala González Nuria , Murata Yonamine Eleonor Paola , González Maeso Iria , Figols Mariona , Marin Alcalá Maria , Reig Òscar 
Published: February 2025

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Background:
The IMDC risk classification is indispensable for managing metastatic renal cell carcinoma (mRCC) patients (pts). However, it was not developed for pts treated with immunotherapy (ICI) and lacks certain clinically relevant prognostic factors. We aim to explore whether the site of metastatic (SM) involvement can improve prognostic accuracy, as organotropism may be dictated by the underlying tumor's biology.
Methods:
This multicenter retrospective study analyzed ICI-treated mRCC pts from 2015 to 2023. Overall survival (OS) and progression-free survival (PFS) were evaluated using Kaplan-Meier and multivariate Cox regression analyses. We developed a new score, IMDC-SM, by incorporating SM independently associated with OS into the IMDC classification. Model fitness was assessed using the AIC and BIC.
Results:
525 pts were enrolled (73% male, 87% clear cell RCC, 10% with sarcomatoid dedifferentiation), including 191 (36.4%) pts treated in first line (1L). Among pts in 1L and ≥2L, 25% and 18%, 56% and 60%, and 25% and 22% were classified as favorable risk (FR), intermediate risk (IR), and poor risk (PR) by IMDC, respectively. In 1L cohort, most pts were treated with ICI + ICI (56%) and ICI + tirosine kinase inhibitors (38%). 70% of pts had lung involvement, 50% nodal, 29% bone, 20% adrenal, 17% liver, 16% tumoral thrombosis, 9% pleural, 9% peritoneal carcinomatosis, and 7% pancreatic involvement. Pleural, bone, and adrenal metastases were independently associated with worse OS in the multivariate analysis after adjusting for IMDC classification, age, sarcomatoid or rhabdoid dedifferentiation and histology. These SM were incorporated into the IMDC, adding 1 point for each SM present, to create the IMDC-SM score. Using the IMDC-SM, in 1L setting, 16 pts (8%) were reclassified from FR to IR and 28 pts (15%) from IR to PR Results of mOS and mPFS in 1L using both scores are shown in the table. IMDC-SM demonstrated better performance than the original IMDC classification for both in OS (Table). Within PR pts, those with ≥5 points had the worst mOS and mPFS (7 and 5.8m) than the remaining PR pts (24 and 14m). When applying the SM-IMDC in ≥2L pts 31 (9%) were reclassified from FR to IR, 66 pts (20%) from IR to PR and 1pt (0,2%) risk changed from FR to PR. The IMDC-SM classification also shows a superior prognostic value (Table).
Conclusions:
Combining site of metastasis information with the IMDC classification into a single scoring system significantly improves prognostic accuracy in ICI-treated mRCC pts, in both 1L and 2L. A validation cohort is necessary to determine a prediction model’s reproducibility.

Group Risk
Score
1L
2L

N

mOS (m)

mPFS (m)

N

mOS (m)

mPFS (m)

FR
IMDCIMDC-SM
4731
NANA
NANA
5927
3748
1015

IR
IMDCIMDC-SM
9684
4254
1318
198164
2026
88

PR
IMDCIMDC-SM
4876
1521
1212
76142
58
33

OS-AIC
IMDCIMDC-SM
691.5686.2
2404.72397.5

OS-BIC
IMDCIMDC-SM
696.2690.9
2411.72404.5