Updated outcomes of patients with metastatic non-clear cell renal cell carcinoma (mnccRCC) treated with first-line (1L) therapies: Results from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC).
Authors: Takemura Kosuke , Graham Jeffrey , Maj David , Zarba Martin , Wells Connor , El Hajj Chehade Razane , Eid Marc , Saad Eddy , Saliby Renee Maria , Lee Jae Lyun , Donskov Frede , Beuselinck Benoit , Jude Evon , McKay Rana R. , Basappa Naveen S. , Pal Sumanta Kumar , Porta Camillo , Agarwal Neeraj , Choueiri Toni K. , Heng Daniel Yick Chin 
Published: February 2025

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Background:
Immuno-oncology (IO)-based combination therapy with or without anti-vascular endothelial growth factor (VE) has become a standard of care for mnccRCC. However, real-world evidence on the effectiveness of contemporary therapies over traditional targeted therapies against mnccRCC is limited.
Methods:
Using the IMDC, patients with mnccRCC were classified into five subgroups based on 1L therapies: IOIO, IOVE, CABO, SUN/PAZ, and mammalian target of rapamycin (mTOR). Baseline patient characteristics, clinician assessment of objective response rates (ORRs) as per RECIST 1.1, and overall survival (OS) were compared across 1L therapies.
Results:
Of 1551 patients with mnccRCC, 180 (11.6%), 90 (5.8%), 45 (2.9%), 1039 (70.0%), and 197 (12.7%) received IOIO, IOVE, CABO, SUN/PAZ, and mTOR, respectively. The most common histology was papillary in 725 (46.7%), followed by unclassified in 287 (18.5%), chromophobe in 200 (12.9%), and translocation in 84 (5.4%), while sarcomatoid dedifferentiation was found in 236 (15.2%). The IMDC prognostic categories (favourable/intermediate/poor) differed significantly across 1L therapies: IOIO (6.7%/52.3%/40.9%), IOVE (26.9%/44.9%/28.2%), CABO (16.1%/53.2%/30.7%), SUN/PAZ (16.1%/53.2%/30.7%), and mTOR (9.6%/51.4%/39.0%). For the papillary subtype, ORRs and median OS were better in IOIO (26.1% and 31.9 months), IOVE (31.0% and 33.2 months), and CABO (36.8% and 30.7 months) than in SUN/PAZ (12.8% and 17.2 months) and mTOR (3.4% and 13.1 months), whereas for the unclassified subtype, CABO did not appear to be as effective as IOIO and IOVE. For the chromophobe and translocation subtypes, there was no significant relationship between 1L therapies and the outcomes. IOIO was associated with the highest ORR and the longest median OS for mnccRCC with sarcomatoid dedifferentiation.
Conclusions:
Contemporary therapies seem to be effective against mnccRCC, although histology-specific strategies may guide personalized treatment selection.

Histologic subtype
IOIO
IOVE
CABO
SUN/PAZ
mTOR
p-value

Papillary

(n = 54)

(n = 31)

(n = 25)

(n = 499)

(n = 116)

ORR, n (%)
12/46 (26.1%)
9/29 (31.0%)
7/19 (36.8%)
52/407 (12.8%)
3/87 (3.4%)
<0.001

Median OS (95% CI), months
31.9 (20.3–NA)
33.2 (18.6–NA)
30.7 (17.5–48.7)
17.2 (15.3–19.6)
13.1 (11.1–15.4)
0.002

Unclassified

(n = 50)

(n = 20)

(n = 10)

(n = 179)

(n = 28)

ORR, n (%)
14/45 (31.1%)
5/17 (29.4%)
0/7 (0%)
22/149 (14.8%)
1/22 (4.5%)
0.018

Median OS (95% CI), months
18.8 (13.8–29.0)
15.5 (11.1–NA)
7.6 (2.1–NA)
13.6 (11.0–16.7)
6.1 (3.6–9.5)
<0.001

mnccRCC with sarcomatoid dedifferentiation

(n = 47)

(n = 12)

(n = 2)

(n = 141)

(n = 34)

ORR, n (%)
16/41 (39.0%)
2/10 (20.0%)
0/2 (0%)
16/106 (15.1%)
1/26 (3.8%)
0.003

Median OS (95% CI), months
31.9 (19.3–NA)
14.0 (2.1–NA)
14.3 (7.6–NA)
12.8 (7.0–13.9)
6.6 (3.6–12.5)
<0.001