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: Kosuke Takemura, Jeffrey Graham, David Maj, Martin Zarba, Connor Wells, Razane El Hajj Chehade, Marc Eid, Eddy Saad, Renee Maria Saliby, Jae Lyun Lee, Frede Donskov, Benoit Beuselinck, Evon Jude, Rana R. McKay, Naveen S. Basappa, Sumanta Kumar Pal, Camillo Porta, Neeraj Agarwal, Toni K. Choueiri, Daniel Yick Chin Heng
Journal: Journal of Clinical Oncology (2025)

494 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%) &lt;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) &lt;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) &lt;0.001