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. 2025 Feb 12;13(2):e010958.
doi: 10.1136/jitc-2024-010958.

Efficacy and safety of nivolumab plus ipilimumab in patients with metastatic variant histology (non-clear cell) renal cell carcinoma

Mohammad Jad Moussa #  1 , Jaanki Khandelwal #  2 , Nathaniel R Wilson #  3 , Kiran L Malikayil  4 , Devaki Shilpa Surasi  5 , Tharakeswara K Bathala  6 , Yiyun Lin  7 , Priya Rao  8 , Pheroze Tamboli  8 , Kanishka Sircar  8 , Helen Ajufo  9 , Khaled M Elsayes  6 , Amishi Shah  1 , Andrew C Johns  1 , Sangeeta Goswami  1 , Elshad Hasanov  10 , Eric Jonasch  1 , Pavlos Msaouel  1 , Matthew T Campbell  1 , Omar Alhalabi  1 , Nizar M Tannir  11
Affiliations

Efficacy and safety of nivolumab plus ipilimumab in patients with metastatic variant histology (non-clear cell) renal cell carcinoma

Mohammad Jad Moussa et al. J Immunother Cancer. .

Abstract

Background: Nivolumab plus ipilimumab (nivo/ipi) is a standard of care first-line (1 L) therapy for patients with metastatic clear-cell renal cell carcinoma (ccRCC), but its role in patients with metastatic, non-ccRCC has not been fully defined. We report a single-institution experience with nivo/ipi in non-ccRCC.

Methods: Between November 2017 and February 2024, 55 patients with metastatic non-ccRCC received nivo/ipi at MD Anderson Cancer Center. The tumor response was assessed by blinded radiologists using RECIST v1.1. The overall response rate (ORR), progression-free survival (PFS), PFS milestone, duration of response (DoR), and overall survival (OS) were determined. Next-generation sequencing (NGS) was performed on available tumor specimens.

Results: Twenty-five (45.5%) patients had papillary histology (pRCC), 12 (21.8%) patients had chromophobe (chRCC), and 18 (32.7%) patients had unclassified RCC (uRCC). Fifty-two (94.5%) patients received nivo/ipi in 1 L. Sarcomatoid features (SF) were found in 20 (36.4%) cases. ORR was 48% (12/25) in pRCC, 25% (3/12) in chRCC (all 3 cases had SF), 27.8% (5/18) in uRCC, and 55% (11/20) across histologies with SF.The median PFS was 10.6 months (95% CI: 2.8 to 22.8) in pRCC, 3.6 months (95% CI: 0.9 - NE) in chRCC, and 3 months (95% CI: 2.1 to 7) in uRCC; 6-month milestone PFS was 56% (95% CI: 36.3 to 75.7), 41.7% (95% CI: 22 to 61.3), and 38.9% (95% CI: 21.7 to 56.1) in pRCC, chRCC, and uRCC, respectively. The median DoR for the entire cohort was 8.5 months (95% CI: 8 - NE). The median OS was 36.7 months (95% CI: 11.5 to 54.8) in pRCC, 25.7 months (95% CI: 0.9 - NE) in chRCC, and 11.1 months (95% CI: 6.5 - NE) in uRCC.Ten (18.2%) patients discontinued treatment due to treatment-related adverse events (AEs). Grade 3/4 immune-mediated AEs were noted in 17 (30.9%) patients. We performed NGS on 26 cases: TP53 (42%), PTEN (23%), and TERT (23%) alterations were most frequently found, with TERT and TP53 mutations enriched in pRCC and chRCC, respectively.

Conclusion: Nivo/ipi produced favorable outcomes in patients with pRCC supporting its use as 1 L therapy. Responses in patients with chRCC were noted exclusively with SF. Despite achieving an ORR of 27.8% with nivo/ipi, patients with uRCC had short PFS and inferior OS.

Keywords: Genitourinary Cancer; Immune Checkpoint Inhibitor; Immunotherapy; Kidney Cancer; Solid tumor.

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Conflict of interest statement

Competing interests: MJM, JK, NRW, KLM, TKB, YL, PR, PT, KS, HA, KME, ACJ, and SG report no disclosures. DSS reports research support from Blue Earth Therapeutics. AS reports scientific advisory board fees from Bristol Myers Squibb, Exelixis, and Pfizer; and research funding from Bristol Myers Squibb, Eisai, EMD Serono, and 4D Pharma. EH reports scientific advisory board fees from Pfizer, Eisai, and Telix Pharmaceuticals; honoraria from Targeted Oncology; and affiliations with Pelotonia Institute for Immuno-Oncology. EJ reports research funding from Arrowhead, Merck, and NiKang, as well as honoraria from Aveo, Aravive, Calithera, Eisai, Exelixis, Ipsen, Merck, NiKang, Novartis, Pfizer, and Takeda. PM reports honoraria for the service on scientific advisory boards for Mirati Therapeutics, Bristol Myers Squibb, and Exelixis; consulting for Axiom Healthcare Strategies; nonbranded educational programs supported by DAVA Oncology, Exelixis, and Pfizer; and research funding for clinical trials from Takeda, Bristol Myers Squibb, Mirati Therapeutics, Gateway for Cancer Research, and the University of Texas MD Anderson Cancer Center. MTC reports consultancy or advisory role for Astellas, AstraZeneca, AXDev, Eisai, EMD Serono, Exelixis, Genentech, Pfizer, and SeaGen; research funding from ApricityHealth, Aravive, AstraZeneca, Exelixis, Janssen, and Pfizer/EMD Serono; nonbranded educational programs from Bristol Myers Squibb, Merck, Pfizer/EMD Serono, and Roche. OA reports scientific advisory board fees from Seagen, Silverback Therapeutics, and Cardinal Health; educational program speaker from Curio Science and Aptitude Health; and research funding to the institution from AstraZeneca, Ikena Oncology, Genentech, and Arcus Biosciences. NMT reports research funding from Bristol-Myers Squibb Company (BMS), Calithera Biosciences, Nektar Therapeutics, Exelixis, Pfizer, Novartis, Arrowhead Pharmaceuticals, Mirati Therapeutics, Takeda, Epizyme, and Eisai Medical Research; consulting, advisory, travel accommodations, and expenses from BMS, Calithera Biosciences, Nektar Therapeutics, Exelixis, Pfizer, Novartis, Eisai Medical Research, Ipsen, Lilly Oncology, Neoleukin Therapeutics, Surface Oncology, ONO Pharmaceutical, and Oncorena; and honoraria from BMS, Exelixis, Nektar Therapeutics, Calithera Biosciences, Eisai Medical Research, ONO Pharmaceutical, Eli Lilly, Oncorena, Ipsen, and Surface Oncology.

Figures

Figure 1
Figure 1. Kaplan–Meier (KM) survival curves showing median progression-free survival in the entire cohort with metastatic renal cell carcinoma treated with nivolumab plus ipilimumab (nivo/ipi) and per histological subtype. Patients were censored if they stopped the treatment for non-progression or remained on treatment at the time of analysis.
Figure 2
Figure 2. Kaplan–Meier (KM) survival curves showing the median overall survival in the entire cohort with metastatic renal cell carcinoma treated with nivolumab plus ipilimumab and per histological subtype. Patients were censored at the last follow-up if they remained live at the time of analysis.
Figure 3
Figure 3. Kaplan–Meier survival curves comparing median overall survival and progression-free survival in patients with unclassified metastatic renal cell carcinoma treated with nivolumab plus ipilimumab.
Figure 4
Figure 4. Oncoplot showing the somatic alterations found in metastatic tumor biospecimens from 26 patients (47.3% of entire sample) treated with nivolumab plus ipilimumab (nivo/ipi), classified by the type of alteration, pathogenicity, vhRCC histological subset, the presence of sarcomatoid features and linked with the objective radiographic response to nivo/ipi.
See this image and copyright information in PMC

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