bluuebunny/crossref_metadata_2025 huggingface dataset:
Observational study of tislelizumab (Tisle) combined with pazopanib in reducing venous tumor thrombus in clear cell renal cell carcinoma with venous invasion.
Authors: Azhati Baihetiya
Published: February 2025

481

Background:
Renal cell carcinoma with venous tumor thrombus (RCC-VTT) presents significant surgical challenges, often requiring complex interventions. Neoadjuvant therapies that can reduce primary tumor size and venous tumor thrombus may simplify surgical procedures and decrease associated risks.
Methods:
The data of pts with RCC-VTT who underwent Tisle combined with Pazopanib neoadjuvant therapy at the First Affiliated Hospital of Xinjiang Medical University from Nov. 2021 to Jan. 2024 were analyzed. Inclusion criteria were as follows: (1) age ≥ 18 years; (2) TNM stage T3-4N0-1M0-1; (3) Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1; (4) a life expectancy of at least 3 months; and (5) adequate bone marrow, kidney, liver function, and normal blood test results. Exclusion criteria were as follows: (1) prior treatment with other antitumor drugs; (2) recent history of cardiac or vascular events or other conditions precluding surgical treatment; (3) participation in other clinical trials within the past 3 months; (4) lack of legal capacity or limited legal capacity; and (5) contraindications, allergies, or adverse reactions to pazopanib and tislelizumab. Eligible Pts received Tisle 200 mg IV. in day 1(D1), every 21 days for 4 cycles; Pazopanib was administered orally at a dose of 800 mg once daily for 12 weeks prior to the scheduled surgery. The primary endpoint of the study was the percentage change in the length of the VTT and the percentage reduction in the longest tumor diameter.
Results:
Nine patients with a median age of 58 years were treated. The median reduction in tumor diameter was 31.0% (range: 3.0%–48.7%), and the median reduction in VTT length was 29.2% (range: -153.1% to 100.0%). Treatment led to decreased surgical complexity in 88.9% of patients. The regimen was well-tolerated, with manageable adverse events primarily including vomiting, itching, and weight loss. No metastasis developed during the study period, though one patient required expedited surgery due to an increase in thrombus size.
Conclusions:
The combination of tislelizumab and pazopanib as neoadjuvant therapy effectively reduces the size of tumors and associated venous tumor thrombi in patients with RCC-VTT, facilitating less complex surgical interventions and potentially leading to better postoperative outcomes.
Clinical utility of measuring steady-state plasma level of lenvatinib in advanced renal cell carcinoma.
Authors: Kim Sang Yoon , Checkley James , Radovanovic Mirjana , Galettis Peter , Zhang Alison Yan , Gurney Howard
Published: February 2025

486

Background:
As a multitarget tyrosine kinase inhibitor, lenvatinib (LEN) efficacy and toxicity are dose-dependent, and dose adjustment is common for toxicity. A therapeutic level of LEN has not been defined in renal cell carcinoma (RCC), leading to uncertainty whether the patient is on an effective dose. LEN is also widely used in combination with immune checkpoint inhibitor (ICI), adding complexity due to overlapping toxicity. In this investigator-initiated study, we aimed to assess: A) inter- and intra-patient variability in LEN steady-state plasma level (C
ss
) after dose adjustment for target toxicity; and B) associations between C
ss
and health-related quality of life (HRQoL) outcomes and treatment-related toxicity (trAE).
Methods:
Patients on LEN for advanced RCC underwent C
ss
assessment – first when LEN dose was stable after adjusting for target of CTCAE grade 1 to 2 toxicities for at least 6 weeks prior; and another 6 weeks or more later to assess for intra-patient variation. HRQoL and trAE data were collected at the time of phlebotomy. Additional C
ss
samples were taken when patients required dose interruption due to significant trAE, as determined by the treating clinician. Bivariate linear regression model was used to analyse association between C
ss
and HRQoL (EORTC-QLQ-C30 Summary Score and QL2 domain), plus C
ss
and CTCAE Composite Score (CTCAE grade multiplied by number of days the event was present during preceding 30 days).
Results:
Between Apr 2023 – Jun 2024, 47 plasma samples from 19 RCC patients were collected and analysed. Patients were predominantly male (95%; 18/19) with clear cell subtype (74%; 14/19). At time of first sample collection: 13/19 (68%) patients have been on their LEN dose for more than 6 months (median time on dose 348 days), and 14/19 (79%) patients were on combination systemic therapy (10 with ICI; 1 with belzutifan; 3 with ICI+belzutifan). The median daily LEN dose was 14 mg (range 8-20). Median C
ss
was 17.9 µg/L (interquartile range, IQR, 14.3-23.0). The median intra-patient variation was low at 1.09% (IQR -11.9 to 11.9%). Moderate correlation was observed between C
ss
and QLQ-C30 Summary Score reflecting overall symptom burden (b= -0.713, R
2
=0.387, p<0.0001). Similar correlation was also observed between C
ss
and QLQ-C30 QL2 domain reflecting global health status (b= -1.20, R
2
=0.456, p<0.0001). There was little correlation between C
ss
and CTCAE Composite Score (b= 2.06, R
2
=0.105, p=0.030).
Conclusions:
LEN C
ss
after dose adjustment for a target toxicity showed minimal intra-patient variation. Our study indicates that after dose adjustment, LEN C
ss
correlates with patient-reported symptom burden and global health status. Future prospective studies to evaluate recommended therapeutic range, and integration of therapeutic drug monitoring in real-world clinical settings may ensure patients are receiving an effective dose.
Real world evidence from a retrospective multi-center analysis on first-line therapy for metastatic renal cell carcinoma with chromophobe histology.
Authors: Paffenholz Pia , Casuscelli Jozefina , Zschaebitz Stefanie , Rinderknecht Emily , Mattigk Angelika , Volk Anna-Lisa , Ivanyi Philipp , Hilser Thomas , Darr Christopher , Flegar Luka , Schlack Katrin , Seidl Daniel , Handke Analena , Klee Melanie , Nestler Tim , Rehlinghaus Marc , Hijazi Sameh , Heidenreich Axel , Grünwald Viktor
Published: February 2025

488

Background:
Chromophobe (chRCC) renal cell carcinoma are rare cancers and obtain a worse prognosis. We evaluated real-world treatment outcomes of 1
st
line treatment in these cohort in Germany.
Methods:
We retrospectively analyzed patients with metastatic chRCC treated at 17 German tertiary cancer centres being treated from 2008-2023. Adverse events (AE) were reported according to CTCAE 5.0, objective response rate (ORR) according to local standard of radiological and clinical judgement. Progression free survival (PFS) and overall survival (OS) were calculated from start of treatment to progression or death, respectively and determined by KM plots.
Results:
We included 39 patients with a median age of 59 (IQR 55-71) years. ECOG PS was 0/1/≥2 in 70/17/12%. IMDC risk was favorable/intermediate/poor in 13/61/26%. 87% received prior nephrectomy. Lymphatic (58%), pulmonary (37%) bone (34%) and metastases were the most common metastatic sites. 52% patients received first-line IO-combinations (IO-IO: 43%, TKI-IO: 57%) and 48% patients TKI-monotherapy, predominantly sunitinib. Subsequent therapy was mostly Cabozantinib (after IO-IO), Lenvatinib/Everolimus (after IO-TKI) or Nivolumab (after TKI mono). AE of all grades occurred in 59% and 71% during IO-based therapy or TKI monotherapy, and CTCAE grade ≥3 in 29% or 25%, respectively. ORR and survival outcomes with median follow-up of 14 months (IQR 7-28) are described in the table.
Conclusions:
IO-combinations are frequently applied in chRCC. Our data suggests that first-line IO-/TKI-based combinations yields higher ORR compared to IO-/IO-based combinations and single agent TKI, but did not translate into an improved PFS or OS. The retrospective nature and small sample size are major limitations of our analysis. However, the rarity of metastatic chRCC contributes to inconsistent findings not only in our dataset but also across previously published studies, making it difficult to establish clear treatment guidelines. Further research is essential to refine treatment strategies for patients with metastatic chRCC.

ORR and survival outcomes of study population.

Parameter
All therapies (n=31)
IO/IO (n=8)
IO/TKI (n=10)
TKI (n=13)

ORR (CR+PR)
19%
12,5%
30%
15%

SD
16%
12,5%
40%
0%

PD
65%
75%
30%
85%

ORR vs. SD vs. PD
-
p=0.05

Parameter
All therapies
IO/IO
IO/TKI
TKI

mPFS, months, 95% CI
3 (0,0-10,2)
3 (2,4-3,6)
8 (0,0-19,2)
4 (0,0-10,2)

-
P=0.077

mOS; months, 95% CI
24 (22,7-25,3)
12 (2,3-21,7)
NR (NR-NR)
24 (22,5-25,5)

-
p=0.183
Avelumab in combination with axitinib (Ave + Axi) for first-line (1L) treatment of advanced renal cell carcinoma (aRCC): A systematic literature review (SLR) of real-world effectiveness and safety.
Authors: Kearney Mairead , Taneja Ankush , Sharma Aniket , Elsada Ahmed , Fontrier Anna-Maria , Alexopoulos Stamatia , Roskell Neil
Published: February 2025

491

Background:
Ave + Axi combination is an approved option worldwide for 1L treatment of patients with aRCC based on the results of the JAVELIN Renal 101 phase 3 trial. The results of the final analysis (data cutoff: Aug 31, 2023) confirmed the long-term efficacy and manageable safety profile of this immunotherapy (IO)/tyrosine kinase inhibitor combination with the longest follow-up (≥68 months in all patients). The aim of this SLR was to summarize the real-world effectiveness, safety, and tolerability of Ave + Axi in aRCC and compare with outcomes from JAVELIN Renal 101.
Methods:
A SLR was conducted using 3 online databases (MEDLINE, Embase, and Cochrane) to identify publications (to Jul 29, 2024) and recent conference abstracts of Ave + Axi real-world studies reporting outcomes for 1L treatment of aRCC, with no geographical or observational study-type restrictions.
Results:
A total of 9 studies met the inclusion criteria; most were retrospective (7/9), including multicenter, single-center, or database/registry studies relying on secondary data sources. Studies were conducted in the UK (4/9), Japan (3/9), USA (1/9), and Russia (1/9). Median age was 61.5-70 years; most patients were male (68%-90.5%), had an ECOG performance status of 0-1 (60%-94%), and had metastatic tumors with clear cell histology (66.7%-100%). High attrition between lines of treatment was noted, with only 35% of patients receiving second-line treatment after disease progression (most commonly with cabozantinib monotherapy, 52.2%). Median progression-free survival (PFS) ranged from 9.1-15.3 months (vs 13.9 months in JAVELIN Renal 101). Landmark 1-year PFS and overall survival rates from Ave + Axi start were 27%-68.2% and 15%-98.8%, respectively. Overall response rate was numerically higher in International Metastatic RCC Database Consortium (IMDC) risk favorable- (70.5%) vs intermediate- (64.7%) or poor-risk (39%) subgroups (reported in 1 UK study). Rates of grade ≥3 adverse events (AEs; 17%-36%) and discontinuation due to AEs (10%-27%) were low.
Conclusions:
Overall, findings from global real-world studies of Ave + Axi in 1L aRCC align with those of the JAVELIN Renal 101 trial, validating the long-term efficacy and safety of this combination. The high rate of attrition between lines of therapy supports the use of the most effective IO-based treatments upfront. Despite the limited number of studies and data heterogeneity, results from this SLR of real-world studies conducted in the IO era in several countries provide a good representation of Ave + Axi use in an evolving treatment landscape. Additional prospective data (eg, the ongoing multi-country AVION study; NCT04941768) and extended follow-up are required to inform the optimal use of Ave + Axi in patient subgroups, such as those with IMDC favorable-risk disease.
Clinicopathological features and prognosis of MED15-TFE3 rearrangement renal cell carcinoma: An updated report.
Authors: He Sike , Liu Haoyang , Hu Xu , Chen Junru , Liu Zhenhua , Shen Pengfei , Zeng Hao
Published: February 2025

492

Background:
TFE3-rearranged renal cell carcinoma (rRCC) is uncommon, and demonstrates unique heterogenous morphological features and distinct immune characteristics. MED15-TFE3 is a rare gene fusion that usually present as an extensive cystic mass with low malignant potential and is more susceptible to immune check point inhibitor. Identifying the clinical characteristics is crucial for the treatment.
Methods:
All samples were collected retrospectively from West China Hospital between 8/2011 and 5/2024. Diagnosis of MED15-TFE3 gene fusion was confirmed by RNA sequencing and fluorescence in situ hybridization. Both clinicopathological features and follow-up prognosis information were collected for further analysis.
Results:
The detailed information of 16 cases were described in the table. The median age was 47.5 years (range, 22 to 70 years). Majority of the cases were female (12/16). All patientes were surgically treated (radical nephrecomy: 8; partial nephrectomy: 7; cytoreductive surgery: 1). At initial diagnosis, most cases (14/16) were localized disease, while two patients had positive regional lymph nodes metastasis, and one patient had distant metastasis. For the patients without distant metastasis (n=15), two patients developed metastasis with disease-free survival of 11.4 and 29.0 months, respectively. As for the pathological features, 14 (87.5%) of the casess presented cystic morphologically, and other two (12.5%) were papillary. Except for one patient with diatant metastasis at initial diagnosis, all patients (15/16) were in G2 by ISUP score. For metastatic patients, 3 received first-line therapy (1 axitinib, 1 axitinib + sintilimab, 1 sunitinib), 2 received second-line therapy (1 axitinib + sintilimab, 1 axitinib + toripalimab), 1 received third-line therapy (axitinib + toripalimab and combined with everolimus). They are still under follow-up.
Conclusions:
MED15-TFE3rRCC mainly present low-grade cystic renal neoplasm with favorable prognosis. For metastatic MED15-TFE3 rRCC, there is no standard therapy currently.

Clinicopathological characteristics and prognosis of 16 MED15-TFE3 rRCC cases.

Characteristics
Cases

Age, median (range), years
47.5 (22, 70)

Gender

Male
4

Female
12

Morphology

Cystic
2

Papillary
14

Tumor size, median (range), cm
5.6 (3.3, 14.0)

Nephrectomy

Radical
8

Partial
7

Cytoreductive
1

T stage

T1
10

T2
3

T3
3

N stage

N0
14

N1
2

M stage

M0
15

M1
1

ISUP grade

2
15

3
1

Distant metastasis

Synchronous
2

Metachronous
2

No
12

Survival status

Alive
15

Dead
1
Clinicopathological characteristics and prognosis of metastatic non-clear cell renal cell carcinoma.
Authors: Wu Jie , Cui Hong-Lei , Shi Hongzhe , Guan Youyan , Bi Xin-Gang , Zhou Aiping , Shou Jianzhong
Published: February 2025

504

Background:
Non-clear cell renal cell carcinoma (nccRCC) is a clinicopathological heterogeneous disease that comprises a complex mixture of different pathology subtypes, accounting for approximately 20% of all RCC cases. Due to its heterogeneity and rarity, standard treatment strategy for metastatic nccRCC remain poorly defined.
Methods:
We conducted retrospective analysis of 105 metastatic nccRCC patients at our center from June 2010 to April 2022. Demographic, clinicopathological, and systemic therapy data were collected. The data of 872 metastatic ccRCC patients were also collected for comparison.The end points included progression-free survival (PFS) and overall survival (OS).
Results:
Among 105 metastatic nccRCC patients, the most prevalent histology was papillary RCC (pRCC, 39.0%). The second most common histological type was translocation RCC (tRCC, 29.5%), followed by unclassified RCC (24.8%). The median age of metastatic nccRCC patients was 50 years old. 68.6% patients had advanced primary tumor stage of T3/4, and 48.6% patients had regional lymph node metastasis. The most common distant metastasis site was lung metastasis (52.4%), followed by bone metastasis (33.3%), and 21.0% patients had liver metastasis. The proportion of the favorable, intermediate, and poor IMDC risk group were 19.0%, 54.3%, and 26.7%, respectively. Among metastatic nccRCC patients, 26 received first-line IO-TKI therapy, 79 received first-line TKI monotherapy therapy. During the median follow-up of 22.2 months, there was no statistical significance between the prognosis of IO-TKI and TKI monotherapy group (PFS: 10.9 months vs. 8.6 months, P = 0.23; OS: 23.3 months vs. 24.0 months, P = 0.39). The PFS of tRCC was significantly longer than pRCC and unclassified RCC (P＜0.001). According to the Cox regression model, unclassified RCC pathology (HR=2.027，P=0.023) and poor IMDC risk group (HR=2.285，P=0.011) were identified as the independent risk factors for PFS. Poor IMDC risk group was also identified as the independent risk factors for OS (HR=2.638，P=0.007). Compared to metastatic ccRCC, the metastatic nccRCC patients were younger, with more advanced T and N stage, having a higher proportion for liver metastasis. The outcome of metastatic nccRCC was also poorer than metastatic ccRCC patients (P＜0.001), with a median OS of 24.0 months and 38.0 months, respectively.
Conclusions:
Compared to metastatic ccRCC, the prognosis of the patients with metastatic nccRCC was poorer, and the metastatic nccRCC patients were younger, with more advanced T and N stage, having a higher proportion for liver metastasis. Unclassified RCC pathology and poor IMDC risk group were the independent risk factors for poor prognosis. For metastatic nccRCC, the efficacy of IO-TKI was not superior than TKI monotherapy.Therefore, it is of great significance to investigate novel therapeutic targets for metastatic nccRCC.
Development of a FKSI-23: A new bespoke health-related quality of life (HRQOL) questionnaire for the advanced and adjuvant setting in renal cell carcinoma (RCC).
Authors: Bergerot Cristiane Decat , Bergerot Paulo Gustavo , Castro Daniela V. , Mercier Benjamin , Nally Elizabeth , Ali Adil , Hutson Thomas E. , Bex Axel , Psutka Sarah P. , Rini Brian I. , Plimack Elizabeth R. , Master Viraj A. , Grünwald Viktor , Albiges Laurence , Choueiri Toni K. , Pal Sumanta Kumar , Cella David , Powles Thomas
Published: February 2025

526

Background:
Existing HRQOL measures may not fully capture the experiences of patients with localized and advanced RCC. This study aimed to develop a validated, patient-centered HRQOL metric by incorporating insights from patients, advocates, and clinical experts for both localized and advanced RCC. We previously developed a questionnaire for advanced RCC (Bergerot et al., JCO 2024). In this study, we integrate it into the FKSI-19 model and create a new questionnaire.
Methods:
A four-phase approach was used. Previous work in advanced RCC assessed item relevance from established HRQOL measures (FKSI-19, EORTC QLQ-C30, EQ-5D), refined through patient feedback and expert review. This phase expanded to include localized RCC in the adjuvant setting. In Phase 1, patients with localized RCC rated the the relevance of 54 items from the metastatic cohort. Phase 2 included a panel of 11 expert refining the adjuvant-specific items. Phase 3 gathered feedback from patient advocates, and Phase 4 further refined the items by harmonizing them with the FACT library for consistency across RCC stages.
Results:
In Phase 1, 6 of 54 items were rated as most relevant by patients with localized RCC. Phase 2 refined these further, excluding redundant items and adding 4 new questions focused on adjuvant therapy. Phase 3 led to minor revisions after advocate review, and Phase 4, the new items were harmonized with validated FACT library questions. The final adjuvant-specific questionnaire comprises 10 items, addressing concerns such as long-term side effects, surveillance anxiety, and post-surgery emotional distress. The advanced-specific version includes 13 items. Both versions deemed to be of utmost importance to patients with localized and advanced disease. These items can be used as standalone scoring options, resulting in the creation of a novel FKSI-23 metric, allowing for customized questionnaires tailored to specific clinical scenarios.
Conclusions:
Through collective input from patients, advocates and experts, novel items that aid in capturing the experience of RCC patients were identified and existing metrics were refined to generate separate “scoring options” for patients with localized and metastatic disease. Validation of the resulting FKSI-23 tool is underway in forthcoming studies in RCC.
Efficacy and safety of SABR with TKI and IO therapy in patients with mRCC.
Authors: Yang Kaiwei , Ma Mingwei , Yu Wei , He Zhisong , Gao Xianshu
Published: February 2025

529

Background:
Metastatic RCC is a deadly disease and TKI in combination with IO has become a standard therapy for most patients. But some of the pts may present with oligo-metastasis and some with meta site related symptoms. SABR (Stereotactic Ablative Body Radiotherapy) has been proved to be highly effective for RCC in some studies and with potential immune-enhancing ability. The purpose is to investigate the efficacy and safety of SABR with TKI and IO therapy in pts with mRCC.
Methods:
This is an ambispective cohort study including pts receiving SABR with TKI and IO at the same time. The primary endpoint was PFS. Secondary endpoints included OS, ORR, DCR and TTTC (Time to treatment change). We also analyzed some of the pts’ gene characteristics to investigate the relationship between gene alterations and prognosis. Adverse events were evaluated according to CTCAE 5.0.
Results:
Until Aug 2024, we retrospectively analyzed pts from Mar 2020 to Mar 2024, and prospectively from Mar 2024 to May 2024. A total of 79 pts were included, of whom 72.2% were with ccRCC, 68.4% were with oligo-metastases (≤5 meta sites), and 83.5% were combined with SABR before 1st-line systemic therapy failure. All pts were categorized to IMDC intermediate or poor prognosis group and TKI and IO combination was used in all pts. All pts with oligo-metastases received SABR for all tumor sites and others were for cytoreductive purpose.The median follow-up was 20.3 mo. The mPFS was 28.6 mo and TTTC was 31.8 mo. The ORR was 68.4% and the DCR was 89.9%. The DCR of radiation lesions was 96.2%. The mOS was 44.8 mo. For pts received SABR before or after 1
st
-line systemic therapy failure, the mPFS were 30.6 mo vs. 9.6 mo, respectively (p=0.004). In addition, The NGS analysis was performed in 25 pts tumor samples. The most frequent genes mutated were VHL (60%), SETD2 (24%), ARID1A (24%), TP53 (20%), PTEN (20%), TEF3 (16%), BAP1 (12%), RET (12%), and PBRM1 (12%). We discovered a favorable trend in the prognosis for PFS in pts with tumors purely driven by VHL loss. Mutations in the mTOR pathway genes, PTEN and HRR-related genes appeared to lead to poorer PFS. However, due to limited sample size, statistical significance was not reached. Grade 3 or above AE was 50.2%, and there was no treatment-related death.
Conclusions:
Targeted therapy combined with immunotherapy and stereotactic radiotherapy has achieved satisfactory survival results for mRCC, and early intervention by SABR may lead to a better PFS. Clinical trial information:
ChiCTR2200059204
.
Efficacy of nivolumab plus ipilimumab in T1aN0M0 renal cell carcinoma (RCC) patients: Results from 3-year follow-up of the phase 2 pilot study.
Authors: Tsimafeyeu Ilya , Gafanov Rustem , Myslevtsev Igor , Andrianov Andrey , Bex Axel
Published: February 2025

536

Background:
Some patients with primary renal cell carcinoma (RCC) are not candidates for surgery or nephron-sparing interventions due to various factors, such as the presence of a functional single kidney with a central, high-complexity tumor. This study aimed to evaluate whether a combination of nivolumab and ipilimumab could eliminate the primary tumor in patients with T1aN0M0 RCC.
Methods:
This prospective, multicenter, phase 2 pilot study enrolled patients with biopsy-confirmed clear-cell RCC (cT1a) ≤4 cm, no metastases, and who were ineligible for surgery or nephron-sparing procedures. Patients were treated with ipilimumab (1 mg/kg) every 3 weeks for four doses, alongside nivolumab (240 mg) every 2 weeks for eight doses. The primary endpoint was the complete response rate. Simon's two-stage design was used, testing the null hypothesis of a true complete response rate of 11%. A type I error rate of 0.05 and a power of 0.9 were set, with the null hypothesis rejected if 3 or more responses were observed in 8 patients.
Results:
From February 2020 to June 2021, 8 patients were enrolled, with a median age of 77.9 years (range 73–89). The cohort was entirely Caucasian, predominantly male (75%), and 62.5% had centrally located tumors. Six patients had moderate to severe comorbidities. All patients completed the immunotherapy without experiencing grade ≥2 adverse events. After a median follow-up of 37.4 months (95% CI 31.7–44.5), no complete responses were observed. However, partial responses were seen in 4 patients (50%), with continued tumor reduction after therapy. The median tumor size decreased from 3.11 cm (range 2.2–3.9) to 1.89 cm (range 1.1–4.0). Tumor shrinkage was observed in 6 patients (75%), while 1 patient experienced a slight tumor enlargement (+0.5 cm, +13%) after 9 months. The 3-year progression-free survival rate was 100%. Data on 5-year overall survival will be reported later.
Conclusions:
Although complete tumor regression was not achieved, immunotherapy with nivolumab and ipilimumab led to significant and durable tumor shrinkage in two-thirds of T1aN0M0 RCC patients, with minimal toxicity, making it a viable option for patients with significant comorbidities. Further data on long-term survival are awaited. Clinical trial information:
NCT04134182
.
Outcomes with first-line ipilimumab and nivolumab for patients with metastatic renal cell carcinoma by number of doses.
Authors: Doshi Sahil D , Lopez Sanmiguel Andrea , Knezevic Andrea , Kotecha Ritesh R , Shah Neil J. , Carlo Marie , Feldman Darren R. , Motzer Robert J. , Voss Martin H
Published: February 2025

540

Background:
Ipilimumab (IPI) and nivolumab (NIVO) are standard first-line systemic therapy for patients with metastatic renal cell carcinoma (RCC). The regimen is administered in combination once every 3 weeks for 4 doses, followed by NIVO maintenance. The dose and frequency of IPI appears to correlate with treatment safety and tolerability across cancer types. Further, studies in advanced melanoma have demonstrated that the efficacy of IPI + NIVO is largely driven by the first two doses in many patients (Postow MA et al.,
J Clin. Oncol.
2022). We assessed outcomes with IPI + NIVO by number of doses given in patients with metastatic RCC.
Methods:
We conducted a retrospective study of patients with metastatic RCC at Memorial Sloan Kettering Cancer Center treated with first-line IPI + NIVO. Baseline characteristics and treatment outcomes were obtained from electronic health record review. We calculated overall survival (OS) by the Kaplan-Meier method starting at 12 weeks after initiation of combination therapy, including all patients who were still alive and being followed at that time point and excluding those who had disease progression prior to completing 4 doses. We compared survival rates at 12 and 18 months and median OS for patients who received 4 doses versus those who received fewer than 4 doses.
Results:
Patients with metastatic RCC treated with first-line IPI + NIVO were included (N=222); 77% were male, 85% had clear cell RCC, 48% had sarcomatoid and/or rhabdoid features, and 87% had IMDC intermediate or poor risk disease. Regarding IPI + NIVO, 145 patients (65%) received all 4 doses, 30 (14%) received 3 doses, 21 (9%) received 2 doses, and 26 (12%) received 1 dose. The most common reasons for not completing all 4 doses (77, 35%) were toxicity (57%) and disease progression (21%). All 145 patients who received 4 doses and 44 who received fewer than 4 doses for reasons other than early progression or death were included in the analysis. OS in the 4 dose and <4 dose group at 18 months was 83% (95% CI: 76%, 89%) and 79% (95% CI: 63%, 88%), respectively.
Conclusions:
In this observational analysis, we found comparable OS rates in those patients who received all 4 doses of IPI + NIVO compared to those who received fewer than 4 doses for reasons other than disease progression, primarily toxicity.

Four Doses of IPI + NIVO (N=145)
Fewer Than Four Doses of IPI + NIVO, Excluding Early Disease Progression (N=44)

12-month OS (95% CI)
89% (82%, 93%)
86% (72%, 94%)

18-month OS (95% CI)
83% (76%, 89%)
79% (63%, 88%)

Median OS, months (95% CI)
67.1 (40.1, NR)
82.5 (27.1, 109.3)

Log-rank p value = 0.595
Efficacy and safety of fruquintinib combined with serplulimab as 1
st
line treatment in metastatic or unresectable non-clear cell renal cell carcinoma (nccRCC): Updated results from a single-arm, multicentre clinical trial.
Authors: Huang Jiwei , Hu Xiaoyi , Wang Hang , Guo Jianming , Xue Wei
Published: February 2025

542

Background:
For advanced non-clear cell renal cell carcinoma (nccRCC), systemic therapy is the main option but the treatment standard remains unclear. In the past decade, promising results have emerged from clinical trials with vascular endothelial growth factor receptor (VEGFR) inhibitors, or anti-programmed death-1 (PD-1) antibodies. Fruquintinib (FRU) is a potent VEGFR inhibitor approved for metastatic colorectal cancer. This trial aims to evaluate the efficacy and safety of FRU combined with serplulimab (an anti-PD-1 antibody) in patients (pts) with advanced nccRCC.
Methods:
This is a multicentre single-arm prospective trial planning to enroll 39 pts with pathologically confirmed metastatic or unresectable nccRCC. Eligible patients were 18 to 80 years old with an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1, and had not received prior systemic therapy. All pts received FRU (5mg, qd, po, 2w on/1w off) plus serplulimab (4.5mg/kg, d1, i.v.gtt, q3w). The primary endpoint was progression-free survival (PFS), and the secondary endpoints included objective response rate (ORR), disease control rate (DCR), safety, etc.
Results:
As of Sep.20
th
, 2024, 16 nccRCC pts were enrolled. The median age was 63.5 years (range 24-78) and 75.0% were male. Seven (43.8%) pts had an ECOG PS of 2. Histologically, papillary subtype was the most prevalent (12, 75.0%), followed by chromophobe (2, 12.5%), 1 collecting duct carcinoma and 1 unclassified subtype, and sarcomatoid features were observed in 5 (31.3%) patients. The metastatic sites were primarily lymph nodes (56.3%), lungs (37.5%), peritoneum (25.0%) and abdominal cavity (25.0%). Among the 16 evaluable pts, 8 achieved partial response and 6 had stable disease, resulting in an ORR of 50.0% (95% CI: 25.5%-74.5%) and a DCR of 87.5% (95% CI: 61.7%-98.4%). Three pts experienced rapid progression, all with sarcomatoid features (2 papillary, 1 chromophobe). The median PFS was not reached. The most common treatment-related adverse events (TRAEs) were rash (37.5%), fever (31.3%), ALT increased (25.0%), AST increased (25.0%), hypertension (18.8%), hypothyroidism (18.8%), fatigue (18.8%) and most were grade 1/2 except 1 pt experiencing grade 3 AST increased.
Conclusions:
The preliminary data showed promising efficacy and tolerable toxicity of FRU combined with serplulimab in pts with metastatic or unresectable nccRCC. Clinical trial information:
NCT05831891
.
Results from the prior treatment cohort of a phase I/II study of nivolumab and axitinib in patients with advanced renal cell carcinoma.
Authors: Zibelman Matthew R. , Ged Yasser , Carducci Michael A , Molina Ana M. , Ravilla Rahul , Basiura Rachel , Lambert Courtney , Wargins Madeline , Jerome Erika , Mikkelsen Eli , Devarajan Karthik , Ruth Karen J , Kokate Rutika , Anari Fern , Ghatalia Pooja , Geynisman Daniel M. , Plimack Elizabeth R.
Published: February 2025

548

Background:
Combination tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (IO) are an established standard of care for patients with metastatic renal cell carcinoma (mRCC). We report updated analysis of a multi-center, investigator-initiated (IIT), phase I/II study of axitinib (axi) with nivolumab (nivo) in the previously treated patient cohort.
Methods:
The study investigated the combination of axi/nivo in an initial dose finding phase I portion and a phase II portion including 2 parallel arms: treatment naïve mRCC patients and mRCC patients previously treated with TKIs or IO/IO combination (NCT03172754). We are presenting final results from the previously treated cohort. Included patients had pathology with any clear cell component, ECOG performance status of 0-1, no known or symptomatic brain metastases, and no history of autoimmune disease. The recommended phase 2 dose of axi was 5 mg BID and patients were treated for up to 2 years then could stop one or both therapies. The primary endpoint of the phase II portion was objective response rate (ORR) per investigator assessment.
Results:
Twenty-six patients were accrued to the previously treated arm, all evaluable for efficacy and toxicity. The median age was 62 yrs (range: 42-81), 80.8% were male and 88.5% were white. Twenty pts had 1 prior line of therapy (18 TKI alone), 6 pts had 2 or more prior lines of Tx. Two pts had prior nivo with ipilimumab. Median follow-up was 47.2 months. The ORR was 30.8% (all PRs) and 57.7% achieved stable disease. The primary PD rate was 11.5%. Median OS was 48.4 months and median PFS was 13.0 months. Six pts (23.1%) completed two years of Tx on trial and elected to stop one or both drugs (2 elected to stay on axi alone). Five pts remain progression-free and have received no subsequent therapy with a median progression-free interval of 23.2 months. None had received prior IO. Adverse event (AE) data was similar to published data for IO/TKI combinations. There was one Gr4 TRAE of elevated lipase and 12 pts (46%) experienced a Gr3 TRAE. One pt (4%) discontinued the study due to TRAEs.
Conclusions:
Final results from the previously treated cohort of this IIT of axi/nivo for pts with mRCC demonstrated an ORR of 30.8% and a DCR of 88.5% with no unexpected AEs. Though there were no CRs, disease control rate and median OS were encouraging in this previously treated population. This is the only reported IO/TKI trial that allowed for stopping of all Tx at 2 years, with 6 pts (23.1%) meeting this milestone, 5 of whom (19% of all pts) remain progression-free for a median period close to 2 years. Clinical trial information:
NCT03172754
.
T suppression and recovery with AAP after early discontinuation of LHRH-A in high-risk localized (HRL), lymph node-positive (N+), or oligometastatic (OM) prostate cancer (PC).
Authors: Gagnon Autumn , Zhong Caiwei , Xie Wanling , Morlock Lynne , Freeman Dory , Trowbridge Rachel , Kilbridge Kerry L. , McGregor Bradley Alexander , Taplin Mary-Ellen , Choudhury Atish Dipankar
Published: February 2025

55

Background:
Intensified androgen deprivation therapy (iADT) with the addition of abiraterone acetate + prednisone (AAP) to a luteinizing hormone releasing hormone agonist or antagonist (LHRH-A) is commonly used in conjunction with radiation therapy for HRL, N+ or OM hormone-sensitive PC. However, prolonged LHRH-A has been associated with delayed or incomplete testosterone (T) recovery after discontinuation (dc). As AAP monotherapy leads to castrate T, we investigated T kinetics with early discontinuation of LHRH-A when given in combination with AAP.
Methods:
The Dana-Farber/Harvard Cancer Center (DF/HCC) Oncology Data Retrieval System (OncDRS) was queried to identify patients (pts) planned to receive 18-24 mo of AAP for HRL, N+ or OM PC. Pts who previously received AAP for > 12 mo, with baseline T <150 ng/dl, received AAP for castration-resistant PC, received AAP >30 mo, or LHRH-A dc > 3 mo after AAP were excluded. T values at AAP end of treatment (EOT) and at each clinical follow up visit were tabulated to assess time to T recovery (TTR) to ≥150 ng/dl in pts with LHRH-A dc ≤3 mo, 3-12 mo and ≥12 mo prior to AAP EOT. Gray’s competing risk regression model was applied to assess the relationship between TTR and time between LHRH-A dc and AAP EOT.
Results:
The OncDRS query returned 350 pts, 105 meeting eligibility criteria with available T follow up after AAP EOT. 99 of 105 pts had available T at EOT, 99/99 (100%) with T < 20 ng/dl across the three groups. TTR was statistically significantly shorter for pts with LHRH-A dc ≥12 months prior to AAP EOT (median 3.2 mo [95% CI 1.8, 4.1]) compared to ≤3 mo prior to LHRH-A dc (median 20.0 mo [9.0, 27.6]) with all T recovery events within 6 months of EOT in the former group (Table).
Conclusions:
In this real-world cohort, early discontinuation of LHRH-A when given in combination with AAP led to ongoing T suppression while on AAP and shorter TTR after AAP EOT. This strategy warrants consideration when iADT is indicated but the patient seeks rapid and reliable T recovery after completion of treatment for the actual duration of T suppression desired. DF/HCC protocol # 23-322.

TTR outcome summary.

Timing of discontinuation of LHRH-A
≥ 12 months (N=13)
3 – 12 months (N=36)
≤ 3 months (N=56)

No. T recovery events
10
26
26

No. competing events*
0
1
6

6-month cumulative TTR rate (95% CI)
82% (38%, 96%)
39% (23%, 55%)
15% (6.8%, 26%)

12-month cumulative TTR rate (95% CI)
82% (38%, 96%)
64% (46%, 78%)
39% (25%, 52%)

Median (95%), month
3.2 (1.8, 4.1)
7.5 (3.7, 15.5)
20.0 (9.0, 27.6)

Hazard ratio (95% CI)
ref
0.40 (0.16, 1.02)
0.20 (0.08, 0.49)

p-value
ref
0.06
0.01

*New treatment without T recovery.
Comprehensive proteomic profiling of plasma samples associated with response or resistance to immune checkpoint inhibitors (ICI) in patients with renal cell carcinoma (RCC).
Authors: Kashima Soki , Xu Wenxin , Canniff John , Saliby Renee Maria , Sun Maxine , Lee Gwo-Shu Mary , Machaalani Marc , Signoretti Sabina , McGregor Bradley Alexander , McKay Rana R. , Choueiri Toni K. , Braun David A.
Published: February 2025

562

Background:
ICI-based therapies are the cornerstone of treatment for advanced RCC. While many studies have focused on tumor-based biomarkers, circulating factors play an important role in therapeutic response. This study utilized a high dimensional proteomic platform to investigate plasma proteins from RCC patients undergoing ICI-based therapies to identify potential biomarkers associated with treatment outcomes.
Methods:
A total of 43 plasma samples (n = 40 clear cell; n = 3 non-clear cell) were collected from 33 advanced RCC patients, with 16 paired samples (pre- and post-treatment) from 6 patients and 27 unpaired samples. The cohort included patients treated with ICI monotherapy (n = 22), ICI + ICI (n = 13), ICI + VEGF inhibitors (n = 7), and ICI + CCR2/CCR5 antagonist (n = 1). For this study, we analyzed pre-treatment samples from responders (R) (n = 8; complete or partial responses), and non-responders (NR) (n = 4; progressive disease). We performed plasma proteomic analysis using the SomaScan 11k proteomic platform, and Mann-Whitney U-test comparisons between ICI-naïve samples of R and NR groups. We also performed a paired test between ICI-naïve and ICI-exposed samples in R (n = 3 patients with paired samples). Nominal p-values are reported.
Results:
All 43 samples passed quality control. In ICI-naïve samples, we observed that ICAM1 and ITIH3 levels were significantly higher in R compared to NR (p = 0.016 for both). Conversely, CILP2 and leptin were significantly elevated in NR (p = 0.016, p = 0.004, respectively). Further analysis for treatment evolution through paired samples showed that PD-1, CXCL9, and HLA-B were significantly elevated in ICI-exposed samples compared to ICI-naïve samples in R (p = 0.021, p = 0.022, p = 0.041, respectively).
Conclusions:
Our exploratory proteomic analysis identified higher ICAM1 and ITIH3 levels in ICI responders, which may reflect anti-tumor inflammation and the recruitment of immune cells to tumors. Elevated CILP2 and leptin levels were observed in ICI non-responders, highlighting their potential contributions to an immunosuppressive environment through Tregs and the TGF-β pathway. Beyond the potential biomarkers, the post-ICI elevation of CXCL9 and HLA-B in responders suggests that these may be linked to sustained immune activation during treatment, offering a foundation to understand treatment evolution in RCC.
Prognostic value of preoperative fibrinogen in metastatic clear cell renal cell carcinoma patients undergoing cytoreductive nephrectomy: A propensity score-matched study.
Authors: Shou Jianzhong , Cui Honglei , Bi Xingang , Guan Youyan , Shi Hongzhe , Zhou Aiping
Published: February 2025

563

Background:
The measurement of serum fibrinogen (FIB) levels is often overlooked in metastatic clear cell renal cell carcinoma (mccRCC). This study aims to investigate the prognostic value of preoperative serum FIB levels in mccRCC patients undergoing cytoreductive nephrectomy (CN) followed by systemic therapy.
Methods:
This retrospective study analyzed 209 mccRCC patients who underwent CN from 2010 to 2022. The optimal cutoff value of preoperative serum FIB levels was determined via receiver operating characteristic (ROC) curve. Survival outcomes were evaluated by the Kaplan-Meier method and Cox proportional hazards models. The predictive ability was evaluated by ROC curve. Propensity Score Matching (PSM) was performed to equate demographic and clinical characteristics.
Results:
An optimal cutoff value of 4.39 g/L for the FIB levels was determined and patients were categorized into high and low FIB groups. With a median follow-up time of 61.1 months, patients in the low FIB group exhibited significantly higher median OS compared with the high FIB group (53.1 vs 27.9 months, p < 0.001). The ROC curve demonstrated that the serum FIB predicted a 36-month overall survival with an AUC of 0.652, while the AUC for the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk category was 0.558. After PSM matching, high FIB levels remained significantly associated with poorer OS (24.0 vs 50.2 months; p = 0.019).
Conclusions:
Serum FIB level is a significant prognostic factor for mccRCC patients undergoing CN followed by systemic therapy. This finding underscores the potential of FIB as a biomarker that could be integrated into the prognostic model for preoperative risk stratification and management strategies.
Metabolic determinants of exceptional response to immune checkpoint inhibition in renal cell carcinoma.
Authors: Saliby Renee Maria , Labaki Chris , Jammihal Tejas , Soulati Hanna , Gallegos Juan , Peris Arnau , McCurry Dustin Barrett , Shah Valisha , Poduval Deepak , El Zarif Talal , El Ahmar Nourhan , Nabil Laimon Yasmin , Bagheri Sheshdeh Aseman , Eid Marc , Krajewski Katherine , Signoretti Sabina , Van Allen Eliezer , Shukla Sachet A , Choueiri Toni K. , Braun David A.
Published: February 2025

571

Background:
Immune checkpoint inhibitors (ICI) have led to remarkable, long-lasting responses in a subset of patients with metastatic renal cell carcinoma (RCC). However, the molecular mechanisms driving these exceptional responses (ER) are not fully characterized. We previously observed that a high tertiary lymphoid structure (TLS) signature is associated with ER. Here, we explore metabolic molecular determinants that may influence ER in patients treated with ICI and VEGF inhibitors.
Methods:
We analyzed genomic and transcriptomic data from 357 treatment-naïve patients with advanced clear cell RCC who were given PD1/L1 and VEGF inhibitors (ICI/VEGFi) in a phase III clinical trial. Patients were categorized into three groups: (a) extreme responders (ER), including those with complete response (CR) and progression-free survival (PFS) of at least 12 months, or partial response (PR) with significant tumor shrinkage and prolonged PFS; (b) intermediate responders (IR), patients with CR or PR not meeting ER criteria; and (c) patients with progressive disease (PD). Whole exome sequencing (WES) was used to analyze somatic mutations, copy number changes, and compute clonal neoantigen load (CNL). Gene set enrichment analysis (GSEA) was performed to explore molecular pathways, and multivariate Cox proportional hazards analysis identified PFS predictors.
Results:
Metabolic pathway enrichment was notable in ER patients with low TLS signatures, with pathways such as peroxisome function, xenobiotic and bile acid metabolism, adipogenesis, fatty acid metabolism, and oxidative phosphorylation showing upregulation. These findings held after adjusting for tumor purity. Next, we defined a metabolic gene signature based on the enriched metabolic genes in TLS-low ER samples compared to TLS-high ER samples. ER patients with low TLS scores had significantly higher metabolic signature scores than IR (p=0.00062) and PD (p=0.00012) patients. Higher metabolic signature scores correlated with improved PFS (p=0.054) and overall survival (OS) (p=0.0037). Multivariable analysis confirmed that favorable IMDC risk (p<0.001) and a high metabolic signature (p=0.01) were independent predictors of ER.
Conclusions:
Metabolic pathways are critical drivers of exceptional responses to ICI in RCC, especially in patients with low TLS scores. A high metabolic gene signature may serve as a predictive biomarker for ER, offering insights into new therapeutic strategies targeting metabolic reprogramming in this unique subset of patients.
Vasculo-immune modulatory effects of anti-VEGF therapy in metastatic clear cell renal cell carcinoma: The A-PREDICT trial.
Authors: Au Lewis , Tippu Zayd , Pallikonda Husayn , Cattin Anne-Laure , Whitton Georgia , Rowan Andrew , Fendler Annika , Malik Jahangeer , Boleti Ekaterini , Vasudev Naveen , Highley Martin , Michael Agnieszka , Eisen Tim , Penegar Steven , Lewis Rebecca , Kilburn Lucy , Bliss Judith , Swanton Charles , Larkin James , Turajlic Samra
Published: February 2025

572

Background:
Anti-vascular endothelial growth factor (VEGF) tyrosine kinase inhibitors and checkpoint inhibitors (CPI) a standard-of-care treatment for clear cell renal cell carcinoma (ccRCC). We investigated the biology underpinning benefit of anti-VEGFR TKI in the phase II A-PREDICT trial (NCT01693822), evaluating pre- and post-treatment, fresh multiregion tumour biopsies in patients with metastatic ccRCC treated with first-line axitinib.
Methods:
We analysed 123 tumour samples from 52 patients, 28 with paired pre/post-treatment samples. Post-treatment samples included week-9, nephrectomy, and on-progression timepoints. ‘Responders’ had progression-free survival (PFS) ≥6 months (n=35), ‘non-responders’ with PFS <6 months (n=17). We applied a custom Nanostring panel for gene expression analysis and multiplex immunofluorescence (mIF) for orthogonal validation. Wilcoxin test was used to analyze paired observations.
Results:
At baseline, angiogenesis scores were similar between responders and non-responders (p=0.22). Post-treatment, the angiogenesis, vascular sprouting, and endothelial cell proliferation signature scores were significantly decreased (p=0.023, 0.0034, & 0.0082, respectively) in all patients, suggesting suppression of angiogenesis and neovascularisation irrespective of clinical outcomes. mIF in 3 patients (with PFS of 3, 5.6, & 100 months) confirms widespread intratumoral vessel depletion. Immune deconvolution analysis shows total levels of T cells and CD8
+
T cells were similar pre- and post-treatment, suggesting axitinib did not enhance immune cell trafficking. Rather, axitinib promoted increased levels of exhausted CD8
+
T cells post-treatment (p=0.01). M2 tumour-associated macrophages increased post-treatment in responders (p=0.033) but not in non-responders (p=0.44). A minority of patients had durable (>2 years) responses to axitinib (n=7/65, 6 with tissue for analysis). In these patients, we found higher levels of pre-treatment intratumoral cytotoxic immune cells (p=0.041) and NK cells (p=0.015) compared to patients with primary resistant disease.
Conclusions:
Axitinib suppressed angiogenesis and neovascularisation leading to intratumoral vessel depletion, and therapy response associates with features of an immunosuppressive TME. Baseline endogenous immune priming appears critical for durable response to anti-VEGF therapy. These data are relevant to understanding the clinical efficacy of combined anti-VEGF and CPI regimens. Clinical trial information:
NCT01693822
.