The end of May each year signals the beginning of summer and the ASCO Annual Meeting in Chicago. The Kidney Cancer Association’s Clinical Advisory Board (CAB) members conducted reviews of the kidney cancer discussions at this year’s meeting for the entire kidney cancer clinical team. Read on to learn more!
Reporting final efficacy and safety data in the intent-to-treat (ITT) population
Clear cell RCC randomized to receive nivolumab 3 mg/kg and ipilimumab 1 mg/kg followed by nivolumab 3 mg/kg or 240 mg Q 2 weeks OR 6 mg/kg or 480 mg Q 4 weeks versus sunitinib 50 mg/day (4 weeks on / 2 weeks off)
Median follow-up time: 9 years
Important Takeaway:
Longest and final phase 3 follow-up with first-line checkpoint inhibitor combination, milestone rates of OS and PFS with a durable response remained higher with nivo/ipi versus sunitinib
Double-blinded, placebo-controlled trial with patients randomized to receive adjuvant pembrolizumab (pembro) 200 mg (n = 496) or placebo (n = 498) IV every 3 weeks for approximately 1 year or until recurrence, intolerable adverse drug event, or physician decision to discontinue treatment
Results:
Median follow-up time: 69.5 months (range: 60.2-86.9 months)
Primary endpoint: Disease-Free Survival (DFS):
DFS events: 188 (pembro) vs 241 (placebo)
Median DFS: not reach (pembro) vs 68.3 months (HR 0.71, 95% CI 0.59-0.86)
Estimated DFS rate at 5 years: 60.9% (pembro) vs 52.2% (placebo)
Important Takeaways:
DFS and OS outcomes were consistent across key subgroups, including pre-specified risk subgroups (intermediate/high risk, high, M1 NED) and sarcomatoid features
No new serious treatment-related safety signals occurred
Adjuvant pembrolizumab remains on option for clear cell RCC patients at risk of recurrence
Soluble MAdCAM-1 (sMAdCAM-1) is a circulating surrogate marker of gut dysbiosis
Utility as a prognostic biomarker in patient receiving immunotherapy (ICI)-based therapy
Results from JAVELIN Renal 101 trial: in patients receiving avelumab + axitinib vs sunitinib in previously untreated RCC patients
Higher sMAdCAM-1 levels were associated with improved PFS [median 13.9 (11.3-6.6) versus 8.4 (6-9.9 months)] and OS at 18 months [84.2% (80.2-87.4) vs 68.1% (59.2-75.5)]
Potential Utility in the Future:
sMAdCAM-1 may have an added prognostic value to IMDC
Comparing Belzutifan 120 mg/day + Pembrolizumab 400 mg IV Q 6 weeks vs Placebo + Pembrolizumab 400 mg IV Q 6 weeks
Important Takeaway:
Several studies looking at using Belzutifan in combination with other systemic options.
Utility of Kidney Injury Molecule-1 (KIM-1) as a prognostic and potentially predictive biomarker in renal cell carcinoma (RCC)
Abstract 437 presented findings about the prognostic/predictive value of KIM-1 from a post-hoc analysis in patients with metastatic RCC (mRCC) treated with nivolumab + ipilimumab or sunitinib on the Checkmate 214 Trial
Key findings suggested that higher baseline KIM-1 levels were associated with worse survival (regardless of treatment), and an early drop in KIM-1 was associated with improved progression-free survival (PFS) in patients treated with nivolumab + ipilimumab
Abstract 582 presented findings about whether kidney function confounds KIM-1’s reliability as a circulating biomarker that correlates with treatment response and prognosis
Key findings suggested that KIM-1 predicts PFS and OS even after accounting for renal function
Prognostic and biological significance of plasma KIM-1 in mRCC
Abstract 4546 “Integrative clinical, genomic, and transcriptomic characterization of circulating KIM-1 in mRCC” evaluated from a post-hoc analysis of patients from the JAVELIN Renal 101 trial treated with avelumab + axitinib versus sunitinib
First study using clinical, transcriptomic and genomic data
Key objective: Evaluate the prognostic and biological significance of Plasma KIM-1 levels in patients with mRCC using data from the JAVELIN Renal 101 trial treated with avelumab + axitinib versus sunitinib
Key findings:
Higher baseline KIM-1 levels were significantly associated with decreased tumor shrinkage, shorter PFS, shorter OS and higher tumor burden
Higher KIM-1 levels were found in IMDC poor-risk versus intermediate-risk and in intermediate-risk versus favorable-risk groups (p<0.001)
Transcriptomic analysis showed that tumors with high KIM-1 showed upregulation of hypoxia, angiogenesis, and inflammatory pathways; as well as enrichment of IFN-y response and cell proliferation signatures
Genomic analysis showed a strong association between high KIM-1 and BAP1 loss -of-function mutations, which are known to confer poor prognosis in RCC
HAVCR1, the gene encoding KIM-1, was overexpressed in tumors with high circulating KIM-1, suggesting a tumor-intrinsic source
Clinical Implications:
High Kim-1 is a biomarker of poor prognosis in RCC and correlates with specific LOF mutations and transcriptions programs
Future Directions:
Prospective studies are needed for the clinical implementation of KIM-1 as a biomarker in RCC
Background:
Casdatifan is an investigational agent (AB521)
A small molecule inhibitor of HIF- 2 alpha
HIF-2 alpha is a transcription factor that in a hypoxic environment, activates multiple tumor growth pathways leading to growth of the cancer cell
Abstract 441: results of a Phase I Study (ARC-20) presented at GU ASCO of Casdatifan monotherapy in patients with previously treated clear cell renal cell carcinoma
Three dose cohorts- 50 mg twice daily, 50 mg once daily and 100 mg once per day were evaluated with the 100 mg/day regimen confirming the highest ORR.
Similar TEAEs were found within all three dosing cohorts. Known AEs of interest in this class of drugs are
Anemia occurred in 80-90 percent of patients across the three groups
Grade 3 or higher was seen in 14 (42%). 10 (32%) and five (17 %), respectively
Hypoxia, had a grade 3 or greater incidence in 7-10 percent of patients across the three TX groups
Conclusions:
Multiple dosing cohorts of Casdatifan demonstrated well tolerability in a group of heavily pretreated patients with ccRCC and promising early clinical activity across IMDC risk group was observed.
Abstract 4506: speaks to the expansion cohort in the Phase I Study ARC-20 with the combination of casdatifan plus cabozantinib in previously treated patients with clear cell renal cell carcinoma.
Study endpoints included incidence of treatment-emergent events and the objective response rate
All grade AEs occurred in 89% of patients with the most common being anemia (n = 16 [59%]) and fatigue (n = 15 [56%])
Most common (10%) grade 3 AEs were anemia (n = 7 [26%]) and hypoxia (n = 3 [11%])
No cardiac events were reported
Only one (4%) pt discontinued due to an AE, hypoxia related to casdatifan
Responses continue to be observed among the efficacy evaluable population (n = 22; as of January 27, 2025) with ORR of 41% (n = 1 complete response; n = 8 partial response)
Activity was seen across all IMDC risk groups.
Conclusions:
In previously treated patients with ccRCC, casdatifan 100 mg in combination with cabozantinib 60 mg had a manageable AE profile with promising clinical activity
Standard dose is 120 mg (40 mg tablets) taken by mouth daily
Planned Clinical Trials:
The Phase III PEAK-1 study will evaluate casdatifan (100 once daily) plus cabozantinib (60mg) inpatients versus cabozantinib monotherapy with metastatic ccRCC and prior PD-l therapy
Planned accrual in 2025
A planned Phase 1b study, sponsored by AstraZeneca to evaluate casdatifan in combination with volrustomig, and investigational anti-PD-1/CTLA -4 bispecific antibody
Important Takeaways:
Casdatifan is a promising new drug to treat RCC patients
Results from the planned clinical trials will help to answer questions regarding its effectiveness and safety
Accrual to trials will take some time before we have the definitive answer of the drug’s efficacy
Carbonic anhydrases are a superfamily of metalloenzymes present in all kingdom of life that catalyze the conversion of carbon dioxide to bicarbonate and proton
Over-expressed in clear cell renal carcinoma (RCC) and a target “analogous” to PSMA for prostate cancer
In the history of CA-IX development, the 1st humanized antibody targeting CA-IX was developed in 1997
Clinical data:
REDECT trial in 2012:
Open-label multicenter study of 124I-girentuximab PET/CT in patients with renal masses scheduled for resection
PET/CT and contrast-enhanced CT of the abdomen were obtained 2-6 days after IV 124I-girentuximab administration and prior to renal mass resection
Average sensitivity for was 86% (versus 76% for CT) and specificity was 86% (versus 47% for CT) for the PET/CT
First clinical validation of a CA-IX-targeting radiotracer for PET/CT imaging for the accurate and non-invasive identification of clear cell RCC
ZIRCON trial in 2024:
Open-label multicenter study of 89Zr-DFO-girentuximab (TLX250-CDx) PET/CT
Patients with indeterminate renal masses (≤ 7 cm; tumor stage cT1) with planned partial or radical nephrectomy within 90 days of planned TLX250-CDx
Intervention: TLX250-CDx on Day 0 with subsequent PET/CT on Day 5 (+/- 2 days) prior to surgery
Results: sensitivity 86%, specificity 87%, positive predictive value 91%, and negative predictive value 74%
CA-IX cyclic peptide DPI-4452 in 2024:
68Ga-DPI-4452, CA-IX binding radiolabeled peptide developed for selecting and treating patients with carbonic anhydrase IX-expressing tumors
Tumor update was observed at all time points (15 minutes to 4 hours)
68Ga-DPI-4452 showed exceptional tumor uptake in patients with clear cell RCC, with very high tumor-to-background ratios and no significant adverse events
Potential advantages: requires much less time (15 minutes) with less background noise and improved tumor uptake
Important Takeaway:
CA-IX PET/CT may have future utility in diagnosing RCC
A phase 2, open-label, single-arm study evaluating the combination of lutetium-177 (¹⁷⁷Lu)-girentuximab and nivolumab in patients with previously treated clear cell renal cell carcinoma (ccRCC)
The study includes a safety lead-in phase to determine the maximum tolerated dose (MTD) of ¹⁷⁷Lu-girentuximab in combination with nivolumab
Scientific rationale
Carbonic anhydrase IX (CAIX) is a cell surface glycoprotein often expressed in clear cell renal cell carcinoma (ccRCC)
Girentuximab is an anti-CAIX monoclonal antibody
Lutetium-177 (177Lu) is a radioisotope being investigated for targeted radiotherapy in renal cell carcinoma (RCC)
Labeling girentuximab with lutetium-177 (¹⁷⁷Lu-girentuximab) is postulated to provide targeted radiation delivery to ccRCC; this may enhance tumor antigen presentation, priming the immune response
Combination of ¹⁷⁷Lu-girentuximab with nivolumab may potentially improve treatment outcomes
Treatment Plan:
Treatment is in 28-day cycles
C1D1 is the date of the first 177Lu-girentuximab dose, with subsequent doses administered q12-14 weeks for a maximum of three doses
Dose 2 of 177Lu-girentuximab is 75% of Dose 1, and Dose 3 is 75% of Dose 2
Nivolumab 240 mg is given on D1 and D15 of all cycles except C1D1, where the first nivolumab dose is administered on C1D15
Important Takeaway:
This could represent an exciting new approach to treat advanced clear cell RCC
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