A Review of Selected Presentations From the ASCO GU Symposium • February 13-15, 2025 • San Francisco, California
Cabozantinib in Combination With Nivolumab and Ipilimumab in Previously Untreated Advanced Renal Cell Carcinoma: Final Results of COSMIC-313
Combination regimens consisting of a tyrosine kinase inhibitor (TKI) and an immune checkpoint inhibitor (ICI) or 2 ICIs (ipilimumab and nivolumab) are standard approaches for the initial treatment of advanced clear cell renal cell carcinoma (ccRCC).1 However, there remains a need for more effective regimens.
Cabozantinib is a multitargeted TKI that is approved by the US Food and Drug Administration (FDA) for use as a single agent in patients with advanced RCC (aRCC) and as first-line treatment in combination with nivolumab.2 In an exploratory analysis of the CheckMate 9ER trial, the triplet combination of cabozantinib, nivolumab, and ipilimumab demonstrated clinical activity in patients with previously untreated aRCC, a finding supporting additional study of this regimen.3
The randomized, double-blind, phase 3 COSMIC-313 trial was undertaken to evaluate further the efficacy and safety of adding cabozantinib to nivolumab and ipilimumab in patients with previously untreated intermediate- or poor-risk aRCC per the International Metastatic RCC Database Consortium (IMDC) criteria. A total of 855 patients with previously untreated intermediate- or poor-prognostic-risk aRCC were randomly assigned to 40 mg of cabozantinib daily (n=428) or placebo (n=427). Either was administered with nivolumab at 3 mg/kg and ipilimumab at 1 mg/kg once every 3 weeks for 4 cycles, followed by nivolumab maintenance (480 mg once every 4 weeks) for up to 2 years.4
The trial met its primary endpoint, demonstrating a significant improvement in progression-free survival (PFS) with cabozantinib, nivolumab, and ipilimumab vs placebo, nivolumab, and ipilimumab (hazard ratio [HR], 0.73; 95% CI, 0.57-0.94; P=.01) after a median follow-up of 14.9 months.4 In the primary analysis, the PFS benefit in the experimental arm vs the control arm appeared to be greater in intermediate-risk disease (HR, 0.63; 95% CI, 0.47-0.85) than in poor-risk disease (HR, 1.04; 95% CI, 0.65-1.69).
Laurence Albiges, MD, PhD, presented the final results of COSMIC-313 after a median follow-up of 45 months.5 In this update, cabozantinib, nivolumab, and ipilimumab continued to demonstrate a significant improvement in PFS in comparison with placebo, nivolumab, and ipilimumab, with median PFS of 16.6 and 11.2 months, respectively (HR, 0.82; 95% CI, 0.69-0.98) (Figure 1).
As in the primary analysis, in this update, the benefit of the triplet regimen in this update was restricted to patients in the intermediate-risk subgroup, who made up 75% of the population. Among intermediate-risk patients, the median PFS was 22.1 months with cabozantinib, nivolumab, and ipilimumab vs 11.3 months with placebo, nivolumab, and ipilimumab (HR, 0.76; 95% CI, 0.62-0.93). In the 25% of patients with poor-risk disease, the median PFS was 9.5 months with cabozantinib and 11.2 months with placebo (HR, 1.04; 95% CI, 0.73-1.48).
Overall survival (OS) outcomes were similar in the treatment arms overall and in the 2 IMDC risk groups. In the overall population, the median OS was 41.9 months with cabozantinib, nivolumab, and ipilimumab vs 42.0 months with placebo, nivolumab, and ipilimumab (Figure 2). Approximately half of the patients in each treatment arm subsequently received at least one systemic anticancer therapy. However, the median time to first subsequent systemic therapy was longer with the triplet regimen than with placebo (14.5 vs 9.7 months).
Safety outcomes were consistent with previously reported results.1 The incidence of grade 3/4 treatment-related AEs was higher with the experimental regimen than with the control regimen (75% vs 43%). The most common grade 3/4 treatment-related AEs in the experimental and control arms were increased alanine aminotransferase (ALT; 26% and 6%, respectively), increased aspartate aminotransferase (AST; 19% and 5%), and diarrhea (5% and 3%). Treatment-related AEs led to discontinuation of at least one regimen component in 49% of patients in the triplet arm and 26% of those in the control arm. Systemic immune-modulating medications for AEs were used in 73% and 56.7% of patients, respectively.
Exploratory biomarker analyses conducted on 398 tumor samples found no clear association between any molecular subset and a PFS or OS benefit with the triplet regimen. However, small sample sizes are a potential limitation of these analyses.
Investigators did report that levels of M2-like macrophages, which are associated with suppression of immune responses and poor prognosis in different cancers,6,7 were higher in patients with IMDC poor-risk disease than in those with intermediate-risk disease (P=.0005) and in patients with visceral metastases at baseline (P=.01).
Exploratory analyses found that among patients with levels of M2-like macrophage expression in the highest 25%, the triplet regimen appeared to provide a particular benefit vs the control regimen as assessed by PFS (HR, 0.48; 95% CI, 0.29-0.81; P=.0058) and OS (HR, 0.51; 95% CI, 0.31-0.86; P=.012), suggesting that the addition of cabozantinib to nivolumab and ipilimumab may overcome M2-like macrophage–mediated immune suppression. Preclinical and clinical validation studies to explore these observations further are ongoing.
References
1. National Comprehensive Cancer Network (NCCN) guidelines: kidney cancer. Version 3.2025. https://www.nccn.org/professionals/physician_gls/pdf/kidney.pdf. Accessed March 5, 2025.
2. CABOMETYX® (cabozantinib) prescribing information. Alameda, CA: Exelixis, Inc. Revised September 2023.
3. Apolo AB, Powles T, Escudier B, et al. Nivolumab plus ipilimumab plus cabozantinib triplet combination for patients with previously untreated advanced renal cell carcinoma: results from a discontinued arm of the phase III CheckMate 9ER trial. Eur J Cancer. 2022;177:63-71.
4. Choueiri TK, Powles T, Albiges L, et al; COSMIC-313 Investigators. Cabozantinib plus nivolumab and ipilimumab in renal-cell carcinoma. N Engl J Med. 2023;388(19):1767-1778.
5. Albiges L, Motzer R, Trevino S, et al. Cabozantinib (C) in combination with nivolumab (N) and ipilimumab (I) in previously untreated advanced renal cell carcinoma (aRCC): final results of COSMIC-313 [ASCO GU abstract 438]. J Clin Oncol. 2024;42(4)(suppl).
6. Qu X, Zhao X, Lin K, et al. M2-like tumor-associated macrophage-related biomarkers to construct a novel prognostic signature, reveal the immune landscape, and screen drugs in hepatocellular carcinoma. Front Immunol. 2022;13:994019.
7. DeRyckere D, Huelse JM, Earp HS, Graham DK. TAM family kinases as therapeutic targets at the interface of cancer and immunity. Nat Rev Clin Oncol. 2023;20(11):755-779.
Nivolumab Plus Cabozantinib vs Sunitinib for Previously Untreated Advanced Renal Cell Carcinoma: Final Follow-Up Results From the CheckMate 9ER Trial
The combination of nivolumab and cabozantinib received FDA approval for the first-line treatment of patients with aRCC in January 2021 on the basis of findings from the randomized, open-label, phase 3 CheckMate 9ER trial, in which nivolumab plus cabozantinib demonstrated significantly improved PFS, OS, and confirmed overall response rate (ORR) in comparison with sunitinib.1
The CheckMate 9ER trial randomly assigned 651 patients with previously untreated aRCC of any IMDC risk group to receive 240 mg of nivolumab intravenously every 2 weeks plus 40 mg of cabozantinib once daily (n=323) or 50 mg of sunitinib orally once daily on a 4-weeks-on/2-weeks-off schedule (n=328).2
In the primary analysis after a median follow-up of 18.1 months, the trial met its primary endpoint, demonstrating a significant improvement in PFS with nivolumab plus cabozantinib vs sunitinib in a blinded independent central review (BICR; median PFS, 16.6 vs 8.3 months; HR, 0.51; 95% CI, 0.41-0.64; P<.001). In addition, improvements were noted in 12-month OS rates (85.7% vs 75.6%; HR, 0.60; 95% CI, 0.40-0.89; P=.001) and ORR per BICR (55.7% vs 27.1%; P<.001).2
Robert J. Motzer, MD, presented final follow-up results from the CheckMate 9ER trial.3 After a median follow-up of 67.6 months, nivolumab plus cabozantinib continued to show efficacy benefits vs sunitinib in PFS and OS. The median PFS per BICR in the intention-to-treat (ITT) analysis was 16.4 months with nivolumab plus cabozantinib and 8.3 months with sunitinib (HR, 0.58; 95% CI, 0.49-0.70) (Figure 3); 5-year PFS rates were 13.6% with nivolumab plus cabozantinib and 3.6% with sunitinib.
At this final analysis, the 5-year OS rates were 40.9% with nivolumab plus cabozantinib and 35.4% with sunitinib; median OS was 46.5 months with nivolumab plus cabozantinib and 35.5 months with sunitinib (HR, 0.79; 95% CI, 0.65-0.96) (Figure 4). ORR rates were 55.7% and 27.4%, respectively, and the median duration of response (DOR) was 22.0 months with nivolumab plus cabozantinib and 15.2 months with sunitinib.
Exploratory subgroup analyses found differences in the relative benefit of nivolumab plus cabozantinib by IMDC risk group. In the IMDC favorable-risk group, the HR for PFS with nivolumab plus cabozantinib vs sunitinib was 0.67 (95% CI, 0.46-0.97) and the HR for OS was 1.08 (95% CI, 0.70-1.66). In the intermediate-/poor-risk group, the HR for PFS was 0.56 (95% CI, 0.46-0.69) and the HR for OS was 0.74 (95% CI, 0.60-0.92).
PFS, OS, and ORR all favored nivolumab plus cabozantinib over sunitinib across subgroups by organ site of metastasis, including liver, bone, and lung, at baseline. Subsequent systemic therapy was administered to 43% of patients in the nivolumab-plus-cabozantinib arm and 55% of those in the sunitinib arm.
Dose reductions were required for 62% of patients in the nivolumab-plus-cabozantinib arm and 55% of patients in the sunitinib arm; treatment-related AEs led to discontinuation of any treatment drug in 28% and 11% of patients, respectively. The most frequent grade 3/4 treatment-related AEs reported with nivolumab plus cabozantinib vs sunitinib were diarrhea (7% vs 5%), palmar-plantar erythrodysesthesia (PPE) (8% vs 8%), hypertension (13% vs 13%), fatigue (3% vs 5%), anemia (1% vs 4%), thrombocytopenia (<1% vs 5%), and increased ALT (6% vs 1%). Of 320 patients who received nivolumab plus cabozantinib, 22% required corticosteroids to manage an immune-related AE.
Investigators concluded that this updated analysis demonstrates a long-term efficacy benefit with nivolumab plus cabozantinib vs sunitinib in addition to manageable and consistent safety and tolerability of the regimen, supporting the use of nivolumab plus cabozantinib as a standard of care for patients with previously untreated aRCC.
Subcutaneous nivolumab has shown noninferiority to intravenous nivolumab on the basis of pharmacokinetic properties and ORR.4 Accordingly, the investigators noted that subcutaneous nivolumab could be considered as an alternative to standard intravenous dosing.
References
1. U.S. Food & Drug Administration. FDA approves nivolumab plus cabozantinib for advanced renal cell carcinoma. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-nivolumab-plus-cabozantinib-advanced-renal-cell-carcinoma. Accessed March 5, 2025.
2. Choueiri TK, Powles T, Burotto M, et al. Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2021;384(9):829-841.
3. Motzer R, Escudier B, Burotto M, et al. Nivolumab plus cabozantinib (N+C) vs sunitinib (S) for previously untreated advanced renal cell carcinoma (aRCC): final follow-up results from the CheckMate 9ER trial [ASCO GU abstract 439]. J Clin Oncol. 2024;42(4)(suppl).
4. Albiges L, Bourlon MT, Chacón M, et al. Subcutaneous versus intravenous nivolumab for renal cell carcinoma. Ann Oncol. 2025;36(1):99-107.
KEYMAKER-U03 Substudy 03B: Pembrolizumab and Targeted Therapy Combinations for Advanced Clear Cell Renal Cell Carcinoma
In most patients with ccRCC, disease progression develops within 4 years after they have received ICI-based first-line combination therapy.1-3 Although second-line treatment often consists of single-agent regimens,4 combination therapy for these patients could play a role.
The open-label, rolling arm, umbrella platform, phase 1/2 KEYMAKER-U03 trial is evaluating different combination therapies for patients with locally advanced or metastatic ccRCC previously treated with a programmed death (ligand) 1 (PD-[L]1) inhibitor and a vascular endothelial growth factor (VEGF) TKI. Dr Albiges presented results from 3 arms of KEYMAKER-U03 Substudy 03B, in which 263 patients were randomly assigned to pembrolizumab plus the hypoxia-inducible factor (HIF)-2α inhibitor belzutifan (n=62), lenvatinib plus belzutifan (n=64), or pembrolizumab plus lenvatinib (n=73).5
The median age of enrolled patients was approximately 60 to 63 years (range, 32-86 years), 77% were male, and the majority had favorable-risk (22%) or intermediate-risk (65%) disease. Most patients (85%) had received at least 2 prior lines of therapy.
Lenvatinib plus belzutifan was associated with a high ORR of 46.9%, a median DOR of 22.1 months, a median PFS of 12.5 months by BICR, and an 18-month OS rate of 74.4% (Figure 5).5 Pembrolizumab plus lenvatinib was associated with an ORR of 39.7%, a median DOR of 8.3 months, a median PFS of 9.4 months, and an 18-month OS rate of 73.2%. Pembrolizumab plus belzutifan was associated with an ORR of 19.4%, a median PFS of 5.4 months, and an 18-month OS rate of 57.6%.
The most frequent treatment-related AEs that were observed with pembrolizumab plus belzutifan were anemia (69.4%) and fatigue (24.2%). The most frequent treatment-related AEs that were observed with lenvatinib plus belzutifan were anemia (65.1%), fatigue (46.0%), diarrhea (42.9%), nausea (38.1%), hypertension (36.5%), proteinuria (36.5%), decreased appetite (27.0%), and PPE (23.8%). The most frequent treatment-related AEs that were observed with pembrolizumab plus lenvatinib were diarrhea (56.2%), hypertension (52.1%), fatigue (34.2%), proteinuria (31.5%), PPE (26.0%), and hypothyroidism (26.0%).
Investigators noted that the AEs were generally manageable, and safety profiles were consistent with the established safety profiles for each agent. The ongoing randomized, phase 3 LITESPARK-011 trial is comparing lenvatinib plus belzutifan vs cabozantinib in patients with aRCC previously treated with anti–PD-(L)1 therapy.5
References
1. Motzer RJ, McDermott DF, Escudier B, et al. Conditional survival and long-term efficacy with nivolumab plus ipilimumab versus sunitinib in patients with advanced renal cell carcinoma. Cancer. 2022;128(11):2085-2097.
2. Motzer RJ, Powles T, Burotto M, et al. Nivolumab plus cabozantinib versus sunitinib in first-line treatment for advanced renal cell carcinoma (CheckMate 9ER): long-term follow-up results from an open-label, randomised, phase 3 trial. Lancet Oncol. 2022;23(7):888-898.
3. Motzer RJ, Porta C, Eto M, et al; CLEAR Trial Investigators. Lenvatinib plus pembrolizumab versus sunitinib in first-line treatment of advanced renal cell carcinoma: final prespecified overall survival analysis of CLEAR, a phase III study. J Clin Oncol. 2024;42(11):1222-1228.
4. National Comprehensive Cancer Network (NCCN) guidelines: kidney cancer. Version 3.2025. https://www.nccn.org/professionals/physician_gls/pdf/kidney.pdf. Accessed March 5, 2025.
5. Albiges L, Suárez C, Powles T, et al. KEYMAKER-U03 Substudy 03B: pembrolizumab (pembro) and targeted therapy combinations for advanced clear cell renal cell carcinoma (ccRCC) [ASCO GU abstract 440]. J Clin Oncol. 2024;42(4)(suppl).
Lenvatinib Plus Tislelizumab as First-Line Therapy for Advanced Fumarate Hydratase-Deficient Renal Cell Carcinoma: A Single-Center, Single-Arm, Phase II Study
Fumarate hydratase-deficient RCC (FH-RCC) is a rare, aggressive type of RCC that is caused by germline or sporadic mutations in the FH gene. These mutations lead to the accumulation of fumarate, which activates HIF, in turn promoting tumorigenesis.1 The combination of bevacizumab and erlotinib is considered a standard therapy for FH-RCC; it demonstrated an ORR of 72.1% in patients with hereditary leiomyomatosis and RCC (HLRCC) and of 35% in patients with sporadic papillary RCC in a prospective phase 2 trial.2,3
In a retrospective study, response rates were comparable with bevacizumab plus erlotinib and an ICI plus a TKI (30% vs 33%), but OS on systemic treatment appeared to be longer in the ICI-plus-TKI group (HR, 0.19; 95% CI, 0.04-0.90).4
Wen Kong, MD, presented results of a single-center, single-arm, phase 2 study evaluating lenvatinib plus tislelizumab as first-line therapy for patients with advanced FH-RCC.5 The trial enrolled 20 patients with previously untreated advanced FH-RCC (median age, 41.5 years; range, 24-62 years); 80% of the patients were male, and most had intermediate- (55%) or poor-risk (30%) disease by IMDC classification. Prior nephrectomy had been performed in 75% of the patients, and the median number of disease sites was 3 (range, 1-6). Most patients (75%) had germline mutations.
Patients received 200 mg of tislelizumab intravenously every 3 weeks plus 20 mg of lenvatinib orally once daily. Efficacy was assessed after a median follow-up of 9.7 months. The ORR was 90%, including a 20% complete response (CR) rate (Figure 6). The disease control rate (DCR), defined as attainment of at least stable disease (SD) at 12 weeks, was 100%, indicating no cases of primary progression during the study. Responses were observed in both hereditary and sporadic FH-RCC.
The median time to response to lenvatinib plus tislelizumab was 6 weeks. At the time of the last assessment, progressive disease (PD) had occurred in 4 patients. In this small cohort with limited follow-up, the 6-month PFS and OS rates were 85% and 100%, respectively. Three patients proceeded to undergo definitive surgery with or without radiotherapy, and 17 of 20 patients remained on treatment at the time of last follow-up.
Grade 3 or higher AEs occurred in 45% of patients; dose reductions of lenvatinib were required in 45% of patients, and tislelizumab was discontinued in 15%. The most frequent AEs were hypertension (80%), thyroid-stimulating hormone elevation (80%), proteinuria (65%), pharyngolaryngeal pain (45%), and hyperuricemia (40%).
Investigators concluded that the regimen showed encouraging efficacy and an acceptable safety profile. However, follow-up is limited, the data are immature, and the sample size is small for this single-center study, highlighting the need for an expanded validation study.
References
1. Lindner AK, Tulchiner G, Seeber A, Siska PJ, Thurnher M, Pichler R. Targeting strategies in the treatment of fumarate hydratase deficient renal cell carcinoma. Front Oncol. 2022;12:906014.
2. National Comprehensive Cancer Network (NCCN) guidelines: kidney cancer. Version 3.2025. https://www.nccn.org/professionals/physician_gls/pdf/kidney.pdf. Accessed March 5, 2025.
3. Srinivasan R, Gurram S, Al Harthy M, et al. Results from a phase II study of bevacizumab and erlotinib in subjects with advanced hereditary leiomyomatosis and renal cell cancer (HLRCC) or sporadic papillary renal cell cancer [ASCO abstract 5004]. J Clin Oncol. 2020;38(15)(suppl).
4. Xu Y, Kong W, Cao M, et al. Genomic profiling and response to immune checkpoint inhibition plus tyrosine kinase inhibition in FH-deficient renal cell carcinoma. Eur Urol. 2023;83(2):163-172.
5. Kong W, Wu G, Xu Y, Wang Z, Zhang J. Lenvatinib plus tislelizumab as first-line therapy for advanced fumarate hydratase-deficient renal cell carcinoma: a single-center, single-arm, phase II study [ASCO GU abstract 443]. J Clin Oncol. 2024;42(4)(suppl).
Racial Disparities in Renal Cell Carcinoma Histology and Outcomes: Insights From the French Kidney Cancer Research Network (UroCCR-191)
Racial disparities in RCC have been reported in US populations. Multiple studies have shown that papillary RCC occurs more frequently in Black than in non-Black individuals.1-3 Moreover, among patients with ccRCC, data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results program have reported lower 5-year OS rates in Black than in White patients (67.1% vs 72.6%).3
Whereas disparities in the United States have been well documented, they have not been evaluated to the same extent in Europe, which uses a universal healthcare system. Xiaofan Lu, PhD, reported outcomes from UroCCR-191, a retrospective study conducted by the French Kidney Cancer Research Network that evaluated racial disparities among patients with RCC in France.4
The UroCCR database analysis included 9404 patients with data collected between 1987 and 2024. Black patients accounted for 3.6% of the cohort. The median follow-up was 28.5 months.
Investigators reported differences in the incidence of various RCC histologies by race. Among non-Black patients, 68.8% of cases were ccRCC and 23.9% were non-ccRCC (Figure 7). In contrast, among Black patients, 47.6% of cases were ccRCC and 44.7% were non-ccRCC.
The most frequent morphologically defined non-ccRCC histologies were papillary RCC, accounting for 23.1% of cases in Black patients and for 11.8% of cases in non-Black patients (odds ratio [OR], 2.23; P<.001), chromophobe RCC (9.8% vs 7.1%; OR, 1.42; P=.068), and clear cell papillary renal cell tumor (1.5% vs 0.5%; OR, 2.76; P=.044).
Rare molecularly defined non-ccRCC histologies included TFE3-rearranged/TFEB-altered RCC, which was reported in 2.1% of Black patients and 0.6% of non-Black patients (OR, 3.60; P=.005), FH-deficient RCC (0.6% vs 0.1%; OR, 5.39; P=.067), and renal medullary carcinoma (SMARCB1 loss; 0.3% vs 0%; OR>10; P=.001). The false discovery rate was below 0.15 for all subsets.
Investigators stated that Black patients were younger at diagnosis than non-Black patients, had earlier-stage tumors, and had higher rates of partial nephrectomy, although these data were not reported.
In a multivariate Cox regression analysis, distant recurrence–free survival (dRFS) was not significantly shorter in Black than in non-Black patients (adjusted HR, 0.96; 95% CI, 0.51-1.80; P=.894). Factors that were independently associated with dRFS outcomes included age at diagnosis, sex, nephrectomy type, tumor (T) stage, node (N) stage, and Fuhrman grade.
The investigators concluded that in France, non-ccRCC histologies, including rare molecularly defined histologies, were more common in Black than in non-Black patients with RCC. Moreover, race was not independently predictive of clinical outcomes in this analysis from a universal healthcare system.
Reported limitations include a small number of rare non-ccRCC cases, the use of binary Black vs non-Black race categories, and a short median follow-up of less than 2.5 years.
References
1. Sankin A, Cohen J, Wang H, Macchia RJ, Karanikolas N. Rate of renal cell carcinoma subtypes in different races. Int Braz J Urol. 2011;37(1):29-32.
2. Olshan AF, Kuo TM, Meyer AM, Nielsen ME, Purdue MP, Rathmell WK. Racial difference in histologic subtype of renal cell carcinoma. Cancer Med. 2013;2(5):744-749.
3. Chow WH, Shuch B, Linehan WM, Devesa SS. Racial disparity in renal cell carcinoma patient survival according to demographic and clinical characteristics. Cancer. 2013;119(2):388-394.
4. Lu X, Bernhard JC, Audenet F, et al. Racial disparities in renal cell carcinoma histology and outcomes: insights from the French Kidney Cancer Research Network (UroCCR-191) [ASCO GU abstract 442]. J Clin Oncol. 2024;42(4)(suppl).
Casdatifan Monotherapy in Patients With Previously Treated Clear Cell Renal Cell Carcinoma: Safety, Efficacy and Subgroup Analysis Across Multiple Doses from ARC-20, a Phase 1 Open-Label Study
Casdatifan is an investigational HIF-2α inhibitor that is being evaluated as monotherapy and in combination with other agents in patients with advanced RCC and other solid tumors in the phase 1 dose-escalation and dose-expansion ARC-20 study (Figure 8).1
Toni K. Choueiri, MD, presented results of ARC-20 in 3 cohorts of patients with previously treated ccRCC.2 Patients received 50 mg of casdatifan as monotherapy twice daily (BID; n=33), 50 mg once daily (QD; n=31), or 100 mg QD (n=29). The primary outcomes were AEs and dose-limiting toxicities (DLTs); secondary outcomes included ORR and pharmacokinetics, and exploratory outcomes included PFS, OS, and biomarkers.
The median age of enrolled patients was 60 to 65 years across dose cohorts (range, 41-82 years); most patients (83%-94%) had received at least 2 prior regimens, and all patients had previously received a VEGF receptor TKI and a PD-(L)1 inhibitor. Outcomes were reported after median follow-up periods of 15 months with 50 mg of casdatifan BID, 12 months with 50 mg of casdatifan QD, and 5 months with 100 mg of casdatifan QD.
The incidence rates of grade 3 or higher treatment-emergent AEs (TEAEs) considered to be related to casdatifan were 49% with 50 mg of casdatifan BID, 32% with 50 mg of casdatifan QD, and 28% with 100 mg of casdatifan QD. Rates of serious TEAEs considered to be related to casdatifan were 3%, 10%, and 7%, respectively. Grade 3 or higher casdatifan-related anemia occurred in 42%, 32%, and 17% of patients, respectively, and led to discontinuation in 1 of 93 treated patients. Grade 3 or higher casdatifan-related hypoxia occurred in 9%, 7%, and 10% of patients, respectively, and led to discontinuation in 2 patients.
The confirmed ORR with casdatifan was 25% at the 50-mg BID dose (0% CR rate), 29% at the 50-mg QD dose (4% CR rate), and 33% at the 100-mg QD dose (0% CR rate). Rapid responses and a trend of decreasing tumor size were noted at the 100-mg QD dose level. Investigators concluded that the study showed promising clinical activity with casdatifan and favorable tolerability. The planned randomized, phase 3 PEAK-1 study will evaluate 100 mg of casdatifan QD plus 60 mg of cabozantinib in patients with metastatic ccRCC who previously received PD-1–targeted therapy.
References
1. ClinicalTrials.gov. A phase 1 study of AB521 monotherapy and combination therapies in renal cell carcinoma and other solid tumors (ARC-20). https://clinicaltrials.gov/study/NCT05536141. Accessed February 6, 2025.
2. Choueiri T, Lee JL, Merchan J, et al. Casdatifan (Cas) monotherapy in patients (pts) with previously treated clear cell renal cell carcinoma (ccRCC): safety, efficacy and subgroup analysis across multiple doses from ARC-20, a phase 1 open-label study [ASCO GU abstract 441]. J Clin Oncol. 2024;42(4)(suppl).
Cabozantinib in Patients With Non-Locally Pretreated Brain Metastases From Renal Cell Carcinoma: Results of the Multicenter CABRAMET Phase II Trial (NCT03967522)
The multicenter, phase 2 CABRAMET trial, presented by Sylvie Négrier, MD, PhD, was undertaken to evaluate prospectively the efficacy of cabozantinib in patients with brain metastases that have not been locally pretreated.1 The trial enrolled patients with brain metastases larger than 5 mm (≥8 mm if solitary), including at least one metastasis that was not locally pretreated. Patients could have received up to 40 mg of corticosteroids per day and could have received up to 2 prior systemic treatments (excluding cabozantinib). Cabozantinib was administered at a dose of 60 mg/d.
The 26 patients enrolled had a median age of 67 years (range, 44-86 years); 92% of patients had ccRCC. At baseline, patients primarily had either 1 (35%) or 2 to 5 (57%) brain metastases. Prior anticancer treatments included immunotherapy (35%) and a TKI with or without immunotherapy (38%).
In the 25 evaluable patients, the 6-month brain metastasis PFS (BM-PFS) rate was 56%, according to central and investigator reviews (Table), and the median BM-PFS was 10.7 months.
The best brain metastasis response rate in the overall cohort was 61%, and all responses were partial responses (PRs). The best brain metastasis PR rate was 86% (6/7) in patients without prior treatment, 67% (6/9) in patients with prior immunotherapy, and 40% (4/10) in patients treated with a prior TKI with or without immunotherapy.
After a median follow-up of 38.8 months, the median duration of brain metastasis response had not been reached; 58.3% of responses were ongoing beyond 24 months. The median duration of treatment was 9.6 months, and in 4 patients, treatment was ongoing beyond the 24-month protocol-defined period.
The best extracranial response rate was 40% (all PRs). The median BM-PFS was 10.7 months, median PFS was 8.1 months, and median OS was 15.0 months.
Reference
1. Négrier S, Mourey L, Blanc E, et al. Cabozantinib in patients (pts) with non-locally pretreated brain metastases (BM) from renal cell carcinoma (RCC): results of the multicenter CABRAMET phase II trial (NCT03967522) [ASCO GU abstract 533]. J Clin Oncol. 2024;42(4)(suppl).