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RECOMMENDED ABSTRACTS in RENAL CANCERS

ABSTRACT TPS 496

Barragan-Carrillo R et al.

BACKGROUND: Complete response (CR) is still a rare event in patients with advanced clear cell renal cell carcinoma (ccRCC). The combination of nivolumab plus cabozantinib was recently approved for the firstline treatment of ccRCC based on the CheckMate 9ER phase 3 study demonstrating improved progressionfree survival (PFS) & objective response rate (ORR) in comparison to sunitinib. However, the CR rate was only 9%. Since the anti-tumor effects of immune checkpoint inhibitors are dependent on the presence of activated tumor-infiltrating T cells, drugs that could synergize with T cells' anti-tumor activity can allow us to improve CR rates. Activation of the cGAS-STING pathway which is induced by radiation-induced DNA damage, is one promising mechanism that has been investigated. Many studies have shown that radiation treatment augments immune checkpoint inhibition. However, it is not always possible to radiate all metastatic lesions. Therefore, targeted peptide receptor radionuclide therapies have been developed by conjugating radioisotopes to receptor binding analogs targeting specific cancer cell surface proteins, thereby delivering targeted radiation to cancer cells in the body with minimal damage to surrounding healthy cells. 177Lu girentuximab is the first antibody-radioisotope designed for ccRCC, targeting carbonic anhydrase 9-expressing cells, which includes > 90% of ccRCC. It has been tested in metastatic ccRCC as a single agent & shown to be safe and effective in stabilizing disease in 57% of pts. In this study, we hypothesize 177Lu girentuximab-induced DNA damage will potentiate the STING pathway, and this activation will synergize with nivolumab and cabozantinib to promote trafficking and infiltration of activated T cells to tumors and achieve higher CR rates. METHODS: Up to 100 patients with treatment na'i"ve, biopsy-proven ccRCC with adequate organ/ marrow function with 1 evaluable lesion by RECIST 1.1 will be enrolled. A 5-patient safety lead-in will evaluate myelosuppression. Ongoing safety, & futility monitoring will employ a Bayesian approach. The sample size was chosen for reasonable operating characteristics to distinguish a CR rate (primary endpoint) of 18% as better than 9% using a beta(0.09, 0.91) prior. Secondary endpoints are ORR, PFS by RECIST 1.1, and overall survival. 177Lu-girentuximab 1480 MBq/m2 (61% of single agent MTD) will be administered every 12 weeks for up to 3 cycles. Starting with the 2nd cycle, nivolumab & cabozantinib will be added at standard dose. To explore the effects of the treatment on inducing activated T cell infiltration, patients will undergo pre/post-treatment PET scan with [18F]F-AraG radiotracer as well as biopsies for single cell, spatial transcriptomics and proteomics studies. Clinical trial information: NCT05239533

ABSTRACT 361

Thomas Powles et al.

BACKGROUND: In the randomized, open-label, phase 3 LITESPARK-005 (NCT04195750) study, belzutifan treatment showed superior PFS (primary endpoint; HR 0.75 [95% CI 0.63–0.90]; P<.001) and ORR (key secondary endpoint; estimated percentagepoint difference 18.4 [95% CI 14.0–23.2]; P<.00001) vs everolimus in pts with advanced/metastatic clear cell RCC that progressed after prior immune checkpoint and anti-angiogenic therapies. We present PRO findings for belzutifan vs everolimus in LITESPARK-005. METHODS: PROs were evaluated by FKSI-DRS and EORTC QLQ-C30 questionnaires in all randomized pts with ≥1 dose study treatment and ≥1 completed PROs assessment, administered electronically on d 1 of wk 1, 3, 5, and 9, Q4W thereafter, at treatment discontinuation, and d 30 after last dose. Time to deterioration (TTD) and least square (LS) mean change from baseline as measured by FKSI-DRS and QLQ-C30 global health status/quality of life (GHS/ QoL) and physical functioning (PF) scales were prespecified as secondary endpoints. PROs were not formally statistically tested and 95% CI and P-values were nominal and descriptive. RESULTS: As of June 13, 2023 (data cutoff date at second prespecified interim analysis), median (range) follow-up was 25.7 mo (16.8–39.1). Median (range) duration of treatment was 7.6 mo (0.1–35.8) with belzutifan vs 3.9 mo (0.0–33.2) with everolimus; 84 (22.6%) vs 18 (5.0%) pts remained on treatment. 366 of 374 pts randomized to belzutifan and 354 of 372 pts randomized to everolimus were included in the PRO analysis population. Completion rates for FKSIDRS and QLQ-C30 were >90% at baseline and >55% at wk 17 (~4 mo) in each arm. Meaningfully longer TTD in FKSI-DRS and QLQ-C30 GHS/QoL scores were observed for belzutifan vs everolimus (Table). LS mean changes in FKSI-DRS and QLQ-C30 GHS/ QoL scores suggested stability from baseline to wk 17 with belzutifan vs worsening with everolimus, and a potential greater worsening in PF scores with everolimus vs belzutifan. CONCLUSIONS: Belzutifan was associated with prolonged TTD in FKSI-DRS and EORTC QLQ-C30. Score changes from baseline to wk 17 also favored belzutifan over everolimus. Overall, PRO results indicate better disease-specific symptoms and quality of life among pts treated with belzutifan compared with everolimus. Clinical trial information: NCT04195750

ABSTRACT 363

Nizar Tannir et al. BACKGROUND: First-line NIVO+IPI has provided substantial long-term survival benefits over SUN in patients (pts) with aRCC in CheckMate 214. We report survival, response per independent radiology review committee (IRRC) and safety after 6 y minimum (80 mo median) follow-up in all randomized pts, by IMDC risk and in pts with overall survival (OS) ≥ 6 y (long-term survivors; LTS). Longer follow-up data (minimum, 7.5 y) will be presented.

METHODS: Pts with clear cell aRCC were randomized 1:1 to NIVO 3 mg/kg + IPI 1 mg/kg Q3W×4 then NIVO 3 mg/kg Q2W vs SUN 50 mg QD for 4 wk on, 2 wk off. Endpoints: OS, progression-free survival (PFS) and objective response rate (ORR; both per IRRC using RECIST v1.1) in IMDC intermediate/poor risk (IP; primary), intent-to-treat (ITT; secondary) and favorable risk (FAV; exploratory) pts. Exploratory outcomes in LTS pts were assessed post hoc. RESULTS: OS with NIVO+IPI vs SUN remained superior in ITT (HR 0.72) and IP (HR 0.68) pts; OS benefits were similar between arms in FAV pts (HR 0.87; Table). Median PFS was consistent with previous reports. ORR per IRRC was higher with NIVO+IPI vs SUN, with more ongoing responses in ITT (60% vs 50%) and IP (60% vs 50%) pts. In FAV pts, ORR was lower with NIVO+IPI vs SUN, yet more responses were ongoing (59% vs 52%, respectively). Median duration of response (DOR) was longer and complete response (CR) rate was higher with NIVO+IPI vs SUN regardless of IMDC risk. Incidence of any and grade 3-4 treatment-related adverse events remained largely unchanged. One additional drug-related death occurred with NIVO+IPI and zero with SUN since the previous database lock. In the LTS subgroup (NIVO+IPI, n = 208; SUN, n = 151), ORR was higher (66% vs 53%), more pts had a CR (27% vs 9%) and fewer progressed (4% vs 11%) with NIVO+IPI vs SUN. Median DOR was longer with NIVO+IPI (n = 137) vs SUN (n = 80) among LTS with confirmed response (76 vs 40 mo). Updated survival, response and safety data with 7.5 y minimum follow-up, along with additional subgroup analyses, will be presented. CONCLUSIONS: NIVO+IPI demonstrated long-term survival and more durable response benefits vs SUN in ITT and IP pts. CR rates were higher and median DOR was longer with NIVO+IPI vs SUN regardless of IMDC risk group, and in LTS pts. No new safety signals emerged. Clinical trial information: NCT02231749.

ABSTRACT 364

Viktor Grünwald et al.

BACKGROUND: In the primary analysis of the phase 3 open-label CLEAR trial, lenvatinib + pembrolizumab (L+P) showed statistically significant and clinically meaningful improvements in progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) compared with sunitinib (S) in patients (pts) with advanced renal cell carcinoma (aRCC) (Motzer NEJM 2021). Outcomes were further corroborated by results of the final prespecified analysis of CLEAR (Motzer ASCO 2023). We report efficacy outcomes per baseline tumor size in the L+P arm of CLEAR. METHODS: 1069 treatment-naïve pts with aRCC and a clear-cell component were randomized (1:1:1) to: L 20 mg PO QD + P 200 mg IV Q3W; or L 18 mg + everolimus 5 mg PO QD; or S 50 mg PO QD (4 wks on/2 wks off). Stratification factors included geographic region and MSKCC prognostic risk group. IMDC risk groups (derived programmatically) are presented in this analysis. Efficacy outcomes were evaluated by quartiles of baseline sums of diameters of target lesions. Tumor assessments were performed by independent imaging review per RECIST v1.1. RESULTS: Pts were grouped into 4 categories: ≤Q1 (34.72 mm), >Q1 - ≤Q2 (60.06 mm), >Q2 - ≤Q3 (108.56 mm) and >Q3 per baseline tumor sizes (Table). For pts with ≤Q1 baseline tumor sizes, 40.7% and 58.0% were in the favorable and intermediate + poor IMDC risk subgroups, respectively. For pts with >Q3 baseline tumor sizes, 6.3% and 93.8% were in the favorable and intermediate + poor IMDC risk groups, respectively. Median OS, PFS, ORR, complete response (CR), partial response (PR), and near-CR (PR with maximum tumor shrinkage ≥75%) by baseline tumor size categories are in the Table. CONCLUSIONS: In CLEAR, clinically meaningful efficacy with L+P was observed across pts with aRCC irrespective of their baseline tumor sizes. These results support the use of L+P for the 1L treatment of aRCC across pts with both low and high baseline tumor size. Clinical trial information: NCT02811861.

ABSTRACT 365

Voss MH et al.

BACKGROUND:Patients(pts)with mRCC require a tailored HRQOL assessment. Previous research (Bergerot et al. Oncologist 2023; Bergerot et al. J Clin Oncol 2023) explored FKSI-19, EORTC QLQ-C30, and EQ-5D item relevance. We aimed to develop a tailored HRQOL measure for pts with mRCC through a three-phase approach involving patient engagement, expert input, and advocacy. METHODS: In Phase 1, 117 pts with mRCC (83:34 M:F, median age=64) from the US, Europe and Brazil participated in a survey study to assess the relevance of items from established measures (FKSI-19, EORTC QLQ-C30, EQ-5D). In this cohort, 88% of pts had clear cell histology received immunotherapy alone, targeted therapy alone or combination therapy, respectively. Questions identified as relevant (base on $66%consensus) were selected for inclusion in a preliminary survey. Phase 2 involved assembling a panel of 11 experts who rigorously reviewed and refined survey questions. In Phase 3, preliminary version were presented to 8 patient advocates (5:3 F:M; 6:2 pts:caregivers) to ensure alignment with pts’ needs and experiences. Results: Phase 1 analysis identified 10 items. Pts requested the inclusion of a question about social/family issues and better coverage of emotional symptoms. An 12-item questionnaire was created, and the expert committee refined three items to incorporate patient suggestions and added one item related to functional status (Table). This questionnaire included 1 cancer-specific item, 3 cancer or treatmentspecific items, 3 nonspecific emotional items, and 4 non-specific physical items. Patient advocates provided feedback, agreeing with the items excluded from previous questionnaires and those included. They suggested minor edits to item wording. CONCLUSIONS: The novel approach holds the potential to replace traditional HRQOL measures that may lack relevance to specific clinical circumstances. Further validation is planned in a phase 3 trial, ensuring its applicability in clinical practice.

ABSTRACT 373

Michael S Hofman et al.

BACKGROUND: Carbonic anhydrase IX (CA IX) is overexpressed in clear cell renal cell carcinoma (ccRCC) and is associated with aggressive tumor behavior, treatment resistance and overall poor outcomes. DPI-4452 is a first-in-class, cyclic peptide that binds with high affinity to CA IX. Radiolabeling DPI-4452 with gallium-68 ([68Ga]Ga- DPI-4452) or lutetium-177 ([177Lu]Lu-DPI-4452) is an innovative, theranostic approach for identifying and treating patients with CA IX-expressing tumors. Compared with existing antibody approaches, a radiolabeled peptide may confer better characteristics for both PET-CT imaging and therapy. This firstin- human study (NCT05706129) is evaluating the theranostic potential of [68Ga]Ga-DPI-4452 and [177Lu]Lu-DPI-4452 in patients with unresectable metastatic ccRCC, colorectal cancer or pancreatic ductal adenocarcinoma tumors. Here we report safety, tolerability, pharmacokinetics, dosimetry and imaging characteristics of [68Ga]Ga-DPI-4452 from the completed ccRCC imaging cohort. METHODS: 1The DPI-4452 peptide contains a DOTA cage and is radiolabelled with [68Ga]Ga. Following intravenous injection of [68Ga]Ga-DPI-4452, patients underwent serial PET-CT imaging, urine and blood sampling to assess imaging characteristics, biodistribution, and dosimetry of [68Ga]Ga-DPI-4452. Patients were followed for 7 days post-injection for safety observations.RESULTS: Pts were grouped into 4 categories: ≤Q1 (34.72 mm), >Q1 - ≤Q2 (60.06 mm), >Q2 - ≤Q3 (108.56 mm) and >Q3 per baseline tumor sizes (Table). For pts with ≤Q1 baseline tumor sizes, 40.7% and 58.0% were in the favorable and intermediate + poor IMDC risk subgroups, respectively. For pts with >Q3 baseline tumor sizes, 6.3% and 93.8% were in the favorable and intermediate + poor IMDC risk groups, respectively. Median OS, PFS, ORR, complete response (CR), partial response (PR), and near-CR (PR with maximum tumor shrinkage ≥75%) by baseline tumor size categories are in the Table. RESULTS: A mean activity of 185 MBq [68Ga]Ga- DPI-4452 was administered to 3 patients with ccRCC. No clinically significant toxicities were observed. PETCT images showed rapid and sustained tumor uptake over 4 h, as well as rapid renal elimination. At 1 h, the maximum tumor standardized uptake value (SUVmax) across 36 lesions ranged from 6.8 to 211.6, with a mean of 64.6. Seventeen of these lesions (found in lymph nodes, lung, pancreas, parotid gland and other sites) were not detectable on prior contrast-enhanced CT. OLINDA dosimetry estimates revealed that the organs receiving the highest absorbed doses (mean [SD] mGy/ MBq) were stomach wall (0.33 [0.10]), small intestine wall (0.33 [0.08]) and gallbladder wall (0.21 [0.12]), with a mean whole body effective dose of 0.06 [0.02] mSv/MBq. Absorbed doses in the kidney, liver and bone marrow were low. Over 80% of total administered radioactivity cleared from the bloodstream within 1 h. CONCLUSIONS: [68Ga]Ga-DPI-4452 provides exceptional images in patients with ccRCC without clinically significant toxicity. Very high SUVs and tumor-to-background ratios suggest potential for use in both diagnostics and patient selection for therapy. The tumor retention and rapid elimination support potential of [177Lu] Lu-DPI-4452 radioligand therapy. Clinical trial information: NCT05706129.

ABSTRACT 684

- Cabozantinib in combination with atezolizumab in non-clear cell renal cell carcinoma: Extended follow-up results of cohort 10 of the COSMIC-021 study.

Bradley Alexander McGregor et al.

Background: In the COSMIC-021 phase 1b study (NCT03170960) evaluating cabozantinib plus atezolizumab in advanced solid tumors, this combination therapy demonstrated encouraging clinical activity in patients with advanced non-clear cell renal cell carcinoma (nccRCC) with a median follow-up of 13 mo (Pal. JCO 2021). Results after extended follow-up in nccRCC are presented. Methods: Patients with advanced nccRCC and ECOG PS 0/1 who had ≤1 prior VEGFR-targeting tyrosine kinase inhibitor (TKI) were eligible. Prior treatment with TKIs targeting MET or immune checkpoint inhibitors was not allowed. Patients received cabozantinib 40 mg PO QD plus atezolizumab 1200 mg IV Q3W until unacceptable toxicity or progression; dose reductions of cabozantinib (40 mg QD to 20 mg QD, then to 20 mg QOD) were permitted to manage adverse events. The primary endpoint was objective response rate (ORR) per RECIST v1.1 by the investigator; other endpoints included safety, duration of response (DOR), PFS, and OS. Results: The study enrolled 32 patients with nccRCC (2 from dose escalation phase, and 30 from expansion phase of the study): median age, 62 y; male, 81%; ECOG PS 0/1, 75%/25%; histology, papillary/chromophobe/clear cell/other, 47%/28%/3%/22%; sarcomatoid feature, 13%; IMDC risk favorable/intermediate/poor, 50%/41%/9%; ≥3 tumor sites, 56%; tumor sites, lung/kidney/bone/liver, 50%/25%/16%/16%; prior nephrectomy, 63%; prior VEGFR TKI, 22%; 0/1 lines of prior therapy (locally advanced/metastatic setting), 81%/19%. As of July 21, 2022, median follow-up was 37.2 mo (range 32.1–58.5) with 5 (16%) patients remaining on study treatment. ORR by investigator was 31% (all PRs) and disease control rate was 94% (Table); median DOR was 8.1 mo. Median PFS was 9.3 mo (95% CI 5.5–12.3), and median OS was not reached (95% CI 23.0–NE). PFS and OS estimates at 12 mo were 34% and 84%, respectively; 24-mo estimates were 6% and 70%. Treatment-related AEs occurred in 97% (grade 3/4, 53%); the most common AEs included diarrhea (69%), palmar-plantar erythrodysesthesia (50%), fatigue (44%), dysgeusia (41%), hypertension (31%) and nausea (31%). One grade 5 treatment-related AE of pulmonary hemorrhage occurred. Treatment-related AEs leading to discontinuation of both study treatments occurred in 13% of patients. Conclusions: Extended 3-year follow-up reinforces the encouraging clinical activity of cabozantinib plus atezolizumab in advanced nccRCC with a manageable safety profile. Clinical trial information: NCT03170960.

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ABSTRACT 714

- - Evaluation of PBRM1, PD-L1, CD31, and CD4/CD8 ratio as a predictive signature of response to VEGFR-TKI–based therapy in patients with metastatic renal cell carcinoma (mRCC) with IMDC intermediate prognosis: Results from the APAChE-I Study.

Chiara Ciccarese et al.

Background: Intermediate IMDC group is the largest and most heterogeneous group of mRCC. Current first-line (1L) therapy options for these patients (pts) are based on either an anti-angiogenic agent (VEGFR-TKI) combined with immunotherapy (IO), or a combo of IO (ipilimumab+nivolumab [I/N]). No biomarkers (BM) for selecting the most effective regimen have been identified so far. Methods: Immunohistochemical expression of PBRM1, PD-L1, CD31, and CD4/CD8 ratio was evaluated on histological samples of intermediate-risk mRCC pts treated with VEGFR-TKI monotherapy, and then in pts receiving a VEGFR-TKI-based therapy or the immune doublet I/N. PBRM1 positivity score was based on the percentage of positive cells and on the intensity of nuclear expression; PD-L1 positivity was defined as CPS≥10; CD31 high-density had moderate to strong nuclear staining; and the CD4/CD8 ratio cut-off for positivity was >0.2. Cox model was used to assess the correlation between BM and outcomes; PFS and OS were estimated by Kaplan-Meier method. Results: After screening of tumor tissues from 150 pts, a total of 111 were included in the final analysis (Table). In pts treated with VEGFR-TKI monotherapy, a significant correlation with PFS was observed with loss of PBRM1 expression (HR 0.58, p=0.035), PD-L1 negativity (HR 0.44, p=0.048), and high CD4/CD8 ratio (HR 0.62, p=0.073). CD31 density did not significantly correlate with PFS. A profile potentially predictive of angiogenesis (AP+) was defined based on the PBRM1 loss, PD-L1 negative, and high CD4/CD8. In pts treated with VEGFR-TKI monotherapy, tumors with the AP+ (43% of all cases) had a significantly longer median PFS (mPFS 23.8 vs. 11.8 months, p=0.003) and mOS (41.5 vs. 26.9 months, p=0.024) compared to the others. The AP+ retained its significant correlation with PFS (mPFS 23.8 vs. 11.1 months, p<0.001) and OS (41.5 vs. 24.9, p=0.006) in pts receiving VEGFR-TKI-based therapies. The rate of AP+ tumors was 55.6% and 32.7% in pts with one or two IMDC risk factors, respectively (p=0.022). In the small cohort of pts treated with I/N, no differences were observed in PFS (p=0.64) and OS (p=0.75) between AP+ and AP-negative. Conclusions: The AP+ signature (loss of PBRM1, PD-L1 negative, and CD4/CD8 high ratio) was associated with improved clinical outcomes in mRCC pts at IMDC intermediate prognosis treated with VEGFR-TKI-based therapy; this correlation was significant regardless from the addition of IO to VEGFR-TKI monotherapy. Prospective validation of this signature is required for guiding the selection of the most appropriate 1L therapy.

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ABSTRACT TPS747

- -LITESPARK-024: A randomized phase 1/2 study of belzutifan with or without palbociclib in patients with advanced renal cell carcinoma.

David F. McDermott, et al.

Background: The combination of immunotherapy with antiangiogenic agents is a well-established first-line treatment option for patients (pts) with advanced renal cell carcinoma (RCC), but many pts develop resistance, and effective second- or subsequent-line options are needed. The von Hippel-Lindau (VHL) gene is inactivated in approximately 90% of RCC cases, which results in the constitutive activation of hypoxia-inducible factor 2α (HIF-2α) signaling. HIF-2α is involved in angiogenesis, tumor growth, proliferation, and metastasis, and is a key oncogenic driver in RCC. The HIF-2α inhibitor belzutifan has demonstrated promising antitumor activity with manageable safety in pts with heavily pretreated RCC. The cyclin-dependent kinase (CDK) pathway is altered in several cancer types, including RCC, and is associated with poor clinical outcomes. The CDK 4/6 inhibitor palbociclib inhibited cell growth in RCC cell lines, and the antiproliferative effects of CDK 4/6 inhibition were synergistic with HIF-2α inhibition in HIF-2α–dependent VHL -/- clear cell RCC cell lines. We hypothesized palbociclib could potentially enhance the efficacy of belzutifan as combination therapy for previously treated pts with advanced RCC. Methods: LITESPARK-024 (NCT05468697) is an open-label, multicenter, phase 1/2 randomized study of belzutifan + palbociclib versus belzutifan monotherapy in pts with advanced RCC. Pts must have histologically confirmed unresectable stage IV RCC with a clear cell component, received at least 2 prior systemic regimens (both an anti–PD-1/PD-L1 monoclonal antibody and a VEGF receptor–targeted TKI, in sequence or in combination), have measurable disease per RECIST v1.1 by BICR, have KPS score of ≥70%, and have radiographic disease progression on or after the most recent regimen per investigator. Part 1 will evaluate the safety of belzutifan + palbociclib and determine the recommended phase 2 dose (RP2D) for the combination using a modified toxicity probability interval design. Part 2 will evaluate the safety and efficacy of belzutifan + palbociclib versus belzutifan alone. In part 1, ≤30 pts will be enrolled into 3 dose groups and receive belzutifan 120 mg once daily + palbociclib (75, 100, or 125 mg) daily for 21 consecutive days followed by 7 days off. In part 2, approximately 150 pts will be randomly assigned 2:1 to receive belzutifan 120 mg once daily + palbociclib RP2D (21 consecutive days/7 days off) or belzutifan 120 mg once daily. Pts will be stratified by IMDC risk (0 vs 1-2 vs 3-6) and sarcomatoid histology (yes vs no) at randomization in part 2. The primary end point for part 1 is to assess dose-limiting toxicities and adverse events to determine the RP2D of belzutifan + palbociclib. The primary end point for part 2 is ORR per RECIST v1.1 by investigator assessment. Secondary end points for part 2 are clinical benefit rate, DOR, PFS, OS, and safety and tolerability. Clinical trial information: NCT05468697.

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ABSTRACT TPS748

- - Phase 3 LITESPARK-022: Pembrolizumab (pembro) plus hypoxia-inducible factor 2α (HIF-2α) inhibitor belzutifan as adjuvant treatment for clear cell renal cell carcinoma (ccRCC).

Toni K. Choueiri, et al.

Background: Treatment with the PD-1 inhibitor pembro produced significant improvement in disease-free survival after surgery for patients (pts) with ccRCC in the phase 3 KEYNOTE-564 trial. Based on these results, pembro was approved by the US Food and Drug Administration and the European Medicines Agency for adjuvant treatment of pts with RCC at increased risk of recurrence following nephrectomy or following nephrectomy and resection of metastatic lesions. Despite advances in the treatment landscape for RCC, more effective adjuvant treatment strategies are needed for pts at risk of recurrence after surgery. HIF-2α is an established oncogenic driver in ccRCC, and promising antitumor activity in advanced ccRCC and von Hippel-Lindau disease–associated RCC has been demonstrated with the HIF-2α inhibitor belzutifan. The multicenter, double-blind, randomized, phase 3 LITESPARK-022 study (NCT05239728) will evaluate the efficacy and safety of pembro plus belzutifan compared with placebo plus pembro as adjuvant treatment following nephrectomy in pts with ccRCC. Methods: Key eligibility criteria include adults with histologically or cytologically confirmed intermediate-high risk, high risk, or M1 with no evidence of disease (NED) RCC with a clear cell component; pts with no prior systemic therapy, nephrectomy, and/or metastasectomy ≤12 weeks before randomization; and pts who are tumor free per computed tomography/magnetic resonance imaging. Approximately 1600 pts will be randomly assigned to receive belzutifan 120 mg orally once daily plus pembro 400 mg intravenously (IV) every 6 weeks (Q6W) for ≤9 administrations (~54 weeks) or oral placebo plus pembro 400 mg IV Q6W for ≤9 administrations (~54 weeks) or until verified disease recurrence by blinded independent central review, start of new anticancer treatment, unacceptable toxicity, or decision to withdraw. Stratification factors are tumor grade (1 or 2 vs 3 or 4) and risk type (intermediate-high risk versus high risk versus M1 NED). Pts will be radiologically evaluated Q12W from randomization through year 2, Q16W in years 3 to 5, and Q24W in years 6 and beyond. Adverse events will be monitored throughout the study and for 30 days following cessation of study treatment (90 days for serious adverse events). The primary end point is disease-free survival. Secondary end points include overall survival, safety, disease recurrence–specific survival, and patient-reported outcomes. Recruitment is underway in Asia, Australia, Europe, North America, and South America. © 2022 American Society of Clinical Oncology, Inc. Reused with permission. This abstract was accepted and previously presented at the 2022 ASCO Annual Meeting. All rights reserved. Clinical trial information: NCT05239728.

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