Zanzalintinib (zanza) + nivolumab (nivo) ± relatlimab (rela) in patients (pts) with previously untreated clear cell renal cell carcinoma (ccRCC): Results from an expansion cohort of the phase 1b STELLAR-002 study.

4515 Background: VEGFR-targeted tyrosine kinase inhibitors (TKIs) in combination with immune checkpoint inhibitors (ICIs) are standard of care for previously untreated metastatic ccRCC. Zanza (XL092) is a novel, oral, multi-targeted TKI of VEGFR, MET, and TAM kinases (TYRO3, AXL, MER), with a short half-life that may have an improved therapeutic index. In the phase 1 STELLAR-001 study, the tolerability profile of single-agent zanza was manageable and antitumor activity was observed in patients with previously treated advanced ccRCC (Pal et al, IKCS NA 2023). STELLAR-002 (NCT05176483) is a phase 1b, open-label study evaluating the tolerability and activity of zanza alone and in combination with ICIs in pts with advanced solid tumors. Here, data from the expansion cohort of pts with previously untreated ccRCC receiving zanza + nivo ± rela are presented. Methods: Adult patients with unresectable advanced or metastatic (adv/met) ccRCC of any IMDC risk, and no prior systemic anticancer therapy for adv/met ccRCC were enrolled into one of two non-randomized arms. Patients received zanza 100 mg orally with either nivo 480 mg IV every 4 weeks (q4w) or nivo/rela 480/480 mg IV q4w (fixed-dose combination). Primary endpoints were investigator-assessed ORR per RECIST 1.1 and safety. Results: In the zanza + nivo arm (n = 40), 75% had intermediate or poor IMDC risk disease. After median follow-up of 16.1 months, the ORR was 63% (4 complete responses [CRs], 21 partial responses [PRs]), and disease control rate (DCR: CR+PR+SD) was 90%. The 6- and 12-month PFS rates were 83.2% and 64.2%, respectively. The most common any grade (G) treatment-emergent adverse events (TEAEs) were diarrhea (78%), hypertension (58%), and nausea (58%). The most common G3/4 AEs related to zanza were hypertension (30%) and diarrhea (15%). Treatment-related palmar-plantar erythrodysesthesia (PPE) was reported in 28% (8% G3, 0% G4). Two (5%) pts discontinued both study treatments due to treatment-related AEs (TRAEs). Median average daily zanza dose was 49.5 mg (range: 26-100). In the zanza + nivo/rela arm (n = 40), 70% had intermediate or poor IMDC risk disease. After a median follow-up of 11.9 months, the ORR was 33% (1 CR, 12 PRs) and DCR was 90%. The 6- and 12-month PFS rates were 80.2% and 58.8%, respectively. The most common any G TEAEs were diarrhea (60%) and nausea (50%). The most common G3/4 AE related to zanza was hypertension (13%). Treatment-related PPE occurred in 5% (0% G3/4). Seven (18%) pts discontinued all study treatment due to TRAEs. Median average daily zanza dose was 54.9 mg (range: 31-100). No G5 TRAEs occurred in either arm. Conclusions: First-line zanza had acceptable tolerability in combination with nivo or nivo/rela with a low rate of PPE; zanza+nivo showed promising preliminary activity in pts with adv/met ccRCC. Clinical trial information: NCT05176483 .