Zanzalintinib (zanza) + nivolumab (nivo) ± relatlimab (rela) in patients (pts) with advanced solid tumors: Results from two dose-escalation cohorts of the phase 1b STELLAR 002 study.

3101 Background: Zanza (XL092) is a novel, multi-targeted tyrosine kinase inhibitor (TKI) that inhibits VEGFR, MET, and TAM kinases. In tumor models, zanza showed antitumor activity alone and in combination with an anti-PD-1 immune checkpoint inhibitor (ICI). The addition of a VEGFR-TKI to ICI combinations of anti-PD-1 + anti-LAG-3 may enhance clinical activity. STELLAR-002 (NCT05176483) is a phase 1b, open-label, dose escalation and expansion study evaluating the safety and efficacy of zanza as monotherapy and in combination with ICIs in pts with advanced solid tumors. Data from dose escalation cohorts treated with zanza + nivo and zanza + nivo/rela are presented. Methods: Adults with advanced/metastatic solid tumors were enrolled. Starting doses were zanza 100 mg po qd + nivo 360 mg IV q3w (zanza + nivo cohort), and zanza 60 mg po qd + nivo/rela 480/480 mg IV q4w (zanza + nivo/rela cohort). Pts were enrolled in a rolling six design. Sparse pharmacokinetic (PK) samples were collected. The primary endpoint was safety. Exploratory endpoints included investigator-assessed ORR per RECIST 1.1 and PK. Results: Among 19 pts in the zanza 100 mg + nivo cohort, the most common tumor types were prostate cancer (26%) and colorectal cancer (26%). Median number of prior therapies was 6 (range: 2–16). No dose-limiting toxicities (DLTs) were observed in the first 11 DLT-evaluable pts; zanza 100 mg is the recommended dose (RD). The most common treatment-emergent adverse events (TEAEs) were fatigue (68%) and diarrhea (58%). The most common grade (G) 3/4 TEAEs were fatigue (26%) and hypertension (16%). Palmar-plantar erythrodysesthesia (PPE) occurred in 11% of pts (all G1/2). No responses were observed; the disease control rate (DCR: CR+PR+SD) was 42%. In the zanza + nivo/rela cohort, 24 pts received zanza 60 mg + nivo/rela and 25 pts received zanza 100 mg + nivo/rela. One DLT was observed in the first 6 DLT-evaluable pts at zanza 60 mg (G3 ALT increase) and none in the first 5 DLT-evaluable pts at zanza 100 mg. Zanza 100 mg is the RD with nivo/rela. In zanza 100 mg-treated pts, the most common tumor type was renal cell carcinoma (RCC; 56%). Median number of prior therapies was 4 (range: 0–15). The most common TEAEs were diarrhea (68%) and fatigue (56%). The most common G3/4 TEAE was fatigue (20%). PPE occurred in 28% (4% G3/4). ORR was 28% and DCR was 80%; these rates were 36% and 86% in pts with RCC (n = 14). Plasma zanza concentrations 2 hrs after the first dose (C max , mean ± SD) were 595 ± 353 and 838 ± 689 ng/mL for the 60-mg and 100-mg dose levels, respectively. Conclusions: The tolerability of zanza + nivo and zanza + nivo/rela was manageable and consistent with each monotherapy agent. Preliminary safety, PK, and response data support selection of the 100-mg zanza dose in combination with nivo or nivo/rela for further investigation. Expansion cohorts are ongoing in various tumor types. Clinical trial information: NCT05176483 .