zanzalintinib (XL092)

P2, N=29, Recruiting, Northwestern University | Not yet recruiting --> Recruiting

P1/2, N=25, Active, not recruiting, Exelixis | Recruiting --> Active, not recruiting | N=140 --> 25

P2, N=29, Not yet recruiting, Northwestern University

P2, N=32, Not yet recruiting, University of Utah

Presented is the design of STELLAR-303, a global, phase III, open-label, randomized study evaluating zanzalintinib plus atezolizumab versus regorafenib in patients with non-MSI-H mCRC who progressed during/after or are refractory/intolerant to standard-of-care therapy. The primary end point is overall survival in patients without liver metastases.Clinical Trial Registration: NCT05425940 (ClinicalTrials.gov).

P2/3, N=500, Recruiting, Exelixis | Initiation date: Nov 2023 --> Jun 2024

P3, N=874, Active, not recruiting, Exelixis | Recruiting --> Active, not recruiting

P1/2, N=675, Active, not recruiting, Hoffmann-La Roche | Trial primary completion date: Jun 2026 --> Sep 2025 | Recruiting --> Active, not recruiting | Trial completion date: Sep 2027 --> Nov 2026

P1, N=325, Active, not recruiting, Exelixis | Trial primary completion date: Nov 2023 --> Nov 2024

P1/2, N=675, Recruiting, Hoffmann-La Roche | N=470 --> 675 | Trial completion date: Nov 2026 --> Sep 2027 | Trial primary completion date: Aug 2025 --> Jun 2026

P3, N=874, Recruiting, Exelixis | N=600 --> 874

P1/2, N=140, Recruiting, Exelixis

P2/3, N=500, Recruiting, Exelixis | Not yet recruiting --> Recruiting | Trial completion date: Dec 2027 --> Mar 2028

Most recently, in the phase 3 LEAP-017 study of patients with non–MSI-high/mismatch repair deficient (dMMR) mCRC, although pembrolizumab + lenvatinib did not improve overall survival (OS) vs standard of care, subgroup analysis suggested the potential for clinical benefit in patients without LM (Kawazoe et al, ESMO-WCGI 2023)...Prior regorafenib, trifluridine/tipiracil, or PD-L1/PD-1 ICIs are not allowed...Enrollment is ongoing in the US, Europe, and Asia-Pacific region. Clinical trial information: NCT05425940.

Sunitinib is the only single-agent tyrosine kinase inhibitor (TKI) to have demonstrated a clinicalbenefit (vs everolimus) in a study population with a broad range of histologic subtypes of metastatic nccRCC (Armstrong et al. The secondary endpoint is OS; safety will also be assessed. Enrollment is ongoing, and patients will be recruited across sites inEurope, North and South America, and the Asia-Pacific region.

P1, N=325, Active, not recruiting, Exelixis | Recruiting --> Active, not recruiting | N=921 --> 325

P2/3, N=500, Not yet recruiting, Exelixis

P1/2, N=470, Recruiting, Hoffmann-La Roche | Trial completion date: Aug 2025 --> Nov 2026 | Trial primary completion date: Apr 2024 --> Aug 2025

Sunitinib is the only TKI to have shown a clinical benefit (vs everolimus) in a broad range of histologic subtypes of metastatic nccRCC (Armstrong et al. The secondary endpoint is OS; safety will also be assessed. STELLAR-304 is currently recruiting patients in 29 countries in Europe, North and South America, and the Asia-Pacific region.

No abstract available

Immune checkpoint inhibitor (ICI) therapy with nivolumab ± ipilimumab or single-agent pembrolizumab is approved in patients with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) mCRC, which constitutes a small subgroup (∼5%) of the overall patient population...Phase 1/2 studies evaluating cabozantinib (an inhibitor of MET, AXL, and VEGFR2) in combination with atezolizumab and durvalumab have demonstrated encouraging clinical activity (Abrams TA, et al...Patients must have progressed during/after or be intolerant to SOC therapies for mCRC; prior regorafenib, trifluridine-tipiracil, or anti–PD-L1/PD-1 ICIs are not allowed...The primary endpoint is duration of overall survival and secondary endpoints include progression-free survival, objective response rate, and duration of response (all per RECIST v1.1 by investigator), as well as safety and tolerability. Enrollment is ongoing in 16 countries, located in North America, Europe, and Asia-Pacific regions.Clinical trial identification: NCT05425940.Editorial acknowledgement: Editorial assistance was provided by Fishawack Communications Inc., part of Fishawack Health, and funded by Exelixis, Inc.Legal entity responsible for the study: Exelixis, Inc.

This activity is supported by educational grants from Bayer HealthCare Pharmaceuticals, Exelixis Inc, Lilly, Natera Inc, and Seagen Inc. Key data informing the rational incorporation of pembrolizumab, nivolumab and nivolumab/ipilimumab for microsatellite instability-high/mismatch repair-deficient mCRC Early results with and ongoing investigation of immune checkpoint inhibitors in combination with other systemic approaches (eg, chemotherapy, targeted therapy) for MSI-H/dMMR advanced CRC Biologic rationale for the investigation of immune checkpoint inhibition for microsatellite-stable (MSS) mCRC Clinical activity and safety observed with cabozantinib in combination with anti-PD-1/PD-L1 antibodies among patients with MSS mCRC in early-phase trials (eg, COSMIC-021 cohort 16, CAMILLA cohort 2) Pharmacologic and pharmacodynamic comparison of cabozantinib and XL092 Design, eligibility and efficacy and safety endpoints for the Phase III STELLAR-303 trial comparing XL092/atezolizumab to regorafenib for relapsed/refractory (R/R) MSS mCRC Available data with and ongoing investigation of other immune checkpoint inhibitor-based strategies (eg, lenvatinib/pembrolizumab, regorafenib/pembrolizumab) for MSS mCRC Available data with and ongoing investigation of other immune checkpoint inhibitor-based strategies (eg, lenvatinib/pembrolizumab, regorafenib/pembrolizumab) for patients with MSS mCRC

Additionally, XL092 promoted M2 to M1 repolarization of macrophages in vitro and inhibited primary human macrophage efferocytosis in a dose-dependent manner. In summary, XL092 was shown to have significant antitumor and immunomodulatory activity in animal models both alone and in combination with immune checkpoint inhibitors, supporting its evaluation in clinical trials.

P1, N=1195, Recruiting, Exelixis | N=800 --> 1195

P3, N=600, Recruiting, Exelixis

P1, N=826, Recruiting, Exelixis

P1 | "Patients will receive escalating doses of XL092 alone or in combination with ICIs (atezolizumab 1200mg Q3W or avelumab 800mg Q2W). The study is open for enrollment. Trial Registration NCT03845166"

P1, N=800, Recruiting, Exelixis | N=425 --> 800 | Trial completion date: May 2022 --> Nov 2024 | Trial primary completion date: May 2022 --> Nov 2023

P1, N=425, Recruiting, Exelixis | N=151 --> 425 | Trial completion date: Feb 2021 --> May 2022 | Trial primary completion date: Feb 2021 --> May 2022