zanzalintinib (XL092) / Exelixis - LARVOL DELTA

EXACT: Trial of XL092 in Combination With Immunotherapy in Patients Who Progress on Adjuvant Therapy in Clear Cell RCC (clinicaltrials.gov) - P2 | N=70 | Recruiting | Sponsor: Karie Runcie | Initiation date: Jun 2025 ➔ Sep 2025

Trial initiation date • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor

Dose Finding Study of Zanzalintinib With Pembrolizumab and Cetuximab in Head and Neck SCC (clinicaltrials.gov) - P1 | N=36 | Not yet recruiting | Sponsor: University of Chicago | Initiation date: Jun 2025 ➔ Oct 2025

Trial initiation date • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

EXACT: A Randomized phase II trial of XL092 (Zanzalintinib) in combination with immunotherapy in patients who progress on Adjuvant therapy in Clear Cell RCC [NCT06863311] (KCRS 2025) - P2 | "The EXACT Trial seeks to determine if Zanzalitinib and Zanzalitinib plus Nivolumab are effective treatments in patients who progress on adjuvant pembrolizumab. Trial Schema This study is in collaboration with Exelixis Inc."

Clinical • Combination therapy • P2 data • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor

EXPLORE-RCC: a phase II study of neoadjuvant zanzalintinib (ZANZA) plus nivolumab (NIVO) in patients with locally advanced and/or inoperable clear cell renal cell carcinoma (ccRCC) (ESMO 2025) - No abstract available

Clinical • Metastases • P2 data • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor

STELLAR-304: Study of XL092 + Nivolumab vs Sunitinib in Subjects With Advanced or Metastatic Non-Clear Cell Renal Cell Carcinoma (clinicaltrials.gov) - P3 | N=317 | Active, not recruiting | Sponsor: Exelixis | Recruiting ➔ Active, not recruiting

Enrollment closed • Genito-urinary Cancer • Non Clear Cell Renal Cell Carcinoma • Oncology • Renal Cell Carcinoma • Solid Tumor

Exelixis leans on zanzalintinib as cabozantinib nears patent exp (S&P Global) - "Pending regulatory approval, Zanzalintinib is projected to generate $14 million in risk-adjusted sales from colorectal cancer in 2025, according to Visible Alpha consensus, with analysts assigning a 61% probability of approval in this indication. Broader commercial potential lies ahead, with peak global risk-adjusted sales estimated at $518 million by 2035....If successful across indications, zanzalintinib could reach blockbuster status with risk-adjusted global sales of $1 billion by 2031 and peak sales of $1.6 billion by 2035. Exelixis is hoping the drug will succeed cabozantinib -its current blockbuster sold under the brand names Cabometyx and Cometriq -which generated $1.8 billion in 2024. Sales are projected to rise to $2.2 billion in 2025 and peak at $2.8 billion by 2029, before generic competition begins to erode revenues following patent expiry in 2026."

Patent expiry • Sales projection • Colorectal Cancer • Hepatocellular Cancer • Renal Cell Carcinoma • Thyroid Gland Carcinoma

XL092 (Zanzalintinib) for the Treatment of Patients With Metastatic or Unresectable Leiomyosarcoma (clinicaltrials.gov) - P2 | N=29 | Recruiting | Sponsor: Northwestern University | Trial completion date: Jul 2026 ➔ Jul 2029 | Trial primary completion date: Jul 2025 ➔ Jul 2028

Trial completion date • Trial primary completion date • Leiomyosarcoma • Oncology • Sarcoma • Solid Tumor

Zanzalintinib Pivotal Development Program Updates (Businesswire) - "Today, Exelixis announced several updates to the zanzalintinib development program, including: (i) STELLAR-304 study enrollment completed in May 2025....Top-line results are expected in the first half of 2026, depending on study event rates; (ii) Based on the company’s evaluation of emerging data from the phase 2 portion of the STELLAR-305 trial in advanced squamous cell carcinoma of the head and neck (SCCHN), emerging competition in this indication, and assessment of other, potentially larger, commercial opportunities, Exelixis has decided not to proceed to phase 3; (iii) Initiation of the STELLAR-311 phase 3 pivotal trial in advanced NET. STELLAR-311 is evaluating zanzalintinib versus everolimus as a first oral therapy in patients with advanced NET, regardless of site of origin; (iv) Plans to announce the next wave of zanzalintinib pivotal trials in the coming months."

New trial • P3 data: top line • Trial status • Neuroendocrine Tumor • Renal Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

Zanzalintinib Maintenance in Patients With High Grade Neuroendocrine Neoplasms (HG-NENs) (clinicaltrials.gov) - P2 | N=32 | Not yet recruiting | Sponsor: Washington University School of Medicine | Trial completion date: Jul 2032 ➔ Aug 2034 | Trial primary completion date: Jul 2032 ➔ Aug 2034

Trial completion date • Trial primary completion date • Endocrine Cancer • Neuroendocrine Carcinoma • Neuroendocrine Tumor • Oncology • Solid Tumor

Zanzalintinib for Metastatic Clear Cell Renal Cell Carcinoma With Bone Metastases (clinicaltrials.gov) - P2 | N=20 | Not yet recruiting | Sponsor: Kelly Fitzgerald, MD

Checkpoint inhibition • New P2 trial • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Kidney Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor

Substudy 03C: A Study of Combination Therapies in Participants With Renal Cell Carcinoma With Recurrent Disease During or After Anti-PD-(L)1 Therapy (MK-3475-03C/KEYMAKER-U03) (clinicaltrials.gov) - P1/2 | N=100 | Not yet recruiting | Sponsor: Merck Sharp & Dohme LLC

New P1/2 trial • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor

Zanzalintinib in Second Line and Beyond for the Treatment of Advanced Liver Cancer (clinicaltrials.gov) - P1/2 | N=53 | Not yet recruiting | Sponsor: Northwestern University

New P1/2 trial • Hepatocellular Cancer • Immunology • Liver Cancer • Oncology • Solid Tumor

Pharmacokinetics (PK) and Safety of Zanzalintinib in Participants With Moderate Hepatic Impairment (HI) (clinicaltrials.gov) - P1 | N=20 | Recruiting | Sponsor: Exelixis | Not yet recruiting ➔ Recruiting

Enrollment open • Hepatology

Exelixis Announces Zanzalintinib in Combination with an Immune Checkpoint Inhibitor Improved Overall Survival in STELLAR-303 Phase 3 Pivotal Trial in Patients with Metastatic Colorectal Cancer (Businesswire) - P3 | N=874 | STELLAR-303 (NCT05425940) | Sponsor: Exelixis | "Exelixis...announced positive topline results from the STELLAR-303 phase 3 pivotal trial in which zanzalintinib in combination with atezolizumab (Tecentriq) demonstrated a statistically significant improvement in overall survival (OS) versus regorafenib in the intent-to-treat (ITT) population of patients with previously treated non-microsatellite instability (MSI)-high metastatic colorectal cancer (CRC). These topline findings are from the final analysis conducted by the Independent Data Monitoring Committee of one of the dual primary endpoints of the STELLAR-303 phase 3 trial. The trial will proceed to the planned final analysis for the other dual primary endpoint of OS in patients without liver metastases....No new safety signals were identified....Exelixis plans to submit detailed results of STELLAR-303 for presentation at an upcoming medical conference."

P3 data: top line • Colorectal Cancer

Study of Zanzalintinib (XL092) + AB521 and Zanzalintinib + AB521 + Nivolumab in Participants With Advanced Clear Cell Renal Cell Carcinoma (ccRCC) or Other Advanced Solid Tumors (STELLAR-009) (clinicaltrials.gov) - P1 | N=25 | Terminated | Sponsor: Exelixis | Phase classification: P1/2 ➔ P1 | Trial completion date: Jan 2027 ➔ May 2025 | Active, not recruiting ➔ Terminated | Trial primary completion date: Jan 2026 ➔ May 2025; The study was terminated prior to starting the Phase 2 portion due to a business decision.

Phase classification • Trial completion date • Trial primary completion date • Trial termination • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor

STELLAR-311: Zanzalintinib Versus Everolimus in Participants With Locally Advanced or Metastatic Neuroendocrine Tumors (clinicaltrials.gov) - P2/3 | N=440 | Recruiting | Sponsor: Exelixis | Not yet recruiting ➔ Recruiting

Enrollment open • Endocrine Cancer • Neuroendocrine Tumor • Solid Tumor

Maintenance Zanzalintinib With Etoposide After HDCT in GCT (clinicaltrials.gov) - P1/2 | N=38 | Not yet recruiting | Sponsor: Indiana University | Initiation date: Apr 2025 ➔ Jul 2025

Trial initiation date • Germ Cell Tumors

XL092 for the Treatment of Locally Advanced or Metastatic Radioiodine Refractory Differentiated Thyroid Cancer (clinicaltrials.gov) - P2 | N=33 | Recruiting | Sponsor: Northwestern University | Not yet recruiting ➔ Recruiting | Initiation date: Sep 2026 ➔ Jun 2025

Enrollment open • Trial initiation date • Endocrine Cancer • Oncology • Solid Tumor • Thyroid Gland Carcinoma • Thyroid Gland Follicular Carcinoma • Thyroid Gland Hurthle Cell Carcinoma • Thyroid Gland Papillary Carcinoma

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. (ASCO 2025) - P1 | "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 • Metastases • P1 data • Colorectal Cancer • Dermatology • Fatigue • Genito-urinary Cancer • Hypertension • Oncology • Prostate Cancer • Renal Cell Carcinoma • Solid Tumor

Phase II trial of zanzalintinib (XL-092) in combination with durvalumab and tremelimumab in unresectable hepatocellular carcinoma (ZENOBIA). (ASCO 2025) - P2 | "A Phase II study (CHECKMATE 040) reported an impressive objective response rate (ORR) of 29% with the combination of ipilimumab/nivolumab and Cabo but noted high toxicity rates...Comprehensive translational analyses include bulk RNA sequencing, spatial transcriptomics of baseline tumor biopsies, & serial ctDNA monitoring. Trial enrollment commenced in December 2024."

Combination therapy • P2 data • Gastroenterology • Gastrointestinal Disorder • Hepatocellular Cancer • Immunology • Oncology • Solid Tumor • AXL

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. (ASCO 2025) - P1 | "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 • P1 data • Clear Cell Renal Cell Carcinoma • Dermatology • Genito-urinary Cancer • Hypertension • Oncology • Solid Tumor • AXL

NEO-COMBATXL: XL092 and Cemiplimab in BRAF WT Thyroid Cancer (clinicaltrials.gov) - P1 | N=12 | Recruiting | Sponsor: UNC Lineberger Comprehensive Cancer Center | Not yet recruiting ➔ Recruiting

Enrollment open • Endocrine Cancer • Oncology • Solid Tumor • Thyroid Gland Anaplastic Carcinoma • Thyroid Gland Carcinoma • BRAF

Zanzalintinib plus nivolumab shows promising clinical activity in ccRCC (Urology Times) - P1b | N=1,274 | STELLAR-002 (NCT05176483) | Sponsor: Exelixis | "First-line zanzalintinib in combination with nivolumab demonstrated encouraging preliminary activity with acceptable tolerability in patients with advanced or metastatic clear cell renal cell carcinoma (ccRCC), according to data from the phase 1b STELLAR-002 trial (NCT05176483) presented at the...ASCO Annual Meeting....Overall, data showed an ORR of 63% (95% CI, 46 to 77) in the zanzalintinib plus nivolumab arm vs 40% (95% CI, 25 to 57) in the zanzalintinib plus nivolumab/relatlimab arm. In the doublet arm, the ORR included 8 patients who achieved a confirmed complete response (CR) and 22 patients who achieved a confirmed PR. In the triplet arm, the ORR included 1 patient who achieved a confirmed CR and 15 patients who achieved a confirmed PR. The disease control rate was 90% (95% CI, 76 to 97) in each arm. At the time of data report, the median duration or response had not been reached in either arm."

P1 data • Clear Cell Renal Cell Carcinoma

Moffitt to Present Plenary and Late-Breaking Data on Blood, Melanoma and Brain Metastases at ASCO 2025 (Newswise) - "Moffitt will be prominently featured at this year’s ASCO Annual Meeting, including a plenary presentation on polycythemia vera. Additional highlights include several oral presentations on melanoma, renal cell carcinoma and head and neck squamous cell carcinoma. Moffitt researchers will also present multiple posters covering a wide range of cancer types, including lung, breast, cervical and biliary tract cancers."

Clinical data • Biliary Tract Cancer • Breast Cancer • Cervical Cancer • Cholangiocarcinoma • Clear Cell Renal Cell Carcinoma • Lung Cancer • Melanoma • Merkel Cell Carcinoma • Polycythemia Vera • Squamous Cell Carcinoma of Head and Neck

Zanzalintinib for the Treatment of Advanced Thyroid Cancer Before Surgery (clinicaltrials.gov) - P2 | N=45 | Not yet recruiting | Sponsor: M.D. Anderson Cancer Center | Trial completion date: Jan 2030 ➔ Oct 2029 | Initiation date: Oct 2025 ➔ Jul 2025

Trial completion date • Trial initiation date • Endocrine Cancer • Oncology • Solid Tumor • Thyroid Gland Carcinoma