Exelixis Announces Encouraging Results from Phase 1b/2 STELLAR-001 Trial Evaluating Zanzalintinib Alone or in Combination with an Immune Checkpoint Inhibitor in Metastatic Colorectal Cancer at ASCO GI 2025

Rhea-AI Summary

Exelixis (NASDAQ: EXEL) has released results from the phase 1b/2 STELLAR-001 trial evaluating zanzalintinib alone or combined with atezolizumab in previously-treated metastatic colorectal cancer patients. The study included 107 patients randomized 1:1, with median prior therapy lines of 3.0 and 2.5 respectively.

Key findings show improved progression-free survival (PFS) and overall survival (OS) when combining the treatments, particularly in patients without liver metastases. In this subgroup, median PFS increased from 3.3 to 8.2 months, and the 6-month survival rate reached 87.8% for the combination versus 64.7% for zanzalintinib alone.

Regarding safety, Grade 3/4 treatment-related adverse events occurred in 40% of patients on zanzalintinib alone and 48% on the combination therapy. Common side effects included nausea, diarrhea, fatigue, and hypertension. The company expects data from the related STELLAR-303 trial in the second half of 2025.

Positive

• Improved PFS from 3.3 to 8.2 months in patients without liver metastases
• Higher 6-month survival rate (87.8% vs 64.7%) in patients without liver metastases
• Increased overall response rate (18.0% vs 5.9%) in patients without liver metastases
• PD-L1 positive patients showed improved PFS and OS with combination therapy

Negative

• High rate of Grade 3/4 adverse events (40-48%)
• Higher treatment discontinuation rate in combination therapy (30% vs 19%)
• overall response rate in total population (7.4% for combination, 1.9% for monotherapy)
• One Grade 5 treatment-related adverse event in each group

Insights

Clinical Trial Analyst

The STELLAR-001 trial results reveal several critical insights for Exelixis's oncology program. The combination of zanzalintinib with atezolizumab demonstrated particularly compelling results in patients without liver metastases, showing a 148% improvement in median PFS (8.2 vs 3.3 months) and a significantly better objective response rate of 18% versus 5.9%.

The biomarker analysis showing improved outcomes in PD-L1 positive patients is especially significant, as it suggests a potential predictive marker for patient selection. This could lead to more targeted therapeutic approaches and better resource utilization in clinical practice.

The safety profile presents an acceptable risk-benefit ratio, though the higher discontinuation rate in the combination arm (19% vs 8%) warrants attention. The types of adverse events observed are consistent with the known profiles of both drugs, with no unexpected safety signals.

Looking ahead, the completed enrollment of STELLAR-303 comparing this combination against regorafenib is particularly noteworthy. Regorafenib is currently a standard third-line treatment for metastatic CRC and positive results from STELLAR-303 could potentially establish a new treatment paradigm. The anticipated data release in H2 2025 could be a significant catalyst for Exelixis's oncology portfolio.

– In a subgroup analysis of patients without liver metastases, adding atezolizumab to zanzalintinib led to enhanced progression-free survival and overall survival –

ALAMEDA, Calif.--(BUSINESS WIRE)-- Exelixis, Inc. (Nasdaq: EXEL) today announced results from an expansion cohort of the phase 1b/2 STELLAR-001 trial evaluating zanzalintinib alone or in combination with atezolizumab (Tecentriq^®) in patients with previously-treated metastatic colorectal cancer (CRC). The findings will be presented during Poster Session C: Cancers of the Colon, Rectum and Anus, at 7:00 a.m. PT on January 25 at the American Society of Clinical Oncology 2025 Gastrointestinal Cancers Symposium (ASCO GI 2025).

This cohort of the STELLAR-001 trial included 107 patients randomized 1:1 to receive single-agent zanzalintinib or zanzalintinib in combination with atezolizumab. Patients had unresectable, locally advanced or metastatic RAS wild-type CRC that was non-microsatellite instability-high or non-mismatch repair-deficient. The median number of prior lines of therapy was 3.0 for patients treated with zanzalintinib alone and 2.5 for patients treated with zanzalintinib in combination with atezolizumab. Thirty-two percent and 31% of patients did not have liver metastases in baseline scans, respectively.

Both progression-free survival (PFS) and overall survival (OS) were numerically improved by the addition of atezolizumab to zanzalintinib. Detailed efficacy results of the overall population and the subgroup analysis of patients without liver metastases are in Table 1 below.

TABLE 1	Zanzalintinib alone	Zanzalintinib + atezolizumab
Overall population
Patients, n	53	54
Median follow-up, months	19.2	18.9
Median PFS, months	3.0	4.0
PFS HR (95% CI)	0.65 (0.42-0.99)
Median OS, months	11.1	11.7
OS HR (95% CI)	0.89 (0.56-1.42)
ORR, %	1.9	7.4
Partial response, n	1	4
Patients without liver metastases
Patients, n	17	17
Median PFS, months	3.3	8.2
PFS HR (95% CI)	0.37 (0.15-0.91)
Median OS, months	21.1	18.5
OS HR (95% CI)	0.74 (0.27-2.04)
6-month survival rate, %	64.7	87.8
12-month survival rate, %	52.3	62.7
ORR, %	5.9	18.0
Partial response, n	1	3
CI: confidence interval; HR: hazard ratio; ORR: objective response rate; OS: overall survival; PFS: progression-free survival.

In a biomarker analysis, a PD-L1 combined positive score greater than 1 was associated with improved PFS and OS in patients treated with zanzalintinib in combination with atezolizumab versus zanzalintinib alone.

“This cohort of the STELLAR-001 trial was designed to inform the contribution of atezolizumab to zanzalintinib in patients with previously treated metastatic colorectal cancer,” said Amy Peterson, M.D., Executive Vice President, Product Development & Medical Affairs, and Chief Medical Officer, Exelixis. “Data from this randomized expansion cohort reaffirms our decision to initiate STELLAR-303 evaluating zanzalintinib in combination with atezolizumab compared with regorafenib in patients with metastatic colorectal cancer, which completed enrollment in August 2024, and we anticipate data from that trial in the second half of 2025, dependent on study event rates.”

Detailed safety results for the overall population are in Table 2 below. Grade 3/4 treatment-related adverse events (AEs) occurred in 40% of patients receiving zanzalintinib alone and 48% of patients receiving zanzalintinib in combination with atezolizumab. One grade 5 treatment-related AE occurred in each group, both of which were also determined by investigator as related to the disease under study. Zanzalintinib was discontinued in 19% of patients receiving zanzalintinib alone and 30% of patients receiving zanzalintinib in combination with atezolizumab. Treatment-related AEs leading to discontinuation of any drug occurred in 8% and 19% of patients, respectively.

TABLE 2	Zanzalintinib alone		Zanzalintinib + atezolizumab
	Any Grade	Grade 3/4	Any Grade	Grade 3/4
Most Common TRAE, %
Nausea	36	6	54	0
Diarrhea	49	8	52	9
Fatigue	21	4	43	11
Hypertension	30	13	19	7
Other TRAE, %
Proteinuria	17	0	13	0
Palmar-plantar erythrodysesthesia	11	0	6	0
Stomatitis	2	2	6	0
TRAE: treatment-related adverse event

About STELLAR-001
STELLAR-001 (NCT03845166) is a global, open-label phase 1b/2 study of zanzalintinib as a single agent or in combination with atezolizumab in patients with inoperable locally advanced or metastatic solid tumors. The trial is divided into two parts: a dose-escalation stage and an expansion cohort stage. The expansion cohorts evaluating zanzalintinib (100 mg) as a single agent or in combination with atezolizumab also include patients with clear cell renal cell carcinoma (RCC), non-clear cell RCC, breast cancer that is hormone receptor-positive and HER-2 negative and castration-resistant prostate cancer. More information about the trial is available at ClinicalTrials.gov.

About STELLAR-303
The global phase 3 pivotal study, STELLAR-303, is evaluating zanzalintinib (100 mg) in combination with atezolizumab compared with regorafenib in patients with metastatic, refractory non-microsatellite instability-high or non-mismatch repair-deficient CRC. The primary endpoint in the study is OS in patients without active liver metastases. If OS is positive in the population of patients without liver metastases, the study will evaluate OS in the intent-to-treat population that includes patients with and without liver metastases. The study completed enrollment in the third quarter of 2024, and preliminary results are expected in the second half of 2025, dependent on study event rates. More information about the trial is available at ClinicalTrials.gov.

About Zanzalintinib
Zanzalintinib is a third-generation oral tyrosine kinase inhibitor that inhibits the activity of receptor tyrosine kinases implicated in cancer growth and spread, including VEGF receptors, MET, AXL and MER. These receptor tyrosine kinases are involved in both normal cellular function and in pathologic processes such as oncogenesis, metastasis, tumor angiogenesis and resistance to multiple therapies, including immune checkpoint inhibitors. With zanzalintinib, Exelixis sought to build upon its extensive experience with the target profile of cabozantinib, the company’s flagship medicine, while improving key characteristics, including pharmacokinetic half-life. Zanzalintinib is currently being developed for the treatment of advanced solid tumors, including genitourinary, colorectal and head and neck cancers. A phase 3 pivotal trial evaluating zanzalintinib compared with everolimus as a first oral therapy in patients with advanced neuroendocrine tumors (NET), regardless of site of origin, is expected to be initiated in the first half of 2025.

About CRC
Colorectal cancer is the third most common cancer and the second leading cause of cancer-related deaths in the U.S.¹ Approximately 154,000 new cases will be diagnosed in the U.S. with around 53,000 expected deaths from the disease in 2025.¹ Colorectal cancer is most frequently diagnosed among people aged 65-74 and is more common in men and in people of non-Hispanic American Indian/Alaska Native descent.² Nearly a quarter of colorectal cancer cases are diagnosed at the metastatic stage, at which point the five-year survival rate is just 15.7%.²

About Exelixis
Exelixis is a globally ambitious oncology company innovating next-generation medicines and regimens at the forefront of cancer care. Powered by drug discovery and development excellence, we are rapidly evolving our product portfolio to target an expanding range of tumor types and indications with our clinically differentiated pipeline of small molecules, antibody-drug conjugates and other biotherapeutics. This comprehensive approach harnesses decades of robust investment in our science and partnerships to advance our investigational programs and extend the impact of our flagship commercial product, CABOMETYX^® (cabozantinib). Exelixis is driven by a bold scientific pursuit to create transformational treatments that give more patients hope for the future. For information about the company and its mission to help cancer patients recover stronger and live longer, visit www.exelixis.com, follow @ExelixisInc on X (Twitter), like Exelixis, Inc. on Facebook and follow Exelixis on LinkedIn.

Forward-Looking Statements
This press release contains forward-looking statements, including, without limitation, statements related to: the presentation of data from STELLAR-001 at ASCO GI 2025; the expectation for initial clinical data readouts from STELLAR-303 in the second half of 2025, dependent on study event rates; the therapeutic potential of zanzalintinib, both alone and in combination with atezolizumab, in patients with metastatic CRC; and Exelixis’ scientific pursuit to create transformational treatments that give more patients hope for the future. Any statements that refer to expectations, projections or other characterizations of future events or circumstances are forward-looking statements and are based upon Exelixis’ current plans, assumptions, beliefs, expectations, estimates and projections. Forward-looking statements involve risks and uncertainties. Actual results and the timing of events could differ materially from those anticipated in the forward-looking statements as a result of these risks and uncertainties, which include, without limitation: the availability of data at the referenced times; complexities and the unpredictability of the regulatory review and approval processes in the U.S. and elsewhere; Exelixis’ continuing compliance with applicable legal and regulatory requirements; the potential failure of zanzalintinib, both alone and in combination with atezolizumab to demonstrate safety and/or efficacy in STELLAR-001, STELLAR-303 and in future clinical testing; unexpected concerns that may arise as a result of the occurrence of adverse safety events or additional data analyses of clinical trials evaluating zanzalintinib; the costs of conducting clinical trials; Exelixis’ dependence on third-party vendors for the development, manufacture and supply of zanzalintinib; Exelixis’ ability to protect its intellectual property rights; market competition; changes in economic and business conditions; and other factors affecting Exelixis and its development programs detailed from time to time under the caption “Risk Factors” in Exelixis’ most recent Annual Report on Form 10-K and subsequent Quarterly Reports on Form 10-Q, and in Exelixis’ future filings with the Securities and Exchange Commission. All forward-looking statements in this press release are based on information available to Exelixis as of the date of this press release, and Exelixis undertakes no obligation to update or revise any forward-looking statements contained herein, except as required by law.

Exelixis, the Exelixis logo and CABOMETYX are registered U.S. trademarks of Exelixis.

TECENTRIQ (atezolizumab) is a registered trademark of Genentech, a member of the Roche Group.

^{_________________
1} Key Statistics for Colorectal Cancer. ACS. Available at: https://www.cancer.org/cancer/types/colon-rectal-cancer/about/key-statistics.html. Accessed January 2025.
² Cancer Stat Facts: Colorectal Cancer. SEER. Available at: https://seer.cancer.gov/statfacts/html/colorect.html. Accessed January 2025.

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Investors Contact:

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Investor Relations

Exelixis, Inc.

650-837-8194

shubbard@exelixis.com

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Exelixis, Inc.

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Source: Exelixis, Inc.

FAQ

What were the key results of Exelixis's STELLAR-001 trial for colorectal cancer?

The trial showed improved progression-free survival and overall survival when combining zanzalintinib with atezolizumab, particularly in patients without liver metastases, where PFS increased from 3.3 to 8.2 months.

How many patients participated in the EXEL STELLAR-001 trial?

The trial included 107 patients who were randomized 1:1 to receive either single-agent zanzalintinib or zanzalintinib in combination with atezolizumab.

What are the main side effects reported in the STELLAR-001 trial for EXEL?

The most common treatment-related adverse events included nausea (36-54%), diarrhea (49-52%), fatigue (21-43%), and hypertension (19-30%).

When will Exelixis (EXEL) release results from the STELLAR-303 trial?

Exelixis expects to release data from the STELLAR-303 trial in the second half of 2025, depending on study event rates.

What was the treatment discontinuation rate in the EXEL STELLAR-001 trial?

The discontinuation rate was 19% for patients receiving zanzalintinib alone and 30% for patients receiving the combination therapy.