A groundbreaking clinical study conducted by researchers at UCLA has illuminated a new path forward for patients suffering from metastatic colorectal cancer, a disease notorious for being the second leading cause of cancer mortality in the United States. This study introduces an innovative treatment regimen combining zanzalintinib, a novel targeted therapy agent, with atezolizumab, an immune checkpoint inhibitor. Remarkably, this combination demonstrated a significant survival advantage compared to the currently standard treatment involving regorafenib, which has been a cornerstone in late-stage colorectal cancer management. This pivotal research represents a watershed moment in oncology, signaling the first time an immunotherapy-containing protocol has conferred a clear survival benefit across the majority of metastatic colorectal cancer patients regardless of their tumor’s genetic profile.
Metastatic colorectal cancer remains a formidable challenge in oncology, with dismal survival statistics; typically, only about 15% of these patients survive beyond five years after diagnosis. The therapeutic landscape has been stagnant for years, particularly for patients who develop resistance to standard chemotherapies and targeted therapies. The new combination therapy spearheaded by Dr. J. Randolph Hecht and his UCLA team tackles this clinical impasse by deploying an approach that aims to modify the tumor microenvironment, rendering it susceptible to immune-mediated destruction. The key lies in zanzalintinib’s multi-kinase inhibitory effects, which offset tumor-induced immunosuppression and foster conditions favorable for the immune system’s T cells to recognize and eradicate malignant cells more effectively when combined with an immune checkpoint blockade.
Historically, immune checkpoint inhibitors like atezolizumab have revolutionized cancer treatment in subsets of malignancies by reinvigorating exhausted cytotoxic T lymphocytes. However, their efficacy in metastatic colorectal cancer has been largely confined to a minority of patients harboring microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR) tumors—genomic anomalies that predispose tumors to heightened immunogenicity. Unfortunately, these patients account for only about 5% of the metastatic colorectal cancer population. The remaining 95%, characterized by microsatellite stable (MSS) tumors, experience marginal benefit from immunotherapy due to inherently immunosuppressive tumor niches that thwart immune effector mechanisms. The UCLA-led study challenges this paradigm by demonstrating how modulating tumor-associated signaling pathways with zanzalintinib can overcome these barriers.
The molecular underpinnings of zanzalintinib’s efficacy lie in its targeted inhibition of vascular endothelial growth factor receptor (VEGFR), hepatocyte growth factor receptor (MET), and TAM family receptor tyrosine kinases. Each of these proteins orchestrates critical processes that sustain tumor proliferation, angiogenesis, and immune evasion. VEGFR blockade inhibits abnormal new blood vessel formation that tumors exploit for oxygen and nutrients, while MET signaling suppression impairs tumor cell motility and invasiveness. Crucially, TAM kinases—comprising TYRO3, AXL, and MERTK—have been implicated in mediating immunosuppressive signaling and the recruitment of tumor-associated macrophages that dampen anti-tumor immunity. By concurrently targeting these kinases, zanzalintinib remodels the tumor ecosystem into one more permissive for immune engagement.
Acknowledging this mechanistic rationale, the STELLAR-303 trial, a large-scale international Phase 3 study, was designed to validate clinical benefit. Encompassing an impressive cohort of 901 patients treated across 121 clinical sites spanning 16 countries, the trial randomized subjects with previously treated metastatic colorectal cancer to receive either the zanzalintinib plus atezolizumab combination or the standard monotherapy with regorafenib. The diversity and global scale of this trial confer robust external validity to the findings, enhancing their applicability across contemporary oncology practice.
After a median follow-up duration of approximately 18 months, the study outcomes revealed a compelling survival benefit with the combination therapy. Patients in the experimental arm exhibited a median overall survival of 10.9 months compared to 9.4 months in the control group. This 1.5-month increment translates into a notable 20% relative reduction in mortality risk, an achievement particularly meaningful in a population with limited therapeutic options and poor prognosis. Furthermore, long-term survival analyses showed an impressive doubling in two-year survival rates, from 10% in the regorafenib group to 20% in those receiving the combination, indicating sustained benefit beyond the initial treatment period.
Importantly, this survival advantage was consistent across several clinically relevant subgroups, notably including patients with hepatic metastases—a cohort historically resistant to immunotherapeutic interventions. This consistency underscores the hypothesis that zanzalintinib’s tumor microenvironment reprogramming capabilities effectively sensitize otherwise refractory tumors to immune checkpoint blockade. Alongside survival, the combination regimen also delivered superior disease control metrics, with median progression-free survival extended to 3.7 months versus 2.0 months under regorafenib and a doubled objective response rate (4% vs. 1%), confirming enhanced anti-tumor activity.
Safety and tolerability profiles are critical considerations in advancing new oncology therapeutics. The study reported that adverse events were predictable and manageable, largely mirroring known toxicities associated with VEGFR inhibitors and immune checkpoint blockade. Fatigue, hypertension, and diarrhea emerged as the most frequent side effects but did not significantly impede treatment continuation or diminish patients’ quality of life. This favorable safety cohort reinforces the combination’s viability as a new standard for patients with otherwise refractory disease.
These trial results hold profound implications for the future management of metastatic colorectal cancer, indicating that rationally designed combination immunotherapy can surmount longstanding biological hurdles in MSS colorectal tumors. By integrating zanzalintinib’s multi-faceted kinase inhibition with atezolizumab’s immune checkpoint blockade, the study pioneers an approach that recalibrates tumor immunity to engender tangible survival gains. This progress resonates especially with clinicians and patients striving to extend therapeutic options beyond the limited scope of current standard regimens.
In summary, the UCLA-led STELLAR-303 trial substantiates that the concurrent administration of zanzalintinib and atezolizumab not only enhances overall survival and delays disease progression but also redefines treatment paradigms for metastatic colorectal cancer in the post-standard therapy setting. This investigation demarcates a critical advancement, demonstrating for the first time that immunotherapy’s promise can be realized in the majority of metastatic colorectal cancer patients through innovative combination strategies targeting tumor-induced immune suppression. As such, it offers a renewed beacon of hope to a patient population in dire need of improved outcomes.
Research funded by Exelixis, the producer of zanzalintinib, in collaboration with Roche, which supplied atezolizumab, this study’s findings were concurrently published in the esteemed journal The Lancet and unveiled at the European Society for Medical Oncology (ESMO) Congress 2025. The clinical and mechanistic insights gained from this work are expected to stimulate further research efforts exploring multi-targeted combination therapies in colorectal and other malignancies. The oncology community eagerly anticipates integrating these findings into clinical protocols to optimize patient survival and redefine care standards in metastatic colorectal cancer therapy.
Subject of Research: Metastatic Colorectal Cancer Treatment
Article Title: Not Provided
News Publication Date: Not Provided
Web References:
– The Lancet article DOI: 10.1016/S0140-6736(25)02025-2 (http://dx.doi.org/10.1016/S0140-6736(25)02025-2)
References: The Lancet, ESMO Congress 2025 presentation
Image Credits: Not Provided
Keywords: Cancer immunotherapy, Colorectal cancer, Cancer research, Clinical research
Tags: advanced colorectal cancer treatmentclinical study on cancer treatmentsimmune checkpoint inhibitors in oncologyimmunotherapy and targeted therapy combinationinnovative cancer therapieslate-stage colorectal cancer managementmetastatic colorectal cancer survival ratesnew cancer treatment protocolsovercoming resistance to chemotherapytumor microenvironment modificationUCLA cancer research breakthroughszanzalintinib and atezolizumab
