Exelixis Announces Positive Phase 3 Results for Zanzalintinib and Atezolizumab Combination in Metastatic Colorectal Cancer

Analysis reveals significant industry trends and economic implications

Release Date

2025-10-20

Category

Clinical Trial Event

Reference

Source

Breakthrough Clinical Results

Exelixis announced detailed results from the Phase 3 STELLAR-303 trial evaluating zanzalintinib in combination with atezolizumab versus regorafenib in patients with previously treated non-MSI-high metastatic colorectal cancer (CRC). The study met one of its dual primary endpoints, demonstrating a 20% reduction in the risk of death with the combination. Median overall survival (OS) in the ITT population was 10.9 months with the combination versus 9.4 months with regorafenib. Exelixis plans to complete its first new drug application submission for zanzalintinib in the U.S. in 2025.

Key Highlights

  • Zanzalintinib plus atezolizumab improved median overall survival compared to regorafenib in metastatic colorectal cancer patients.
  • The combination significantly reduced the risk of death by 20% in the intention-to-treat population.
  • Consistent OS benefits were observed across pre-specified subgroups, including geographic region, RAS status, liver involvement and prior anti-VEGF therapy.
  • Exelixis plans to submit a new drug application for zanzalintinib in the U.S. in 2025.

Incidence and Prevalence

Global Estimates of Colorectal Cancer Incidence and Prevalence

Incidence Trends

The global burden of colorectal cancer is expected to increase more than 60% by 2030. Recent data shows concerning trends, particularly in early-onset colorectal cancer (diagnosed before age 50), which is increasing at faster rates compared to older populations in many regions worldwide.

According to a 2020 study, the annual percent change (APC) for colorectal cancer in those under 50 years was increasing more rapidly than in those 50 and older across multiple regions: - Australia (+1.10% vs. -0.35%) - Brazil (+9.20% vs. +5.72%) - Canada (+2.60% vs. -0.91%) - China-Hong Kong (+1.82% vs. -0.10%) - China-Shanghai (+1.13% vs. -2.68%) - Japan (+2.63% vs. +0.90%) - United Kingdom (+3.33% vs. +0.77%) - United States (+1.98% vs. -2.88%)

These trends were largely driven by rectal cancer, except in Brazil and the United Kingdom.

Regional Variations

Historical patterns show colorectal cancer has been common in North America and Europe, rare in Asia, and particularly uncommon in Africa. International variation in colon cancer rates has been as high as 60-fold, with a 4-fold difference within Europe between highest and lowest rates. For rectal cancer, variation internationally has been 18-fold and within Europe 3-fold.

In Asian registries, there is substantial variation in subsite distributions, with the proportion of rectal cancer highest among Korean men (51.39%) and lowest among Israeli women (26.6%).

In Germany, early-onset colorectal cancer accounted for 5.1% of all colorectal cancers, with incidence rising annually by 1.16% in men and 1.32% in women.

In Isfahan province (Iran), colorectal cancer was among the most common cancers with age-standardized incidence rates (ASRs) per 100,000 of 19.6 in men and 15.6 in women.

Prevalence and Survival

A 2024 meta-analysis involving 9,278 colorectal cancer survivors reported a global prevalence of: - 12.10% for severe malnutrition - 33.13% for moderate malnutrition - 47.78% for overall malnutrition

Asia showed higher rates of severe malnutrition (16.67%) and overall malnutrition (53.17%), while low-middle income countries demonstrated higher rates of overall malnutrition (67.46%).

Survival disparities exist across high-income countries, with Australia, Canada, and Norway consistently showing higher survival rates. 5-year net survival for colon cancer varied between 59.1% and 70.9% across seven high-income countries during 2010-2014, while rectal cancer survival varied between 61.6% and 70.9%.

In Korea, 5-year relative survival rates improved from 58.7% in 1996-2000 to 75.0% in 2011-2015, while Malaysia reported a national 5-year colorectal cancer-specific survival rate of 42%.

Study Design Parameters

Study Design Parameters and Endpoints in Key Colorectal Cancer Trials

Study Designs

  • Randomized controlled trials are the cornerstone for evaluating treatments in metastatic colorectal cancer (mCRC)

  • Common designs include single-blind, parallel-arm, superiority trials with treatment allocation methods such as:

  • Simple randomization

  • Stratified randomization

  • Minimization (providing best balance between groups)

  • Sample sizes typically range from 50-200 patients in small-scale trials
  • The FIRE-3 study compared FOLFIRI plus cetuximab to FOLFIRI plus bevacizumab in RAS wild-type patients
  • Retrospective analyses and next-generation sequencing (NGS) are used to evaluate biomarkers
  • Enhanced recovery pathways and multimodal programs (exercise, nutrition, psychological interventions) are incorporated into modern trial designs

Patient Selection Parameters

  • Molecular biomarkers including RAS, BRAF, and DNA mismatch-repair (MMR) status stratify patients
  • Primary tumor location (right vs. left colon) serves as an important stratification parameter
  • Gene expression signatures classify patients into molecular subtypes including the four consensus molecular subtypes (CMS)
  • Tumor-infiltrating lymphocytes (TIL) density is assessed as a prognostic marker

Endpoints

  • Overall survival (OS) is considered the gold standard endpoint for phase III trials
  • Disease-free survival (DFS) is a primary endpoint in non-metastatic colon cancer trials
  • Progression-free survival (PFS) serves as an endpoint in metastatic colorectal cancer trials
  • Cause-specific survival (CSS) is used in some studies
  • Health-related quality of life (HRQoL) is now considered a relevant clinical outcome
  • Intermediate endpoints can reduce trial duration, patient numbers, and study costs

Key Trials and Their Impact

  • MOSAIC trial and National Surgical Adjuvant Breast and Bowel Project C-07 confirmed DFS benefit with oxaliplatin added to 5-fluorouracil/leucovorin in stage III colon cancer
  • X-ACT trial showed capecitabine to be equivalent to bolus 5-FU/LV
  • PRODIGE 23 and RAPIDO trials demonstrated that total neoadjuvant therapy (TNT) improves DFS in locally advanced rectal cancer
  • PROSPECT, OPRA, and OPERA trials explored organ preservation approaches in rectal cancer
  • MOUNTAINEER trial led to FDA approval of tucatinib plus trastuzumab in HER2-amplified metastatic colorectal cancer
  • Janus Rectal Cancer Trial is studying chemotherapy intensification via consolidation chemotherapy

Statistical Methods

  • Kaplan-Meier estimators and Cox regression models assess prognostic significance
  • Pearson correlation analysis, univariate analysis, and multivariable-adjusted binary Logistic regression models explore risk factors
  • For minimization allocation, probability should be adjusted based on sample size (0.95 for 50 patients to 0.70 for 200 patients)

These design parameters and endpoints have evolved to create more efficient trials that better identify effective treatments while considering patient quality of life and molecular characteristics of colorectal cancer.