Chemo-free treatment combination prolongs survival in previously treated mCRC

Treatment with the multitargeted tyrosine-kinase inhibitor (TKI) zanzalintinib, when combined with atezolizumab, confers an overall survival (OS) benefit in previously treated metastatic colorectal cancer (mCRC), according to the phase III STELLAR-303 trial.

Over a median follow-up of 18 months, the median OS was 10.9 months with zanzalintinib plus atezolizumab vs 9.4 months with regorafenib in the intention-to-treat (ITT) population, with the combination yielding a 20-percent reduction in the risk of death (stratified hazard ratio [HR], 0.80, 95 percent confidence interval [CI], 0.69–0.93; p=0.0045). [Lancet 2025;doi:10.1016/S0140-6736(25)02025-2]

The OS estimates were 46 percent in the combination arm and 38 percent in the regorafenib arm at 12 months and 20 percent and 10 percent, respectively, at 24 months.

OS benefits were consistent across prespecified subgroups, including those defined by geographic region, RAS status, prior anti-VEGF therapy, and presence or absence of liver metastases.

Interim analysis in the subset of patients without liver metastases showed an OS trend favouring zanzalintinib plus atezolizumab, with a median of 15.9 vs 12.7 months (stratified HR, 0.79, 95 percent CI, 0.61–1.03; p=0.087).

“STELLAR-303 is the first phase III trial to show improved OS with an immune checkpoint inhibitor (ICI)-based combination in mCRC that is not microsatellite instability-high or mismatch repair-deficient,” noted senior investigator Prof Anwaar Saeed from the University of Pittsburgh Medical Center in Pittsburgh, Pennsylvania, US, who spoke to an audience at the ESMO annual meeting.

Zanzalintinib is a novel small molecule inhibitor of multiple kinases, including TAM kinases (TYRO3, AXL, and MER), MET, and VEGF receptors. Saeed pointed out that inhibition of these kinases might help reprogram the tumour microenvironment to support immune cell activation, which could improve responsiveness to immune checkpoint inhibitors (ICIs). [Mol Cancer Ther 2023;22:179-191]

“[The zanzalintinib–atezolizumab] combination represents a chemotherapy-free treatment option with a novel mechanism of action for heavily pretreated patients in need of improved therapies,” she said.

STELLAR-303

The trial included 901 adult patients (median age 60 years, 59 percent male, 38 percent Asian) with confirmed metastatic adenocarcinoma of the colon or rectum, who had previously received standard-of-care therapy, and did not have microsatellite instability-high or mismatch repair deficient tumours. These patients were randomly assigned to receive zanzalintinib–atezolizumab (n=451) or regorafenib (n=450).

In the combination arm, zanzalintinib was administered orally at 100 mg daily, while atezolizumab was administered intravenously at 1,200 mg every 3 weeks. In the regorafenib arm, treatment was given orally at 160 mg daily on days 1–21 of each 28-day cycle.

The dual primary endpoints were OS in the ITT population and in the subset of patients without liver metastases.

The combination showed a trend toward improved progression-free survival in the ITT population compared with regorafenib (3.7 vs 2 months; HR, 0.68, 95 percent CI 0.59–0.79), although statistical significance could not be established due to the study’s prespecified hierarchical testing strategy.

Disease control rates were 54 percent in the combination arm and 41 percent in the regorafenib arm. Objective response rates were 4 percent and 1 percent, respectively.

“Safety for this [zanzalintinib plus atezolizumab] regimen was consistent with other ICI-VEGFR TKI combinations. No new safety signals emerged,” according to Saeed.

Grade 3/4 treatment-related adverse events (AEs) occurred in 59 percent of patients in the combination arm and 37 percent of those in the regorafenib arm. Serious treatment-related AEs were reported in 26 percent and 10 percent of patients in the respective arms. AEs led to treatment discontinuation in 18 percent of patients in the combination arm and 15 percent of those in the regorafenib arm or dose reduction in 61 percent and 40 percent, respectively.

The most common grade 3/4 treatment-related AEs in the combination and regorafenib arms were hypertension (15 percent vs 9 percent), fatigue (6 percent vs 2 percent), diarrhoea (6 percent vs 2 percent), and proteinuria (6 percent vs 2 percent). Treatment-related deaths included intestinal perforation with zanzalintinib (n=2), pneumonitis and renal failure with atezolizumab (n=1 each), altered state of consciousness with zanzalintinib plus atezolizumab (n=1), and jejunal perforation with regorafenib (n=1).

More data needed

Study discussant Dr Elena Elez from the Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology in Barcelona, Spain, acknowledged the potential value of the chemotherapy-free treatment combination in mCRC but stressed the need for additional data.

“The next step will be to understand which patients derive most benefit. Further biomarker research is needed. Outcomes of the final analysis of OS particularly in patients without active liver metastasis will also help to clarify the role of zanzalintinib plus atezolizumab in the current treatment landscape considering the safety profile, which is fundamental in this heavily pretreated population,” Elez said.