Immunotherapy in Late-Line Treatment of Colorectal Cancer

Multitargeted tyrosine kinase inhibitors (TKIs), including regorafenib, have modest activity in the late-line treatment of metastatic colorectal cancer. Zanzalintinib is an investigational (not FDA-approved) TKI that targets VEGF, TAM kinases (TYRO3, AXL, and MER) and MET. Promising results combining zanzalintinib with the anti-PD-L1 agent atezolizumab prompted the STELLAR-303 trial, an open-label, randomized, phase 3 trial in chemotherapy-refractory colorectal cancer. Patients with microsatellite-stable metastatic colorectal cancer received 100 mg of oral zanzalintinib daily and 1200 mg of atezolizumab intravenously every 3 weeks (ZA), or received standard-of-care treatment with 160 mg of regorafenib daily on days 1 to 21 every 28 days.

Key results were as follows:

• Of the 901 patients treated, the majority were male (58%), with liver metastases (57%) and RAS mutations (59%); they were treated with a median of 2 prior therapies, mainly VEGF-targeted therapy (in 81%).
• 36% of patients had rectal primaries, and 41% had left-sided primaries.
• The primary endpoint of overall survival was significantly better with ZA than with regorafenib (median, 10.9 vs. 9.4 months; hazard ratio, 0.80), with improved survival at 12 months (46% vs. 38%) and 24 months (20% vs. 10%).
• Objective response rates were limited with both ZA (4%) and regorafenib (1%), but disease control was more common with ZA (54% vs. 41%). Progression-free survival was longer with ZA than with regorafenib (median, 3.7 months vs. 2.0 months).
• Treatment-related grade 3 or 4 serious adverse events were more common with ZA than with regorafenib (60% vs. 37%), including hypertension, proteinuria, fatigue, and diarrhea, but no new safety signals emerged.