SUNRISE-CRC: a randomized phase II study of high-dose intermittent sunitinib versus trifluridine/tipiracil in metastatic colorectal carcinoma

Abstract

Background: Patients with metastatic colorectal cancer often have poor or short responses to currently available therapies. Drug repurposing with alternative dosing schedules may offer unexpected clinical benefit, even for agents that previously failed for this indication.

Methods: We explored a high-dose treatment strategy for sunitinib, assessing its potential for both cancer cell killing and inducing immunogenic cell death in patient-derived tumor organoids (PDTOs) of metastatic colorectal cancer (mCRC). In a randomized clinical trial, we studied the efficacy of high-dose intermittent sunitinib (700 mg once every 2 weeks) in patients with advanced CRC compared to standard therapy with trifluridine/tipiracil. The primary outcome measure was progression-free survival (PFS); secondary outcomes included overall survival, safety and tolerability, quality of life, and exploratory biomarker analyses.

Results: While high, intermittent dosing was found to effectively kill PDTOs in vitro, no support for immunogenic cell death was found. In our clinical trial, among a total of 63 evaluable patients, median PFS was 2.8 months (95% CI 0.9-4.7) for the investigation arm compared to 1.9 months (95% CI 1.6-2.3) for the trifluridine/tipiracil group (P = .78, HR 1.22; 95% CI 0.73-2.04). The trial was halted prematurely due to toxicities: in particular, hemorrhage, fever and gastrointestinal adverse events.

Conclusion: High-dose intermittent sunitinib treatment did not improve PFS for patients with heavily pretreated mCRC compared to standard 3rd or 4th-line treatment with trifluridine/tipiracil, whereas significant toxicity was observed. In addition, this approach provoked no relevant immunological responses in vitro, discouraging further research for potential combinations with immunotherapeutics.

Identifier: NCT03909724.

Keywords: high-dose; metastatic colorectal cancer; patient-derived tumor organoids; tyrosine kinase inhibitors.

Figure 1.

Investigating immunogenic cell death in HDST sunitinib-treated PDTOs. (A) Schematic for treatment and analyses of mCRC PDTOs. (B) PDTO viability effect after HDST sunitinib. Representative images for 3 h of 20 µM (Sun20) or control (DMSO)-treated PDTOs, taken 7 d after drug wash-out. (C) Representative western blots (n = 3) analysis of the expression of (phospho-)MLKL along with loading control in PDTOs after 6 h and 15 h of Sun20 and 20 µM osimertinib (Osi20). TSZ (TNF-α, SMAC mimetic LCL-161, and Z-VAD-FMK) treated HT29 cells were used as positive control. Additionally, low-dose (2 µM, Sun2, and Osi2) treatments were performed for 6 h. (D) Quantification of normalized relative protein expression from (C). (E) Enzymatic caspase-1 activity measured in PDTOs after 3 h and 24 h of Sun20. HT-29 treatments were 24 h. Experiments were performed with three replicates and repeated at least two times. (F) RT-qPCR measurement of expression of GSDMD relative to GAPDH in indicated PDTOs. * P < .05, ** P < .005 (One-way ANOVA with Dunnett’s multiple comparisons post hoc test).

Figure 2.

Survival outcomes of the sunrise trial. Progression-free survival (A) and overall survival (B) of patients (N = 63).