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Key findings published in Signal Transduction & Targeted Therapy

Modest efficacy, manageable safety

• Efficacy:  Of the 43 TLS-negative patients who were assessable, the objective response rate was 11.4 % (all partial responses), whereas 50 % progressed on treatment. Median progression-free survival was 1.8 months.


• Safety: Forty-nine patients received at least one dose of either regorafenib or avelumab and were included in the safety analysis. Toxicities were generally low-grade and controllable; importantly, no treatment-related deaths occurred, indicating that the combination is well tolerated.

Plasma proteomics: stronger immune signals but red flags for checkpoint resistance

• Immune-cell influx: Gene-ontology analysis of up-regulated proteins showed marked enrichment of CD8⁺ T-cell and B-cell signatures.


• Soluble PD-L1 surge: Soluble PD-L1 (CD274) —a known negative predictor of response to PD-(L)1 blockade—was the most strongly up-regulated protein.


• Tryptophan depletion: complementary metabolomics showed a pronounced drop in circulating L-tryptophan, a metabolic hallmark of immune activation.

Digital pathology: deeper—yet still not optimal—immune engagement

• More lymphocytes: Intratumoral CD8⁺ T-cell and CD20⁺ B-cell densities rose in respectively 6 and 4 patients, yet progressive disease occurred in patients with the highest increases in CD8+ T and B cell density, showing that infiltration alone is insufficient to trigger clinical benefit.


• No TLS formation: Lymphocytes failed to organise into productive immune niches.


• Immunosuppressive myeloid niche: The density of M2-polarised macrophages increased, likely damping cytotoxic activity.


• Adaptive PD-1 up-shift: Post-treatment T cells displayed higher PD-1 expression, suggesting re-engagement of the PD-1/PD-L1 axis and a mechanism of resistance to avelumab.