WntResearch : Foxy-5 Poster ESMO GI 2024 WntResearch |juni 2024 (2024)

Scientific rationale

High tumour-expression of WNT5A is associated with better overall survival in colon cancer.

A WNT5A-mimicking peptide, Foxy-5, was developed and shown to effectively reduce cancer cell ­invasion and metastasis in pre-clinical models.

Methodology

A randomised, controlled, and open multicenter phase 2 clinical study was conducted in patients with stage II/III colon cancer. Patients received three doses (1.8 mg/kg) per week of neoadjuvant Foxy-5 treatment for at least 3 weeks, followed by up to 10 weeks of adjuvant treatment. Primary efficacy evaluations were based on ctDNA relapse (analyses still ongoing). An ad hoc analysis was performed on surgically removed material from 110 patients at the time indicated by the red arrow (figure 1).

• Figure 2 Histopathological assessment of perineural invasion after 3-4 weeks of treatment with Foxy-5 (n=100).

Discussion

The significance of histologic findings in a neo- adjuvant setting is supported by the FOxTROT trial. Six weeks of preoperative FOLFOX treatment produced substantial reductions in T stage, N stage, and EMVI, resulting in better 2-year disease control. Table 2 illustrates an indirect comparison between preoperative FOLFOX and Foxy-5 treatment: fewer patients had venous invasion after 3 weeks of Foxy-5 treatment compared to after 6 weeks of FOLFOX treatment.

• Table 2 Local pathology comparison: FOxTROT vs NeoFox

Morton, Dion et al., Journal of clinical oncology vol. 41,8 (2023): 1541-1552 Data on file, NeoFox

• Figure 1 Original study design

• Figure 3 Histopathological assessment of venous invasion after 3-4 weeks of treatment with Foxy-5 (n=96).

Implication

The indications of rapid effects of preoperative Foxy-5 on local invasion and TN(M) downstaging in patients with stage II/III colon cancer led to a decision to amend the study to focus solely on short- term neoadjuvant treatment. Also, given the excellent safety profile of Foxy-5, a dose-escalation was performed, which indicated that 8 mg/kg of Foxy-5 given 5 times per week was safe and well-tolerated.

New study design

The new study evaluates the effects of at least 3 weeks of preoperative Foxy-5 treatment on tumour growth and local spread in patients with stage III colon cancer. Patients (n=80) are randomly assigned to receive either Foxy-5 or standard of care. CT assessments are performed at the study start and pre-surgery, and resected material is analysed.

Safety

Based on 127 patients (64 patients in the Foxy-5 arm, treatment period completed), there were 27 Foxy-5 related adverse events, 26 of which were Grade 1 and one Grade 2 (table 1). Foxy-5 was considered safe and well-tolerated.

• Table 1 Foxy-5 safety profile

Foxy-5

(versus Standard of Care)

• Figure 5 New study design

Results

Pathological examination suggested an effect of Foxy-5 on the local spread of the primary tumours within 3-4 weeks of treatment:

• Fewer patients had perineural invasion (p=0.0088, figure 2)
• Fewer patients had venous invasion (p=0.0097, figure 3)

In addition, Foxy-5 was associated with TN(M) downstaging (p=0.012, figure 4).

• Figure 4 TN(M) staging (M not analysed since metastatic disease was an exclusion criteria) was performed by CT at study start, and by histopathological assessment using material from the surgical resection (n=110).

Conclusion

Preoperative Foxy-5 treatment was associated with an excellent safety profile, reduced perineural and venous invasion, and TN(M) downstaging in patients with stage II/III colon cancer. Foxy-5 is being evaluated as a potential neoadjuvant treatment for stage III colon cancer.

Author affiliations.

1. Institut Catala d'Oncologia - Hospital Duran i Reynals (ICO L'Hospitalet), Hospitalet De Llobregat, Spain; 2. Institut Català d'Oncologia l'Hospitalet (Hospital Duran i Reynals), L'Hospitalet De Llobregat, Spain; 3. Parc Taulí Hospital Universitari, Barcelona, Spain; 4. Hospital Clinico Universitario Lozano Blesa, Zaragoza,Spain; 5. Pandy Kalman Hospital, Gyula, Hungary; 6. Hospital General Universitario de Elche, Elche, Spain; 7. Tolna County Teaching Hospital, Szekszárd, Hungary; 8. Hospital Clinico Universitario de Valencia, Valencia, Spain; 9. Hospital General Universitario Gregorio Maranon, Madrid, Spain;

1. Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; 11. University Hospital Puerta de Hierro Majadahonda, Majadahonda, Spain; 12. HUMV - Hospital Universitario Marques de Valdecilla, Santander, Spain; 13. Debrecen University Clinical Center, Debrecen, Hungary; 14. Debrecen University Clinical Center, Debrecen, Hungary; 15. Hospital Universitario La Paz, Madrid, Spain; 16. Hospitals Santa Tecla, Tarragona, Spain, 17. Hospital HM - Sanchinarro, Madrid, Spain; 18. National Institute of Oncology, Budapest, Hungary; 19. Hospital Universitario Ramon y Cajal, Madrid, Spain; 20. Hospital Universitario Arnau de Vilanova, Lleida, Spain