KEY TAKEAWAYS
- The phase II trial aimed to evaluate monotherapy with RXC004 and its combination with nivolumab in pts with MSS CRC characterized by RNF43/RSPO aberrations.
- The primary enpoints were DCR and ORR.
- The RXC004 monotherapy compares to late-line standard care; RXC004 with nivolumab shows promising improvements, hinting at further investigation.
Dysregulated Wnt signaling initiates and drives colorectal cancer (CRC) through immune evasion and proliferation. There are poor patient outcomes in patients (pts) with Microsatellite stable (MSS) CRC after 3rd line (L3) standard of care (SoC). They are immune cold and refractory to immune checkpoint inhibition (ICI).
Loss of function RNF43 mutations or RSPO2/3 fusions helped favors the identification of Wnt ligand dependent MSS CRCs; this subgroup often exhibits concurrent mutations in MAPK pathway (81%) and leads to poor prognosis.
Natalie Cook and the team evaluated the efficacy of RXC004 alone and in combination with nivolumab in treating MSS metastatic CRC with specific genetic aberrations.
Researchers enrolled pts aged 18 years and older with histologically confirmed MSS mCRC showing RNF43 or RSPO aberrations, verified via FFPE tumor samples. Eligible pts had disease progression despite prior SoC treatment.
They randomized the pts between 2 treatment arms to receive either RXC004 monotherapy at 2mg once daily (Arm A) or RXC004 in combination with nivolumab at 1.5mg once daily (Arm B). Denosumab was administered to prevent bone mineral density loss, which is a known effect of Wnt pathway inhibition.
The primary endpoint for Arm A was disease control rate (DCR), while Arm B assessed objective response rate (ORR). Secondary objectives included safety, pharmacokinetics (PK), and assessing changes in Wnt pathway activity, immune cell profiles, FDG-PET imaging of tumors, and circulating tumor DNA (ctDNA).
Results revealed that of 25 enrolled pts (Arm A=17, Arm B=8) there were 20 pts with an evaluable efficacy. In Arm A, 5 out of 13 pts (38%) achieved stable disease (SD) as their best objective response (BOR), with 15% (2 of 13) achieving DCR for ≥16 weeks.
Contrastingly, in Arm B, 2 out of 7 pts (29%) had a BOR of partial response (PR) (1 confirmed, 1 unconfirmed), and 2 out of 7 (29%) achieved SD. This resulted in a confirmed ORR of 14% (1 out of 7) and a DCR of 57% (4 out of 7) for ≥16 weeks according to RECIST criteria.
Common adverse events (AEs) like dysgeusia, nausea, decreased appetite, diarrhoea, vomiting, alopecia, TBL increased and fatigue were observed. No bone fragility events or BMD loss occurred. Occurrences like Wnt pathway, SUVmax and ctDNA reductions, and immune evasion reversal were recored.
The study concluded that RXC004 showed tolerability, and denosumab effectively prevented bone mineral density loss. In pts with poor prognosis MSS mCRC, RXC004 monotherapy demonstrated comparable efficacy vs late-line standard of care, whereas the combination with nivolumab demonstrated promising improvements, suggesting a need for further clinical corraboration.
The trial was sponsored by Redx Pharma Plc.
Source: https://cslide.ctimeetingtech.com/esmogi24hybrid/attendee/confcal/show/session/3
Clinical Trial: https://www.clinicaltrialsregister.eu/ctr-search/search?query=2020-003132-24
Cook N, Bridgewater J A, Saunders M P, et al. (2024). “Phase II results of the porcupine (PORCN) inhibitor zamaporvint (RXC004) in genetically selected microsatellite stable colorectal cancer patients.” Presented at ESMO-GI 2024, (Abstract 37P)
