Bone Toxicity Case Report Combining Encorafenib, Cetuximab and WNT974 in a Phase I Trial

More than 90% of colorectal cancers (CRC) have alterations in WNT signaling. Eight to ten percent of patients with metastatic Kirsten rat sarcoma virus - wild type (KRAS-WT) CRC have B-Raf Proto-Oncogene, Serine/Threonine Kinase (BRAF) mutations and do not benefit from epidermal growth factor receptor (EGFR) antibodies. The addition of a porcupine inhibitor could increase the response rate in patients with BRAFV600E-mutated KRAS-WT metastatic CRC (mCRC) with WNT pathway alterations.

We report two cases of severe bone toxicities during treatment with the BRAF inhibitor encorafenib, the EGFR-targeting monoclonal antibody cetuximab, and the porcupine inhibitor WNT974 in the phase 1B study NCT02278133.

Patient 1, a 66-year-old man with BRAFV600E-mutated KRAS-WT mCRC and an RNF43 mutation, developed multiple rib fractures and collapse of thoracic vertebrae 10 and 11. Autopsy revealed no metastases at fracture sites; histology demonstrated a thin, porous cortex and poor trabecular bone structure. Immunohistochemistry assessed key WNT pathway components. Patient 2, a 70-year-old man with similar mutations, experienced a toe fracture, multiple rib fractures, osteopenia, and altered bone biomarkers indicative of disrupted bone turnover.

The two patients described developed severe bone toxicities including rib fractures, a toe fracture, osteoporotic thoracic collapses, hypercalcemia, and alternated bone biomarkers. These cases highlight the potential skeletal risks associated with dual MAPK and WNT pathway inhibition.