Research ArticleClinical Studies
Open Access

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

MARK T.J. VAN BUSSEL, NATHALIE BRAVENBOER, HUIB VAN ESSEN, PETUR SNAEBJORNSSON, NATASHA M. APPELMAN-DIJKSTRA, JAN HM SCHELLENS and FRANS L. OPDAM
Anticancer Research July 2025, 45 (7) 3137-3147; DOI: https://doi.org/10.21873/anticanres.17677

Abstract

Background/Aim: 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.

Patients and Methods: 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.

Results: 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.

Conclusion: 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.

Keywords:

Introduction

WNTs are a large family of 19 secreted cysteine rich glycoproteins that trigger multiple signaling cascades essential for control of gene expression, cell fate determination, proliferation and migration (1, 2). WNTs are required for several processes such as embryonic development, tissue regeneration and protein synthesis and are also involved in bone remodeling (1, 3–5). Porcupine is a membrane bound O-acyl transferase, which adds a palmitoyl group to WNT ligands. Palmitoylation of WNT ligands by the membrane bound O-acyltransferase porcupine is necessary for WNT signaling (6). WNTs bind to receptor complexes containing one of 10 Frizzled (Fzd) receptors and also to the low-density lipoprotein receptor-related protein (LRP) five or six co-receptors where they stimulate multiple signaling cascades in various tissues, including the “canonical” β-catenin pathway, and are being classified as “canonical” on the basis of their ability to inhibit glycogen synthase kinase three phosphorylation of β-catenin (4, 7). In the bone, phosphorylation of β-catenin results in its degradation and prevents translocation of β-catenin to the nucleus to stimulate bone formation and to inhibit bone resorption (3). WNT inhibition can therefore result in reduced bone formation and increased resorption. Since the discovery of the WNT pathway, many attempts have been made to address this pathway as a therapeutic target to reduce tumor growth and to treat osteoporosis. However, finding a tissue specific WNT inhibitor is challenging. The mitogen-activated protein kinases (MAPK) pathways in osteoblasts also play a role in osteoblast differentiation (8). Adult patients with epidermal growth factor receptor (EGFR) positive, RAS wild-type metastatic colorectal cancer with the BRAF V600E mutation, who have received prior systemic therapy can be treated with EFGR and BRAF inhibitors to inhibit the MAPK pathway. In colon carcinoma, WNT signaling is often upregulated (9, 10). More than 90% of colorectal cancers (CRC) have alterations in WNT signaling. WNT974/LGK974 has been developed to inhibit the WNT pathway by porcupine inhibition (11). WNT974/LGK974 inhibits porcupine and can inhibit WNT signaling. E3 ubiquitin-protein ligase RNF43 inhibits WNT-signaling under normal conditions (12). Mutations in RNF43 lead to activation of WNT signaling. Mutations in the WNT pathway co-occur frequently with BRAF-mutations and induce tumor growth (13). Combination therapy with EGFR inhibitors, BRAF inhibitors and porcupine inhibitors could potentially inhibit tumor growth in patients with mutations in BRAF and in the WNT pathway. This strategy has been explored in the phase Ib/II clinical trial NCT02278133 (14). The phase Ib dose-escalation study evaluated the maximum tolerated dose of WNT974 in combination with encorafenib and cetuximab in patients with BRAF V600E-mutant metastatic CRC (mCRC) with RNF43 mutations or R-spondin fusions. Patients received once-daily (QD) encorafenib and weekly cetuximab, in addition to WNT974 QD, in sequential dosing cohorts. In the first cohort, patients received 10-mg WNT974 (COMBO10), which was reduced in subsequent cohorts to 7.5-mg (COMBO7.5) or 5-mg (COMBO5) after dose-limiting toxicities (DLTs) were observed. Twenty patients were enrolled. DLTs were observed in four patients, including grade three hypercalcemia (COMBO10, n=one; COMBO7.5, n=one), grade two dysgeusia (COMBO10, n=one), and lipase increase (COMBO10, n=one). A high incidence of bone toxicities (n=nine) was reported, including rib fracture, spinal compression fracture, pathological fracture, foot fracture, hip fracture, and lumbar vertebral fracture. Two of these patients are described in this case report.

Patients and Methods

Human bone specimens were collected from the iliac crest, decalcified in 10% buffered ethylenediaminetetraacetic acid (EDTA) solution, and embedded in paraffin. Immunohistochemistry was performed using in-house developed methods (15). Briefly, sections were deparaffinized in xylene and rehydrated through a graded ethanol series. Endogenous peroxidase activity was blocked by incubating the sections in 3% hydrogen peroxide (H2O2) in 40% methanol/PBS for 15 min. For sclerostin detection, sections were pretreated with Proteinase K solution (5 μg/ml) for 10 min at room temperature for antigen retrieval, followed by incubation with a mouse anti-human sclerostin antibody (1:10) for 3 h at room temperature. For LRP5 detection, sections were blocked with 5% normal goat serum for 1 h, then incubated overnight at 4°C with rabbit anti-LRP5 antibody (1:200). For non-phospho β-catenin detection, sections underwent trypsin antigen retrieval for 15 min at 37°C, were blocked with 5% normal goat serum for 1 h, and incubated overnight at 4°C with rabbit anti-non-phospho β-catenin antibody (1:200). Detection involved incubation with appropriate secondary antibodies and visualization using an AEC substrate mix, followed by counterstaining with hematoxylin. Sections were mounted with Clearmount or Glycergel and covered with Depex and a coverslip.

Results

Patient 1. This 66-year-old male patient was initially diagnosed with stage IIIB colon carcinoma. His medical history included atrial fibrillation and a coronary artery bypass grafting (CABG). The patient’s concomitant medications included atorvastatin, perindopril, phenprocoumon and acetaminophen and colchicine as needed. The patient was not known to have bone-related problems and did not have risk factors for osteoporosis. He underwent a hemicolectomy followed by adjuvant capecitabine-oxaliplatin treatment. After 11 months he developed progressive disease with liver metastases. Next, the patient was treated with second-line irinotecan-bevacizumab and had stable disease for 14 months. At disease progression (stage IVB) the patient was referred to The Netherlands Cancer Institute to explore treatment opportunities in clinical trials. The patient was screened for clinical trial NCT02278133 with cetuximab (an EGFR inhibitor), encorafenib (a BRAF inhibitor), and WNT974 (a porcupine inhibitor). Molecular prescreening revealed that he was KRAS-WT and carried a RNF43 mutation besides the BRAFV600E mutation. Therefore, the patient was eligible for the trial and was treated with cetuximab (200 mg/m2), encorafenib (200 mg once daily), and WNT974 (7.5 mg once daily). He gradually developed back pain after treatment initiation, attributed to the collapse of thoracic vertebra 10, which had not been present on the baseline computed tomography (CT)-scan. The patient was treated with zoledronic acid, furosemide, and rehydration therapy with saline due to a grade 2 hypercalcemia [3.17 mmol/l (2.28-2.74 mmol/l)] on day 63 (Figure 1). Thereafter, the patient had acute renal dysfunction with elevated creatinine and hypocalcemia, and he was hospitalized. The study medication and perindopril were temporary interrupted due to hypercalcemia and renal dysfunction on day 69. The patient also developed hypophosphatemia on day 70, which was treated via intravenous phosphate infusion and later switched to oral phosphate 40 mmol daily from day 77. Cetuximab was restarted on day 77. Encorafenib was restarted and the patient was discharged from the hospital on day 78. Calcium and cholecalciferol were started together with the restart of the porcupine inhibitor on day 80. Further evidence of an effect on bone homeostasis by the study treatment was provided by the rise in calcium levels to 2.83 mmol/l on day 112 following rechallenge with the treatment. On day 119 the study treatment was put on hold due to clinical deterioration. Figure 1 shows the calcium levels of patient 1 before and during the study. The patient’s best anti-tumor response according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 was stable disease on day 84. A CT-scan confirmed the osteoporotic thoracic vertebra 10 and 11 collapse on day 84. Thereafter, the patient was treated with an analgesic corset to relieve chest pain on day 100. The patient was hospitalized due to back-pain, dyspnea and right sided pleural effusion on day 119. Pleurodesis was performed on day 119. After the pleurodesis the study medication was restarted on day 119. The patient was informed about the increased risk of bone toxicities in the study and decided to continue in the trial on day 120. The patient went off study due to progressive disease (malignant ascites) and clinical deterioration on day 126. Palliative sedation was started on day 131. The patient died on day 132. Autopsy revealed six rib fractures on the right side, three rib fractures on the left side and collapse of thoracic vertebra 10 and 11. Metastases were not detected at the sites of the bone fractures. Bone histology of two samples from the iliac crest, showed a thin and porous cortex and poor trabecular structure (Figure 2). Total osteoclast number was low indicating a low turnover state, as can be expected after bisphosphonate therapy. Immunohistochemistry was performed to detect the presence of known factors involved in the WNT signaling pathway including sclerostin, a bone specific endogenous WNT-antagonist, LRP5 and non-phospho β-catenin (Figure 3, Figure 4, Figure 5) (16). No markers related to EGFR or BRAF inhibition were analyzed. Sclerostin expression was normal (Figure 3). Osteoblast express LRP5 (17). Since osteoblasts were rarely observed, LRP5 expression was low (Figure 4). Non-phospho β-catenin expression, a sign of activated WNT signaling in the bone, was observed in osteocytes (Figure 5), but not in osteoblasts. In conclusion we observed increased skeletal fragility with multiple severe osteoporotic fractures with histological signs of osteoporotic bone with increased cortical porosity, extremely low turnover after bisphosphonates whereas biochemically there was a clearly increased resorption leading to hypercalcemic episodes while on treatment.

Figure 1.
Figure 1.

Calcium levels of patient 1 and patient 2. Both patients started with once-daily (QD) encorafenib and weekly cetuximab, in addition to the porcupine inhibitor WNT974 QD on day 1. Patient 1 received zoledronic acid, furosemide, and rehydration treatment with saline therapy due to hypercalcemia on day 63. Thereafter, the patient had acute renal dysfunction with elevated creatinine and hypocalcemia. The porcupine inhibitor and perindopril were temporary interrupted due to hypercalcemia and renal dysfunction on day 69. The patient also developed hypophosphatemia on day 70. Calcium and cholecalciferol were started together with the restart of the porcupine inhibitor on day 80. Patient 2 received zoledronic acid on day 154. WNT974 was stopped at day 157. Calcium levels immediately decreased on day 161 to 1.8 mmol/l (reference range=2.28-2.74 mmol/l).

Figure 2.
Figure 2.

Bone specimen from the iliac crest of Patient 1 (day 132) showing a thin, porous cortical bone and impaired trabecular structure characterized by thin trabeculae and low connectivity. Goldner’s trichrome staining; magnification 10×.

Figure 3.
Figure 3.

Immunohistochemical detection of sclerostin in cortical bone. Black arrows indicate osteocytes expressing sclerostin, while arrowheads indicate osteocytes lacking sclerostin expression. A similar pattern of both sclerostin-positive and -negative osteocytes is observed in the cortical bone of Patient 1 (A, day 132) and in the control bone (B).

Figure 4.
Figure 4.

Immunohistochemical detection of LRP5 in the trabecular bone of Patient 1 (A) and control bone (B). In control bone, LRP5 is expressed in osteoblasts covering the bone surface, as indicated by the arrows. In Patient 1, treated with the porcupine inhibitor, osteoblasts are largely absent, and consequently, LRP5 expression in osteoblasts is not observed. However, LRP5 expression is present in osteocytes, as indicated by the arrows in (B); arrowheads indicate osteocytes lacking LRP5 expression.

Figure 5.
Figure 5.

Immunohistochemical staining for non-phospho β-catenin in the bone of Patient 1 (A) and in a transiliac bone biopsy from an osteoporosis patient as control (B). In Patient 1, non-phospho β-catenin is present in osteocytes (black arrows in A), while osteoblasts show low expression (red arrows in A). In the control sample, non-phospho β-catenin is typically expressed in osteoblasts (arrows in B), but not in osteocytes (arrowheads). These findings indicate reduced bone formation in Patient 1.

Patient 2. A 70-year-old man was diagnosed with stage IV BRAFV600E mutated mCRC. The patient had essential hypertension. The patient was treated with folinic acid, fluorouracil and oxaliplatin (FOLFOX). At the second cycle bevacizumab was added. The patient progressed after three months and was screened for the phase I clinical trial NCT02278133. The molecular profile of the tumor showed KRAS-WT, a BRAFV600E mutation and a RNF43 mutation. The patient was therefore included in the referred study and treated with cetuximab [400 mg/m2 (initial infusion) and 250 mg/m2 (subsequent infusions)], encorafenib 200 mg QD and WNT974 5 mg QD. Patient had a best overall response of Partial Response (PR) which lasted 1.5 years. Four months after initiation of the combination therapy the patient suffered a toe fracture on day 112. The patient had not experienced trauma or bone metastases. A dual X-ray absorptiometry (DEXA) scan of the lumbar spine and hips was performed for further bone analysis. The DEXA scan showed osteopenia of the right hip and lumbar spine, and no vertebral fractures on day 139. Treatment with WNT974 was definitively stopped on day 157 and zoledronic acid 4 mg monthly was started due to bone toxicity. Treatment with encorafenib and cetuximab were continued on day 157. The patient had several rib fractures on day 161. The calcium levels alterations are shown in Figure 1. Initiation of the triple combination induced a rise in calcium levels. Once WNT974 treatment was definitely stopped and with the initiation of 4 mg zoledronic acid on day 154, the calcium levels dropped to 1.80 mmol/l on day 161. The hypocalcemia was treated with 1 g calcium twice daily and the calcium levels were within the reference values on day 182. In this patient we were able to evaluate biochemical markers of bone turnover before zoledronic acid administration. The patient gave written informed consent and donated additional fasting blood during regular laboratory visits, in order to further investigate the effect of study treatment on the bone. Bone metabolism was monitored by measuring serum levels of specific collagen fragments, which are released into the circulation during bone remodeling (18). Procollagen type 1 Amino-terminal propeptide (P1NP) is a bone formation marker specific for proliferating osteoblasts and fibroblasts (19). Carboxy-terminal cross-linked telopeptides of type 1 collagen (CTX) is cleaved from type 1 collagen by cathepsin-K during bone resorption and is used as a bone resorption marker. Bone biomarkers in the serum may be affected by circadian rhythm and food intake. To minimize these effects, fasting blood samples were obtained at the same time each morning. The levels of P1NP and CTX are shown in Figure 6. During treatment with the three study treatment agents, CTX was increased up to 1.3x of the upper limit of normal. P1NP was low but increased after stopping treatment with WNT974 to 1.8x of the upper limit of reference values on day 175. Furthermore, we measured serum sclerostin levels at the time of stopping WNT974 and twice during bisphosphonate therapy which were 36 pg/ml, 31 pg/ml and 49 pg/ml, respectively, indicating that changes in sclerostin did not cause the change in bone turnover [reference value sclerostin 40.0 pg/ml; 95% confidence interval (CI)= 37.2 to 42.9 pg/ml] (20). On study day 209 a DEXA scan of the lumbar spine and hips showed normal bone density of both hips and osteopenia of the lumbar spine without indication of vertebral fractures. On study day 210 a CT scan of the chest and abdomen showed stable disease with unchanged liver metastases. On study day 252, a repeated CT scan of the chest and abdomen showed PR and extensive bilateral rib fractures, old and new. In total the patient suffered 25 rib fractures after 9 months on encorafenib and cetuximab treatment, the first five of which also included WNT974.

Figure 6.
Figure 6.

The levels of the bone biomarkers P1NP and CTX in patient 2. P1NP (procollagen type 1 amino-terminal propeptide) is a marker of bone formation specific to proliferating osteoblasts and fibroblasts, while CTX (carboxy-terminal cross-linked telopeptides of type 1 collagen) serves as a marker of bone resorption.

In summary, this patient developed skeletal fragility/bone toxicity with biochemical signs of suppressed bone formation and increased bone resorption, thus uncoupling of formation and resorption, starting after study treatment.

Discussion

Detailed overviews about WNT signaling in bone homeostasis have been published (3). WNT activation leads to bone formation, whereas WNT inhibition leads to bone resorption. WNT974/LGK974 inhibits porcupine, a membrane bound O-acyl transferase which adds a palmitoyl group to WNT ligands (11). Palmitoylation of WNT ligands is necessary for WNT signaling. The mitogen-activated protein kinases (MAPK) pathways in osteoblasts also play a role in osteoblast differentiation (8). No bone toxicity has been reported for the combination therapy with cetuximab and encorafenib to inhibit the MAPK pathway in CRC (21). Inhibition of both the MAPK and WNT pathways could pharmacologically explain the severe bone toxicity seen in the two patients described above.

Since the biopsy material was gathered post mortem and especially post-bisphosphonate therapy we had to rely on the biochemistry obtained during treatment. However, the specimens obtained are still very useful to fully comprehend the observed toxicity. In mice it has been shown that porcupine inhibition increased bone marrow adiposity (22). Inhibition of DNA methylation by 5-aza-2′-deoxycytidine in preadipocytes inhibited adipogenesis and promoted osteoblastogenesis (23). This coincided with up-regulation of Wnt10a. The effects of 5-aza-2′-deoxycytidine on osteoblastogenesis were prevented by the porcupine inhibitor IWP-2. Perhaps alterations of bone cell differentiation in patient 1 could explain the observation that osteoblasts were hardly present in the trabecular bone of patient 1 shown in Figure 4. Osteocytes, which express LRP5, have a long-live span and constitute 90% of bone cells and were present in the trabecular bone of patient 1 (24, 25). Bone turnover markers (BTMs), such as P1NP, a marker for bone formation, and CTX, a marker for bone resorption, were measured in patient 2 while on study therapy, after discontinuation of WNT974 and initiation of zoledronic acid. Bone resorption was high during therapy while bone formation was low, suggesting an uncoupling between bone formation and resorption. It has been shown that WNT974-treated mice had impaired trabecular and cortical bone mass and reduced serum levels of P1NP and increased serum levels of CTX (26). Considering these biochemical findings, we hypothesize that WNT974 induced this uncoupling and accordingly is responsible for the high calcium levels and severe osteoporosis, shown in the biopsy material. The CTX levels after zoledronic acid therapy cannot be considered reliable since zoledronic acid is known to be a very potent anti-bone resorption drug. Nevertheless, bone formation markers are higher than what would be expected after antiresorptive therapy and both patients developed hypocalcemia after bisphosphonate treatment, which further supports our hypothesis of a disruption of the bone formation/resorption balance in patients treated with this triple therapy. A similar phenomenon has been observed after cessation of anti-RANKL therapy (27).

Upfront we did not expect this severe bone toxicity in the adult population. Therefore, no baseline levels of bone biomarkers had been collected. The phase 1 monotherapy study of WNT974 concluded that WNT974 was generally well tolerated (28). Bone related disorders have been reported in six out of 94 patients. Suspected related bone-associated adverse events (AEs) included osteoporosis, pathological fracture, osteopenia and Grade 3 spinal fracture. The maximum tolerated dose was not determined and 10 mg WNT974 QD was the recommended dose for the expansion cohorts based on pharmacokinetics, pharmacodynamics and tolerability. No responses were observed according to RECIST v1.1; 16% of patients had stable disease (median duration 19.9 weeks). Across all dose levels 25.5% of the patients experienced hypercalcemia. Cetuximab and encorafenib combination therapy generally do not induce bone toxicity in mCRC according to the summary of product characteristics (21).

Adult bone homeostasis is a dynamic process in which 2-5% of cortical bone is being remodeled each year in a normal situation (29). In elderly patients with cancer, several treatments will influence bone remodeling making them more prone to fractures. Disruption of the bone remodeling process by WNT-inhibition may therefore be a contributing cause of negative effects leading to toxicity as observed in this trial with high fracture incidence. The supportive function of the skeleton might become affected by inhibiting bone formation during the remodeling process. Investigational medicinal products need detailed pre-clinical investigation before initiating clinical studies. There may be molecular differences in LRP5/6 receptors between tumor cells and osteoblasts exist, enabling more specific targeting of tumor cells rather than osteoblasts. Hence, porcupine inhibition by WNT974 in combination with cetuximab and encorafenib seems to affect the skeleton and have detrimental effects in these two patients with BRAF mCRC receiving the combination of encorafenib/cetuximab and the porcupine inhibitor WNT974.

Conclusion

Both patients developed severe bone toxicities including rib fractures, a toe fracture, osteoporotic thoracic collapses, hypercalcemia, and alternated bone biomarkers.

Acknowledgements

The Authors would like to acknowledge the NKI-AVL Department of Pathology for their support with facilitating the autopsy and providing the bone samples. The Authors would also like to acknowledge the NKI-AVL Core Facility Molecular Pathology & Biobanking (CFMPB) for supplying NKI-AVL Biobank material and /or lab support.

Footnotes

  • Authors’ Contributions

    van Bussel MTJ: Conceptualization; Data curation; Formal analysis; Investigation; Methodology; Project administration; Software; Visualization; original draft; Writing. Bravenboer N, van Essen HW, Snaebjornsson P, Appelman-Dijkstra NM: Data curation; Formal analysis; Investigation; Methodology; Project administration; Software; Visualization; Writing – review & editing. Schellens JHM, Opdam FL: Data curation; Formal analysis; Investigation; Methodology; Project administration; Writing – review & editing. All Authors contributed to writing the manuscript, reviewing its drafts, approving its final version and agreed with its submission.

  • Conflicts of Interest

    van Bussel MTJ, Bravenboer N, van Essen HW, Snaebjornsson P, and Appelman-Dijkstra NM declare no conflicts of interest. Schellens JHM is an (part time) employee, stock- and patent holder of Modra Pharmaceuticals, a spin out company developing oral taxane formulations; Jan Schellens is also a part time employee of Byondis BV and received consultancy fees from Debiopharm, all not related to the contents of the manuscript. Opdam FL is principal investigator of phase 1 institutionally sponsored trials by Astra Zeneca, Boehringer ingelheim, Crescendo, Cytovation, GSK, Incyte, Int1B3, Lilly, Merus, Pierre Fabre, Relay, RevMed, Roche and Taiho.

  • Funding

    This manuscript received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

  • Artificial Intelligence (AI) Disclosure

    No artificial intelligence (AI) tools, including large language models or machine learning software, were used in the preparation, analysis, or presentation of this manuscript.

  • Received April 6, 2025.
  • Revision received May 1, 2025.
  • Accepted May 2, 2025.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).

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