Discussion
toxicities, bone pain, fractures
COMPLICATIONS, HYPERCALCEMIA
This phase Ib trial of the triplet combination of WNT974 + encorafenib + cetuximab showed the safety of the combination was not established in patients with BRAF In this single-arm trial of encorafenib + cetuximab + WNT974 in the same type of patient population, bone-related complications were among the most common and the most serious treatment-related toxicities observed. The combination treatment was associated with a higher incidence of bone-related toxicities, including increased susceptibility to fractures, bone pain, and hypercalcemia, compared with doublet treatment (encorafenib + cetuximab) or WNT974 monotherapy. In the phase III BEACON trial for BRAF The role of the Wnt pathway in bone homeostasis, repair, and regeneration is well known.The PK data for WNT974 and LHA333 should be interpreted with caution. Ninety-one of 446 WNT974 and LHA333 samples included in the calculation of the WNT974 and LHA333 PK parameters were analyzed after the validated storage stability time of 345 days. None of the samples analyzed for encorafenib were affected by stability issues. The study was not adequately powered to assess specific ­biomarker-related hypotheses. However, the molecular landscape should be evaluated in this patient population in future trials to better understand how best to treat these patients.The 2 patients who achieved a response had a duration of response of 106 and 291 days, respectively. Neither patient had any specific characteristics that appeared to enhance their chance of response. The patient with the longest duration of response experienced an SAE of grade 2 hypercalcemia, which resolved, followed by a grade 3 AE that was not suspected to be treatment-related but resulted in permanent discontinuation of the study treatment.It is unknown whether 