Small bowel obstruction and short bowel syndrome may impair the efficacy of Avutometinib and Defactinib in recurrent low grade serous ovarian cancer: A case report

The treatment of recurrent low grade serous ovarian cancer (LGSOC) is a challenge, but when complicated by recurrent small bowel obstructions (SBO) and/or major small bowel resections, the decreased absorption/efficacy of oral medications must be considered. We report the case of a patient with recurrent LGSOC previously treated with multiple debulking surgeries, neoadjuvant and adjuvant carboplatin/paclitaxel, and maintenance aromatase inhibitor therapy. A few weeks after initiating treatment within the RAMP-201 trial with the combination of Avutometinib (MEK inhibitor) and Defactinib (FAK inhibitor), two drugs recently approved by the FDA for the treatment of adult patients with KRAS-mutated LGSOC, she developed a small bowel obstruction that ultimately required extensive bowel resections, resulting in short bowel syndrome. Whole-exome sequencing (WES) of the recurrent LGSOC collected at the time of the bowel resection revealed copy number gains in multiple key genes within the RAS/RAF/MEK/ERK and FAK pathways, conferring potential tumor sensitivity to MEK/FAK inhibitors. In agreement with the WES results, the matched patient-derived xenograft (PDX) model established from the recurrent LGSOC demonstrated a remarkable sensitivity to the avutometinib/defactinib combination in vivo. Despite the high sensitivity of the PDX model, the patient progressed on the drug combination and had to be removed from the clinical trial. The experimental PDX results combined with our patient's clinical data strongly suggest that recurrent SBO and/or major bowel resections may represent unrecognized causes of resistance to avutometinib and defactinib significantly impairing the absorption of the oral drugs and decreasing the effectiveness of the regimen in recurrent heavily pretreated LGSOC patients. An earlier use of the novel oral drug combination in recurrent LGSOC is warranted.