Hill, Elizabeth G.

TPS350 Background: Mutations in isocitrate dehydrogenase 1 (mIDH1) are found in approximately 20-30% of patients with intrahepatic cholangiocarcinoma (CCA), and less commonly in glioma, chondrosarcoma, and other gastrointestinal malignancies. Despite documented clinical activity of mIDH1 inhibition in solid tumors, there are no approved targeted therapies for this patient population. LY3410738 is a potent, selective, and covalent inhibitor of mIDH1 R132. LY3410738 is differentiated from prior mIDH1 inhibitors by 1) its unique covalent binding mode, 2) its increased potency, and 3) its unique binding site outside of the dimer interface, which enables activity in the setting of known common second-site IDH1 mutations. Methods: This is an open-label, multicenter, global phase 1 study with oral LY3410738 currently enrolling patients with advanced CCA and other solid tumor types (NCT04521686). A dose escalation cohort will be followed with 4 exploratory expansion cohorts. The primary objective for dose escalation is determination of the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D). The primary objective for dose expansion is to assess the preliminary anti-tumor activity by ORR of LY3410738 when administered alone or in combination with cisplatin plus gemcitabine. Secondary objectives include evaluating safety and tolerability, pharmacokinetics, pharmacodynamics, progression free survival, and overall survival. Key inclusion criteria include any solid tumor with the presence of mIDH1 R132, ECOG performance status ≤1, and adequate organ function. Any prior treatment including an IDH1 inhibitor is allowed in the dose escalation cohort. Exclusion criteria include presence of active central nervous system metastases, leptomeningeal disease, and active or uncontrolled infection. CCA patients must not have had locoregional therapy within 4 weeks prior to the initial study dose, history of hepatic encephalopathy or refractory ascites, ongoing cholangitis, or mixed hepatocellular-CCA histology. Dose escalation will follow a 3+3 design and will allow patient back-fill to dose levels previously cleared for safety. Each cycle will be 28 days (4 weeks). Once the RP2D is determined, LY3410738 will be evaluated as monotherapy in expansion cohorts 1-3, and in combination with cisplatin plus gemcitabine in expansion cohort 4. Cohort 1 will enroll CCA patients with measurable disease who have received prior chemotherapy. Cohort 2 will enroll patients with advanced solid tumors except CCA who have measurable disease and received standard therapies. Cohort 3 will enroll patients with advanced solid tumors who have non-measurable disease and received standard therapies. Cohort 4 will enroll CCA patients with measurable disease who are treatment naïve for advanced disease. Clinical trial information: NCT04521686.

Purpose To provide recommendations on the appropriate use of breast tumor biomarker assay results to guide decisions on systemic therapy for metastatic breast cancer. Methods A literature search and prospectively defined study selection identified systematic reviews, meta-analyses, randomized controlled trials (RCTs), prospective–retrospective studies, and prospective comparative observational studies published from 2006 through September 2014. Results The literature search revealed 17 articles that met criteria for further review: 11 studies reporting discordances between primary tumors and metastases in expression of hormone receptors or human epidermal growth factor receptor 2 (HER2), one RCT that addressed the use of a biomarker to decide whether to change or continue a treatment regimen, and five prospective–retrospective studies that evaluated the clinical utility of biomarkers. Recommendations In patients with accessible metastases, biopsy for confirmation of disease process and retesting of estrogen receptor, progesterone receptor, and HER2 status should be offered, but evidence is lacking to determine whether changing anticancer treatment on the basis of change in receptor status affects clinical outcomes. With discordance of results between primary and metastatic tissues, the Panel consensus is to use preferentially the estrogen receptor, progesterone receptor, and HER2 status of the metastasis to direct therapy if supported by the clinical scenario and patient's goals for care. Carcinoembryonic antigen, cancer antigen 15-3, and cancer antigen 27-29 may be used as adjunctive assessments, but not alone, to contribute to decisions regarding therapy. Recommendations for tumor rebiopsy and use of circulating tumor markers are based on clinical experience and Panel informal consensus in the absence of studies designed to evaluate the clinical utility of the markers. As such, it is also reasonable for clinicians to not use these markers as adjunctive assessments.