Clinical resistance mechanisms to CDK4/6 inhibitors in HR+ breast cancer have not been clearly defined. Whole exome sequencing of 59 tumors with CDK4/6i exposure revealed multiple candidate resistance mechanisms including RB1 loss, activating alterations in AKT1, RAS, AURKA, CCNE2, ERBB2, and FGFR2, and loss of ER expression. In vitro experiments confirmed that these alterations conferred CDK4/6i resistance. Cancer cells cultured to resistance with CDK4/6i also acquired RB1, KRAS, AURKA, or CCNE2 alterations, which conferred sensitivity to AURKA, ERK, or CHEK1 inhibition. Besides inactivation of RB1, which accounts for ~5% of resistance, seven of these mechanisms have not been previously identified as clinical mediators of resistance to CDK4/6 inhibitors in patients. Three of these-RAS activation, AKT activation, and AURKA activation-have not to our knowledge been previously demonstrated preclinically. Together, these eight mechanisms were present in 80% of resistant tumors profiled and may define therapeutic opportunities in patients. SignificanceWe identified eight distinct mechanisms of resistance to CDK4/6 inhibitors present in 80% of resistant tumors profiled. Most of these have a therapeutic strategy to overcome or prevent resistance in these tumors. Taken together, these findings have critical implications related to the potential utility of precisionbased approaches to overcome resistance in many patients with HR+ MBC..

AbstractClinical resistance mechanisms to CDK4/6 inhibitors in HR+ breast cancer have not been clearly defined. Whole exome sequencing of 59 tumors with CDK4/6i exposure revealed multiple candidate resistance mechanisms including RB1 loss, activating alterations in AKT1, RAS, AURKA, CCNE2, ERBB2, and FGFR2, and loss of ER expression. In vitro experiments confirmed that these alterations conferred CDK4/6i resistance. Cancer cells cultured to resistance with CDK4/6i also acquired RB1, KRAS, AURKA, or CCNE2 alterations, which conferred sensitivity to AURKA, ERK, or CHEK1 inhibition. Besides inactivation of RB1, which accounts for ∼5% of resistance, seven of these mechanisms have not been previously identified as clinical mediators of resistance to CDK4/6 inhibitors in patients. Three of these—RAS activation, AKT activation, and AURKA activation—have not to our knowledge been previously demonstrated preclinically. Together, these eight mechanisms were present in 80% of resistant tumors profiled and may define therapeutic opportunities in patients.SignificanceWe identified eight distinct mechanisms of resistance to CDK4/6 inhibitors present in 80% of resistant tumors profiled. Most of these have a therapeutic strategy to overcome or prevent resistance in these tumors. Taken together, these findings have critical implications related to the potential utility of precision-based approaches to overcome resistance in many patients with HR+ MBC.

T riple negative breast cancer (TNBC) is associated with a poor prognosis compared to other types of breast cancer. The classification of 'triple negative' is not one homogenous tumor type, but rather is made up of multiple molecularly and biologically diverse tumor subtypes. At present, no approved targeted therapy exists and the standard remains cytotoxic chemotherapy. The identification of TNBC subtypes has provided a basis for identifying possible targeted therapeutic options. In addition, the recognition that some TNBCs share characteristics similar to tumors arising in patients with germline BRCA mutations has led to consideration of DNA damaging agents as a potential treatment option. Multiple investigational approaches are also underway, including immune checkpoint inhibition, poly (ADP-ribose) polymerase inhibition, and androgen receptor blockage. The limited options available for systemic treatment of TNBC will hopefully expand as more is learned about the complex biology and molecular targets of this group of breast cancers. This review will discuss the biology of TNBC, current treatment options, and promising experimental strategies. KeywordsTriple negative, breast cancer, therapeutics 1 It is more common in African American women, younger women, and those with a germline BRCA1 mutation. Due to lack of ER, PR, and HER2 and the significant heterogeneity among TNBC, no approved targeted therapies exist and standard treatment remains cytotoxic chemotherapy. While response rates to chemotherapy in early stage disease are high, patients remain at high risk for relapse and prognosis remains inferior to other types of breast cancer. Subtyping and molecular characteristicsIn a seminal paper by Perou et al., gene expression profiling was used to categorize breast cancers into five molecular subtypes. The basal-like type is characterized by lack of ER, PR, and HER2 expression, expression of cytokeratins and EGFR, and a clinically more aggressive phenotype.2 This subtype overlaps with TNBC but the terms are not synonymous; in fact, about one fourth of TNBCs are not basal-like by gene expression, and some non-TNBCs are basal-like by molecular profiling (see Figure 1). 3,4 As more is discovered about the biology of TNBC, it has become clear that this category of breast cancer is not one homogeneous tumor type, but rather is made up of a group of molecularly diverse tumor subtypes. These subtypes have varying gene expression profiles, clinical characteristics, and responses to treatment. In an effort to translate the heterogeneity of TNBC into rational clinical design, Lehmann and colleagues further characterized TNBC into six distinct subtypes based on molecular profiles, each with unique drivers and clinical phenotypes. These subtypes include basal-like 1 (BL1), basal-like 2 (BL2), immunomodulatory (IM), mesenchymal (M), mesenchymal stem-like (MSL), and luminal androgen receptor(LAR).5 Each exhibited different sensitivities to therapeutic agents, both in cell line models and in some retrospective clinical trials...

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Background This is the first-in-human study of novel anti-angiopoietin-2 (Ang-2) monoclonal antibody LY3127804 as monotherapy and in combination with ramucirumab in advanced solid tumours. Methods Patients received intravenous LY3127804 monotherapy (4, 8, 12, 16, 20 and 27 mg/kg) in part A; LY3127804 (8, 12, 16, 20 and 27 mg/kg) with 8 mg/kg ramucirumab in part B; and LY3127804 (20 mg/kg) with 12 mg/kg ramucirumab in part C. Treatments were administered every 2 weeks (Q2W) during 28-day cycles. Dose-escalation was based on cycle 1 dose-limiting toxicities (DLTs). Results Sixty-two patients were treated in part A (n = 20), part B (n = 35) and part C (n = 7). Constipation, diarrhoea and fatigue were the most common treatment-emergent adverse events (TEAEs) in part A; hypertension and peripheral oedema were the most frequent TEAE in parts B and C. No DLT was observed and maximum tolerated dose for LY3127804 was not reached. Four patients achieved partial response with combination therapy (clear cell endometrial carcinoma, cervix squamous cell carcinoma, carcinoma of unknown primary and gastroesophageal junction carcinoma), 29 achieved stable disease, and 24 had progressive disease. Conclusions LY3127804 monotherapy and its combination with ramucirumab are well tolerated. LY3127804 20 mg/kg was the recommended Phase 2 dose.

TPS10561 Background: Aurora kinase A (AurA) has been implicated in high-risk neuroblastoma, including roles stabilizing and increasing expression of MYCN protein. AurA impacts the function of MYCN in mediating transcription in a cell cycle dependent manner, suggesting that neuroblastoma and other MYC/MYCN-driven tumors may be sensitive to AurA inhibition. LY3295668 is a selective AurA inhibitor. The lack of AurB inhibitory activity is hypothesized to minimize on-target hematologic toxicity associated with AurB inhibition. The molecule’s selectivity is intended to allow for continuous dosing at exposures associated with > 90% target inhibition at trough. In an analysis of LY3295668 antiproliferative effects in 560 cancer cell lines, neuroblastoma was among the most sensitive histologies tested. This screen also separately evaluated genomic predictors of response to LY3295668, with MYC/ MYCN amplification identified as among the strongest predictors of sensitivity to this agent. LY3295668 is currently being evaluated in early phase adult trials. The current trial (J10-MC-JZHD) was uniquely designed to hasten time to first-in-child oncology development for a rare unmet need of relapsed/refractory neuroblastoma patients. Methods: Study J1O-MC-JZHD (NCT04106219) is a multicenter, dual collaboration (NANT and ITCC), randomized, open-label, Phase 1 study of oral LY3295668 in children with relapsed/refractory neuroblastoma. A rolling 6 design will be followed for dose escalation in both a monotherapy cohort and a combination cohort testing LY3295668 together with cyclophosphamide and topotecan. The starting monotherapy dose will be equivalent to 80% of the adult maximum tolerated dose. Key eligibility criteria include recurrent/refractory neuroblastoma not amenable to curative treatment, age 2-21 years, mandatory archival tissue submission, ability to swallow capsules, and adequate hematologic and organ function. LY3295668 is administered in capsule form orally BID continuously. Primary objectives include assessments of safety and tolerability of study drug to identify RP2D as monotherapy and combination, and assess antitumor activity. Secondary objectives include assessment of the pharmacokinetic profile as monotherapy and in combination, and assessment of the relationship between study drug exposure and efficacy. Following determination of the RP2Ds, an expansion phase will randomize patients to monotherapy or to the combination arm. Enrollment began 16 Dec 2019 and is ongoing. Clinical trial information: NCT04106219.

Background: LY3295668 erbumine (AK-01) is a selective, reversible, ATP-competitive small molecule inhibitor of aurora kinase A (AurA). LY3295668 erbumine treatment in xenograft and patient-derived xenograft models resulted in tumor growth arrest or regression of several tumor types with an acceptable safety profile. This study evaluated dose-limiting toxicities (DLTs), maximum tolerated dose (MTD) and safety of LY3295668 erbumine monotherapy in patients with locally advanced or metastatic solid tumors. Methods: This ongoing phase I/II, open-label, multicenter study enrolled patients with locally advanced or metastatic solid tumors, ECOG PS 0-1, estimated life expectancy ≥ 12 weeks, adequate organ function, disease progression after 1 - 4 regimens for locally advanced or metastatic disease and no history of clinically significant cardiac disease. The primary objective was to determine MTD; secondary objectives included evaluation of tolerability and overall safety profile of LY3295668 erbumine. All patients received oral, twice daily (BID) doses of LY3295668 erbumine in cycles of 21 days in a multiple ascending dose schedule. Adverse events (AEs) were graded per NCI CTCAE v4.03. Results: Twelve patients median age of 60 (range 39-74, 5 male and 7 female) were enrolled in the phase I study at the following dose levels: 25 mg (n=8); 50 mg (n=2); 75 mg (n=2). One patient in the 25 mg cohort experienced a DLT of grade (G) 3 mucositis. One patient in the 50 mg cohort experienced a DLT of G3 mucositis and G3 diarrhea. Both patients in the 75 mg cohort experienced DLTs (1=G3 mucositis, 1=G4 mucositis and G3 corneal deposits). The treatment-related AEs (TRAEs) observed in each cohort were as follows: in the 25 mg treatment group, six patients experienced various G1/2 TRAEs with only mucositis reported in > one patient (n=2); G3 TRAEs were anemia (n=1) and mucositis (n=1). In the two patients receiving 50 mg, G3 TRAEs were: mucositis (n=1), diarrhea (n=1), and upper chest rash (n=1). In the two patients receiving 75 mg, G3/4 TRAEs were: mucositis (n=2), corneal deposits (n=1), neutropenia (n=1) and diarrhea (n=1). There were no treatment-related deaths. During this study, three patients died due to disease progression: one patient died < 30 days and two patients died > 30 days after the last treatment dose. At the time of data lock, two of the eight patients in the 25 mg BID phase I cohort remained on treatment for ≥ 8 months. In addition to the 12 patients in phase I, one patient was enrolled in phase II after the MTD was determined, totaling 13 patients who received treatment in the entire study. Conclusion: The MTD of LY3295668 erbumine was determined to be 25 mg BID and found to be well tolerated in patients with locally advanced or metastatic solid tumors. Trial Registration: NCT03092934 Citation Format: Quincy Chu, Nathaniel Bouganim, Caroline Fortier, Sara Zaknoen, John R. Stille, Jill D. Kremer, Eunice Yuen, Yu-Hua Hui, Amparo de la Peña, Andrew Lithio, Patricia S. Smith, Gerald Batist. A Phase I/II study of aurora kinase A inhibitor, LY3295668 erbumine (AK-01): Safety as monotherapy in patients with locally advanced or metastatic solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT083.

Background: The aurora kinase family plays a vital regulatory role in mitotic and meiotic events, with aurora kinase A (AurA) critical to centrosome maturation, mitotic spindle formation and checkpoint activation. LY3295668 erbumine (AK-01) is an inhibitor of AurA with 1000-fold selectivity for inhibition of AurA over aurora kinase B (AurB). Pharmacokinetic-pharmacodynamic (PK-PD) nonclinical models have shown that 90% inhibition of AurA phosphorylation (pAurA) over an extended period (≥ 16 hours per day) was required to yield efficacy in H446 (small cell lung cancer) xenograft models. Nonclinical plasma LY3295668 concentrations associated with 90% pAurA inhibition (IC90) were estimated previously using a direct sigmoidal relationship between PK and pAurA. In this first-in-man study, PK of LY3295668 in patients with advanced/metastatic cancer were evaluated. Human PK profiles were simulated subsequently and compared to pAurA IC90 to estimate a human efficacious dose range. Methods: LY3295668 erbumine was administered to 13 patients with locally advanced or metastatic solid tumors over a dose range of 25 to 75 mg given twice daily (BID). In the first cycle, serial plasma PK samples were collected up to 8 hours on Day 1 and Day 15. Additional trough samples were obtained prior to dosing on Day 2, on Day 8 and at discontinuation if applicable. PK parameter estimations were performed using non-linear mixed effects models in NONMEM v7.3. Results: The population PK model was developed using 146 plasma concentrations collected from 13 patients. A 2-compartment PK model with first order absorption best described the disposition of LY3295668. Following oral administration, LY3295668 was rapidly absorbed with peak concentrations occurring within 1 to 2 hours. The estimated elimination half-life was approximately 21 hours; therefore, steady state was attained within 4 to 5 days of dosing. Simulations of plasma concentration-time profiles showed that at the maximum tolerated dose (MTD) of 25 mg BID, 90% of patients are expected to achieve steady-state plasma concentrations greater than the pAurA IC90 for the entire day. Patients with dose limiting toxicities (DLTs) had the highest model-predicted exposures amongst the 13 patients. Conclusion: At the MTD of 25 mg BID, steady state LY3295668 plasma concentrations are maintained above the pAurA IC90 for the entire dosing interval, exceeding the minimum requirements for efficacy associated with non-clinical xenograft models. Trial Registration: NCT03092934 Citation Format: Eunice Yuen, Yu-Hua Hui, Amparo de la Peña, Sonya C. Tate, John R. Stille, Andrew Lithio, Patricia S. Smith, Quincy Chu, Gerald Batist, Nathaniel Bouganim, Caroline Fortier, Sara Zaknoen, Jill Kremer. Population pharmacokinetics of an aurora kinase A inhibitor, LY3295668 erbumine (AK-01), in patients with locally advanced or metastatic solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT019.