First-in-Human Dose-Escalation Study of the Novel Oral Depsipeptide Class I-Targeting HDAC Inhibitor Bocodepsin (OKI-179) in Patients with Advanced Solid Tumors.

(1) Background: Histone deacetylases (HDACs) play a critical role in epigenetic signaling in cancer; however, available HDAC inhibitors have limited therapeutic windows and suboptimal pharmacokinetics (PK). This first-in-human phase I dose escalation study evaluated the safety, PK, pharmacodynamics (PDx), and efficacy of the oral Class I-targeting HDAC inhibitor bocodepsin (OKI-179). (2) Patients and Methods: Patients (n = 34) with advanced solid tumors were treated with OKI-179 orally once daily in three schedules: 4 days on 3 days off (4:3), 5 days on 2 days off (5:2), or continuous in 21-day cycles until disease progression or unacceptable toxicity. Single-patient escalation cohorts followed a standard 3 + 3 design. (3) Results: The mean duration of treatment was 81.2 (range 11-447) days. The most frequent adverse events in all patients were nausea (70.6%), fatigue (47.1%), and thrombocytopenia (41.2%). The maximum tolerated dose (MTD) of OKI-179 was 450 mg with 4:3 and 200 mg with continuous dosing. Dose-limiting toxicities included decreased platelet count and nausea. Prolonged disease control was observed, including two patients with platinum-resistant ovarian cancer. Systemic exposure to the active metabolite exceeded the preclinical efficacy threshold at doses lower than the MTD and was temporally associated with increased histone acetylation in circulating T cells. (4) Conclusions: OKI-179 has a manageable safety profile at the recommended phase 2 dose (RP2D) of 300 mg daily on a 4:3 schedule with prophylactic oral antiemetics. OKI-179 is currently being investigated with the MEK inhibitor binimetinib in patients with NRAS-mutated melanoma in the phase 2 Nautilus trial.

Moving Towards Targeted Therapies for Triple-Negative Breast Cancer.

PURPOSE OF REVIEW: In this review, we discuss targets of interest in Triple-negative breast cancer (TNBC), approved targeted agents and the results of the clinical trials that led to their approval. Additionally, we review ongoing clinical trials evaluating the use of novel targeted agents in the treatment of TNBC. RECENT FINDINGS: TNBC accounts for 15-20% of all breast cancer cases and is associated with worse clinical outcomes. Patients have a higher risk of metastatic recurrence and inferior overall survival compared to other breast cancer subtypes. Cytotoxic chemotherapy has historically been the mainstay of treatment for TNBC. In recent years, we have seen a surge in clinical trials investigating the use of targeted agents in TNBC and now have approval for targeted therapies in select patients. Inhibitors of PARP (olaparib and talazoparib), PD-L1 (atezolizumab) and an antibody drug conjugate targeting Trop-2 (sacituzumab govitecan-hziy) are now approved for the use in select groups of patients with TNBC. SUMMARY: Various novel targeted agents as monotherapy, dual targeted combinations, and chemotherapy combinations are currently under investigation. The results are promising and may significantly improve patient outcomes in TNBC.

Clinical Outcomes for Patients With Metastatic Breast Cancer Treated With Immunotherapy Agents in Phase I Clinical Trials.

BACKGROUND: Immuno-oncology (IO) agents have demonstrated efficacy across many tumor types and have led to change in standard of care. In breast cancer, atezolizumab and pembrolizumab were recently FDA-approved in combination with chemotherapy specifically for patients with PD-L1-positive metastatic triple-negative breast cancer (TNBC). However, the single agent PD-1/PD-L1 inhibitors demonstrate only modest single agent efficacy in breast cancer. The purpose of this study was to investigate the efficacy of novel IO agents in patients with metastatic breast cancer (MBC), beyond TNBC, treated in phase I clinical trials at the University of Colorado. METHODS: We performed a retrospective analysis using a database of patients with MBC who received treatment with IO agents in phase I/Ib clinical trials at the University of Colorado Hospital from January 1, 2012 to July 1, 2018. Patient demographics, treatments and clinical outcomes were obtained. RESULTS: We identified 43 patients treated with an IO agent either as a single agent or in combination. The average age was 53 years; 55.8% had hormone receptor-positive/HER2-negative breast cancer, 39.5% TNBC and 4.7% HER2-positive. Patients received an average of 2 prior lines of chemotherapy (range 0-7) in the metastatic setting. Most patients (72.1%) received IO alone and 27.9% received IO plus chemotherapy. Median progression-free survival (PFS) was 2.3 months and median overall survival (OS) was 12.1 months. Patients remaining on study ≥ 6 months (20.9%) were more likely to be treated with chemotherapy plus IO compared to patients with a PFS < 6 months (77.8% v. 14.7%). No differences in number of metastatic sites, prior lines of chemotherapy, breast cancer subtype, absolute lymphocyte count, or LDH were identified between patients with a PFS ≥ 6 months vs. < 6 months. CONCLUSIONS: Our phase I experience demonstrates benefit from IO therapy that was not limited to patients with TNBC and confirms improved efficacy from IO agents in combination with chemotherapy. A subset of patients with MBC treated in phase I clinical trials with an IO agent derived prolonged clinical benefit. Predictors of response to immunotherapy in breast cancer remain uncharacterized and further research is needed to identify these factors.

Paraneoplastic Encephalitis Associated with Locally Advanced Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer.

Paraneoplastic neurologic diseases (PND) are rare but can occur in patients with common malignancies including breast cancer. In patients with hormone receptor (HR)-negative human epidermal growth factor receptor 2 (HER2)-positive breast cancer, PND have been reported in association with anti-Yo antibodies and with clinical presentation of paraneoplastic cerebellar degeneration. We describe the case of a woman with progressively altered mental status and seizures, ultimately requiring admission. Based on her clinical presentation, imaging findings, and evidence of neural-directed antibodies in her serum and cerebrospinal fluid, she was diagnosed with paraneoplastic limbic encephalitis (LE) due to an underlying HR-negative, HER2-positive breast cancer. She showed a transient response to immunosuppression but had more significant improvement after surgical resection and initiation of chemotherapy along with HER2-directed therapy. To the best of our knowledge, this is the first documented case of paraneoplastic LE in a patient with HR-negative, HER2-positive breast cancer likely caused by the production of an unclassified anti-neuronal antibody.

Clinical outcomes of breast cancer patients treated in phase I clinical trials at University of Colorado Cancer Center.

Patients with metastatic breast cancer (MBC) refractory to standard of care therapies have a poor prognosis. The purpose of this study was to assess patient characteristics and clinical outcomes for patients with MBC treated on phase I clinical trials. We performed a retrospective review of all patients with MBC who were enrolled in phase I clinical trials at the University of Colorado Cancer Center from January 2012 to June 2018. A total of 208 patients were identified. Patients had a mean age of 57 years and received on average 2.1 (range 0-10) prior lines of chemotherapy. The majority of patients had hormone receptor-positive/HER2-negative breast cancer (58.6%) and 30.3% had triple-negative breast cancer. The median progression free survival (PFS) was 2.8 months (95% CI, 2.3-3.9) and median overall survival (OS) was 11.5 months (95% CI, 9.6-13.2). Independent factors associated with longer PFS in multivariable analysis were treatment in a breast cancer-selective trial or cohort (p = 0.016), age >50 years (p = 0.002), and ≤2 prior lines of chemotherapy in the metastatic setting (p = 0.025). Phase I clinical trials remain a valuable option for select patients with MBC and enrollment should be encouraged when available.

Nab-paclitaxel and atezolizumab for the treatment of PD-L1-positive, metastatic triple-negative breast cancer: review and future directions.

INTRODUCTION: Breast cancer is the most common malignancy in women in the United States and triple-negative breast cancer (TNBC) accounts for 15-20%. The standard of care for metastatic TNBC has been limited to cytotoxic chemotherapy with modest efficacy. TNBC is associated with high levels of tumor-infiltrating lymphocytes and PD-L1 expression, supporting the investigation of immune checkpoint inhibitors in this breast cancer subtype. AREAS COVERED: This review summarizes the clinical data supporting the use of atezolizumab and nab-paclitaxel in the treatment of metastatic PD-L1-positive TNBC. It examines the pharmacology and toxicity profile of the combination in patients with metastatic TNBC. EXPERT OPINION: The addition of atezolizumab to nab-paclitaxel prolonged progression-free survival in both the intention-to-treat and PD-L1-positive subgroups in the first line setting in patients with metastatic TNBC. The IMpassion 130 trial led to FDA-approval of this combination in patients with PD-L1-positive, metastatic TNBC and represents the first approval of immunotherapy for TNBC. This work supports ongoing investigations of other immunotherapy combinations in TNBC, predictive biomarker development and immunotherapy in patients with early stage TNBC. Immunotherapy combinations in TNBC have the potential to lead to improved survival in this group of patients with high risk disease.