Clinical Outcomes With Abemaciclib After Prior CDK4/6 Inhibitor Progression in Breast Cancer: A Multicenter Experience.

BACKGROUND: Inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6i) are widely used as first-line therapy for hormone receptor-positive metastatic breast cancer (HR+ MBC). Although abemaciclib monotherapy is also FDA-approved for treatment of disease progression on endocrine therapy, there is limited insight into the clinical activity of abemaciclib after progression on prior CDK4/6i. PATIENTS AND METHODS: We identified patients with HR+ MBC from 6 cancer centers in the United States who received abemaciclib after disease progression on prior CDK4/6i, and abstracted clinical features, outcomes, toxicity, and predictive biomarkers. RESULTS: In the multicenter cohort, abemaciclib was well tolerated after a prior course of CDK4/6i (palbociclib)-based therapy; a minority of patients discontinued abemaciclib because of toxicity without progression (9.2%). After progression on palbociclib, most patients (71.3%) received nonsequential therapy with abemaciclib (with ≥1 intervening non-CDK4/6i regimens), with most receiving abemaciclib with an antiestrogen agent (fulvestrant, 47.1%; aromatase inhibitor, 27.6%), and the remainder receiving abemaciclib monotherapy (19.5%). Median progression-free survival for abemaciclib in this population was 5.3 months and median overall survival was 17.2 months, notably similar to results obtained in the MONARCH-1 study of abemaciclib monotherapy in heavily pretreated HR+/HER2-negative CDK4/6i-naïve patients. A total of 36.8% of patients received abemaciclib for ≥6 months. There was no relationship between the duration of clinical benefit while on palbociclib and the subsequent duration of treatment with abemaciclib. RB1, ERBB2, and CCNE1 alterations were noted among patients with rapid progression on abemaciclib. CONCLUSIONS: A subset of patients with HR+ MBC continue to derive clinical benefit from abemaciclib after progression on prior palbociclib. These results highlight the need for future studies to confirm molecular predictors of cross-resistance to CDK4/6i therapy and to better characterize the utility of abemaciclib after disease progression on prior CDK4/6i.

Pilot Randomized Trial of a Pharmacy Intervention for Older Adults with Cancer.

BACKGROUND: Oncology clinicians often struggle with managing medications and vaccinations in older adults with cancer. We sought to demonstrate the feasibility and preliminary efficacy of integrating pharmacists into the care of older adults with cancer to enhance medication management and vaccination administration. METHODS: We randomly assigned patients aged ≥65 years with breast, gastrointestinal, or lung cancer receiving first-line chemotherapy to the pharmacy intervention or usual care. Patients assigned to the intervention met with a pharmacist once during their second or third chemotherapy infusion. We obtained information about patients' medications and vaccinations via patient report and from the electronic health record (EHR) at baseline and week 4. We determined the number of discrepant (difference between patient report and EHR) and potentially inappropriate (Beers Criteria assessed by nonintervention pharmacists blinded to group assignment) medications. We defined the intervention as feasible if >75% of patients enrolled in the study and received the pharmacist visit. RESULTS: From January 17, 2017, to October 27, 2017, we enrolled and randomized 60 patients (80.1% of patients approached). Among those assigned to the intervention, 96.6% received the pharmacist visit. At week 4, intervention patients had higher rates of acquiring vaccinations for pneumonia (27.6% vs. 0.0%, p = .002) and influenza (27.6% vs. 0.0%, p = .002) compared with usual care. Intervention patients had fewer discrepant (5.82 vs. 8.07, p = .094) and potentially inappropriate (3.46 vs. 4.80, p = .069) medications at week 4, although differences were not significant. CONCLUSION: Integrating pharmacists into the care of older adults with cancer is feasible with encouraging preliminary efficacy for enhancing medication management and improving vaccination rates. IMPLICATIONS FOR PRACTICE: Results of this study showed the feasibility, acceptability, and preliminary efficacy of an intervention integrating pharmacists into the care of older adults with cancer. Notably, patients assigned to the intervention had fewer discrepant medications and were more likely to acquire vaccinations for pneumonia and influenza. Importantly, this work represents the first randomized controlled trial involving the integration of pharmacists into the outpatient oncologic care of older adults with cancer. In the future, a larger randomized trial is needed to demonstrate the efficacy of this care model to enhance medication management and improve vaccination outcomes for older patients with cancer.

Clinical Management of Potential Toxicities and Drug Interactions Related to Cyclin-Dependent Kinase 4/6 Inhibitors in Breast Cancer: Practical Considerations and Recommendations.

Aberrations of the cell cycle are pervasive in cancer, and selective cell cycle inhibition of cancer cells is a target of choice for a number of novel cancer therapeutics. Cyclin-dependent kinases (CDKs) are key regulatory enzymes that control cell cycle transitions and the commitment to cell division. Palbociclib and ribociclib are both orally active, highly selective reversible inhibitors of CDK4 and CDK6 that are approved by the U.S. Food and Drug Administration (FDA) for hormone receptor-positive metastatic breast cancer in combination with specific endocrine therapies. A third oral CDK4/6 inhibitor, abemaciclib, received Breakthrough Therapy designation status from the FDA and is also being developed in breast cancer. The most common adverse events associated with palbociclib and ribociclib are hematologic, particularly neutropenia. However, the neutropenia associated with CDK4/6 inhibitors is distinct from chemotherapy-induced neutropenia in that it is rapidly reversible, reflecting a cytostatic effect on neutrophil precursors in the bone marrow. Most hematologic abnormalities seen with CDK4/6 inhibitors are not complicated and are adequately managed with standard supportive care and dose adjustments when indicated. Cytopenias are less prevalent with abemaciclib, although fatigue and gastrointestinal toxicity is more common with this agent. This review focuses on the clinical management of potential toxicities and drug interactions seen with the use of CDK4/6 inhibitors in breast cancer, with a focus on palbociclib and ribociclib, and summarizes practical management strategies for an oncologist. IMPLICATIONS FOR PRACTICE: The emergence of modern cyclin-dependent kinase (CDK) inhibitors has changed the treatment paradigm for metastatic hormone receptor (HR)-positive breast cancer. Palbociclib, ribociclib, and abemaciclib are highly selective reversible inhibitors of CDK4 and CDK6. Palbociclib is U.S. Food and Drug Administration (FDA)-approved in the first- and second-line settings in combination with endocrine therapy for HR-positive metastatic breast cancer. Ribociclib is FDA-approved in the first-line setting. Abemaciclib has received FDA Breakthrough Therapy designation status. This review focuses on the clinical management of potential toxicities and drug interactions seen with the use of CDK4/6 inhibitors in breast cancer.

Ruxolitinib for secondary hemophagocytic lymphohistiocytosis: First case report.

Hemophagocytic lymphohistiocytosis (HLH) is an immune-mediated disorder resulting in hyper-activation of inflammatory cytokines. If left untreated, the uncontrolled inflammatory response can lead to significant tissue injury and potentially life-threatening multi-organ dysfunction. Conventional immunosuppressive agents are available for the management of HLH, including dexamethasone, cyclosporine, and etoposide; however, patients may not respond to these therapies. Clinicians may turn toward alternative pharmacologic agents that likely have less clinical evidence. We describe a case of secondary HLH that did not respond favorably to conventional treatments. Serum inflammatory markers continued to rise significantly with clinical deterioration and worsening pancytopenia. The severe thrombocytopenia and neutropenia were deemed to have contributed to a spontaneous subdural hematoma and candidemia, respectively. Ruxolitinib, a Janus kinase (JAK) 1/2 inhibitor, was then utilized as a novel salvage therapy based on available in vivo murine data at the time. Following initiation, there was improvement seen in several disease markers, including serum ferritin, lactate dehydrogenase, fibrinogen, and liver function tests. However, the pancytopenia did not show signs of recovery. The patient ultimately expired after 7days of ruxolitinib treatment. It is unclear if the improvement in disease markers was attributed to JAK inhibition alone. However, this experience combined with the positive in vivo murine data suggests that ruxolitinib may serve as a potential treatment option for HLH, pending the release of more robust data. To our knowledge, this is the first human case report describing the use of ruxolitinib for HLH. Future studies are warranted to determine the role of ruxolitinib in this setting.

Sacituzumab for the treatment of triple-negative breast cancer: the poster child of future therapy?

INTRODUCTION: Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer that disproportionately impacts younger women and is associated with a poor prognosis. Systemic treatment options for metastatic TNBC (mTNBC) are limited to cytotoxic chemotherapy agents with low response rates. This encouraged the clinical development of sacituzumab govitecan (IMMU-132), an antibody-drug conjugate targeting Trop-2, a potential target in epithelial cancer such as TNBC. Areas covered: We summarize the key features, pharmacokinetics, and the safety and efficacy data of sacituzumab govitecan. We also discuss the future directions of this novel therapeutic agent for mTNBC. Expert opinion: Based on the efficacy and tolerability observed in the phase 1/2 clinical trial, sacituzumab govitecan was granted breakthrough therapy designation by the Food and Drug Administration as ≥3rd line therapy for mTNBC. Novel treatment modalities for the management of mTNBC are necessary to improve the care of this aggressive disease. Sacituzumab govitecan represents an important advance in the treatment of mTNBC because of its efficacy and tolerability.

Ribociclib for post-menopausal women with HR+/HER2- advanced or metastatic breast cancer.

INTRODUCTION: The introduction of CDK4/6 inhibitors, such as ribociclib, has changed the treatment landscape for post-menopausal women with HR+/HER2- advanced or metastatic breast cancer. As first-line treatment of HR+/HER2- MBC, the addition of a CDK4/6 inhibitor to an aromatase inhibitor improves progression-free survival compared to an aromatase inhibitor alone. Areas covered: In this drug profile, we review the current market for HR+/HER2- MBC, as well as the characteristics, mechanism, pharmacology, pharmacodynamics, pharmacokinetics, metabolism, clinical efficacy, toxicities, monitoring, and dosing modification of the CDK4/6 inhibitor ribociclib. Expert commentary: CDK4/6 inhibitors, such as ribociclib, improve outcomes in post-menopausal women with HR+/HER2- MBC. The most common toxicity of ribociclib is neutropenia, which is generally not complicated and can be managed with dose modification and/or supportive care measures. Additional research will help better define the optimal clinical use of ribociclib.