Cabozantinib use in metastatic renal cell carcinoma patients in clinical practice: Evaluation of dosing patterns, tolerability, and outcomes compared to clinical trials.

INTRODUCTION: Despite first-line approval in metastatic renal cell carcinoma (mRCC), the tyrosine kinase inhibitor cabozantinib is associated with frequent treatment-limiting side effects. Dose reductions in published trials of the drug and in clinical practice are commonplace. We analyzed our institution's real-world experience with cabozantinib dosing in patients with mRCC to assess strategies to improve tolerability and patient outcomes. OBJECTIVES: The purpose of our study is to retrospectively analyze dose intensity, tolerability, and duration of exposure in mRCC patients who received cabozantinib at our institution. METHODS: In this retrospective, single-center chart review, we identified 35 adult patients who received at least one cycle cabozantinib for mRCC during a two-year period. Dosing patterns were reviewed for each patient to allow calculation of median dose intensity and median duration of exposure. RESULTS: The median dose intensity for cabozantinib was 55.4% and the median actual daily dose was 33.2 mg. Median duration of cabozantinib exposure was 10.4 months. Several alternative dosing strategies were employed with 60% of patients requiring at least one dose intervention to manage toxicities. CONCLUSIONS: Patients in this analysis received a median actual daily dose of 33.4 mg, less than the reported median doses in the METEOR and CABOSUN trials. However, our median duration of cabozantinib treatment was 10.4 months compared to 8.3 months and 6.5 months in these respective trials. Further investigation is warranted to determine if alternative dosing strategies and lower median actual daily doses produce survival results comparable to published clinical trials.

Evaluation of arthralgias in adult oncology patients receiving immune checkpoint inhibitors.

Immune checkpoint inhibitors are being commonly used as anticancer therapies to treat malignancies. Immune checkpoint inhibitors have been associated with numerous immune-related adverse events (irAEs). IrAEs are well documented; however, rheumatic irAEs are infrequently reported in published literature. The objective of this single-center retrospective chart review study was to evaluate the incidence of arthralgias with immune checkpoint inhibitor therapy as well as the management of these immune-related events. Patients were included if they received one or more doses of nivolumab, pembrolizumab, atezolizumab, ipilimumab, or a combination of agents within the last year. Exclusion criteria included documented history of autoimmune disease, off-label use of immune checkpoint inhibitor, and non-FDA-approved weight-based dosing. This study included 98 patients for review and identified 11 patients that developed arthralgias with immune checkpoint inhibitor therapy. Median time to event was 63 days. Seven patients were treated with corticosteroids. Immune checkpoint inhibitor therapy was held in six patients with arthralgias. Inflammatory markers were collected for six patients and elevated in four of these cases. One patient was referred to rheumatology. The three patients who had grading of arthralgias were not managed optimally according to guideline recommendations. These findings show that 11% of patients treated with immune checkpoint inhibitors had documented arthralgias, consistent with previous reports in the literature. Also, the report shows that management and treatment of these events at our institution was not consistent between providers. Lastly, collaboration with rheumatology may be essential in managing arthralgias and other rheumatologic irAEs.

A pilot study to assess the pharmacy impact of implementing a chemotherapy-induced nausea or vomiting collaborative disease therapy management in the outpatient oncology clinics.

BACKGROUND: Collaborative drug therapy management is a formal partnership between a pharmacist and physician to allow the pharmacist to manage a patient's drug therapy. Literature supports collaborative disease therapy management can improve patient outcomes, improve medication adherence, enhance medication safety, and positively influence healthcare expenditures. Chemotherapy induced nausea or vomiting is considered one of the most distressing and feared adverse events among patients receiving chemotherapy. Chemotherapy induced nausea or vomiting can impact a patient's quality of life and may affect compliance with the treatment plan. PURPOSE: The objective of this pilot study was to determine the pharmacy impact of implementing a chemotherapy induced nausea or vomiting collaborative disease therapy management protocol in the outpatient oncology clinics at a National Cancer Institute (NCI)-designated cancer center associated with an academic medical center. The primary endpoint was to determine the number and type of chemotherapy induced nausea or vomiting clinical interventions made by the oncology pharmacists. Secondary endpoints included comparing patient's Multinational Association for Supportive Care in Cancer scores and revenue of pharmacists' services. METHODS: The credentialed oncology pharmacists were consulted by an oncologist to manage chemotherapy induced nausea or vomiting. Patients were included in the chemotherapy induced nausea or vomiting collaborative disease therapy management if they were seen in an outpatient oncology clinic from October 2016 to January 2017 and had a referral from a qualified provider to help manage chemotherapy induced nausea or vomiting. Patients admitted to the hospital at the time of consult were excluded from the study. The pharmacists interviewed patients and provided recommendations. The pharmacists followed up with the patient via a telephone call or during the next scheduled clinic visit to assess their symptoms. RESULTS: The chemotherapy induced nausea or vomiting collaborative disease therapy management pilot study was implemented in October 2016. From October 2016 to January 2017, there were 45 consults for the management of chemotherapy induced nausea or vomiting. The pharmacists made 188 clinical interventions, which included addition of new medications (37%), patient education (34%), deletion of medications (10%), changing a dose/duration/frequency (8%), and other interventions (11%). Multinational Association for Supportive Care in Cancer symptom scores were available for 5 patients, in which all showed improvements from baseline with the pharmacists' clinical interventions. CONCLUSIONS: The implementation of our chemotherapy induced nausea or vomiting collaborative disease therapy management pilot study has shown favorable results after a 4-month evaluation period. The pharmacists have made a substantial number of clinical interventions and provided patient education to patients undergoing chemotherapy.

ALT-803, an IL-15 superagonist, in combination with nivolumab in patients with metastatic non-small cell lung cancer: a non-randomised, open-label, phase 1b trial.

BACKGROUND: Immunotherapy with PD-1 or PD-L1 blockade fails to induce a response in about 80% of patients with unselected non-small cell lung cancer (NSCLC), and many of those who do initially respond then develop resistance to treatment. Agonists that target the shared interleukin-2 (IL-2) and IL-15Rßγ pathway have induced complete and durable responses in some cancers, but no studies have been done to assess the safety or efficacy of these agonists in combination with anti-PD-1 immunotherapy. We aimed to define the safety, tolerability, and activity of this drug combination in patients with NSCLC. METHODS: In this non-randomised, open-label, phase 1b trial, we enrolled patients (aged ≥18 years) with previously treated histologically or cytologically confirmed stage IIIB or IV NSCLC from three academic hospitals in the USA. Key eligibility criteria included measurable disease, eligibility to receive anti-PD-1 immunotherapy, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received the anti-PD-1 monoclonal antibody nivolumab intravenously at 3 mg/kg (then 240 mg when US Food and Drug Administration [FDA]-approved dosing changed) every 14 days (either as new treatment or continued treatment at the time of disease progression) and the IL-15 superagonist ALT-803 subcutaneously once per week on weeks 1-5 of four 6-week cycles for 6 months. ALT-803 was administered at one of four escalating dose concentrations: 6, 10, 15, or 20 µg/kg. The primary endpoint was to define safety and tolerability and to establish a recommended phase 2 dose of ALT-803 in combination with nivolumab. Analyses were per-protocol and included any patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT02523469; phase 2 enrolment of patients is ongoing. FINDINGS: Between Jan 18, 2016, and June 28, 2017, 23 patients were enrolled and 21 were treated at four dose levels of ALT-803 in combination with nivolumab. Two patients did not receive treatment because of the development of inter-current illness during enrolment, one patient due to leucopenia and one patient due to pulmonary dysfunction. No dose-limiting toxicities were recorded and the maximum tolerated dose was not reached. The most common adverse events were injection-site reactions (in 19 [90%] of 21 patients) and flu-like symptoms (15 [71%]). The most common grade 3 adverse events, occurring in two patients each, were lymphocytopenia and fatigue. A grade 3 myocardial infarction occurred in one patient. No grade 4 or 5 adverse events were recorded. The recommended phase 2 dose of ALT-803 is 20 µg/kg given once per week subcutaneously in combination with 240 mg intravenous nivolumab every 2 weeks. INTERPRETATION: ALT-803 in combination with nivolumab can be safely administered in an outpatient setting. The promising clinical activity observed with the addition of ALT-803 to the regimen of patients with PD-1 monoclonal antibody relapsed and refractory disease shows evidence of anti-tumour activity for a new class of agents in NSCLC. FUNDING: Altor BioScience (a NantWorks company), National Institutes of Health, and Medical University of South Carolina Hollings Cancer Center.

Initial Management of Noncastrate Advanced, Recurrent, or Metastatic Prostate Cancer: ASCO Guideline Update.

PURPOSE: Update all preceding ASCO guidelines on initial hormonal management of noncastrate advanced, recurrent, or metastatic prostate cancer. METHODS: The Expert Panel based recommendations on a systematic literature review. Recommendations were approved by the Expert Panel and the ASCO Clinical Practice Guidelines Committee. RESULTS: Four clinical practice guidelines, one clinical practice guidelines endorsement, 19 systematic reviews with or without meta-analyses, 47 phase III randomized controlled trials, nine cohort studies, and two review papers informed the guideline update. RECOMMENDATIONS: Docetaxel, abiraterone, enzalutamide, or apalutamide, each when administered with androgen deprivation therapy (ADT), represent four separate standards of care for noncastrate metastatic prostate cancer. Currently, the use of any of these agents in any particular combination or series cannot be recommended. ADT plus docetaxel, abiraterone, enzalutamide, or apalutamide should be offered to men with metastatic noncastrate prostate cancer, including those who received prior therapies, but have not yet progressed. The combination of ADT plus abiraterone and prednisolone should be considered for men with noncastrate locally advanced nonmetastatic prostate cancer who have undergone radiotherapy, rather than castration monotherapy. Immediate ADT may be offered to men who initially present with noncastrate locally advanced nonmetastatic disease who have not undergone previous local treatment and are unwilling or unable to undergo radiotherapy. Intermittent ADT may be offered to men with high-risk biochemically recurrent nonmetastatic prostate cancer. Active surveillance may be offered to men with low-risk biochemically recurrent nonmetastatic prostate cancer. The panel does not support use of either micronized abiraterone acetate or the 250 mg dose of abiraterone with a low-fat breakfast in the noncastrate setting at this time.Additional information is available at www.asco.org/genitourinary-cancer-guidelines.

Immune-related adverse events are linked with improved progression-free survival in patients receiving anti-PD-1/PD-L1 therapy.

BACKGROUND: Immune-related adverse events (irAEs) are commonly encountered, when using programmed death-1/programmed death-ligand-1 (anti-PD-1/PD-L1) therapy and are often managed with corticosteroids. The effect of irAEs, particularly when steroids are required, on patient survival is not well established. METHODS: In this retrospective analysis, data for 157 patients with various tumor types treated with anti-PD-1/PD-L1 therapy were obtained. Kaplan-Meier and Cox regression analyses were used to assess the effect of irAEs and corticosteroids on progression-free survival (PFS). RESULTS: A total of 45 irAEs were recorded for 157 patients. Twenty-one patients received systemic corticosteroids. Patients who developed irAEs, as well as those who received systemic corticosteroids, had improved PFS by Kaplan-Meier estimate. Multivariate Cox regression showed that irAEs were associated with improved PFS (hazard ratio of 0.33, P <0.001) which persisted even with use of systemic corticosteroids (hazard ratio of 0.38, P = 0.03). CONCLUSIONS: irAEs are associated with improved PFS in patients receiving anti-PD-1/PD-L1 therapy. This association does not appear to be altered by the use of systemic corticosteroids.

CYP2D6 polymorphisms and the impact on tamoxifen therapy.

The cytochrome P450 2D6 (CYP2D6) is an enzyme known to metabolize a variety of xenobiotics and drugs. Inter-individual variation in the metabolic capacity of this enzyme has been extensively studied and associations with genotype have been established. Genetic polymorphisms have been grouped as nonfunctional, reduced function, functional, and multiplication alleles phenotypically. Individuals carrying these alleles are presumed to correspond to poor, intermediate, extensive, and ultrarapid metabolizers (UM), respectively. Tamoxifen has been shown to be metabolized by CYP2D6 to the more potent metabolite endoxifen. Poor metabolizers (PM) of tamoxifen have lower levels of endoxifen and poorer clinical outcomes as compared to extensive metabolizers (EM). Here, we will provide an overview of the history and application of CYP2D6 pharmacogenetics, and will discuss the clinical implications of recent developments relating to the involvement of CYP2D6 in tamoxifen treatment.

Lysyl oxidase (LOX) and hypoxia-induced metastases.

Angiogenesis is a critical process in the transition of tumors from a localized, primary site to a distant site of metastases. Hypoxic conditions within the tumor mass lead to the activation of signalling pathways which initiate tumor cell invasion, migration, adhesion and subsequent angiogenesis. Several key molecular players in hypoxia-induced tumor progression are well-described, e.g., hypoxia-inducible factor-1 (HIF-1) and angiopoietin-2; however, drug development aimed at suppressing individual members of this signalling cascade has proven to be challenging. The article by Erler et al. published in Nature (Vol. 440, April 2006) identifies lysyl oxidase (LOX) as an essential enzyme for hypoxia-induced metastases. This Journal Club reviews the findings presented by Erler and colleagues and briefly discusses the implications of LOX in cancer.

Inhibition of JNK reduces G2/M transit independent of p53, leading to endoreduplication, decreased proliferation, and apoptosis in breast cancer cells.

c-Jun N-terminal kinase (JNK) is activated by diverse cell stimuli, including stress, growth factors, and cytokines. Traditionally, activation of JNK by stress treatment is thought to induce cell death. However, our recent data indicate that JNK's ability to sensitize cells to apoptosis may be, in part, cell cycle dependent. Here, we show that the majority of both paclitaxel- and UV-induced apoptosis can be inhibited by the pharmacological JNK inhibitor, SP600125, in MCF-7 cells. However, inhibition of JNK does little to reverse doxorubicin-induced apoptosis in MCF-7 cells or doxorubicin- and UV-mediated death in MDA MB-231 cells. SP treatment causes G2/M arrest of three breast cancer cell lines and results in the endoreduplication (cellular DNA content >4N) of MCF-7 and MDA MB-231 cells. These effects on cell cycle and apoptosis are not significantly altered by the inhibition of p53, indicating that JNK is functioning independently of p53. Lastly, inhibition of JNK using both SP and antisense oligonucleotides targeted to JNK1 and JNK2 reduced proliferation of all three breast cancer cell lines. Taken together, these results suggest that the activation of JNK is important for the induction of apoptosis following stresses that function at different cell cycle phases, and that basal JNK activity is necessary to promote proliferation and maintain diploidy in breast cancer cells.

An inhibitory function for JNK in the regulation of IGF-I signaling in breast cancer.

Insulin-like growth factor-I receptor (IGF-IR) is frequently overexpressed in a variety of cancer types. Since many breast tumors and cancer cell lines overexpress IGF-IR, we tested IGF-I effects on chemotherapy-treated breast cancer cells. IGF-I protects from chemotherapy-induced apoptosis, suggesting that overlapping signaling pathways modulate IGF-I and chemotherapy treatment outcomes. Taxol and other chemotherapy drugs induce c-Jun N-terminal kinase (JNK), a kinase that conveys cellular stress and death signals. Notably, in this paper we show that IGF-I alone induces a potent JNK response and this activity is reversed by inhibition of phosphatidylinositol 3-kinase (PI 3-kinase) with LY294002 in MCF-7 but not T47D cells. Cotreatment of cells with chemotherapy and IGF-I leads to additive JNK responses. Using cells overexpressing Akt, we confirm that IGF-I-mediated survival is Akt dependent. In contrast, overexpression of JNK significantly enhances Taxol-induced apoptosis and inhibits IGF-I survival effects. Further, JNK attenuates anchorage-independent growth of MCF-7 cells. The inhibitory effect of JNK appears to be mediated by serine phosphorylation of IRS-1 (insulin receptor substrate) since both Taxol and IGF-I treatment enhanced Ser(312) IRS-1 phosphorylation, while LY294002 blocked IGF-I-mediated phosphorylation. Taken together, these data provide a mechanism whereby stress or growth factors activate JNK to reduce proliferation and/or survival in breast cancer cells.

Stress and IGF-I differentially control cell fate through mammalian target of rapamycin (mTOR) and retinoblastoma protein (pRB).

Significant discoveries have recently contributed to our knowledge of intracellular growth factor and nutrient signaling via mTOR (mammalian target of rapamycin). This signaling pathway is essential in cellular metabolism and cell survival by enhancing protein translation through phosphorylation of 4EBP-1 and p70S6K. Growth factors like insulin-like growth factor-I induce mTOR to prevent cell death during cellular stress. Agents targeting mTOR are of major interest as anticancer agents. We show here, using human breast cancer cells, that certain types of stress activate mTOR leading to 4E-BP1 and p70S6K phosphorylation. UV treatment increased phosphorylation of the translation inhibitor eIF2alpha, suggesting a potential mechanism for UV activation of Akt and mTOR. c-Myc, a survival protein regulated by cap-dependent protein translation, increased with IGF-I treatment, but this response was not inhibited by rapamycin. Additionally, UV treatment potently increased c-Myc degradation, which was reduced by co-treatment with the proteasomal inhibitor, MG-132. Together, these data suggest that protein translation does not strongly mediate cell survival in these models. In contrast, the phosphorylation status of retinoblastoma protein (pRB) was mediated by mTOR through its inhibitory effects on phosphatase activity. This effect was most notable during DNA damage and rapamycin treatment. Hypophosphorylated pRB was susceptible to inactivation by caspase-mediated cleavage, resulting in cell death. Reduction of pRB expression inhibited IGF-I survival effects. Our data support an important role of phosphatases and pRB in IGF-I/mTOR-mediated cell survival. These studies provide new directions in optimizing anticancer efficacy of mTOR inhibitors when used in combination with DNA-damaging agents.

PKCdelta and mTOR interact to regulate stress and IGF-I induced IRS-1 Ser312 phosphorylation in breast cancer cells.

IRS-1 (Insulin Receptor Substrate-1) is an adaptor protein important for insulin and IGF-I receptor (Insulin-like Growth Factor-IR) transduction to downstream targets. One mechanism recently identified to downregulate IGF-I or insulin receptor signaling in diabetic models is IRS-1 Ser(312) phosphorylation. To date, the importance of this residue in cancer is unknown. This paper identifies mechanisms leading to Ser(312) regulation in MCF-7 breast cancer cells. Whereas IGF-I phosphorylation of IRS(312) is PI (phosphatidylinositol) 3-kinase dependent, anisomycin stress treatment requires JNK activation to induce phosphorylation of IRS(312). We show that both IGF-I and anisomycin stress treatment converge downstream onto mTOR (Mammalian Target of Rapamycin) and PKCdelta (Protein Kinase C-delta) to induce IRS-1 Ser(312) phosphorylation. mTOR associates with IRS-1 and is primarily required for Ser(312) phosphorylation in response to stress or IGF-I treatment. PKCdelta binds to mTOR and its activity is also important for stress or IGF-I mediated Ser(312) phosphorylation. Thus, mTOR and PKCdelta convey diverse signals to regulate IRS-1 function.