Authors: Akito Hata, Yoshimasa Shiraishi, Naoki Inui, Morihito Okada, Masahiro Morise, Kohei Akiyoshi, Masayuki Takeda, Yasutaka Watanabe, Shunichi Sugawara, Naofumi Shinagawa, Kaoru Kubota, Toshiaki Saeki & Tomohide Tamura Abstract Introduction We describe the results of an exploratory analysis performed on the first head-to-head study (JapicCTI-194611) comparing two different intravenous (IV) neurokinin 1 (NK 1 ) receptor antagonists, fosnetupitant and fosaprepitant, in combination with palonosetron (PALO) and dexamethasone (DEX) for the prevention of highly emetogenic chemotherapy (HEC)-induced nausea and vomiting (CINV).

ODM-208 was administered orally alongside androgen deprivation therapy and glucocorticoid (primarily dexamethasone) and mineralocorticoid (fludrocortisone) replacement therapy.

Of these, 42.5% were receiving dexamethasone ≤4 mg/day at baseline.

“There is so much enthusiasm about dexamethasone, but our findings in a relatively small subgroup suggest that steroids could be associated with increased mortality in the cancer population,” said Warner in a press statement.

Adding olanzapine 5 mg to standard aprepitant, palonosetron, and dexamethasone antiemetic therapy significantly reduces the number of patients vomiting and needing rescue medication following cisplatin-based chemotherapy, Japanese researchers report.

Combining abiraterone acetate with a relatively high dose of prednisone or dexamethasone may reduce mineralocorticoid excess toxic effects, but can result in increased metabolic toxicity, study data show.

Sixty minutes prior to receiving cisplatin, fosnetupitant, a neurokinin 1 receptor antagonist, was intravenously administered alongside palonosetron (0.75 mg) and dexamethasone (13.2 mg) to 392 patients at a dose of 81 mg (n=197) or 235 mg (n=195), while the remaining 195 patients received placebo plus palonosetron and dexamethasone.

This review discusses the safety and efficacy data for aprepitant and fosaprepitant from key clinical trials on the prevention of chemotherapy-induced nausea and vomiting (CINV). Summary Early clinical trials revealed that, compared with dual therapy, triple therapy with aprepitant, a serotonin (5-hydroxytryptamine-3; 5-HT 3 ) receptor antagonist and dexamethasone provided improved control of acute and delayed CINV. The safety and efficacy of aprepitant were subsequently evaluated in several milestone clinical trials in patients receiving highly emetogenic chemotherapy. Research into multiple-day dosing revealed: Aprepitant and fosaprepitant were more effective than ondansetron for control of delayed-phase emesis and need for rescue medication Aprepitant plus dexamethasone was effective for control of delayed emesis with highly emetogenic chemotherapy Aprepitant treatment was associated with significantly improved complete response rate over the total treatment period and during acute and delayed phases. Although originally recommended to be given for 3 days to control CINV, single doses (oral or intravenous) of aprepitant have been shown to be effective in preventing both acute and delayed CINV. Studies have also shown aprepitant to protect against CINV over multiple cycles of cisplatin-based chemotherapy, with control of CINV sustained over six cycles. Studies have shown aprepitant to be generally well tolerated. A systematic review of 17 trials of neurokinin-1 (NK 1 ) receptor antagonists added to antiemetic regimens for the prevention of CINV showed statistically significant, but clinically trivial differences, in fatigue, hiccups and lower constipation than controls. Importantly, aprepitant does not appear to alter the pharmacokinetics of high-dose melphalan when used as conditioning therapy prior to stem cell transplantation in patients with multiple myeloma. Clinical trials have demonstrated that most drug-drug interactions with aprepitant have few/no clinical consequences, with no differences in severe adverse events noted between treatment arms with or without aprepitant. All clinical practice guidelines recommend aprepitant be added to combination 5-HT 3 receptor antagonist and dexamethasone for patients receiving highly emetogenic chemotherapy; adherence to antiemetic clinical practice guidelines resulted in a significantly reduced incidence of CINV. Aapro M et al.  Oncologist 2015; 20: 450–458. doi: 10.1634/theoncologist.2014-0229

This paper reviews the role of the neurokinin-1 (NK 1 ) receptor antagonists in the prevention of chemotherapy-induced nausea. Summary Assessment of nausea is challenging due to its subjective nature. As a result many studies have evaluated nausea as either part of a complete response or as a secondary endpoint to emesis. Overall, studies have not shown any consistent superiority of the addition of aprepitant/fosaprepitant to a serotonin (5-hydroxytryptamine-3; 5-HT3) receptor antagonist and dexamethasone for the control of nausea after highly or moderately emetogenic chemotherapy. Aprepitant/fosaprepitant has been shown to be as effective as prochlorperazine in delayed nausea control, while olanzapine was superior to aprepitant/fosaprepitant both in the delayed phase and overall. During the delayed phase, no significant differences were observed in rates of nausea or in maximum nausea severity or nausea duration in patients receiving aprepitant/palonosetron/dexamethasone before chemotherapy who were randomized to receive aprepitant or dexamethasone on days 2–3. Similar results were shown for the delayed phase in a study comparing aprepitant on days 2–3 with metoclopramide on days 2–4. Regarding the use of rolapitant, discrepancies between studies mean that no clear conclusions can be drawn regarding its use in nausea associated with highly emetogenic chemotherapy. NEPA is a fixed-combination antiemetic comprising netupitant and palonosetron, which has found to be associated with significantly better nausea control compared with oral palonosetron. Additional factors to consider when selecting an NK1 receptor antagonist for the control of chemotherapy-induced nausea include: Safety Schedule and convenience of administration, and implications of such for patient compliance The choice of 5-HT3 receptor antagonist International guideline recommendations. Studies are needed to define the overall potential for chemotherapy-induced nausea in individual patients, including factors related to the patient and the disease, as well as to the specific anticancer treatments. Bošnjak SM et al. Support Care Cancer  2017. doi: 10.1007/s00520-017-3585-z

This chapter provides a detailed review of the place of the 5-hydroxytryptamine receptor antagonist palonosetron in the management of chemotherapy-induced nausea and vomiting. Summary Palonosetron has several pharmacologic characteristics that set it apart from first generation serotonin (5-hydroxytryptamine-3; 5-HT3) receptor antagonists, including much higher affinity for the 5-HT3 receptor and a longer plasma half-life (40 hours versus 5–12 hours). In terms of safety, while palonosetron has the same class-related adverse effects as first generation drugs, it is associated with significantly less mean QTc interval prolongation. Clinical trials demonstrated palonosetron to be associated with higher complete response rates for CINV in the delayed and overall, but not acute, phases, compared with first-generation 5-HT3 receptor antagonists. Palonosetron has demonstrated efficacy has part of triplet CINV prophylaxis regimens, in combination with aprepitant and dexamethasone, as well as in combination with olanzapine and dexamethasone. Cost-effectiveness studies have shown that while palonosetron was associated with higher acquisition and treatment costs than first-generation treatments, this was offset by reduced healthcare utilization for CINV, giving lower overall than those of other treatments. All guidelines recommend palonosetron as the 5-HT3 receptor antagonist of choice in moderately emetogenic chemotherapy, with guidelines for highly emetogenic chemotherapy recommending a three-drug combination, comprising a 5-HT3 receptor antagonist, dexamethasone and an NK1 receptor antagonist (or olanzapine). Schwartzberg L. In: Management of Chemotherapy-Induced Nausea and Vomiting . Edited by: Navari R. Springer International Publishing Switzerland 2016. doi: 10.1007/978-3-319-27016-6_4

A phase II proof-of-concept study has shown that clinically stable patients with metastatic castration-resistant prostate cancer and limited disease progression during treatment with abiraterone acetate plus prednisone can experience biochemical and radiologic responses following a steroid switch to dexamethasone.

The combination of carfilzomib and dexamethasone should be considered a standard of care in patients with relapsed or refractory multiple myeloma, say researchers who conducted a head to head comparison with bortezomib plus dexamethasone.

One in five patients with heavily pretreated, refractory multiple myeloma may respond to treatment with the selective exportin 1 inhibitor selinexor, plus low-dose dexamethasone, phase II study findings indicate.

Moreau et al say they “plan to address the gap in the A.R.R.O.W. study in a future analysis by comparing once weekly carfilzomib at 70 mg/m 2 plus dexamethasone with the approved standard of twice weekly carfilzomib at 56 mg/m 2 plus dexamethasone.”

. --- The results of the 4-year follow-up of the phase III ELOQUENT-2 trial comprising patients with relapsed or refractory MM show that the progression-free survival benefit afforded by the addition of elotuzumab to lenalidomide and dexamethasone is maintained in the long term.

Combination therapy with lenalidomide, bortezomib, and dexamethasone plus transplantation halts disease progression more effectively than drug treatment alone in patients with newly diagnosed multiple myeloma, study findings indicate.