Annals of Oncology Advance Access published March 9, 2015

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Recent developments in the prevention of chemotherapy‐induced nausea and vomiting (CINV): A comprehensive review

Karin Jordan1, Franziska Jahn1, Matti Aapro2 1

Department of Hematology and Oncology, University of Halle, Ernst-Grube-Str. 40,

Halle 06120, Germany 2

Clinique de Genolier, Multidisciplinary Oncology Institute, Switzerland

Corresponding author: Karin Jordan, Department for Hematology/Oncology, [email protected], Tel.: +49-345-557-2019, Fax: +49-345-557-2950

Key Message: "This review summarizes the research efforts in the field of chemotherapy  induced nausea and vomiting over the past years. Emerging from this research are two new  antiemetic agents, NEPA, the first antiemetic combination agent and rolapitant, a new  NK1RA. In addition, studies have evaluated the benefits of olanzapine and ginger, and  evaluated the value of NK1RAs in carboplatin based chemotherapy."

© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]

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University of Halle, Ernst-Grube-Str. 40, Halle 06120, Germany, E-mail:

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Abstract The prevention of chemotherapy-induced nausea and vomiting (CINV) has been revolutionized over the past 25 years. Guideline-based treatment means that vomiting can be prevented in the majority, but not in all patients. Therefore, antiemetic research continues with the goal of optimizing CINV control for all patients. This comprehensive review summarizes the research efforts in this field over the past few years. Emerging from this research are two new antiemetic agents, NEPA, the first antiemetic combination agent and ginger, explored optimal combinations of agents for delayed CINV prevention, confirmed that dexamethasone-sparing regimens are effective, and demonstrated the value of NK1RAs in high dose chemotherapy settings as well as with certain moderately emetogenic chemotherapies such as carboplatin. Research has also validated the correlation between antiemetic guideline adherence and improved CINV control. Finally, regulatory authorities have utilized extreme caution in retiring some 5HT3RAs or decreasing their maximum dose.

Key words: chemotherapy-induced nausea and vomiting (CINV), antiemetics, guidelines, NEPA, rolapitant, olanzapine

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rolapitant, a new NK1RA. In addition, studies have evaluated the benefits of olanzapine and

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introduction Advances in our understanding of the pathophysiology of chemotherapy-induced nausea and vomiting (CINV), identification of patient risk factors, and development of new antiemetics have revolutionized the prevention and treatment of CINV. Strategies for antiemetic prophylaxis have evolved in recent years with an understanding that CINV is a complex multi-factorial process involving numerous transmitters and receptors. With the appropriate use of evidence-based antiemetic regimens, vomiting and to a lesser extent nausea, can now be prevented in the majority of patients.

combination product comprised of the new NK1 receptor antagonist (RA), netupitant, and the pharmacologically distinct 5-HT3RA, palonosetron, and also another new NK1RA, rolapitant, with a long plasma half-life. The body of evidence supporting a potential role for the antipsychotic, olanzapine has evolved and the dataset evaluating the benefit of ginger, particularly as an antinausea treatment, has expanded. In addition to evaluation of these new antiemetic agents, research has also explored 1) whether dexamethasone (DEX)-sparing regimens are as effective as multiple day DEX dosing, 2) the role of the NK1RAs in the moderately emetogenic chemotherapy (MEC) setting, 3) prophylactic antiemetic regimens that are effective in high dose/multiple day chemotherapy settings, 4) possible benefits of incorporating patient-related risk factors into the antiemetic guideline recommendations, 5) the potential value in revisiting the emetogenicity classification system, and 6) the correlation between antiemetic guideline adherence and improved CINV control. Furthermore, regulatory authorities have issued warnings about potential cardiac safety issues (particularly QTc interval prolongation) for all 5HT3RAs (with the exception of palonosetron) and have restricted the dose and duration of metoclopramide in order to minimize the risk of potentially serious neurological adverse effects. This article discusses these recent advances in antiemetic research in the context of current antiemetic guideline recommendations.



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Emerging from the most recent research are two new agents, NEPA, the first antiemetic

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antiemetic agents new NK1 RAs: an advance in treatment options? The introduction of the NK1RA class (oral aprepitant [2003] and IV fosaprepitant [2008]) represents the most significant advance in antiemetic prophylaxis since the 5-HT3RAs in the late 1990’s. An NK1RA is now consistently recommended in addition to a 5HT3RA plus DEX in patients receiving highly emetogenic chemotherapy (HEC) and anthracycline/cyclophosphamide (AC)-based chemotherapy. It is encouraging to see two new NK1RAs entering the antiemetic armamentarium, both of which exhibit some

NEPA NEPA is the first antiemetic combination agent developed, comprised of a new, highly selective NK1RA, netupitant, and the 5-HT3 RA, palonosetron. NEPA was recently granted FDA approval (and is under review by the European Medicines Agency [EMA] in Europe) based on three pivotal trials in approximately 2500 patients receiving a variety of highly and moderately (MEC) emetogenic chemotherapies [1-3]. In the clinical program, NEPA was administered as a single oral dose prior to chemotherapy in combination with oral DEX (Day 1 only for AC/MEC, Days 1-4 HEC). NEPA plus DEX showed superiority over oral palonosetron plus DEX for all key efficacy endpoints during the delayed (25-120h) phase and throughout the 5 days (0-120h) following either cisplatin-based HEC or AC chemotherapy (

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differentiating features.

5 Table 1). NEPA-treated patients also reported significantly less impact on daily functioning due to nausea and vomiting than palonosetron-treated patients in the AC study [4]. Sustained efficacy over multiple chemotherapy cycles was demonstrated in over 1000 NEPA-treated patients participating in >4400 cycles in two of the trials (Table 1) [2, 3, 5]. NEPA has a safety profile consistent with that expected for the NK1 RA and 5-HT3RA classes and for a diverse cancer population undergoing cytotoxic chemotherapy [6]. The most frequent treatment-related adverse events were headache, asthenia, fatigue and dyspepsia. Reassuringly, the cardiac adverse events and ECG/QTc data raise no cardiac safety concerns [7, 8]. DEX dose should be reduced when used in conjunction with NEPA [9]. The DEX doses in the NEPA trials were 12 mg PO on Day 1 (for HEC/AC) and additionally, 8 mg on Days 2-4 in the HEC setting [1, 3, 10], the same as those recommended for aprepitant. As there is interest in minimizing the DEX dose and frequency, the long-acting benefit of NEPA allowing for a single day administration of DEX with AC and MEC is advantageous. If the registration trial results are replicated in the “real” clinical world, then the NEPA combination appears to be an advance, particularly with its simplicity of administering guideline-based antiemetic prophylaxis.

Rolapitant Rolapitant is a new highly selective oral NK1RA exhibiting a long (180h) plasma half-life. It is currently under review by the FDA after completion of a clinical program which included three Phase III trials in approximately 2500 patients. In one trial patients received a variety of MEC regimens, including AC and the other two trials were identically designed in patients receiving cisplatin-based HEC. Rolapitant was evaluated in combination with IV/oral granisetron and oral DEX and was compared with granisetron plus DEX in all trials. While rolapitant was administered as a single dose prior to chemotherapy, either granisetron (Days 1-3 MEC, Day 1 HEC) or DEX (Day 1 MEC, Days 1-4 HEC) was administered on subsequent days. The rolapitant regimen showed statistically superior complete response (CR) rates compared with the granisetron control during the delayed phase in all three studies. Significantly higher or numerically higher response rates were seen for the additional efficacy assessments (

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Because netupitant is a moderate inhibitor of the cytochrome P450 3A4 (CYP3A4), the oral

6 Table 2) [11, 12]. All three trials included a multiple cycle extension; however, this data has not yet been presented. The other pending data of interest are the subsets of patients in the MEC study receiving the AC (approximate 50%) and non-AC regimens. As is the case with NEPA, rolapitant was well-tolerated with a safety profile consistent with that expected for these antiemetic classes and patients receiving chemotherapy. Unlike aprepitant and NEPA, rolapitant does not inhibit nor induce CYP3A4 [13]. Therefore, dose adjustments of concomitantly administered drugs metabolized by CYP3A4 (including DEX) are not required. This may be a benefit for some patients where drug-drug interactions

olanzapine Olanzapine is an atypical antipsychotic with interesting antiemetic properties due to its ability to target many different receptors, including dopaminergic (D1, D2, D3, D4), serotonergic (5HT2A, 5-HT2C, 5-HT3, 5-HT6), adrenergic (á1), histaminergic (H1), and muscarinic (m1, m2, m3, m4) [14].

First line prophylaxis of CINV: In a Phase III trial in patients receiving HEC or MEC, an olanzapine/5-HT3RA/DEX regimen resulted in superior delayed and overall CR rates compared with a 5-HT3RA/DEX regimen [15]. However, the 5-HT3RA used was azasetron, an agent reported to be inferior to ondansetron [16]. In another Phase III trial, an olanzapine regimen was compared with an aprepitant regimen, both in combination with palonosetron and DEX in 241 chemotherapy-naive patients receiving cisplatin or AC-based chemotherapy [17]. Complete response rates were comparable for olanzapine (97% acute, 77% delayed/overall phases) and aprepitant (87% acute, 73% delayed/overall phases) regimens. The olanzapine regimen resulted in higher no nausea rates during the delayed/overall phases (87% acute, 69% delayed/overall) compared with the aprepitant regimen (87% acute, 38% delayed/overall). Unfortunately, this study was open-label which could confound the results of subjective endpoints such as nausea. Breakthrough CINV: Relief of breakthrough CINV was investigated in a Phase III trial in 276 patients randomized to receive olanzapine 10 mg PO 3x/day for 3 days or metoclopramide 10 mg PO 3x/day for 3 days if they failed on initial antiemetic prophylaxis (fosaprepitant/palonosetron/DEX on Day 1 and DEX on Days 2-4). Patients had received cisplatin-based or AC-based chemotherapy. No vomiting and no nausea during 0-72h occurred in 70% and 68% of olanzapine patients, respectively, in comparison with 31% and

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should ideally be avoided.

7 23% for metoclopramide [18]. These data support olanzapine as an effective agent for reducing breakthrough CINV. Common side effects associated with olanzapine are mostly tolerable and mild, with somnolence, postural hypotension, constipation, dizziness, fatigue, dyspepsia and restlessness most commonly reported [19, 20]. While surprising, no grade 3 or 4 toxicities were reported in the Phase III trials [17, 18, 21]. Although guidelines published by the National Comprehensive Cancer Network CINV regimen in HEC/MEC settings, this is in contrast to the MASCC/ESMO and ASCO guidelines which do not recommend it [22]. When considering the overall risk/benefit ratio and the current evidence with the shortcomings in the study designs, it seems premature to promote olanzapine for standard antiemetic prophylaxis. Additional well-conducted, doubleblind studies are necessary. It is also worth noting that olanzapine use in the CINV setting is “off label”, as it is currently indicated only as an “anti-psychotic”, and has a series of potential side-effects. Therefore, use in the CINV setting may be complicated, in that a psychiatrist must prescribe it or be consulted prior to first use in some countries [23].

ginger A number of studies have evaluated ginger’s potential benefit in preventing chemotherapyinduced nausea. In the largest study to date (n=576), a randomized, double-blind, dosefinding trial in mostly breast cancer patients (72%), Ryan [24] showed that ginger supplementation at daily doses of 0.5, 1.0, or 1.5 g in patients receiving standard 5-HT3RA plus DEX significantly reduced severity of acute chemotherapy-induced nausea compared with placebo. Interestingly, the highest 1.5 g dose was shown to be the least effective. Unfortunately, patients reported more severe delayed nausea compared with acute nausea and a significant benefit of ginger in the delayed phase was not seen. The authors hypothesized that ginger competitively interacts with the 5-HT3 receptor. Of note, recently it was shown that ginger extracts and its pungent arylalkane constituents inhibit activation of human 5-HT3 receptors in a concentration-dependent manner [25]. In another open-label study, ginger (1.5 g/day) added to granisetron plus DEX in breast cancer patients effectively reduced nausea during 6-24 hours but did not show an advantage in the delayed phase [26]. While these studies offer support for a beneficial effect of supplemental ginger on nausea control in the acute phase, a systematic review summarizing seven randomized studies

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(NCCN) include an olanzapine/palonosetron/DEX regimen as an alternative prophylactic

8 using ginger as either a stand-alone treatment or as additive prophylaxis was unable to draw definitive conclusions [27]. Ginger may slow blood clotting, with potential drug interactions with anticoagulants/antiplatelet agents. In summary, the current studies provide controversial support for use of ginger as a standard part of antiemetic treatment for CINV [27, 28]. Future researchon the appropriate dose, preparation, and timing of ginger administration should be considered.

miscellaneous agents

regimen [29]. However, these results were not replicated in a recent phase III study with 437 patients receiving HEC. Gabapentin/placebo (Days 1-5) were added to a 5-HT3RA/DEX regimen, whereas a NK1RA was not part of the prophylaxis [30]. Gabapentin did not significantly improve CINV control in the delayed phase (CR: 47% gabapentin versus 41% control, p = 0.23). Considering these findings, it does not appear that gabapentin offers any antiemetic benefit over a standard 5-HT3RA/DEX regimen. megestrol acetate: Although interesting results were achieved in a crossover placebo controlled trial in 100 patients receiving HEC or MEC (overall CR 45% megestrol- containing regimen vs 17% control) these findings should be interpreted with great caution [31]. Antiemetic prophylaxis was inadequate, consisting only of granisetron plus metoclopramide (both Days 1-4); a steroid nor NK1RA was part of prophylaxis. In light of this and considering the potential side effects of megestrol acetate, the value of pursuing its development as an antiemetic is questionable. nifedipine: Nifedipine is an L-type calcium channel antagonist currently in the early preclinical stages of investigation as a broad-spectrum antiemetic [32].

prophylaxis of delayed emesis: new options? Two recent trials conducted by the Italian Group for Antiemetic Research explored two different hypotheses for prevention of CINV, specifically in the delayed phase. Study 1 evaluated if DEX was superior to aprepitant in breast cancer patients receiving AC [33] and Study 2 evaluated whether aprepitant plus DEX was superior to metoclopramide (MCP) plus DEX in the cisplatin-based HEC setting [33] (Table 3). In both trials all patients received an aprepitant/palonosetron/DEX regimen on Day 1; similar acute CR rates were seen in each of

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gabapentin: A pilot study demonstrated benefit of adding gabapentin to a 5-HT3RA/DEX

9 the trials. The authors showed similar delayed phase efficacy for DEX and aprepitant in the AC study and also for aprepitant/DEX and metoclopramide/DEX in the HEC study. While these studies present interesting and thought-provoking findings, one also needs to consider possible methodological pitfalls. Celio and Aapro summarized these regarding Study 1, some of which may also be applicable to Study 2 [34]. The use of palonosetron with the Day 1 regimen has the potential to confound the delayed phase results considering that palonosetron has been shown to be superior to first-generation 5-HT3RAs in the delayed phase [35] and also non-inferior in the delayed phase to palonosetron plus 3-days DEX when given with DEX on Day 1 only [36]. Study 1 was also underpowered because of lack of maximum recommended daily dose (30 mg), a guidance established after the completion of this study. Nevertheless, these findings are provocative and likely to result in much discussion and potentially follow-up studies. One can also note that while 125 mg aprepitant can be considered suboptimal dosage, its prodrug fosaprepitant is registered at 150 mg IV Day 1 only, equivalent to 165 mg of aprepitant [37].

dexamethasone‐sparing: is this approach as effective as a multiple day schedule? While dexamethasone plays an integral role in the management of CINV, there has been growing interest in minimizing its dose and frequency. Although generally well tolerated, DEX exhibits side effects, even with short term use. In a study by Vardy, patients receiving 10 or 20 mg DEX prior to MEC and then 4 mg BID ranging from1-3 days post-chemotherapy reported insomnia, gastrointestinal symptoms, agitation, increased appetite, weight gain and skin rash [38]. In an effort to explore whether the frequency of DEX could be reduced without loss of antiemetic efficacy a number of studies have been performed. In two studies a single dose of palonosetron plus DEX on Day 1 only was compared with palonosetron on Day 1 plus DEX on Days 1-3 in patients receiving AC. In the study by Aapro [36], the single-day regimen was non-inferior to that of the 3-day DEX schedule for overall CR (54% for both groups). However, when analyzing the individual study days, patients receiving the single-day regimen experienced numerically (statistically not significant) higher nausea scores on Day 3 compared with the 3-day schedule but these results did not influence the quality of life score. In the other study by Celio [39] in patients receiving either AC or other common MEC regimens the single-day regimen resulted in a non-inferior overall CR rate (68%) to that of the 3-day DEX schedule (71%). However, when examining the

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accrual, and the dose of metoclopramide in Study 2 (80 mg/day) is well above the EMA

10 subgroup of patients taking AC a meta-analysis of both studies indicated a significant difference on day 3 [40]. Acknowledging that nausea remains the greatest unmet need, a third study conducted by Roscoe [41] specifically evaluated efficacy of various antiemetic combinations in controlling nausea during the delayed phase following either platinum-based or anthracycline-based chemotherapy. In this rather complicated study four treatment groups were evaluated with three specific pairwise comparisons/objectives explored between groups. One comparison evaluated whether adding DEX on Days 2-3 to a treatment group receiving palonosetron plus nausea than the same group (ie Day 1: palonosetron + DEX; Days 2-3: prochlorperazine) without DEX on Days 2-3. Severity of nausea on Days 2-3 was the primary endpoint and assessed with a 7-point semantic rating scale ranging from 1 (not at all nauseated) to 7 (extremely nauseated). The results confirmed that addition of DEX on Days 2 and 3 produced significantly better nausea control. The authors, unfortunately, did not examine traditional endpoints of CR and no emesis nor did they confirm if these nausea findings were replicated for this comparison in the subset of patients receiving AC. These results are of particular interest as they relate directly to the current guideline recommendations for DEX use on Days 2 and 3. While both ASCO and MASCC consistently recommend DEX administration on Days 2-3 following palonosetron plus DEX on Day 1 in the non-AC MEC setting, they vary with their recommendations in the AC setting. As a result of the Warr study [42] demonstrating superiority of a triplet aprepitant regimen over a 5-HT3 RA/DEX regimen (with DEX given only on Day 1) in patients undergoing AC chemotherapy, the MASCC guidelines recommend a single day of DEX in patients receiving AC. However, as ASCO reclassified AC as highly emetogenic, DEX is to be administered on Days 2-3, consistent with the HEC recommendation. Interestingly, the Celio study offers support for single-day DEX dosing in combination with palonosetron in patients receiving non-AC MEC. However, the data supporting single-day dosing in the AC setting are somewhat ambiguous. While the Aapro study demonstrated comparable overall CR rates for a single-day vs 3-day DEX schedule, there was evidence of better nausea control with the 3-day schedule on Day 3 following AC, a day when symptoms tend to be most prevalent. The Celio study found the 3-day schedule to be more effective in the AC setting as did the Roscoe trial, specifically for delayed nausea. Absent from all three of these trials is inclusion of an NK1 RA as part of the regimen. Considering that an NK1 triplet regimen is unanimously recommended by antiemetic guidelines in patients receiving

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DEX on Day 1 plus prochlorperazine on Days 2-3 would result in better control of delayed

11 AC, it is possible that adding a NK1RA to the regimen would allow for an effective single-day DEX schedule, as shown in recent NEPA studies where DEX was administered on Day 1 only in AC patients [10].

high dose chemotherapy Studies evaluating the optimal use of antiemetics in settings where high dose chemotherapy is administered have been lacking; however, a body of evidence in favour of NK1RAs is In a prospective, randomized study in 179 patients receiving a variety of high-dose cyclophosphamide preparative regimens before autologous or allogeneic stem cell transplantation, an aprepitant/ondansetron/DEX regimen during and for 3 days after the preparative chemotherapy was compared with an ondansetron/DEX control [43]. The aprepitant arm resulted in a superior CR rate over the 8-10 days of treatment compared with the control (82% vs 66%; p< 0.001). In a recent randomized, double-blind, Phase IIIb trial, a combination regimen of aprepitant(Days 1–4)/granisetron(Days 1–4)/DEX (Days 2–3) was evaluated in 362 myeloma patients treated with high-dose melphalan for autologous transplantation. The aprepitant regimen resulted in significantly better CINV control compared with granisetron/DEX (overall CR: 58% versus 41%, p=0.0042; no emesis: 78% versus 65%, p=0.0036) [44]. Data for the use of NK1RAs in this setting are compelling, with clinically and statistically significant benefits in favor of the NK1 regimen. Though not specifically recommended yet by guideline committees, the addition of a NK1RA in these settings might be considered.

revisiting the emetogenicity classification of chemotherapeutic agents Two challenges currently exist regarding the emetogenicity classification of chemotherapy agents. The first is that a number of newer chemotherapeutic agents have not been evaluated for inclusion in this classification system (Table 4) and the second is that the current category of “moderately emetogenic” is very broad, encompassing a risk of emesis ranging between 30-90%. Consequently, some patients may be receiving antiemetic agents that are not necessary while others would potentially benefit from agents (such as NK1RAs) and are not receiving them. Prior to the 2004 Perugia Antiemetic Consensus Conference, there were five levels of antiemetic classification: 90%, with the 30-60%

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accumulating.

12 range considered moderately emetogenic [45]. After the 2004 Perugia conference, this classification was changed to four levels by MASCC [46] and ASCO [47] by combining the prior level 3 (30%-60%) and level 4 (60%-90%) into a single group of 30%-90%. The change was made because clinical differentiation between the groups had become difficult with the introduction of new antiemetic agents [48]. However, this broad range of agents makes it difficult to give one recommendation for antiemetic treatment appropriate for the entire range (

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13 Table 5). In addition, this broad MEC classification may be a reason for the inconclusive findings in some clinical trials. Consideration could be given to revisiting and redefining the MEC classification system into five categories or to examining data from individual chemotherapeutic agents to identify those patients most likely to benefit from additional antiemetic prophylaxis with an NK1RA.

carboplatin While carboplatin is classified as a MEC agent by guideline committees, the incidence rates the approval of carboplatin were 93% and 94% (versus 98% and 96% for cisplatin, p=0.01 and NS, respectively) [49, 50]. Vomiting rates were 84% for carboplatin vs 97% for cisplatin (p

Recent developments in the prevention of chemotherapy-induced nausea and vomiting (CINV): a comprehensive review.

The prevention of chemotherapy-induced nausea and vomiting (CINV) has been revolutionized over the past 25 years. Guideline-based treatment means that...
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