Mechanism of Action: Novel Mechanisms in CINV Treatment

Mechanism of Action: Novel Mechanisms in CINV Treatment -

The role of the neurokinin-1 (NK-1) pathway in chemotherapy-induced nausea and vomiting (CINV) is now well established following ap-proval of the US Food and Drug Administration (FDA) of aprepitant (Emend; Merck), the first NK-1 receptor antagonist (RA), for the treatment of CINV in 2003. The combination of aprepitant with a sero-tonin/5-hydroxytryptamine (5-HT3) RA plus dexa-methasone resulted in significantly improved efficacy in patients receiving highly emetogenic chemotherapy (HEC).1-3 Although FDA approval of a new drug class marked a major breakthrough in combating CINV, aprepitant and its prodrug fosaprepitant, remain the only approved NK-1 agents to date. The need for new additions to this drug class, or new approaches to im-prove on current efficacy in CINV, remains substantial. Recent work has focused on elucidating the mechanism of cross-talk between the NK-1 and 5-HT3  pathways in order to exploit synergies that may exist when drugs tar-geting these 2 receptor pathways are combined in clinical practice. This supplement reviews the role of the NK-1 pathway within the context of current treatment options for CINV, and explores the rationale behind a fixed-dose combination of the approved 5-HT3 RA palonosetron (Aloxi; Helsinn/Eisai) and netupitant (Helsinn/Eisai), a new NK-1 RA that has undergone clinical evaluation and is awaiting FDA approval for CINV.

Classification of CINV and Associated Risk Factors

CINV is classified as acute, delayed, anticipatory, breakthrough, or refractory. Acute CINV typically oc-curs within a few minutes to several hours following administration of a chemotherapeutic agent, and gener-ally subsides within 24 hours, whereas delayed CINV occurs more than 24 hours after drug administration and can last 6 to 7 days.4 The time frames of 0 to 24 hours, 25 to 120 hours, and 0 to 120 hours correspond to acute, delayed, and overall phases of CINV, respectively. In CINV clinical trials, these time frames provide a stan-dardized point at which to measure efficacy end points when analyzing new antiemetics. While acute and de-layed CINV occur as a direct result of exposure to chemo-therapy, anticipatory nausea and/or vomiting is a learned response that arises due to a patient’s negative past expe-rience or expectations of upcoming treatment, and it can occur in up to 25% of patients by their fourth che-motherapy cycle.5 Breakthrough emesis occurs although prophylactic treatment has been given and/or requires “rescue” antiemetics, and refractory CINV takes place in subsequent chemotherapy cycles when prophylaxis and/ or rescue medications have previously failed.4

Successful treatment of CINV relies on assessment of the emetogenicity of the chemotherapy drug(s) a patient will receive, and a patient’s individual risk factors. Not all chemotherapy drugs are created equal in terms of their potential to induce nausea and vomiting. Cispla-tin, for example, is widely considered to be the most emetogenic of the chemotherapy drugs, and it displays a biphasic pattern of emesis distinguished by an immedi-ate acute phase and a delayed phase, which is in contrast to the monophasic pattern of emesis occurring after ad-ministration of carboplatin or cyclophosphamide.6 In the late 1990s, Hesketh and colleagues proposed a clas-sification system for single agent chemotherapy drugs and their combinations, based on the percentage of pa-tients who experience acute emesis when not receiving prophylactic treatment with antiemetics.7 Updates to the classification system were recently summarized by Grunberg and colleagues, and Table 1 describes how intravenous (IV) chemotherapy agents are categorized by 1 of 4 emetogenic levels. Due to differences in emeto­ genicity and alternate dosing patterns compared with IV chemotherapies, oral drugs are classified separately and fall into 1 of 2 risk groups; high to moderate emetic risk or low to minimal emetic risk.4,8

CINV severity is also influenced by several patient-­ related risk factors. Female gender, <50 years of age, no/ minimal prior use of alcohol, history of motion sickness, and prior episodes of nausea and vomiting can all in-crease the risk of CINV,4 and are factors to be considered when selecting treatment.


Pathophysiology of CINV

Pathophysiology of CINV

The emetic response to chemotherapy is generated when chemotherapeutic agents stimulate specific neu-rotransmitter receptors located in the gastrointestinal tract, pharynx, and the chemoreceptor trigger zone (CTZ), an area in the medulla located outside of the blood-brain barrier. Afferent impulses from these areas are transmit-ted to the vomiting center (VC) of the brain (also in the medulla) and the VC coordinates efferent impulses to the salivation center, abdominal muscles, respiratory center, and cranial nerves to evoke emesis.4,9 Several neurotransmitter receptors are proposed to be involved in potentiating the CINV reflex, including the dopa-mine receptors, serotonin (5-HT3) receptors, and sub-stance P/NK-1 receptors.4,9 It has been hypothesized that the acute and delayed phases of CINV are governed primarily by different pathways.10 Serotonin, released by enterochromaffin cells in the gut in response to chemo-therapy, acts on 5-HT3 receptors on vagal afferent neu-rons sending signals through the CTZ to the VC, to mediate acute emesis.10,11 The regulatory peptide, sub-stance P, acts on NK-1 receptors within the central and peripheral nervous system, and is suggested to be the dominant mediator of delayed emesis.10 Recent work, however, suggests that these neurotransmitters are not exclusively associated with generating acute or delayed emesis, but may be involved in both types of CINV.12 Using antagonists to block the stimulation of these re-ceptors by their natural ligands forms the basis of current treatment with approved antiemetics.


Treatment Options

Prior to FDA approval of the first 5-HT3 RAs in the early 1990s, CINV was mainly treated with corticoste-roids, antihistamines, and dopamine antagonists.13 High doses of the dopamine antagonist metoclopramide were found to significantly impact CINV associated with cisplatin-based HEC,14 but subsequent studies demon-strated that only 40% of patients were completely protect-ed from emesis in the acute phase, and side effects such as extrapyramidal reactions occurred in a number of pa-tients.13 Significant advances in the treatment of CINV were heralded in the 1990s, with FDA approval of several 5-HT3 RAs, including ondansetron (Zofran; GlaxoSmith-Kline), granisetron (Kytril; Roche), and dolasetron (Anzemet;sanofi­-aventis). These drugs demonstrated effi-cacy in acute-phase CINV, but were less effective in pre-venting symptoms in the delayed setting.13 In 2003, the NK-1 RA aprepitant gained FDA approval, becoming the first drug of its class for the treatment of CINV. Two phase 3 trials, comparing aprepitant plus ondansetron/dexa-methasone with ondansetron/dexamethasone alone in patients receiving cisplatin-based chemotherapy, demon-strated significantly improved complete response (CR) rates in acute, delayed, and overall phases of CINV, with a marked improvement in the delayed phase.2,3 On the basis of these results, aprepitant was approved for both acute and delayed CINV in patients receiving HEC. It also has approval for patients receiving moderately eme-togenic chemotherapy (MEC). In the same year as aprep-itant’s approval, another significant breakthrough came with FDA approval of the 5-HT3 RA palonosetron.

Guideline Recommendations

Comprehensive guidelines for the classification and recommended treatment of CINV are published by sev-eral leading oncology groups including the National Comprehensive Cancer Network (NCCN),4 the Amer-ican Society of Clinical Oncology (ASCO),15 and the Multinational Association of Supportive Care in Cancer (MASCC) in conjunction with the European Society for Medical Oncology (ESMO),16 and these are updated regularly to reflect advances in clinical data, new drug approvals, and subsequent changes to patient care. Table 2 summarizes the NCCN, ASCO, and MASCC/ESMO treatment guidelines for patients receiving HEC or MEC and, in general, they demonstrate a high degree of con-cordance across the oncology organizations. All guide-lines recommend that patients receiving HEC are pre-treated with the triplet regimen of 5-HT3 RA plus NK-1 RA plus dexamethasone to combat the severity of acute and delayed emesis resulting from highly emetogenic drugs such as cisplatin. The NCCN Guidelines recom-mend palonosetron as the preferred 5-HT3 RA, al-though this preference is based on data from randomized studies of palonosetron in combination with dexameth-asone only, and not on randomized combination studies with aprepitant.4 For patients receiving MEC, all guide-lines recommend the combination of a 5-HT3 RA with dexamethasone, and palonosetron is the preferred choice.4,15,16 NCCN guidelines advocate the addition of an NK-1 RA in select patients.4 A single agent 5-HT3 RA is among the recommended options for patients re-ceiving chemotherapy drugs of low emetogenicity in both the NCCN and MASCC/ESMO guidelines,4,16 whereas ASCO recommends dexamethasone only for this patient group.15 No routine prophylaxis is recom-mended by all guidelines for patients receiving minimal-ly emetogenic chemotherapy. Guidelines notwithstand-ing, undertreatment of CINV and nonadherence to recommended regimens is an issue.15

Efficacy and Safety of Palonosetron

Prior to palonosetron’s approval in 2003, the available 5-HT3 RAs were considered to be clinically equiva-lent.17,18 In 2 separate phase 3 noninferiority studies, palo-nosetron demonstrated superior efficacy compared with ondansetron19 or dolasetron20 in patients receiving MEC in the acute, delayed, and overall phases of CINV. In a combined analysis of both phase 3 trials, 72% and 64% of patients receiving palonosetron achieved a complete response (CR) in the acute and delayed phases, respec-tively, compared with only 60.6% (acute) and 46.8% (delayed) of patients receiving either ondansetron or dolasetron (P = .21 for paired comparisons).21 In a phase 3 trial investigating palonosetron in patients receiving HEC, pretreatment with palonosetron plus dexametha-sone demonstrated significantly higher CR rates com-pared with ondansetron plus dexamethasone in the de-layed (42% vs 28.6%; P = .21) and overall (40.7% vs 25.2%; P = .005) phases.22 Compared with other 5-HT3  RAs, palonosetron has also demonstrated a significant reduction in the severity of nausea,23 an important achievement when considering that quality-of-life stud-ies show nausea to have a greater impact on patients’ daily life than vomiting.24,25 In terms of safety, palonose-tron is well tolerated with a toxicity profile similar to the older 5-HT3 RAs.26 These studies led to palonosetron’s approval for acute and delayed CINV in patients receiv-ing MEC, and acute CINV in patients receiving HEC.


For patients receiving MEC, all guidelines recommend the combination of a 5-HT3 RA with dexamethasone, and palonosetron is the preferred choice.

Palonosetron’s Effect on the 5-HT3 Receptor

In an attempt to decipher why palonosetron exhibits a superior efficacy profile compared with other drugs of its class, investigators have focused on palonosetron’s inter-action with its receptor. Initial pharmacologic analysis revealed that palonosetron exhibited a longer plasma half-life, and a higher binding affinity by at least 30-fold when compared with older 5-HT3 RAs, as shown in Table 3.17,21,27-32 In addition, palonosetron is structurally different from other drugs in this class.18 Because these features could not fully account for palonosetron’s im-proved efficacy, a research program involving basic scien-tists, pharmacology experts, and clinicians from the United States and Europe was initiated to compare palo-nosetron with older 5-HT3 drugs and to further delineate palonosetron’s mechanism of action.

In 2008, Rojas and colleagues compared palonosetron with ondansetron and granisetron, 2 of the most fre-quently used 5-HT3 RAs in the United States, in a series of experiments analyzing the kinetics of receptor bind-ing and calcium influx.18 Using binding isotherms, equi-librium diagnostic tests, and kinetic diagnostic tests, results demonstrated that palonosetron binds to the 5-HT3 receptor using allosteric binding and positive cooperativity in contrast to the simple bimolecular competitive binding kinetics of ondansetron and granisetron.18 Al-losteric binding allows palonosetron to bind at different or additional sites to the other 5-HT3 RAs, causing a conformational change in the 5-HT3 receptor.18 Positive cooperativity increases the binding affinity of other palo-nosetron molecules to the 5-HT3 receptor, and could be a result of allosteric binding.33

Other data suggested that unlike ondansetron and granisetron, binding of palonosetron to the 5-HT3 re-ceptor resulted in persistent receptor internalization. When cells overexpressing the 5-HT3 receptor were in-cubated with radio-labeled 5-HT3 RAs and subsequently rinsed free of labeled drug, cells treated with labeled palonosetron showed higher levels of radioactivity than those treated with labeled ondansetron or granisetron.18 Further labeling experiments showed that pretreat-ment with an unlabeled palonosetron decreased subse-quent binding of labeled palonosetron, suggesting that pretreatment with unlabeled drug had caused the 5-HT3 receptor to move to a site that was inaccessible to labeled palonosetron.18 Analysis of receptor function showed that palonosetron, ondansetron, and granise-tron all inhibited calcium ion influx, in line with their role as 5-HT3 RAs.27 While receptor function was re-stored when ondansetron and granisetron were re-moved, inhibition was maintained after palonosetron’s removal.18 Taken together, these data supported the idea of 5-HT3 receptor internalization following palonose-tron binding.18 A series of later experiments confirmed the receptor internalization hypothesis, including 1 ex-periment showing that labeled palonosetron remained associated with cells even in the presence of protease or acid treatments that were designed to denature cell sur-face proteins, and another experiment that demonstrat-ed visualization of receptor internalization with confocal fluorescence microscopy.33 Interestingly, these experi-ments also revealed that the palonosetron-induced re-ceptor internalization remains for up to 2.5 hours, which is in contrast to the receptor internalization induced by the 5-HT3 receptor’s natural ligand serotonin, during which 5-HT3 receptors are recycled to the cell surface within 1 hour.33

Palonosetron and the NK-1 Pathway

Palonosetron’s differential binding characteristics make it unique among the 5-HT3 RA drug class (Table 4), but do not fully explain its efficacy in delayed emesis. Because delayed emesis was thought to be mediated through the NK-1 pathway, investigators analyzed palo-nosetron’s ability to bind the NK-1 receptor.33 While such studies were negative, other studies demonstrated that cross-talk between the 5-HT3 and NK-1 signaling pathways did exist,34 providing a possible rationale for palonosetron’s unique efficacy profile. Investigators deter-mined that NG108-15 cells, which are known to express both the 5-HT3 and NK-1 receptor, release intracellular calcium ions when incubated with substance P, and that this response could be potentiated in the presence of serotonin,35 providing evidence of 5-HT3/NK-1 receptor pathway cross-talk.36 To determine what effect, if any, palonosetron, ondansetron, and granisetron could have on the serotonin enhancement of substance P–mediated calcium release, NG108-15 cells were preincubated with a 5-HT3 drug, which was then completely removed from the media.35 Results showed that palonosetron, but not ondansetron or granisetron, could inhibit the serotonin effect on substance P–mediated calcium ion release.35 Investigators hypothesized that this was likely due to palonosetron’s unique ability to cause 5-HT3 receptor internalization upon binding, and then to prevent its subsequent return to the cell surface for at least 2 hours.35

Further experiments used the rat nodose ganglia, which also expresses both the 5-HT3 and NK-1 receptors, as an in vivo model in which to study palonosetron’s effect on receptor cross-talk. Pretreatment of rats with cisplatin, a chemotherapeutic drug known to induce both acute and delayed emesis, results in an increased response in nodose ganglia to substance P.35 In line with the in vitro model in NG108-15 cells, palonosetron, but not ondansetron or granisetron, could inhibit the cisplatin-enhanced sub-stance P response in rat nodose ganglia,35 providing fur-ther evidence of receptor cross-talk inhibition.

Studies to date have established that palonosetron is clearly distinct from other 5-HT3 RAs in several import-ant ways that contribute to its unique and superior effi-cacy profile; however, the exact cellular processes re-sponsible for receptor cross-talk inhibition are still unknown.37 It may be that palonosetron-induced 5-HT3 receptor internalization downregulates a second messen-ger important for NK-1 signaling, or perhaps causes the NK-1 receptor to partially internalize37; such hypotheses require investigation if we are to fully elucidate and un-derstand the 5-HT3/NK-1 cross-talk phenomenon.37

A New NK-1 RA: Netupitant

While prescribers can choose from 1 of several ap-proved 5-HT3 RAs for the treatment of CINV, aprepi-tant and its prodrug fosaprepitant, remain the only avail-able NK-1 RA approved to date.1,38 Development of agents in this drug class are ongoing, with potential candidates netupitant and rolapitant (Tesaro) being closest to FDA approval.

Netupitant is a selective NK-1 RA that is in develop-ment for CINV.39,40 This NK-1 RA competitively binds to and blocks the activity of NK-1 receptors, binding with high affinity and a long plasma half-life of 48 hours41; this compares favorably with aprepitant’s half-life of 9 to 13 hours.1 Because in vitro studies indicated that netupitant could competitively inhibit the cyto-chrome P450 isoenzyme 3A4 (CYP3A4), an enzyme responsible for metabolizing multiple drug substrates, experiments were designed to investigate netupitant’s impact on the pharmacokinetics of the CYP3A4 sub-strates midazolam, erythromycin, and dexamethasone.42 Results demonstrated that, like aprepitant, netupitant is a moderate inhibitor of CYP3A4 suggesting that when coadministered with drugs that are substrates of CYP3A4, dose adjustments may be required.42 For example, the plasma concentration of dexamethasone was significant-ly increased when it was coadministered with netupitant in healthy volunteers.42 Dexamethasone is often a part of antiemetic therapy, and these results suggest the need for a dose reduction of approximately 50% in oral dexa-methasone when given in combination with netupi-tant.42 Similarly, current antiemetic guidelines recom-mend a dose reduction in dexamethasone when given in combination with aprepitant.16

To further characterize netupitant’s activity profile, investigators analyzed receptor occupancy of therapeutic doses of netupitant using positron emission tomography in the brains of healthy volunteers.43 Results showed that netupitant binds potently to NK-1 receptors with a high degree of occupancy for a long duration of time.43 Data also showed that to achieve receptor occupancy of 90% in the striatum, an area of the brain with the high-est NK-1 expression, a single oral dose of 100 mg to 300 mg would be required.43

Netupitant-Palonosetron Fixed-DoseCombination (NEPA)

The clinical program for netupitant is unique in that this NK-1 RA is being developed as a convenient oral fixed-dose combination with palonosetron (NEPA; net-upitant 300 mg plus palonosetron 0.5 mg), to create a CINV medication that will target both the NK-1 and 5-HT3 antiemetic pathways.44

As described above, palonosetron inhibits 5-HT3/NK-1 receptor cross-talk, but the mechanism by which this can occur currently remains unclear.37 To determine whether palonosetron’s ability to inhibit receptor cross-talk would impact netupitant’s inhibition of the sub-stance P response through the NK-1 receptor when the 2 drugs were dosed together, investigators measured cal-cium ion flux in NG108-15 cells, in the presence of these antiemetics.37 Results demonstrated that netupi-tant and palonosetron in combination showed a syner-gistic inhibition of the substance P response, providing a strong rationale for clinical combination.37 Pharmacokinetic studies determined that there were no clinically relevant drug interactions between netupitant and palonosetron, or between NEPA and oral contracep-tives.45 However, when NEPA was administered with ketoconazole, an antifungal medication that is a strong inhibitor of CYP3A4, or rifampicin, an antibiotic that induces CYP3A4 activity, the metabolism of NEPA was affected. These data indicate the possible requirement for dose adjustments if NEPA is coadministered to patients with medications affecting CYP3A4 metabolism.45

Results showed that netupitant binds potently to NK-1 receptors with a high degree of occupancy for a long duration of time


NEPA Clinical Program

Data from the NEPA phase 2 and phase 3 clinical programs were recently published. The phase 2 pivotal study sought to determine the optimal dose of netupi-tant to combine with oral palonosetron in chemothera-py-naïve patients undergoing cisplatin-based HEC. Overall, 694 patients were enrolled into 1 of 4 study arms or an exploratory arm. The study arms compared 3 doses of oral NEPA (netupitant 100 mg, 200 mg, or 300 mg plus palonosetron 0.5 mg) with 0.5 mg of oral palo-nosetron, all given on day 1.46 All patients received dexamethasone on days 1 to 4. An exploratory aprepi-tant/ondansetron arm was also included to assess the relative activity of an approved NK1/5-HT3 RA combi-nation within the context of this trial.46 The primary efficacy end point of the study was CR in the overall phase (0-120 hours).46 Secondary efficacy end points included CR in the acute (0-24 hours) and delayed (25-120 hours) phases as well as no emesis, no significant nausea, and complete protection (CR + no significant nausea) during all 3 phases.46 All NEPA doses demon-strated statistically superior CR rates compared with palonosetron alone in both the overall phase and the delayed phase, with the 300-mg dose of NEPA also achieving superior CR rates compared with palonose-tron in the acute phase.46 NEPA at a dose of 300 mg was well tolerated and showed an incremental clinical benefit over lower NEPA doses for all secondary efficacy end points; this dose was subsequently selected for further development in the phase 3 program.46

Two pivotal clinical trials comprised the phase 3 pro-gram. One of the trials was designed to assess the efficacy and safety of a single dose of NEPA (netupitant 300 mg plus oral palonosetron 0.5 mg) compared with a single dose of oral palonosetron (0.5 mg) in 1455 chemothera-py-naïve patients receiving anthracycline-based MEC.47 In this multinational, randomized, double-blind, parallel study patients received NEPA or palonosetron plus dexamethasone (12 mg in the NEPA arm and 20 mg in the palonosetron arm) on day 1.47 The primary end point of the study was CR in the delayed phase, and key secondary end points included CR in the acute and overall phases; complete protection, no emesis, and no significant nausea during all 3 phases; and Functional Living Index-Emesis questionnaire scores.47 As de-scribed in the Figure, NEPA demonstrated statistically superior CR rates compared with palonosetron in all phases of CINV.47 NEPA also established superiority compared with palonosetron for no emesis in the acute phase and for complete protection, no emesis, and no significant nausea in the delayed and overall phases.47 Analysis of safety data determined that NEPA was well tolerated with a similar toxicity profile to palonosetron; the most commonly reported NEPA treatment-related adverse events included headache (3.3%) and constipation (2.1%), and there was no evidence of cardiac safety concerns for either drug.47

The tolerability and efficacy of NEPA over multiple cycles of HEC and MEC were investigated in the second pivotal phase 3 clinical trial. In this multicenter, multina-tional, double-blind study, 413 patients were randomized in an unbalanced (3:1) approach to receive NEPA or the active control (oral palonosetron + aprepitant) plus dexa-methasone.44 The inclusion of aprepitant plus PALO as a control was intended to help interpret any unexpected safety finding in the NEPA group.48 The primary end point was assessment of adverse events, and secondary end points included analysis of efficacy assessed by the proportion of patients with CR and no significant nausea during all 3 phases.44 With approximately 75% of patients receiving at least 4 cycles of chemotherapy, this trial pro-vided more information than any other multiple cycle antiemetic study, and results showed that NEPA and aprepitant/palonosetron demonstrated very similar safety profiles. The most frequently reported treatment-related adverse events in patients receiving NEPA were constipa-tion and headache during both cycle 1 (2.3% and 1%, respectively) and throughout the entire multiple cycle study period (3.6% and 1%, respectively).48 Efficacy data demonstrated that NEPA was effective in preventing CINV over repeated cycles of chemotherapy,48 and that higher response rates in the delayed and overall phases were achieved by patients receiving NEPA compared with aprepitant/palonosetron (no formal statistical com-parisons were performed; data are descriptive only).48

Data from the NEPA clinical program has demon-strated that this drug combination is an oral alternative that achieves improved clinical control of CINV rela-tive to palonosetron––the evidence-based guideline preferred 5-HT3 RA––for patients receiving MEC and HEC.48 It is well tolerated and has a safety profile similar to aprepitant/palonosetron.48 This novel combination drug has the potential to gain FDA approval for both acute and delayed CINV in patients receiving HEC or MEC.41


Discoveries made at the cellular level are providing a fascinating insight into the mechanisms behind CINV, and affording a strong rationale for clinical combination of drugs that synergistically impact the 2 major pathways involved in mediating this distressing side effect. Research from both the laboratory and the clinic suggest that it is possible to improve upon current clinical achievements, particularly in the delayed phase of CINV, with drugs such as NEPA that act on both the NK-1 and 5-HT3 pathways.


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