Updates on Chemotherapy-Induced Nausea and Vomiting:
From Akynzeo to Zyprexa

Maxwell A. Brown, PharmD
Clinical Pharmacy Manager, Bone Marrow Transplantation
New York–Presbyterian–Weill Cornell Medical Center
New York City, NY

Chemotherapy-induced nausea and vomiting (CINV) remains one of the most feared complications of cancer treatment and can have a significant impact on a patient’s quality of life.^1–3 Furthermore, uncontrolled CINV can necessitate dose reductions or delays in a patient’s treatment regimen, which may negatively affect patient outcomes.⁴ Advances in the understanding of the pathophysiology of CINV, the development of increasingly effective antiemetic agents, and adherence to evidence-based consensus guidelines have resulted in improved control of CINV.⁵ In 2017, the American Society of Clinical Oncology (ASCO) made significant updates to its clinical practice guideline on the use of antiemetics.⁶ This article focuses on the literature supporting key guideline updates on the use of olanzapine, novel neurokinin-1 receptor antagonists (NK₁RAs), and extended-release (ER) injection of granisetron.

Olanzapine
The updated ASCO antiemetic guidelines recommend the addition of olanzapine (Zyprexa) to an NK1RA, a 5-hydroxytryptamine-3 receptor antagonist (5-HT₃RA), and dexamethasone for prevention of CINV in adults receiving cisplatin and other highly emetogenic single agents as well as adults receiving an anthracycline combined with cyclophosphamide (AC).⁶

Olanzapine, a structural relative of clozapine, is a second-generation atypical antipsychotic in the class of thienobenzodiazepine derivatives. Olanzapine binds with high affinity to a variety of neuronal receptors and displays antagonism of dopamine, serotonin, alpha1-adrenergic, histamine H1, and muscarinic receptors.⁷ The oral formulation of olanzapine is currently approved by the U.S. Food and Drug Administration (FDA) for the treatment of schizophrenia, acute treatment of mixed and manic episodes of bipolar 1 disorder, and maintenance treatment of bipolar 1 disorder. However, olanzapine is also frequently used off-label for the treatment of delirium as well as for the prevention and treatment of CINV. Although the exact mechanism remains unknown, it has been suggested that the combined antagonism of olanzapine at the dopamine (D₂), 5-HT_2C, and 5-HT₃ receptors may be responsible for its antiemetic properties.⁸

The activity of olanzapine as an antiemetic agent was first published in a case report of a patient with leukemia who reported a significant improvement in chronic nausea with the use of olanzapine.⁹ Additional publications describing the successful use of olanzapine as a treatment for nausea and vomiting10 prompted a phase 1 study to investigate its utility for preventing CINV. Patients enrolled in the phase 1 study received granisetron and dexamethasone plus escalating doses of olanzapine. Thirteen of the 15 patients enrolled had complete control of delayed emesis, and the maximum tolerated dose (MTD) of olanzapine was identified as 5 mg orally once daily for 2 days prior to chemotherapy and 10 mg orally once daily on the day of chemotherapy and then continued for an additional 7 days.¹³ These encouraging results led to a phase 2 investigation of olanzapine for prevention of CINV in chemotherapy-naive patients.

Using the MTD identified in the phase 1 study, olanzapine was added to granisetron (10 mcg/kg intravenous [IV] on day 1) and dexamethasone (20 mg orally on day 1, 8 mg orally twice daily on days 2 and 3, and 4 mg orally twice daily on day 4) in 30 patients receiving moderately emetogenic chemotherapy (MEC) and highly emetogenic chemotherapy (HEC). The rate of complete response (CR) for the overall period (0–120 hours postchemotherapy) was 85% for the 20 patients receiving MEC and 80% for the 10 patients receiving HEC, and no grade 3 or 4 toxicities were identified.¹⁴ A subsequent phase 2 study in 40 chemotherapy-naive patients receiving MEC or HEC investigated olanzapine (10 mg orally once daily on days 1–4) in addition to palonosetron (0.25 mg on day 1) and dexamethasone (8 mg on day 1 for MEC, 20 mg on day 1 for HEC). Despite the shorter duration of olanzapine and dexamethasone, the CR rate for the overall period (0–120 hours postchemotherapy) was 72% for the 32 patients receiving MEC and 75% for the 8 patients receiving HEC, with no grade 3 or 4 toxicities identified.¹⁵

Two phase 3 studies comparing olanzapine to aprepitant (both in combination with a 5-HT₃RA and dexamethasone) have been published. Both studies demonstrated that the effect of the two regimens on CINV is similar during the acute period (0–24 hours postchemotherapy) but that olanzapine is superior to aprepitant for control of nausea during the delayed period (0–120 hours postchemotherapy).^16,17 The recommendation to incorporate olanzapine into the previously standard three-drug antiemetic regimen for HEC was driven primarily by a phase 3 trial of 380 patients receiving either cisplatin-based or AC-based HEC. Patients were randomly assigned to receive either olanzapine 10 mg orally or placebo on days 1–4 plus a 5-HT₃RA (either palonosetron 0.25 mg IV, granisetron 1 mg IV or 2 mg orally, or ondansetron 8 mg orally or IV) on day 1, dexamethasone (12 mg orally on day 1 and 8 mg orally on days 2–4), and an NK₁RA (fosaprepitant 150 mg IV on day 1 or aprepitant 125 mg orally on day 1 and 80 mg orally on days 2 and 3). The proportion of patients who met the primary end point of no nausea (as defined by a response of 0 on the visual-analogue scale for nausea) was significantly greater in the olanzapine group than in the placebo group for all three assessment periods: early period (0–24 hours postchemotherapy), 74% vs. 45% (p = .002); later period (25–120 hours postchemotherapy), 42% vs. 25% (p = .002); and overall period (0–120 hours postchemotherapy), 37% vs. 22% (p = .002). Although sedation was significantly increased in the olanzapine group on day 2 when compared with baseline, the sedation resolved on days 2–4.¹⁸

One potential limitation of this phase 3 study, outlined in a correspondence article from Bossaer, is the dosing of dexamethasone on days 3 and 4, depending upon which NK₁RA was used. Bossaer asserts that although the recommended dosage of dexamethasone is the same for fosaprepitant and aprepitant on days 1 and 2, the dose of dexamethasone should have been 8 mg orally twice daily on days 3 and 4 for patients receiving fosaprepitant. Because fosaprepitant is given only on day 1, the drug interaction with dexamethasone is no longer present on days 3 and 4. Therefore, the subtherapeutic dexamethasone dosing on days 3 and 4 would create a substandard comparator for evaluation of CINV in the delayed period.¹⁹ In response, the authors state that prior studies²⁰ as well as a subgroup analysis of olanzapine within their phase 3 trial showed no difference in results between aprepitant and fosaprepitant, despite higher dexamethasone dosing on days 3 and 4.

Another limitation of the phase 3 study identified by the authors was that only one dose of olanzapine was evaluated. A recently published phase 2 study compared olanzapine 10 mg to 5 mg orally on days 1–4 in combination with aprepitant, palonosetron, and dexamethasone.²¹ No significant difference in the CR rates for nausea between groups for the acute, delayed, and overall periods was found. Additionally, the most significant adverse effect was somnolence, which was more frequently observed in the 10-mg group (53.3%) than in the 5-mg group (45.5%). The authors therefore recommended an olanzapine dose of 5 mg for future phase 3 investigations.

Netupitant/Palonosetron
Netupitant/palonosetron (Akynzeo) is a novel NK1RA commercially available as a fixed-dose oral combination of netupitant 300 mg and palonosetron 0.5 mg (NEPA). NEPA was FDA-approved in 2014 for prevention of acute and delayed nausea and vomiting associated with repeat courses of cancer chemotherapy, including, but not limited to, HEC. In 2016, ASCO issued a focused update of its antiemetic guidelines to include NEPA as an antiemetic option for patients receiving HEC.²²

Netupitant is a highly selective antagonist at the NK1 receptor, maintaining greater than 75% receptor occupancy for up to 96 hours following a single dose.²³ Netupitant was combined with palonosetron because palonosetron has a greater binding affinity for the 5-HT₃ receptor and a longer half-life than other 5-HT₃RAs. In addition, palonosetron exhibits allosteric binding to the 5-HT₃ receptor with positive cooperativity and may inhibit cross-talk between the NK1 and 5-HT₃ receptor–signaling pathways, further enhancing its antiemetic effect.²⁴

Two phase 3 studies initially evaluated NEPA for prevention of CINV. The first evaluated NEPA plus dexamethasone versus palonosetron and dexamethasone in patients receiving their first cycle of AC-based chemotherapy. The CR rates during the delayed period were significantly higher in the NEPA group compared to the palonosetron group (76.9% vs. 69.5%; p = .001). NEPA also outperformed palonosetron alone during the acute and overall periods of CINV.²⁵ A second phase 3 study evaluated the safety and efficacy of NEPA over multiple cycles of MEC or HEC. Of note, patients in the control arm received aprepitant (in combination with palonosetron and dexamethasone), but comparisons between the NEPA and aprepitant group were made on the basis of safety alone. The most common adverse effects (AEs) noted in the NEPA group were constipation (3.6%) and headache (1%), and no increase in the incidence of AEs was observed over multiple treatment cycles. In addition, the CR rates during the overall period of cycle 1 were 81% and 76% for the NEPA and aprepitant groups, respectively, and continued antiemetic efficacy was demonstrated over multiple treatment cycles.²⁶

An additional phase 3 study directly compared the efficacy of NEPA (plus dexamethasone) versus aprepitant (plus granisetron and dexamethasone) in patients receiving cisplatin-based HEC. This was the first clinical trial to directly compare the effectiveness of two NK₁RAs in a head-to-head fashion. For the primary efficacy end point, NEPA demonstrated noninferiority to aprepitant during the overall period of CINV (73.8% vs. 72.4%). The incidence of AEs was also similar between groups, with constipation (8% vs. 6.3%) and hiccups (2.7% vs. 1.4%) being the most common treatment-related AEs. Of note, the daily rates of patients with CINV events (defined as experiencing emesis or use of rescue medication or both) declined during the overall period of CINV and reached statistical significance on day 5 (8% vs. 13.9%; p = .0063).²⁷

Rolapitant
Rolapitant (Varubi) is also a novel NK₁RA that was FDA-approved in 2015 for prevention of delayed CINV with MEC and HEC. Rolapitant is also quite selective for the NK₁ receptor, binding with high affinity and maintaining greater than 90% receptor occupancy in the brain for up to 5 days following a single 180-mg dose.²⁸ Furthermore, the drug interaction profile of rolapitant is unique when compared to the other NK₁RAs in that rolapitant does not inhibit the metabolic activity of cytochrome P450 (CYP) 3A4 but does have moderate inhibitory effects on CYP 2D6.²⁹ The updated ASCO antiemetic guidelines now recommend rolapitant as one of the NK₁RA options available for patients receiving HEC and for select patients receiving MEC.⁶

Two identical phase 3 studies (HEC-1 and HEC-2) of rolapitant for prevention of CINV after cisplatin-based chemotherapy formed the basis for its FDA approval in patients receiving HEC. In both studies independently, and in the pooled analysis of HEC-1 and HEC-2, use of rolapitant resulted in a significantly higher CR rate for control of nausea during the delayed period (25–120 hours postchemotherapy) when compared to placebo (pooled studies: 71% vs. 60%; p = .0006).³⁰ A third phase 3 study of rolapitant for prevention of CINV after MEC or AC-based chemotherapy gave it the FDA approval for patients receiving MEC. Again, rolapitant outperformed placebo for control of nausea in the delayed period (71% vs. 62%; p = .002).³¹ Of note, this study was designed before the publication of the 2011 ACSO antiemetic guidelines³² in which AC regimens were designated as HEC; prior to the publication of the 2011 ASCO guidelines, AC regimens were considered MEC.

In 2017, the FDA approved an IV formulation of rolapitant for prevention of delayed CINV after a study assessing exposure to rolapitant in healthy volunteers determined that the oral and IV formulations were bioequivalent.³³ A potential benefit of IV rolapitant compared with other NK₁RAs is that it is supplied in ready-to-use vials that do not require dilution, admixture, or refrigeration. However, the FDA recently released a safety alert stating that anaphylaxis, anaphylactic shock, and other serious hypersensitivity reactions have been reported in the postmarketing setting, in some cases requiring hospitalization. Therefore, healthcare professionals should be vigilant for signs of hypersensitivity or anaphylaxis in patients receiving IV rolapitant.³⁴

In the phase 3 MAGIC trial, granisetron ER injection was compared with ondansetron (both in combination with an NK1RA and dexamethasone) in patients receiving HEC, including patients receiving AC-based chemotherapy. For the primary end point of CR during the delayed period (25–120 hours postchemotherapy), granisetron ER injection was significantly better than ondansetron (64.7% vs. 56.6%; p = .014). However, no difference was seen between treatment arms during the acute and overall periods of CINV.³⁷ In addition, a post-hoc analysis of the MAGIC trial examined the rate of CR during the delayed period of CINV in the subgroup of patients receiving AC-based chemotherapy. Although a trend toward significance was noted, no statistically significant difference was seen between granisetron ER injection and ondansetron in this subgroup of patients (63.6% vs. 56.0%; p = .062).³⁸

Another phase 3 trial compared granisetron ER injection with palonosetron (both in combination with dexamethasone) in patients receiving MEC and HEC. Granisetron ER injection demonstrated noninferiority to palonosetron in preventing both acute and delayed CINV after MEC and HEC.³⁹ This remained true in a subgroup analysis of breast cancer patients receiving MEC or HEC.⁴⁰ Of note, because evidence-based consensus guidelines on the use of antiemetics were updated after initiation of this study, patients receiving HEC did not receive an NK₁RA.

Granisetron ER injection was generally well tolerated in the phase 3 trials. The most common AEs observed were constipation, nausea, fatigue, headache, and injection-site reactions.^37,39 Injection-site reactions (primarily bruising, erythema, nodules, and pain, the majority of which were mild or moderate in severity) were seen in 61.8% of patients treated with granisetron ER injection.³⁷ However, healthcare providers should be aware of the risk of injection-site reactions, particularly in patients receiving anticoagulant or antiplatelet medications.

Conclusion
Nausea and vomiting due to chemotherapy can significantly affect a patient’s quality of life, patient compliance, and the provider’s ability to administer further treatment. Adherence to evidence-based consensus guidelines on the appropriate use of antiemetics has been shown to decrease the incidence of CINV.⁵ With the development of increasingly effective medications for the prevention of CINV, it is imperative that healthcare providers maintain expertise in the proper use of antiemetic medications to reduce the burden of CINV and improve patient care.

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