Chemotherapy-induced nausea and vomiting: Guideline update and role of netupitant/palonosetron

International antiemetic guidelines recommend combination regimens, such as a corticosteroid plus a serotonin (5-HT₃) receptor antagonist (RA) with or without a neurokinin-1 (NK1) RA, as standard of care for prevention of chemotherapy-induced nausea and vomiting (CINV). However, despite the availability of various antiemetic agents and combinations, some patients still experience severe CINV that may hinder cancer treatment adherence. At a symposium organized by the Macau Oncology Association, Professor Roger Ngan of the Department of Clinical Oncology, University of Hong Kong, and Dr Cheng-Vai Hui, Consultant in Medical Oncology, Macau Oncology Association, discussed recent updates in clinical guidelines on CINV management and shared their experience in CINV prophylaxis using a fixed oral combination of an NK1 RA and a 5-HT₃ RA (netupitant/palonosetron [NEPA]) in cancer patients receiving moderately emetogenic chemotherapy (MEC) or highly emetogenic chemotherapy (HEC).

Mechanism of action of antiemetic agents
CINV involves an acute phase experienced within 24 hours and a delayed phase that affects some patients on days 2–5 of a chemotherapy cycle. “Acute emesis is associated with activation of 5-HT₃ receptors on vagal nerve terminals in the gastrointestinal system and centrally in the chemoreceptor trigger zone in the area postrema of the fourth ventricle, whereas delayed emesis results from activation of NK1 receptors by the neuropeptide substance P,” explained Ngan. [Front Pharmacol 2022;12:790784]

“Blockade of serotonin using selective 5-HT₃ RAs, such as ondansetron, granisetron and palonosetron, results in powerful antiemetic effects for acute emesis, while NK1 RAs, such as aprepitant and netupitant, have antinausea and antivomiting properties and can prevent both central and peripheral stimulation of vomiting centres,” he noted.

Updated guidelines on emesis control with MEC and HEC
The US National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology for Antiemesis classify anticancer agents into high, moderate, low and minimal emetic risk according to their emetogenic potential. “One recent important update is the reclassification of trastuzumab deruxtecan [T-DXd] from a MEC to a HEC,” noted Hui. (Table) [NCCN Guidelines for Antiemesis Version 1.2023]

“As CINV is one of the most feared side effects associated with T-DXd, the European Society for Medical Oncology [ESMO] guidelines recommend CINV prophylaxis with a standard initial regimen including dexamethasone [DEX] and a 5-HT₃ RA, which can be escalated to include an NK1 RA with or without olanzapine if appropriate, for breast cancer patients receiving T-DXd,” added Hui. [ESMO Open 2022;7:100553]

“The NCCN guidelines also recommend similar CINV prophylaxis options for patients treated with MEC or HEC, but for HEC, the four-drug regimen, including both 5-HT₃ and NK1 RAs plus DEX and olanzapine, is preferred,” commented Ngan. [NCCN Guidelines for Antiemesis Version 1.2023]

NEPA’s mechanism of action
NEPA is a fixed oral combination of an NK1 RA (netupitant 300 mg) and a second-generation 5-HT3 RA (palonosetron 0.5 mg) indicated for prevention of acute and delayed CINV associated with initial and repeat courses of HEC or MEC in adults. [Akynzeo Hong Kong Prescribing Information]

“Netupitant is highly selective and can cross the blood-brain barrier with high expression of brain NK1 receptors. Netupitant has a much longer half-life than aprepitant [88 hours vs 9–13 hours], which allows optimal prevention of CINV in the delayed phase with a single dose,” pointed out Ngan. [Akynzeo Hong Kong Prescribing Information; Aprepitant Hong Kong Prescribing Information] “Moreover, palonosetron’s pharmacologic and clinical properties are distinct from other 5-HT₃ RAs. With the highest affinity for 5-HT₃ receptor in the class and a long half-life of 40 hours, it is more effective than other first-generation 5-HT₃ RAs in controlling CINV in both the acute and delayed phases with MEC and HEC.” [Brunton LL, Lazo JS, Parker KL, Goddman & Gilman’s The Pharmacological Basis of Therapeutics, McGraw-Hill: New York, 2006; Support Care Cancer 2014;22:469-477]

When used separately, both components of NEPA can trigger NK1 receptor internalization. When used in combination, they exhibit synergistic effects in inhibiting substance P–mediated response and additive effects with respect to triggering NK1 receptor internalization. “The synergistic effects were demonstrated exclusively for netupitant and palonosetron, which supports the pharmacologic rationale for the combination targeting both acute and delayed phases of CINV. The oral fixed combination of NEPA provides not only long-lasting protection against CINV, but also convenience of administration that may increase treatment adherence,” commented Ngan. [Eur J Pharmacol 2012;689:25-30; J Clin Pharmacol 2019;59:472-487; Support Care Cancer 2014;22:469-477; Akynzeo Hong Kong  Prescribing Information; Aprepitant Hong Kong Prescribing Information]

Efficacy of NEPA and aprepitant regimens
A pooled analysis of three similarly designed phase II/III, randomized, oral NEPA registration studies (n=1,197) demonstrated superiority of NEPA to a 3-day aprepitant regimen in patients receiving cisplatin-based HEC. Rates of complete response (CR; no emesis and no rescue medication), complete protection (CR and no significant nausea) and total control (CR and no nausea) were similar for the acute (0–24 hours) and overall (0–120 hours) phases, with significantly higher rates of CR (81.8 percent vs 76.9 percent) and complete protection (73.6 percent vs 68.4 percent) reported for oral NEPA plus DEX compared with the aprepitant regimen plus DEX in the delayed (>24–120 hours) phase (both p<0.05). (Figure 1) [Future Oncol 2021;17:3027-3035]

In the subset of patients receiving high-dose cisplatin (>70 mg/m²), oral NEPA plus DEX was also superior to the aprepitant regimen plus DEX in terms of CR (81.5 percent vs 73.9 percent) and total control (54.8 percent vs 47.6 percent) during the delayed phase, as well as complete protection during the delayed (73.1 percent vs 64.9 percent) and overall (69.4 percent vs 61.8 percent) phases (all p<0.05).

Notably, significantly fewer patients receiving oral NEPA plus DEX vs aprepitant plus DEX had breakthrough CINV (emesis and/or use of rescue medication) or breakthrough significant nausea on days 3–5 (all p<0.05). (Figure 2)

“Furthermore, a pragmatic, randomized, open-label, prospective study [n=373] revealed that single-dose NEPA plus DEX was noninferior to a 3-day aprepitant regimen plus DEX in preventing CINV among chemotherapy-naïve patients receiving anthracycline and cyclophosphamide [AC] or non-AC MEC in a real-life setting. In patients on MEC [NEPA, n=109; aprepitant, n=102], NEPA was associated with numerically higher CR rates vs aprepitant in the acute, delayed and overall phases, with the highest difference in risk [12 percent] observed in the overall phase, which was clinically significant,” said Ngan. [Oncologist 2021;26:e1870-e1879]

“NEPA was also more effective than the 3-day aprepitant regimen in preventing CINV in the subgroup of MEC recipients with emetic risk factors [n=181], with a clinically significant difference of >10 percent in overall CR rates [74 percent vs 58 percent],” Ngan added. [Zelek L, et al, ESMO 2021, abstract 1672P]

HK & Macau experience: CINV management with NEPA
Unconventional practice experience in HK
“A protracted course of chemotherapy for up to 5 days is used in treatment of certain cancers, especially in young patients. Examples include bleomycin, etoposide and cisplatin [BEP] for germ cell tumour, and ifosfamide and etoposide for Ewing’s sarcoma. In these cases, CINV prevention with 5-HT₃ and NK1 RAs usually lasts for about 3 days, and patients may experience breakthrough CINV even with DEX ± olanzapine. We suggest NEPA in tandem [on days 1 and 4] with DEX ± olanzapine because this regimen has been effective in preventing breakthrough CINV,” Ngan said. (Figure 3)

In addition, head-and-neck cancer patients treated with high-dose cisplatin with or without concurrent radiotherapy often have swallowing difficulties and need tube feeding. Although NEPA is the preferred antiemetic option for patients receiving HEC, it is only available in capsule form, and breaking the capsule for tube feeding is not recommended. Instead, we tend to use intravenous [IV] aprepitant plus palonosetron and DEX, with or without crushed olanzapine tablet given via a nasogastric tube. There remains a need for IV formulation of NEPA for this subgroup of patients,” said Ngan.

A patient with T-DXd–induced CINV treated in Macau
Hui presented the case of a 31-year-old female diagnosed with metastatic right breast cancer in 2018. Pathology showed grade 3, HER2-positive, oestrogen receptor/progesterone receptor–negative invasive ductal carcinoma with Ki67 level of 92 percent. Her breast cancer was staged cT4b N3c M1 with liver metastasis.

The patient was initially treated with six cycles of paclitaxel plus trastuzumab and pertuzumab, followed by palliative right mastectomy. Stable disease was achieved, but disease progression (new lymph nodes [LNs] in the neck) was subsequently confirmed in late 2019. Second-line treatment with docetaxel plus carboplatin and trastuzumab was given, but CT in February 2020 showed disease progression with bilateral axillary nodal metastases. She was treated with one cycle of cyclophosphamide plus methotrexate and fluorouracil before switching to trastuzumab emtansine (T-DM1) as soon as it became reimbursable.

In July 2021, the patient was switched to fourth-line capecitabine for disease progression (multiple LNs in the left axilla). Lapatinib was added as fifth-line therapy in September 2021 when multiple left breast masses and nodal metastases were detected. However, due to intolerance to lapatinib and marked elevation of serial tumour marker (cancer antigen 15-3 [CA 15-3]), treatment was switched to eribulin plus trastuzumab in February 2022. In April 2022, disease progression was noted with metastases in the left breast, lung and LNs, for which T-DM1 was restarted as seventh-line therapy.

Approximately 5 months later, the patient’s CA 15-3 level increased from 40 U/mL to >100 U/mL, and CT of the head, neck, chest and abdomen showed disease progression, for which eighth-line T-DXd was started in October 2022 when the drug became reimbursable.

The patient experienced severe CINV since the first cycle of T-DXd. Despite the use of a mixture of antiemetics, including granisetron, DEX, famotidine, metoclopramide and benzodiazepine, she vomited immediately after any intake of food or fluids (>10 bags of vomitus a day). Subsequently, she had to avoid food and fluid, and developed dehydration and lost weight. Nevertheless, she responded well to T-DXd rapidly, with marked symptomatic improvement, including healing of the 10 cm tumour necrosis and decrease of CA 15-3 from 160 U/mL to 40 U/mL, within 3 months.

At cycle 5 of treatment, as soon as T-DXd was reclassified as a HEC by the NCCN guidelines, oral NEPA was given for CINV prophylaxis. Vomiting significantly improved on the first 2 days of the treatment cycle, and CINV became tolerable. The patient was able to eat and drink, and her quality of life (QoL) substantially improved.

CINV was the patient’s main complaint during the first seven lines of MEC or HEC, but her QoL was maintained during treatment, with a performance status of 0–1. However, CINV with T-DXd was severe despite all pharmacological and nonpharmacological antiemesis options that had been tried. Although evidence suggests that uncontrolled CINV in the previous treatment cycle is a key risk factor of CINV in the subsequent cycle, the patient’s vomiting significantly improved when NEPA was started from the fifth cycle of T-DXd. (Figure 4) [J Pain Symptom Manage 2016;51:987-993] This case illustrates the efficacy of NEPA in patients at high risk of developing CINV with HEC.

Conclusion
“Combination of NK1 and 5-HT₃ RAs, such as NEPA, is proven to be efficacious in CINV prevention when used with DEX ± olanzapine in patients on MEC or HEC, including T-DXd. The simple dosing of the fixed oral NEPA combination can improve adherence and emesis control, and help optimize cancer treatment,” Ngan concluded.