NEPA effective for chemotherapy-induced nausea and vomiting in Hong Kong patients
Despite the availability of antiemetics, a substantial proportion of patients receiving chemotherapy experience chemotherapy-induced nausea and vomiting (CINV), significantly impacting treatment compliance and quality of life (QoL). At the 24th Annual Scientific Symposium of the Hong Kong Cancer Institute, Professor Winnie Yeo of the Department of Clinical Oncology, Chinese University of Hong Kong, presented results of a local study showing superior efficacy of the fixed-dose netupitant/palonosetron (NEPA) combination regimen vs aprepitant-based regimen in controlling CINV in breast cancer patients receiving highly emetogenic anthracycline-cyclophosphamide (AC) chemotherapy.
CINV: Effects and consequences
“CINV are two of the most frequent and troubling side effects patients experience during chemotherapy,” said Yeo. “CINV can cause dehydration, electrolyte imbalance, malnutrition, have muscular and mental effects, and impact on everyday activities, all of which can lead to impaired QoL, as well as increased morbidity and healthcare expenses. These in turn can interfere with treatment compliance, causing treatment delays, dose reduction and treatment discontinuation.” [Drugs 2009;69:1853-1878; Drug Des Devel Ther 2014;9:155-161; Ann Oncol 2012;23:1986-1992; Expert Opin Pharmacother 2013;14:757-766; Support Care Cancer 2011;19:131-140]
“5-hydroxytryptamine3 [5-HT3] and substance P [a ligand acting largely on neurokinin 1 (NK1) receptors] are proposed to be the two major neurotransmitters involved in the pathophysiology of CINV,” she continued. [N Engl J Med 2008;358:2482-2494] “Highly emetogenic chemotherapy [HEC] induces a biphasic pattern of emesis. The first peak is seen a few hours after the initiation of chemotherapy with the release of serotonin. The second peak is observed from 16 hours onwards and up to 120 hours with the release of substance P.” [Drugs 1996;52:639-648]
“Uncontrolled CINV in a previous cycle of chemotherapy are a key risk factor for repeat CINV in subsequent cycles. Uncontrolled CINV in the previous cycle were found to increase the likelihood of CINV by 6.46 times in cycle 2 and by 14.17 times in cycle 3,” noted Yeo. [J Pain Symptom Manage 2016;51:987-993] “It is therefore important to control CINV from the start, especially for high-risk patients.”
“Corticosteroids, 5-HT3 receptor antagonists [5-HT3 RAs], NK1 receptor antagonists [NK1 RAs], dopamine antagonists, and olanzapine are the currently available antiemetic drugs,” said Yeo.
“In contrast to ondansetron and granisetron, 5-HT3 RA palonosetron exhibits prolonged inhibition of receptor function, triggers receptor internalization, and inhibits 5-HT3/NK1 receptor cross-talk,” she pointed out. [Eur J Pharmacol 2010;626:193-199; J Pharmacol Exp Ther 2010;335:362-368]
“Compared with aprepitant, NK1 RA netupitant has a longer half-life [96 hours vs 9–13 hours],” Yeo continued. [Future Oncol 2014, doi: 10.2217/fon.14.260; Emend® (Aprepitant) Prescribing Information, 2008] “Both drugs can reduce the metabolism of corticosteroids as they are moderate inhibitors of cytochrome P450 enzyme CYP3A4. As a result, the dose of dexamethasone can be reduced when coadministered with aprepitant or NEPA.” [Support Care Cancer 2015;23(Suppl 1):S1-S388; Clin Pharmacol Ther 2012;92:243-250]
In a systematic review of 17 trials evaluating NK1 RAs plus standard antiemetic therapy for CINV prevention, the addition of NK1 RAs was shown to improve complete response (CR) (ie, no emesis/no rescue therapy) rate in the overall phase, from 54 percent to 72 percent (odds ratio [OR], 0.51; 95 percent confidence interval [CI], 0.46 to 0.57; p<0.001). The benefits were observed in patients receiving HEC (OR, 0.46; 95 percent CI, 0.40 to 0.53; p<0.001) or moderately emetogenic chemotherapy (MEC) (OR, 0.59; 95 percent CI, 0.51 to 0.67; p<0.001). [J Natl Cancer Inst 2012;104:1280-1292]
“Our team also evaluated the efficacy of adding aprepitant to standard antiemetic therapy in local settings, but no significant differences were found in any CINV endpoints [CR, complete protection, total control, “no vomiting”, “no significant nausea” and “no nausea”] in acute, delayed and overall periods compared with placebo added to standard antiemetic therapy,” noted Yeo. [Breast Cancer Res Treat 2009;113:529-535]
Interestingly, adding palonosetron to netupitant was shown to enhance the prevention of delayed emesis by inhibition of substance P response. “Notably, netupitant- and palonosetron-mediated inhibition of substance P response is synergistic and dose-dependent,” Yeo pointed out. [Eur J Pharmacol 2012;689:25-30]
NEPA for CINV control
“NEPA is a fixed-dose combination drug with a hard capsule containing three netupitant 100 mg tablets and one soft capsule containing palonosetron 0.5 mg,” Yeo said.
In a phase III study, NEPA-based antiemetic therapy was found to be superior to palonosetron-based therapy in preventing CINV following AC chemotherapy. [Ann Oncol 2014;25:1328-1333]
Another recent phase III study showed that NEPA was noninferior to aprepitant/granisetron combination therapy in the prevention of CINV associated with HEC, with the advantage of less frequent dosing. [Ann Oncol 2018;29:452-458]
Local study: NEPA for CINV control in patients on AC chemotherapy
Recently, Yeo and colleagues conducted a study to evaluate the efficacy of NEPA-based therapy in 60 Chinese patients with early-stage breast cancer who were to receive AC chemotherapy. The results were compared with a historical control group of patients who received an aprepitant-based antiemetic regimen (n=62) in a previously reported local prospective randomized study. [BMJ Support Palliat Care 2020, doi: 10.1136/bmjspcare-2019-002037; Breast Cancer Res Treat 2009;113:529-535]
“Patients in the NEPA group received one NEPA capsule plus dexamethasone 12 mg daily on day 1, followed by dexamethasone 8 mg daily on days 2 and 3. The more protracted use of dexamethasone is due to AC being reclassified from MEC to HEC in major international guidelines. Meanwhile, patients in the aprepitant group received aprepitant 125 mg daily, dexamethasone 12 mg daily and ondansetron 8 mg twice daily on day 1, followed by aprepitant 80 mg daily on days 2 and 3,” explained Yeo. [Ann Oncol 2016;27(Suppl 5):v119-v133; J Clin Oncol 2017;28:3240-3261]
The primary CINV endpoint in this study was CR across acute (0–24 hours), delayed (24–120 hours) and overall phases (0–120 hours). Other CINV endpoints included absence of significant nausea (ie, nausea visual analogue scale [VAS] <25 mm), absence of nausea (ie, VAS <5 mm), complete protection (ie, CR/no significant nausea), and total control (ie, no emesis/no rescue therapy/no nausea). Patients’ QoL was also evaluated using the Functional Living Index Emesis (FLIE) score.
NEPA offers superior efficacy over multiple cycles
“Our results showed superior CR rate in the NEPA vs aprepitant group in the delayed phase [cycle 1, 85.7 percent vs 64.4 percent, p=0.0226; cycle 2, 92.2 percent vs 65.5 percent, p=0.0010; cycle 3, 98.1 percent vs 68.5 percent, p<0.0001; cycle 4, 98.1 percent vs 66.0 percent, p<0.0001],” reported Yeo.
NEPA also showed significantly higher CR, complete protection and total control rates vs aprepitant in the delayed phase. “The superior delayed and overall total control rates with NEPA were shown across four cycles of chemotherapy,” added Yeo. (Table 1)
“The significant improvements observed in the NEPA vs aprepitant group might be attributed to the higher potency of NEPA, as well as the different antiemetics used on days 2 and 3,” Yeo postulated. “With reference to previous NEPA and aprepitant studies, it appears that the current findings support the importance of continuing dexamethasone to achieve better CINV control during the delayed and overall phases.” [J Clin Oncol 2005;23:2822-2830; Breast Cancer Res Treat 2009;113:529-535; Ann Oncol 2014;25:1328-1333] NEPA plus dexamethasone is also recommended for CINV prevention among patients receiving HEC or MEC regimens by the latest NCCN guidelines. [NCCN Clinical Practice Guidelines in Oncology, Antiemesis Version 2.2020]
Significantly better nausea control with NEPA
In addition to higher complete protection and total control rates, nausea control was significantly better during cycle 1 of AC chemotherapy in the NEPA vs aprepitant group in the delayed (no nausea, 76.2 percent vs 47.3 percent; p=0.008) and overall phases (no nausea, 53.3 percent vs 30.6 percent; p=0.011). (Figure 1)
The benefits of CINV control with NEPA were accompanied by improvements in patients’ QoL. The nausea domain (mean score for NEPA vs APR groups: 17.55 vs 27.44, respectively; p=0.0015) and total score (mean score for NEPA vs APR groups: 12.14 vs 15.50, respectively; p=0.0020) among patients in the NEPA group on day 6 of AC chemotherapy were significantly improved vs aprepitant.
“Optimizing CINV control requires agents that target the serotonin- and substance P-mediated pathways,” concluded Yeo. “Effective antiemetic drugs, including 5-HT3 RAs and NK1 RAs in conjunction with corticosteroids, have become the cornerstone for CINV management.”
“Despite our study’s positive findings concerning the efficacy of NEPA vs aprepitant, a substantial proportion of patients continued to experience CINV symptoms, with nearly 40 percent reporting episodes of vomiting, and 22–47 percent reporting episodes of nausea. This highlights the importance of continuous improvement in CINV management,” she added.
“Additional agents such as olanzapine may enhance the antiemetic efficacy of the current regimen, which has been recommended by major international guidelines,” she continued. [Ann Oncol 2016;27(Suppl 5):v119-v133; J Clin Oncol 2017;28:3240-3261; NCCN Clinical Practice Guidelines in Oncology, Antiemesis Version 1.2019] “Further research is required to optimize CINV control and alleviate the potential sequelae associated with CINV.”