Palonosetron

The first-generation 5-HT3 receptor antagonists (ondansetron, dolasetron, granisetron, and tropisetron) form the cornerstone of antiemetic therapy for moderately to highly emetogenic chemotherapy. The efficacy and safety of these agents has been repeatedly demonstrated in controlled clinical trials,³ especially in the prevention of acute emesis (nausea and vomiting occurring in the first 24 h following chemotherapy). Their effectiveness in controlling delayed emesis is, however, substantially lower.⁵

Palonosetron differs from other currently available 5-HT3 receptor antagonists in that it has a markedly longer half-life (40 h) and greater receptor binding affinity (>30-fold). In comparison, the half-lives of ondansetron and dolasetron are approximately 4 h and 8 h, respectively. In phase I and phase II trials, palonosetron demonstrated significant efficacy in controlling emesis with a favorable toxicity profile.⁶ Three phase III trials have been conducted comparing palonosetron to other 5-HT3 receptor antagonists. Two trials with an identical non-inferiority design using moderately emetogenic chemotherapy compared palonosetron with dolasetron⁷ and ondansetron.⁸ The third phase III trial compared palonosetron with ondansetron with highly emetogenic chemotherapy.⁹ All three randomized studies defined the primary endpoint as complete response (no emesis/no rescue antiemetics) in the 24 h after chemotherapy. A number of secondary endpoints, including complete response for the delayed phase (days 2–5) and the entire study period (days 1–5) were also assessed.

One moderately emetogenic trial was conducted in North America that compared a single intravenous palonosetron dose (0.25 mg or 0.75 mg) to a single intravenous dose of dolasetron (100 mg), all given immediately prior to chemotherapy on day 1.⁷ A total of 569 patients enrolled into the trial received a variety of chemotherapy regimens including low-dose (<50 mg/m²) cisplatin, carboplatin, cyclophosphamide and anthracyclines. Both doses of palonosetron resulted in numerically better control of acute and delayed emesis compared with dolasetron. Complete response rates for acute emesis were 63%, 57%, and 52.9% for palonosetron 0.25 mg, palonosetron 0.75 mg, and dolasetron 100 mg, respectively. Corresponding complete response rates for delayed emesis were 54%, 56.6%, and 38.7%, respectively. The differences between palonosetron and dolasetron were statistically significant only for the delayed phases (0.25 mg, P = 0.004; 0.75 mg, P <0.001). Only a minority of patients (5.4%) also received a corticosteroid.

The other moderately emetogenic trial with identical design and eligibility was conducted in Europe, and compared single doses of intravenous palonosetron (0.25 mg vs 0.75 mg) and intravenous ondansetron (32 mg), all administered immediately prior to chemotherapy.⁸ In total, 563 patients were enrolled into this trial. As in the other moderately emetogenic trial, both doses of palonosetron resulted in numerically better control of acute and delayed emesis compared with ondansetron. Acute complete response rates were 81% and 73.5% for the 0.25 mg and 0.75 mg doses of palonosetron, respectively, and 68.6% for 32 mg of ondansetron. The corresponding complete response rates for delayed emesis were 74.1%, 64.6%, and 55.1%, respectively. The differences were significant only for the palonosetron 0.25 mg arm compared with ondansetron for both acute and delayed emesis (P <0.001).

The third trial compared single intravenous doses of palonosetron (0.25 mg and 0.75 mg) with a 32 mg intravenous dose of ondansetron immediately prior to chemotherapy in 667 patients receiving highly emetogenic chemotherapy.⁹ Unlike the two other phase III studies, 67% of patients received corticosteroids prior to chemotherapy. Consistent with the two other trials, both palonosetron arms achieved numerically higher control of acute and delayed emesis compared with the ondansetron arm. Complete response rates for acute emesis were 59.2%, 65.5%, and 57% for palonosetron 0.25 mg and 0.75 mg and ondansetron 32 mg, respectively. The complete response rates for delayed emesis were 45.3%, 48%, and 38.9%, respectively. Unlike the other two trials, however, none of these differences were significant (Table 1).

Table 1 Summary of the main results from the phase III palonosetron trials.

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In all three studies, antiemetic treatment was well tolerated with no significant differences in the frequency of adverse events between the three arms. The most frequent side effects were mild headache (10%) and constipation (5%). The results of these three large trials established palonosetron as an active and well-tolerated new 5-HT3 antagonist. In the setting of moderately emetogenic chemotherapy, there is a suggestion that palonosetron is superior to ondansetron and dolasetron. No significant differences were noted in the setting of highly emetogenic chemotherapy. Although the findings of these trials are encouraging, their study designs preclude reaching any definitive conclusions on the relative efficacy of palonosetron compared with the older 5-HT3 antagonists. The absence of corticosteroids and the lack of repetitive day dosing for the comparator 5-HT3 antagonists are significant limitations of these trials. Corticosteroids are an essential component of antiemetic prophylaxis for both moderate and highly emetogenic chemotherapy. In none of the phase III trials with palonosetron was the addition of a corticosteroid on day 1 prior to chemotherapy mandated. Five percent of patients on one of the moderately emetogenic trials received dexamethasone.⁷ No corticosteroids were used in the other moderately emetogenic trial. In the highly emetogenic trial, 66% of patients received dexamethasone prior to chemotherapy. Whether the superior complete response rates noted in the moderately emetogenic trials on the palonosetron arms would have persisted in the presence of corticosteroids remains to be determined. Notably, in the highly emetogenic trial, where the majority of patients did receive dexamethasone preceding chemotherapy, no significant differences in outcome were seen between the arms. Given the prolonged half-life of palonosetron (40 h) compared with ondansetron (4 h) and dolasetron (<8 h), it is not surprising that greater efficacy was noted in the delayed period with palonosetron in the moderately emetogenic trials. Whether the superiority of a single dose of palonosetron will persist when compared with repetitive daily dosing of ondansetron or dolasetron remains to be seen in future trials; however, even in the absence of clear-cut superiority, its ability to be given as a single intravenous dose prior to chemotherapy is a logistical advantage over the first-generation 5-HT3 antagonists.

Aprepitant

Until very recently, only three neurotransmitter receptors—dopamine D2, 5-HT3, and cannabinoid-1—were identified targets of currently available antiemetic drugs. With the approval of aprepitant in the US in early 2003 for use in highly emetogenic chemotherapy, another neurotransmitter, substance P, became clinically relevant. Substance P is an 11 amino acid regulatory peptide that exerts its biologic effects by binding to the NK-1 receptors, which are found in the gut and peripheral and central nervous systems. Substance P can induce emesis in animal models.¹⁰ Selective antagonists of substance P have been shown to be potent antiemetics in preclinical models.¹¹ Two particularly noteworthy observations from the preclinical studies with the NK-1 antagonists, which differentiated them from the 5-HT3 antagonists, were a broader spectrum of activity with a variety of emetic stimuli, and prominent activity in delayed emesis.^{12, 13} Subsequent early clinical trials with the NK-1 antagonists in CINV in cancer patients have largely confirmed the preclinical data.¹⁴

Aprepitant is the only NK-1 antagonist that has proceeded through full phase III study evaluation, and has received regulatory approval in the US and the European Union. Two identically designed pivotal phase III studies were conducted in North America and Europe (protocol 052, 520 patients) and in South America (protocol 054, 523 patients).^{15, 16} All patients received cisplatin 70 mg/m². Patients assigned to the control arm received ondansetron 32 mg intravenously and dexamethasone 20 mg orally on day 1, dexamethasone 16 mg orally on days 2–4, and aprepitant placebo on days 1–3. Patients on the investigational arm received ondansetron 32 mg intravenously, aprepitant 125 mg orally, and dexamethasone 12 mg orally on day 1, aprepitant 80 mg orally on days 2–3, and dexamethasone 8 mg orally on days 2–4. The primary endpoint was complete response (no emesis/no rescue) for the 5-day period following cisplatin administration. In both trials, the aprepitant arm was significantly superior to the control arm. In the 052 study, the overall complete response was 73% and 52% in the aprepitant and control arms, respectively (P <0.001).¹⁵ In the 054 study, the complete response rates were 63% and 43% for the aprepitant and control arms, respectively (P <0.001).¹⁶ In both trials, when the complete response is analyzed for the acute (day 1) and delayed phases (days 2–5), the aprepitant arm was superior to the control arm in both phases (P <0.001). In addition, control of nausea was better on the investigational arms in both studies, although the difference was significant only in the 054 study.¹⁶ The aprepitant-containing arms displayed similar toxicity profiles to those seen on the control arm. There is some evidence that the addition of aprepitant to the combination of a 5-HT3 receptor antagonist and dexamethasone leads to improved emesis control over multiple cycles of chemotherapy. Patients in both the 052 and 054 studies were permitted to continue treatment with the same antiemetic regimen employed during their initial cisplatin cycle, up to a maximum of six cycles of treatment. In every cycle, the proportion of patients with no emesis and no significant nausea for the 5 days following cisplatin was significantly higher in patients receiving aprepitant.¹⁷

Recently, the results of a double-blind, randomized, placebo-controlled trial were reported, whereby ondansetron plus dexamethasone (control arm) was compared with ondansetron plus dexamethasone plus aprepitant (aprepitant arm) in breast cancer patients receiving moderately emetogenic chemotherapy.¹⁸ Of the 866 patients enrolled, nearly all (99%) were women who received cyclophosphamide combined with an anthracycline. Patients in the control arm received ondansetron 8 mg orally twice daily on days 1–3, dexamethasone 20 mg intravenously on day 1, and aprepitant placebo on days 1–3. Those on the aprepitant arm received ondansetron 8 mg orally twice daily, dexamethasone 12 mg intravenously, and aprepitant 125 mg orally on day 1, and aprepitant 80 mg orally and ondansetron placebo on days 2–3. The primary endpoint was complete response (no emesis/no rescue) for the 5-day period following chemotherapy. Overall complete response was significantly better on the aprepitant arm compared to the control arm—50.8% vs 42.5%, respectively (P = 0.015). When the complete response rate was analyzed for the acute (day 1) and delayed (days 2–5) phases, the aprepitant arm was superior to the control arm for acute control (75.7% vs 69%, P = 0.034), but not for delayed control (55.4% vs 49.1%). Nausea control rates did not differ between the two study arms. Both antiemetic treatments were well tolerated with similar side effects in both arms. The pooled efficacy results for these trials are shown in Table 2.

Table 2 Summary of the main results from the phase III aprepitant trials.

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In summary, there is compelling evidence for the value of incorporating aprepitant into the standard management of patients receiving highly emetogenic chemotherapy. This is reflected in the recently published recommendations from the Perugia Antiemetic Consensus Guideline Conference.¹⁹ For prevention of acute emesis, a three-drug combination of aprepitant, dexamethasone and a 5-HT3 antagonist is recommended. For delayed emesis prophylaxis in this setting, a combination of aprepitant and dexamethasone is recommended. In addition, recent evidence from a single phase III trial demonstrated a modest but significant improvement in outcome with the addition of aprepitant to standard therapy for patients with breast cancer also receiving cyclophosphamide/anthracycline-based chemotherapy. Despite the improved outcome, however, 50% of patients on the investigational arm still had some degree of nausea or vomiting, illustrating the need for further advances in this subset of patients.