Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PRIORITY PRESS - 23rd International Symposium on Supportive Care in Cancer

Vancouver, British Columbia / June 24-26, 2010

According to results of a non-inferiority trial presented here, a convenient antiemetic regimen using a single intravenous (i.v.) dose of an NK-1 receptor antagonist (RA) prior to cisplatin-based chemotherapy has proven equally effective in the prevention of chemotherapyinduced nausea and vomiting (CINV) as the standard three-day oral dosing regimen throughout the overall risk period. As reported by Dr. Steven Grunberg, Professor of Medicine and Pharmacology, Vermont Cancer Center, University of Vermont, Burlington, a single dose of fosaprepitant i.v., a prodrug of the NK-1 RA aprepitant, was compared to the standard, three-day oral aprepitant schedule for the prevention of CINV among a total of 2322 patients receiving cisplatin =70 mg/m2 for the first time. “The primary end point was the proportion of patients with a complete response [CR], defined as no vomiting and no rescue medication during the entire 0 to 120 hours,” Dr. Grunberg told delegates.

On day 1, both groups received ondansetron 32 mg i.v./ dexamethasone 12 mg orally and the investigative arm received fosaprepitant 150 mg i.v. while the control group received aprepitant 125 mg orally. On days 2 through 4, the fosaprepitant group (n=1147) received dexamethasone 8 mg on day 2 and 16 mg on days 3 and 4, while the aprepitant group (n=1175) received aprepitant 80 mg on days 2 and 3, and dexamethasone 8 mg on days 2, 3 and 4.

During the overall phase from 0 to 120 hours, 71.9% of fosaprepitant recipients and 72.3% of aprepitant recipients achieved a CR. During the acute phase (0 to 24 hours), 89% of the single i.v. dose patients vs. 88% of the threeday oral dose patients similarly achieved a CR. During the delayed phase (25 to 120 hours), approximately 74% of each group also had a CR. Approximately 70% of both groups had no significant nausea during the overall phase while approximately half of both groups had no nausea at all. “Side effects were well matched in both groups,” Dr. Grunberg observed. “Equivalence of the fosaprepitant 150 mg i.v. regimen to the aprepitant, three-day oral regimen in the prevention of CINV allows for a more convenient administration of an NK-1 RA.”

Study Results

As pointed out by Dr. Richard J. Gralla, Chief of Hematology and Oncology, North Shore University Hospital, New Hyde Park, New York, platinum agents are among the most important and frequently used chemotherapies in common malignancies. They have a “great risk” for causing emesis, and are classified in both the high (almost all patients will experience emesis) and moderate (30% to 90% of patients will experience emesis) emetogenic risk groups. “NK-1 RAs are effective and unique antiemetics and all major guideline groups recommend the use of such drugs with cisplatin,” he told delegates.

In an analysis of four randomized trials including 1872 patients receiving platinum agents, each trial had a control arm in which patients did not receive the NK-1 RA and an investigative arm in which it was added.

In all trials, the control arm on day 1 was ondansetron/ dexamethasone while in the investigative arm, patients received additional aprepitant 125 mg on day 1 and 80 mg on days 2 and 3. For delayed emesis in the cisplatin trials, control arms received dexamethasone 8 mg b.i.d. in two studies and ondansetron 8 mg b.i.d. in the third, while in the aprepitant arm, only dexamethasone 8 mg/day was given. For delayed emesis in control patients receiving either carboplatin or oxaliplatin, ondansetron 8 mg b.i.d. was given vs. aprepitant for those in the investigative arm. Some 345 patients receiving carboplatin or oxaliplatin were randomized in the fourth study.

Results show that the benefit from aprepitant was of similar magnitude with both carboplatin and cisplatin, although the absolute benefit was greater with cisplatin. Benefit was also seen from the addition of aprepitant in those receiving oxaliplatin but the magnitude of that benefit was less than that seen with the other platinum drugs (Table 1).

“The improvement in CR with the NK-1 RA aprepitant in patients receiving carboplatin was of similar magnitude to that achieved in the cisplatin setting in terms of relative benefit, absolute benefit and number-needed-to-treat,” Dr. Gralla reported. “We concluded that aprepitant is a useful agent in the carboplatin setting [although] further trials are needed to establish whether an NK-1 RA is needed or not in patients receiving oxaliplatin and if so, in which patient groups.”

Moderately Emetogenic Chemotherapy

In reviewing evidence as to whether an NK-1 RA should be used for moderately emetogenic chemotherapy (MEC) other than anthracycline/cyclophosphamide (AC), Dr. David Warr, Associate Professor of Medicine, UHN-Princess Margaret Hospital, Toronto, Ontario, pointed out that a number of guidelines avoid making recommendations for the use of aprepitant in non-AC MEC. The emetogenic potential of MEC regimens “undoubtedly varies,” he noted, but in the recently updated Multinational Association of Supportive Care in Cancer (MASCC) guidelines, a number of nonanthracycline MECs are listed, among them single i.v. agents alemtuzumab, epirubicin, irinotecan and bendamustine. When considering whether to administer an NK-1 RA for a non-AC MEC regimen, Dr. Warr reminded delegates that it is not the risk of emesis in the absence of any antiemetic that needs to be considered but rather the residual risk of emesis following the administration of a 5-HT3 RA and dexamethasone.

Until recently, all aprepitant data were derived from cisplatin or AC-based chemotherapy regimens. The Protocol 130 trial was designed to test aprepitant with a wider range of chemotherapy regimens. In the study, over three-quarters of participants were women and approximately half of both arms were being treated for breast cancer. A total of 848 patients receiving a non-AC chemotherapy regimen— primarily carboplatin and oxaliplatin—received standard antiemetic treatment with ondansetron/dexamethasone but one half also received aprepitant.

In a review of the overall phase (i.e. acute plus delayed phase) of cycle 1, results indicated that 76.2% of the CINV antiemetic regimen including aprepitant experienced no vomiting compared with 62.1% for those on the standard CINV prevention regimen (P<0.0001). A CR was also achieved in 68.7% of the NK-1 RA arm vs. 56.3% in the non- NK-1 RA arm (P=0.0003). “The NK-1 RAs are effective across a broad range of chemotherapies even though level 1 evidence with aprepitant for non-AC MEC does not exist and may well never exist,” Dr. Warr concluded. “But based upon limited data, it is reasonable to consider secondary intervention with aprepitant when standard antiemetic therapy is ineffective.”

ASCC Recommendations

According to MASCC guidelines, women receiving a combination of AC are at particularly high risk for CINV. To prevent acute nausea and vomiting, MASCC recommends a triple-drug regimen consisting of single doses of a 5-HT3 antagonist, dexamethasone and aprepitant (or fosaprepitant) given prior to chemotherapy. The NK-1 RA should also be used to prevent delayed nausea and vomiting in breast cancer patients receiving AC. MASCC recommends the use of palonosetron/dexamethasone for the prevention of acute nausea and vomiting in patients who receive MEC not including AC. Dexamethasone is also recommended for patients receiving MEC other than AC for the prevention of delayed nausea and vomiting.