The addition of 5 mg of olanzapine to triplet antiemetic combination therapy significantly improved the rate of complete response (CR) to antiemetic therapy in the delayed phase for cisplatin-treated patients, according to results of a randomized phase 3 study. These findings were published in Lancet Oncology.1

The antipsychotic agent, olanzapine, has previously been shown to significantly reduce the rates of nausea and vomiting in patients treated with highly emetic chemotherapy (eg, cisplatin; anthracycline/cyclophosphamide combination therapy) when added to triplet antiemetic combination therapy, consisting of a serotonin (5-HT3) receptor antagonist, a neurokinin 1 (NK1) antagonist, and dexamethasone.2 In particular, olanzapine has been shown to be effective in reducing delayed nausea and vomiting, which occurs 24 to 120 hours following chemotherapy administration, and has historically been more difficult to control than acute nausea and vomiting, which occurs within the first day following emetogenic chemotherapy initiation.

On the basis of studies of olanzapine in this setting, the addition of 10 mg of olanzapine to triplet combination therapy was incorporated into antiemesis guidelines from the American Society of Clinical Oncology for patients treated with highly emetogenic chemotherapy with the caveat in some of the guidelines that a dose reduction of olanzapine may be necessary in patients who experience excessive sedation, as well as older patients.

In this double-blind, placebo-controlled, phase 3 study, which was conducted in 26 hospitals in Japan, 710 patients receiving cisplatin (at a dose of 50 mg/m2 or higher) were randomly assigned in a 1:1 ratio to receive 5 mg olanzapine or placebo orally after dinner on days 1 through 4 in combination with triplet therapy (ie, palonosetron, aprepitant, dexamethasone) as prophylaxis for chemotherapy-induced nausea and vomiting.

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All enrolled patients were observed for 120 hours, and also completed daily diaries that included number and timing of vomiting episodes, as well as the severity and timing of both nausea and daytime sleepiness. The primary study end point was the proportion of patients experiencing no vomiting or retching (ie, a CR) in the delayed phase, with secondary end points including CR rates in the acute (0-24 hours) and overall phases (0-120 hours), as well as the proportion of patients in CR experiencing mild nausea only (ie, complete control) or no nausea (ie, total control), and adverse events.  

Key study findings included the following:

  • CR rates (vomiting) in the delayed phase of 79% (olanzapine arm) versus 66% (placebo arm; P <.0001)
  • CR rates (vomiting) in the acute phase of 95% (olanzapine arm) versus 89% (placebo arm; P =.0021)
  • CR rates (vomiting) in the overall period of 78% (olanzapine arm) versus 64% (placebo arm; P <.0001)
  • Complete control rates in the delayed phase of 78% (olanzapine arm) versus 64% (placebo arm; P <.0001)
  • Complete control rates in the acute phase of 76% (olanzapine arm) versus 61% (placebo arm; P <.0001)
  • No difference in rates of daytime sleepiness between the 2 study arms
  • Treatment-related grade 3 constipation (1 patient) and somnolence (1 patient) in olanzapine arm

A study limitation mentioned by the study authors was the exclusion of patients treated with the combination of an anthracycline and cyclophosphamide, another highly emetogenic chemotherapy regimen that is frequently used in the treatment of patients with breast cancer.

In their concluding comments, the researchers stated that “olanzapine 5 mg combined with aprepitant, palonosetron, and dexamethasone could be a new standard antiemetic therapy option in patients undergoing cisplatin-based chemotherapy.”

Based in part on phase 2 studies evaluating a 5 mg dose of olanzapine in this setting, antiemesis guidelines from the National Comprehensive Cancer Network (NCCN) currently recommend the use of 5 to 10 mg of olanzapine in combination with triplet combination therapy for patients treated with highly emetogenic chemotherapy.3

References

1. Hashimoto H, Abe M, Tokuyama O, et al. Olanzapine 5 mg plus standard antiemetic therapy for the prevention of chemotherapy-induced nausea and vomiting (J-FORCE): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial [published online December 11, 2019]. Lancet Oncol. doi:10.1016/S1470-2045(19)30678-3

2. Navari RM, Qin R, Ruddy KJ, et al. Olanzapine for the prevention of chemotherapy-induced nausea and vomiting. N Engl J Med. 2016;375:131-142.

3. National Comprehensive Cancer Network (NCCN) Antiemesis Guidelines. V1.2019. https://www.nccn.org/professionals/physician_gls/pdf/antiemesis.pdf. Updated: February 29, 2019. Accessed January 16, 2019.