'Major Impact': Olanzapine for CINV at 5 mg, Not 10 mg

Helen Leask

January 02, 2020

For years, the antipsychotic olanzapine (Zyprexa, Lilly) has been used off label for chemotherapy-induced nausea and vomiting (CINV), but the currently recommended 10-mg dose causes daytime sedation.

Now a phase 3 randomized controlled trial has shown that a 5-mg dose is effective at controlling CINV but does not have sedation as a side effect.

The results could change clinical guidelines from the American Society of Clinical Oncology (ASCO), the National Comprehensive Cancer Network (NCCN), and the Multinational Association of Supportive Care in Cancer (MASCC), all of which currently recommend use of olanzapine at 10 mg.

The chair of the antiemetics working group of the MASCC, Alex Molassiotis, RN, PhD, from the School of Nursing at the Hong Kong Polytechnic University, told Medscape Medical News that the impact of this new study is "major."

The usefulness of the 10-mg dose is limited, he said, because many patients cannot tolerate the daytime sedation, which can range from being an inconvenience to being a lethal driving hazard.

"We've been debating the question of the 10 mg vs 5 mg in international emetic guidelines groups for many years," he said. "It seems that the 5 mg is appropriate and almost as good as, or equally as good as, the 10 mg."

The phase 3 trial of the 5-mg dose of olanzapine was published online on December 11 in the Lancet Oncology. Molassiotis authored an editorial that accompanies the article.

"Nausea and vomiting associated with chemotherapy remains an area of unmet need for patients," Molassiotis writes in the editorial.

Without prophylaxis, more than 90% of patients who receive highly emetic chemotherapy endure CINV. Up to two thirds of patients experience CINV despite standard prophylaxis with antiemetics, according to a recent Cochrane review. Nausea is the side effect of chemotherapy most dreaded by patients.

New Study Conducted in Japan

The new study of the 5-mg olazepine dose, dubbed J-FORCE, was conducted in Japan and involved 710 patients from 26 hospitals.

The cohort included patients with any malignant solid tumor who were to undergo first-time cisplatin therapy. They were randomly assigned to receive daily oral olanzapine 5 mg or placebo for 4 days, in addition to standard triple-combination antiemetic therapy (aprepitant, palonosetron, and dexamethasone).

The results show that 95% of the patients who took olanzapine experienced no nausea or vomiting during the first 24 hours of chemotherapy, compared to 89% who received placebo (P = .0021). In the delayed phase (24–120 hours after initiation of cisplatin), 79% of patients who received olanzapine were free of CINV, compared to 66% of patients who received placebo (P < .0001).

The proportion of patients who rated the severity of their daytime sleepiness as "very much" was similar between the two groups from day 2 onward, although the proportion was initially higher in the olanzapine group. The authors say the reduced incidence of daytime sleepiness could be attributed to the fact that olanzapine was given in the evening, so peak blood concentrations occurred while patients were sleeping.

Although the authors did not compare the 5-mg dose head to head with 10 mg in J-FORCE, they drew comparisons from the literature. In one study they cited, in which aprepitant was replaced with olanzapine 10 mg in a triple-therapy antiemetic regimen, there was a 97% complete response, similar to the 95% complete response seen with the 5-mg dose in J-FORCE.

In his editorial, Molassiotis writes, "The question of dose...is sufficiently answered by this trial, alongside other smaller studies and phase 2 trials." He also cites a recent meta-analysis of 10 olanzapine trials that show that the 5-mg dose "exhibits similar efficacy (if not better) to the 10mg dose....

"We should not deprive patients of treatments for which we have reasonable (but not perfect) data," Molassiotis writes. He suggests that the 10-mg dose could be reserved for patients who do not respond to the 5-mg dose.

He hopes that olanzapine 5 mg will be incorporated into guidelines without delay.

"It really is an amazing drug, with some problems, but it's here to stay, and we really need to make a decision how we're going to help the patients ― which is the most appropriate dose ― and mounting evidence is that the 5-mg dose is the most appropriate," Molassiotis said.

First Recognized as Antiemetic 20 Years Ago

The use of olanzapine as an antiemetic was initially described in a case report by William Pirl, MD, and Andrew J. Roth, MD, that was published in Psycho-Oncology on February 10, 2000. At the time, the authors were affiliated with the Memorial Sloan Kettering Cancer Center, New York City.

Pirl, who is now at the Dana-Farber Cancer Institute, Boston, Massachusetts, recalled the breakthrough discovery in an email interview with Medscape Medical News: "I had prescribed olanzapine for a hospitalized patient with cancer for mood stabilization but noticed it also had a dramatic effect on her nausea and vomiting." At the time, Pirl attributed the beneficial effect to olanzapine's antagonism of serotonin and, to a lesser extent, dopamine receptors.

Twenty years later, that is still the working theory. The drug has a broad spectrum of neurotransmitter blockade, including action at the serotonin 5-HT2a, 5-HT2c, 5-HT3, 5-HT6, and dopamine D1, D2, D3, and D4 receptors.

Reflecting on his 20-year-old breakthrough case report, Pirl commented: "I am glad that [olanzapine] has been helpful for so many people. It's nice to see the progression of science in the world from observations to clinical trials to standard of care."

The clinical development of olanzapine as an antiemetic has been spearheaded for 16 years by Rudolph Navari, MD, PhD, now professor of medicine at the University of Alabama, Tuscaloosa. In 2004, Navari and colleagues at the Walther Cancer Institute, Indianapolis, Indiana, described a successful phase 1 trial of olanzapine for CINV in the journal Cancer Investigation. Phase 2 trials followed in 2005 and 2007. Then a phase 3 trial, published in 2016 in the New England Journal of Medicine, led to endorsement of olanzapine 10 mg for CINV by the NCCN, ASCO, and MASCC in antiemetic guidelines.

Antiemetic Use Is Off Label

However, 20 years after its first appearance in the literature as an antiemetic, olanzapine remains unlicensed for CINV, so clinicians prescribe it off label.

Olanzapine, which was developed by Eli Lilly and Company, was approved by the US Food and Drug Administration on September 6, 1996, for the treatment of schizophrenia and bipolar disorder. Eli Lilly lost US patent protection for the product in 2011.

Navari told Medscape Medical News that he approached Eli Lilly about developing olanzapine for the CINV indication in 2005, but he said that the company was not interested. "At the time, they were getting a lot of patient lawsuits due to olanzapine causing hyperglycemia and onset of type 2 diabetes when you use it at very high doses, like 30 to 40 mg a day for 6 months," Navari said. "I think because at the time we went to them they were getting these lawsuits, they were less interested in using olanzapine for another indication."

Eli Lilly provided drugs for Navari's early trials, but it provided no funding support, he said. Foundation grants funded the phase 1 and phase 2 trials. The National Cancer Institute supported the pivotal phase 3 trial that was published in the New England Journal of Medicine.

I think it was huge mistake for them not to go for another indication. Dr Rudolph Navari

 

Navari feels that Eli Lilly missed an opportunity by not pursuing olanzapine for prophylaxis of CINV. "It was pretty apparent from our phase 1 and phase 2 clinical trials that olanzapine was a very effective drug for the prevention of chemotherapy-induced nausea and vomiting. And I think it was huge mistake for them not to go for another indication," he said.

Molassiotis reports no relevant financial relationships. Several authors of the J-FORCE trial report relationships with pharmaceutical companies, as listed in the original article.

Lancet Oncol. Published online December 11, 2019. Abstract, Editorial

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