Supportive Care Expert Sees Progress on Parts of CINV Front

Rudolph M. Navari, MD, PhD

Rudolph M. Navari, MD, PhD, has been a leading researcher into the mechanisms of chemotherapy- induced nausea and vomiting (CINV) and the use of antiemetics to prevent its onset. His work has contributed to the recent approval of rolapitant (Varubi) for the prevention of delayed CINV and to the use of the antipsychotic olanzapine to help control breakthrough CINV.

OncLive: How has our understanding of the molecular pathways of CINV evolved and how has this guided the development of antiemetic drugs?

Navari is director of the Cancer Care Program in Central and South America for the World Health Organization and a professor of Medicine at Indiana University School of Medicine, South Bend. In this interview with OncLive, he discusses the evolving landscape of antiemetic therapy.Navari: Since the early 1990s, we’ve developed very effective antiemetics by identifying the receptors that are largely responsible for inducing CINV. The first receptor that was identified was the serotonin receptor. Chemotherapy stimulates the enterochromaffin cells to release serotonin, stimulating the receptor in the GI tract, but also some receptors in the CNS as well. Serotonin receptor antagonists block serotonin in the GI tract and the CNS. So that’s how the drugs ondansetron, granisetron, dolasetron, and palonosetron were developed.

The other important receptor is in the CNS; it is mediated by substance P and is called the neurokinin 1 receptor (NK1). NK1 receptor antagonists block their function primarily in the CNS. We think that the serotonin receptor in the GI tract is primarily responsible for acute CINV, which is what happens in the first 24 hours postchemotherapy, whereas the substance P-mediated effects of the NK1 receptor are responsible for delayed nausea and vomiting, which occurs on days 2-5 postchemotherapy.

Aprepitant was the first NK1 receptor antagonist developed and approved in 2003. It was very effective in preventing delayed emesis, and we know that it works well with dexamethasone. We know dexamethasone is also a good antiemetic to prevent CINV; unfortunately, we don’t fully understand the mechanism of dexamethasone and how it works in preventing CINV.

So those have been the two major mechanisms identified. We also know that there are other receptors, probably also involved, but we’re not sure exactly how. We know dopamine receptors in the CNS are a mediator of CINV and that has been a targeted mechanism in the past but it’s probably not as important as serotonin or NK1 receptors.

How do the most recent drug approvals for NEPA (Akynzeo) and rolapitant fit into the treatment landscape?

There are probably also other receptors like histaminic and muscarinic receptors that have been implicated as well, but for which the mechanism of action also hasn’t been worked out. With the serotonin and NK1 receptors, we have animal models that have been important in developing these antiemetics that we don’t have with these other ones. So it’s fair to say that there are probably other important receptors that we don’t know about at the moment.NEPA is a combination of netupitant, a new NK1 receptor antagonist, and palonosetron. The pharmaceutical company that developed NEPA [Eisai] also has the rights to palonosetron, so what they tried to do was to develop a new NK1 receptor antagonist netupitant, combine it with palonosetron, and deliver it as one pill prior to chemotherapy so that you’re using both an NK1 receptor and a serotonin receptor antagonist as a single preventive agent along with dexamethasone.

As an NK1 receptor antagonist, netupitant has a similar structure and mechanism of action to aprepitant. We don’t have any comparative studies between netupitant and aprepitant so at this point we don’t know for sure that one NK1 receptor antagonist is more efficacious than the other. It’s pretty clear that the side effect profiles of the two drugs are similar, so it’s hard to differentiate between the two. My guess is that, at least for the present, they will compete on a cost basis.

The same thing can be said for rolapitant, the third NK1 receptor antagonist. It seems to have similar efficacy to netupitant and aprepitant when you use it with a serotonin receptor antagonist but, again, no comparative studies on efficacy have been done among the three and its toxicity profile is similar to the other two drugs. Two other aspects, one practical and one theoretical, are that aprepitant and netupitant are metabolized by CYP3A4 and as a result there is a theoretical possibility that their metabolism may be affected by giving them with other drugs, but from a practical point of view we don’t really see that happening in clinical practice.

Rolapitant is not metabolized by CYP3A4 metabolic enzymes, so if there is any difference between the drugs, it’s probably that—how they are metabolized. But we’ve been using aprepitant for over 10 years and we don’t really see any significant interactions between it and any of the other drugs it has been used with.

From a practical point of view, oncologists like to give intravenous NK1 receptor antagonists because many private practices don’t dispense oral medications, just IV drugs. Aprepitant has an IV form called fosaprepitant that works just as well. Aprepitant should be given orally 3 days in a row before and 2 days after chemotherapy in its oral form, while if you give fosaprepitant IV prior to chemotherapy it’s done on the same day, so many oncologists just use the IV formulation because it’s more convenient and patients tend to be more compliant. There’s no IV form of netupitant, NEPA, or rolapitant, they all have to be given orally.

What other promising therapies are in clinical development?

Again, many oncology practices won’t dispense these forms, so they will have to write a prescription a week or two before chemotherapy and the patient will have to pick it up and bring it to the clinic with them, and that makes it a little more impractical. If the patient can’t get it approved by their insurance or they forget their prescription, or they’re away, it can cause a problem. We know that there will be an IV form of rolapitant, probably at the end of 2016, but I don’t know when or if there will be an IV form of netupitant.Olanzapine is available on the market. That’s actually the generic form; Zyprexa is the trade name. It was initially developed by Eli Lilly as an antipsychotic and has been on the market for a long time. It’s not approved as an antiemetic, but it has been used in studies and in the clinic by oncologists as an off-label drug to prevent CINV.

A number of studies have been done using olanzapine as a preventive agent and it seems to be very effective in preventing not only chemotherapy- induced vomiting but also chemotherapy- induced nausea. More and more studies are coming out and, in fact, the NCCN guidelines recommended it as a preventive agent about a year and a half ago and other guidelines are following suit. I think ASCO will recommend it as a preventive agent later this year.

What are the most significant unanswered questions or challenges in tackling CINV?

Olanzapine affects multiple receptors. We know it affects serotonin receptors, dopamine receptors, and muscarinic receptors and likely others, but we don’t know which are most important from an antiemetic perspective. From a practical point of view as an off-label drug, it seems to work relatively well and is being used more and more and, of course, it’s generic so it’s significantly cheaper.Amazingly, most of the antiemetics that have been developed are very effective for preventing emesis. But we still have a problem with nausea. None of the serotonin receptor or NK1 receptor antagonists do a very good job on nausea.

Olanzapine seems to do a much better job of preventing nausea, but we still don’t have the ideal drug or combination to prevent nausea in most patients.

The problem is we don’t have a good animal model for measuring nausea. Also, nausea is very subjective, so what may cause nausea in one subject won’t in another. So even though we have ways of measuring nausea on a visual analog scale in these antiemetic studies, it may differ between populations because it’s so subjective. That still needs a lot of work.