17 Aug Next Generation Drug Rolapitant Helps Prevent Chemotherapy-induced Nausea and Vomiting
Medical Research: What is the background for this study? What are the main findings?
Dr. Rapoport: Chemotherapy-induced nausea and vomiting (CINV) is one of the most feared side effects of chemotherapy, and can lead to dose reductions or discontinuations of life-extending anti-cancer therapy. In the past, the serotonin (5-HT3) receptor antagonists, such as granisetron, palonosetron , and ondansetron, have shown effectiveness in preventing acute CINV (0-24 hours after chemotherapy administration), but many chemotherapies, such as cisplatin, carboplatin, and anthracycline/cyclophosphamide combinations, can cause delayed chemotherapy-induced nausea and vomiting that occurs from >24 hours to 5 days or more after chemotherapy. Neurokinin-1 receptor antagonists (NK-1 RAs) work though the substance P signaling pathway and are effective at preventing the delayed phase of chemotherapy-induced nausea and vomiting. Aprepitant was the first NK-1 RA to come to market in 2003, followed by a fixed dose of netupitant plus palonosetron late last year.
Rolapitant is a next generation NK-1 RA that is long acting (its half-life is about 7 days) and has shown >90% receptor binding in the cortex of normal healthy volunteers 5 days after administration. Thus, we hypothesized that giving a single 180 mg oral dose of rolapitant 1-2 hours before chemotherapy administration would provide strong protection against chemotherapy-induced nausea and vomiting in the delayed phase, when patients were given highly or moderately emetogenic chemotherapy. Across the three phase 3 trials conducted (representing over 2000 patients with various tumor types), which were all large, global, multi-center, randomized and placebo-controlled, two in cisplatin-based chemotherapy (highly emetogenic) and one with about half the patients receiving anthracycline-cyclophosphamide (AC) combinations (highly emetogenic) and the rest moderately emetogenic chemotherapy (comprised mostly of carboplatin, cyclophosphamide without anthracycline, irinotecan, premetrexed, oxaliplatin, and doxorubicin), the studies met their primary endpoint showing that rolapitant was superior to placebo when combined with a 5HT3 RA (granisetron) and dexamethasone in preventingChemotherapy-induced nausea and vomiting in the delayed phase (>24-120 hours). The studies were called HEC1, HEC2, and MEC. The complete response rates (no emesis or use of rescue anti-emetic therapy) in the delayed phase were 73% rolapitant vs 58% control (p= 0.0006) in HEC1, 70% vs. 62% (p=0.0426) in HEC2, and 71% vs. 62% in MEC (p=0.0002). Interestingly, subgroup analyses of the MEC trial revealed that patients who received AC combinations experienced complete response rates of 67% compared to 60% of controls, and patients treated with non-AC combinations (truly moderately emetogenic, as AC is now considered highly emetogenic) achieved complete response rates of 76%, compared to 64% for the control group. Side effects were nearly identical between the rolapitant and control arm, and were largely what would be expected from the chemotherapy.
Medical Research: What should clinicians and patients take away from your report?
Dr. Rapoport: I think rolapitant represents a new and better option for the prevention of delayed chemotherapy-induced nausea and vomiting. The NK-1’s RAs have proven to be a safe and effective class, but the existing options, aprepitant and netupitant, while good, are inhibitors or inducers of CYP3A4, an enzyme that metabolizes a large number ofcommonly prescribed medications. Rolapitant doesn’t induce or inhibit CYP3A4, so that’s one less thing you have to worry about, especially since cancer patients are typically on so many concomitant therapies. I would take away that rolapitant provides effective protection against CINV, not only in highly emetogenic chemotherapy, but also moderately emetogenic CINV, like carboplatin and irinotecan. It also has less potential for clinically significant drug-drug interactions, and consistent with its long half-life, is particularly well suited to protecting patients from delayed CINV. When an NK-1 RA is combined with a 5-HT3 RA and dexamethasone, as most major international guidelines recommend, you should have very strong protection against CINV from the initiation of chemotherapy throughout the entire delayed at-risk period.
Medical Research: What recommendations do you have for future research as a result of this study?
Dr. Rapoport: Rolapitant’s long half-life is probably contributing to its effectiveness in the delayed phase, but this study only looked out to 5 days. Chemotherapy-induced nausea and vomiting may persist longer than that, and rolapitant may continue to exert its effects longer, which will be advantageous for multi-day chemotherapy regimens. In addition, there may be opportunities to give rolapitant even earlier before chemotherapy administration. Certainly, a single oral pill at the start of chemotherapy is advantageous, but the studies gave rolapitant 1-2 hours before chemotherapy. Perhaps rolapitant can be given the day before. Netupitant is also given once at the start of chemotherapy in its fixed dose form with palonosetron and the rolapitant studies used granisetron (or in the case of the phase 2 trials, ondansetron), which is more widely available globally, but palonosetron may be an even better 5-HT3 RA to pair with rolapitant owing to its longer half-life. I think we’d all like to see what the outcomes look like with rolapitant in combination with palonosetron.
Safety and efficacy of rolapitant for prevention of chemotherapy-induced nausea and vomiting after administration of cisplatin-based highly emetogenic chemotherapy in patients with cancer: two randomised, active-controlled, double-blind, phase 3 trials
Dr Bernardo L Rapoport, MD, Martin R Chasen, MD, Cesare Gridelli, MD, Laszlo Urban, MD, Manuel R Modiano, MD,Ian D Schnadig, MD, Allen Poma, MD, Sujata Arora, MSc, Vikram Kansra, PhD, Lee S Schwartzberg, MD,Rudolph M Navari, MD
The Lancet Published Online: 10 August 2015
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Bernardo L. Rapoport M. D. (2015). Next Generation Drug Rolapitant Helps Prevent Chemotherapy-induced Nausea and Vomiting