Randomized, Double-Blind, Phase III Study of Fosnetupitant Versus Fosaprepitant for Prevention of Highly Emetogenic Chemotherapy-Induced Nausea and Vomiting: CONSOLE

Akito Hata, Isamu Okamoto, Naoki Inui, Morihito Okada, Masahiro Morise, Kohei Akiyoshi, Masayuki Takeda, Yasutaka Watanabe, Shunichi Sugawara, Naofumi Shinagawa, Kaoru Kubota, Toshiaki Saeki, Tomohide Tamura, Akito Hata, Isamu Okamoto, Naoki Inui, Morihito Okada, Masahiro Morise, Kohei Akiyoshi, Masayuki Takeda, Yasutaka Watanabe, Shunichi Sugawara, Naofumi Shinagawa, Kaoru Kubota, Toshiaki Saeki, Tomohide Tamura

Abstract

Purpose: We evaluated the efficacy and safety of fosnetupitant (FosNTP) versus fosaprepitant (FosAPR) for preventing highly emetogenic chemotherapy-induced nausea and vomiting. This phase III study was the first head-to-head comparison between two different neurokinin-1 receptor antagonists in combination with palonosetron and dexamethasone.

Patients and methods: Patients scheduled to receive cisplatin-based chemotherapy were randomly assigned 1:1 to FosNTP 235 mg or FosAPR 150 mg in combination with palonosetron 0.75 mg and dexamethasone. The primary end point was overall (0-120 hours) complete response (CR; no emetic event and no rescue medication) rate, stratified by sex and age category, to show the noninferiority of FosNTP to FosAPR (noninferiority margin, -10% for the difference in the overall CR rate).

Results: Overall, 795 patients were randomly assigned, of whom 785 received the study drug (FosNTP [N = 392] v FosAPR [N = 393]) and were evaluated for efficacy and safety. The overall CR rate was 75.2% versus 71.0%, respectively (Mantel-Haenszel common risk difference, 4.1%; 95% CI, -2.1% to 10.3%), demonstrating noninferiority of FosNTP to FosAPR. The CR rates in the acute (0-24 hours), delayed (24-120 hours), and beyond delayed (120-168 hours) phases, and at 0-168 hours were 93.9% versus 92.6%, 76.8% versus 72.8%, 86.5% versus 81.4%, and 73.2% versus 66.9%, respectively. The incidence rates of treatment-related adverse events with FosNTP versus FosAPR were 22.2% versus 25.4%, whereas adverse events or treatment-related adverse events relevant to injection site reactions were 11.0% versus 20.6% (P < .001) and 0.3% versus 3.6% (P < .001), respectively.

Conclusion: FosNTP demonstrated noninferiority to FosAPR, with a favorable safety profile and lower risk for injection site reactions. Thus, FosNTP is valuable in the prophylaxis of acute, delayed, and beyond delayed chemotherapy-induced nausea and vomiting.

Conflict of interest statement

Akito HataConsulting or Advisory Role: Boehringer Ingelheim, Lilly, Chugai Pharma, AstraZeneca, MSDSpeakers' Bureau: Boehringer Ingelheim, Lilly, Chugai Pharma, AstraZeneca, Taiho PharmaceuticalResearch Funding: Boehringer Ingelheim (Inst), MSD (Inst), Lilly (Inst), AstraZeneca (Inst) Isamu OkamotoHonoraria: Ono Pharmaceutical, Bristol Myers Squibb Japan, MSD Oncology, Chugai Pharma, AstraZeneca, Boehringer Ingelheim, Pfizer, Taiho Pharmaceutical, Lilly JapanConsulting or Advisory Role: Lilly Japan, Bristol Myers Squibb Japan, Chugai Pharma, AstraZeneca, Ono Pharmaceutical, PfizerResearch Funding: AstraZeneca (Inst), Taiho Pharmaceutical (Inst), Boehringer Ingelheim (Inst), Ono Pharmaceutical (Inst), MSD Oncology (Inst), Lilly (Inst), Astellas Pharma (Inst), AbbVie (Inst), Bristol Myers Squibb (Inst), Novartis (Inst), Takeda (Inst), Chugai and Roche (Inst) Naoki InuiSpeakers' Bureau: Chugai Pharma, AstraZeneca and Daiichi Sankyo, Lilly, Nippon Boehringer Ingelheim, Novartis, Ono Yakuhin, Taiho PharmaceuticalResearch Funding: Chugai Pharma, Daiichi Sankyo and UCB Japan, Lilly, Nippon Boehringer Ingelheim, MSD K K, Taiho Pharmaceutical Morihito OkadaSpeakers' Bureau: Taiho Pharmaceutical, Johnson & Johnson, Covidien, Lilly, Chugai Pharma, AstraZeneca, Ono Pharmaceutical, CSL BehringResearch Funding: Taiho Pharmaceutical (Inst), Nippon Kayaku (Inst), Chugai Pharma (Inst), Covidien (Inst), Johnson & Johnson (Inst), Daiichi Sankyo (inst), Yakult Honsha (Inst), Lilly Japan (Inst), Nihon Medi-Physics (Inst), Pfizer (Inst), Mochida Pharmaceutical Co, Ltd (Inst), Shionogi (Inst), Ono Pharmaceutical (Inst), Kyowa Hakko Kirin (Inst) Masahiro MoriseSpeakers' Bureau: Chugai and Roche, AstraZeneca, Ono Pharmaceutical, LillyResearch Funding: Boehringer Ingelheim (Inst), Novartis (Inst), AstraZeneca (Inst), Lilly (Inst), Taiho Pharmaceutical (Inst), Chugai and Roche (Inst), Ono Pharmaceutical (Inst), Pfizer (Inst), Merck Serono (Inst), Kissei Pharmaceutical (Inst) Masayuki TakedaHonoraria: AstraZeneca Japan, Chugai Pharma, Bristol Myers Squibb Company, Novartis, Ono Pharmaceutical, Boehringer Ingelheim Shunichi SugawaraHonoraria: AstraZeneca, Chugai Pharma, Nippon Boehringer Ingelheim, Taiho Pharmaceutical, Pfizer, Lilly, Novartis, Bristol Myers Squibb, Ono Pharmaceutical, MSD K K, Yakult Honsha, Kyowa Kirin Naofumi ShinagawaResearch Funding: Olympus Kaoru KubotaHonoraria: Bristol Myers Squibb Japan, Daiichi Sankyo, Boehringer Ingelheim, Taiho Pharmaceutical, Lilly Japan, MSD Oncology, Chugai Pharma, AstraZeneca, Nihonkayaku, Takeda, PfizerResearch Funding: Daiichi Sankyo (Inst), Boehringer Ingelheim (Inst), Taiho Pharmaceutical (Inst), Ono Pharmaceutical (Inst) Toshiaki SaekiResearch Funding: Taiho Pharmaceutical (Inst), Eisai (Inst) Tomohide TamuraHonoraria: Chugai Pharma, Boehringer Ingelheim, Ono Pharmaceutical, Taiho Pharmaceutical, MSD, CMIC, Lilly, NihonkayakuNo other potential conflicts of interest were reported.

Figures

FIG 1.
FIG 1.
CONSORT diagram (S-cycle). A total of 795 patients were enrolled in the S-cycle. The study drug was administered to 785 patients (FosNTP v FosAPR, n = 392 v n = 393, respectively), and all of them were evaluated for efficacy and safety. AE, adverse event; FAS, full analysis set; FosAPR, fosaprepitant; FosNTP, fosnetupitant; S-cycle, single chemotherapy cycle.
FIG 2.
FIG 2.
CR rate by phase (S-cycle). The CR (no emetic event and no rescue medication) rates during the acute (0-24 hours), delayed (24-120 hours), and overall (0-120 hours) phases and at 0-168 hours and 120-168 hours in the full analysis set were calculated and their 95% CIs were estimated. The overall CR rate was stratified by sex and age category. CR, complete response; FosAPR, fosaprepitant; FosNTP, fosnetupitant; S-cycle, single chemotherapy cycle.
FIG 3.
FIG 3.
TTF (S-cycle). The TTF (time to first emetic event or use of rescue medication) curve was estimated using the Kaplan-Meier method. FosAPR, fosaprepitant; FosNTP, fosnetupitant; HR, hazard ratio; S-cycle, single chemotherapy cycle; TTF, time to treatment failure.
FIG 4.
FIG 4.
CINV incidence (S-cycle). CINV incidence (nausea and emetic events) was analyzed every 24 hours from the start of cisplatin administration to 168 hours. CINV, chemotherapy-induced nausea and vomiting; FosAPR, fosaprepitant; FosNTP, fosnetupitant; S-cycle, single chemotherapy cycle.

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