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Ono Pharmaceutical Co., Ltd (Headquarters: Osaka, Japan; President and COO: Toichi Takino; “Ono”) and Bristol-Myers Squibb K.K. (Headquarters:Tokyo, Japan; President: Hidehito Katsuma; “BMSKK”) today announced that the companies have received a supplemental approval of Ono’s anti-PD-1 antibody, Opdivo® (generic name: nivolumab) Intravenous Infusion (“Opdivo”) and BMSKK’s anti-CTLA-4 antibody, Yervoy® (generic name: ipilimumab) Injection (“Yervoy”) in combination therapy in Japan, to expand the use for the treatment of unresectable advanced or recurrent microsatellite instability-high (MSI-High) colorectal cancer. This approval is related to the additional indication for a partial change in approved items of the manufacturing and marketing approval in Japan.
This approval is based on the results from the CheckMate-8HW study, a global multi-center Phase 3 clinical study (CA209-8HW: ONO-4538-87), evaluating Opdivo plus Yervoy compared to Opdivo alone or investigator’s choice of chemotherapy• in patients with unresectable advanced or recurrent MSI-High or mismatch repair deficient (dMMR) colorectal cancer. In this study, Opdivo plus Yervoy demonstrated a clinically meaningful improvement in one of the dual primary endpoints of progression-free survival (PFS) as assessed by Blinded Independent Central Review (BICR) compared to investigator’s choice of chemotherapy in previously untreated patients with centrally confirmed MSI-High or dMMR colorectal cancer at a pre-specified interim analysis. In addition, Opdivo plus Yervoy demonstrated a clinically meaningful improvement in another primary endpoint of PFS assessed by BICR, compared to Opdivo alone in patients across all lines of treatment. The safety profile of Opdivo plus Yervoy remained consistent with previously reported data, with no new safety signals identified.
Any one of the following regimens was selected: mFOLFOX6 (5-fluorouracil, folinic acid, and oxaliplatin), mFOLFOX6 with bevacizumab or cetuximab, FOLFIRI (5-fluorouracil, folinic acid, and irinotecan), or FOLFIRI with bevacizumab or cetuximab.
Opdivo and Yervoy were designated as orphan drugs by the Ministry of Health, Labour and Welfare with the indication of unresectable, advanced or recurrent microsatellite instability-high (MSI-High) colorectal cancer in September 2024.
With respect to the indication of colorectal cancer, Opdivo was approved as monotherapy in February 2020 and in combination with Yervoy in September 2020 for the indication of unresectable advanced or recurrent microsatellite instability-high (MSI-High) colorectal cancer that has progressed following chemotherapy.
About CheckMate-8HW Study (CA209-8HW: ONO-4538-87)
CheckMate-8HW study is a global multi-center, randomized, open-label Phase III clinical study evaluating Opdivo plus Yervoy compared to Opdivo alone or investigator’s choice of chemotherapy (mFOLFOX6 or FOLFIRI with or without bevacizumab or cetuximab) in patients with unresectable advanced or recurrent microsatellite instability-high (MSI-High) or mismatch repair deficient (dMMR) colorectal cancer.
Approximately 830 patients were randomized to receive Opdivo plus Yervoy (Opdivo 240 mg plus Yervoy 1 mg/kg Q3W for four doses, followed by Opdivo 480 mg Q4W), Opdivo monotherapy (Opdivo 240 mg Q2W for six doses, followed by Opdivo 480 mg Q4W), or investigator’s choice of chemotherapy. Patients were treated until disease progression or unacceptable toxic effects. The dual primary endpoints of the study are progression-free survival (PFS) per blinded independent central review (BICR) for Opdivo plus Yervoy compared to investigator’s choice of chemotherapy in previously untreated patients with centrally confirmed MSI-High or dMMR colorectal cancer, and PFS per BICR for Opdivo plus Yervoy compared to Opdivo alone in patients across all lines of therapy.
About Colorectal Cancer
Colorectal cancer (CRC) is the third most common cancer, with approximately 1,926, 000 new cases diagnosed each year worldwide, and approximately 904,000 deaths are reported annually *1. In Japan, CRC is the most common cancer, with approximately 145,000 new cases per year, and approximately 60,000 deaths are reported each year *1.
Approximately 4% of unresectable CRC patients have MSI-High or dMMR tumors *2. For unresectable advanced or recurrent MSI-High or dMMR CRC, conventional chemotherapy has not been effective enough, and the development of new therapeutic drugs is expected.
*1. Globocan 2022.
*2. Japanese Society for Cancer of the Colon and Rectum. JSCCR Guidelines 2024 for the Treatment of Colorectal Cancer.
Overview of Opdivo® Intravenous Infusion
Product name: Opdivo® Intravenous Infusion 20 mg, 100 mg, 120 mg, and 240 mg
Generic name (JAN): Nivolumab (Genetical recombination)
Indication
• Melanoma
• Unresectable, advanced or recurrent non-small cell lung cancer
• Neoadjuvant treatment of non-small cell lung cancer
• Unresectable or metastatic renal cell carcinoma
• Recurrent or refractory classical Hodgkin lymphoma
• Recurrent or metastatic head and neck cancer
• Unresectable advanced or recurrent gastric cancer
• Unresectable advanced or recurrent malignant pleural mesothelioma
• Malignant mesothelioma (excluding malignant pleural mesothelioma)
• Microsatellite instability high (MSI-High) unresectable advanced or recurrent colorectal cancer that has progressed after chemotherapy
• Unresectable advanced or recurrent esophageal cancer
• Adjuvant treatment of esophageal cancer
• Cancer of unknown primary
• Adjuvant treatment of urothelial carcinoma
• Unresectable urothelial carcinoma
• Unresectable advanced or recurrent malignant epithelial tumors
• Unresectable hepatocellular carcinoma
Dosage
Usually, for adults, administer at 240 mg of nivolumab (genetical recombination) every 2 weeks or 480 mg every 4 weeks as intravenous infusion. In the adjuvant therapy of melanoma, the administration period does not exceed 12 months.
In combination therapy with ipilimumab (genetical recombination) for unresectable melanoma, usually, for adults, administer 80 mg of nivolumab (genetical recombination) every 3 weeks for 4 doses. After that, administer 240 mg of nivolumab (genetical recombination) every 2 weeks or 480 mg every 4 weeks as intravenous infusion.
Usually, for adults, administer at 240 mg of nivolumab (genetical recombination) every 2 weeks or 480 mg every 4 weeks as intravenous infusion.
In combination therapy with other anti-tumor drugs, usually, for adults, administer 240 mg of nivolumab (genetical recombination) every 2 weeks or 360 mg every 3 weeks as intravenous infusion.
In combination therapy with other anti-tumor drugs, usually, for adults, administer 360 mg of nivolumab (genetical recombination) every 3 weeks as intravenous infusion. The administration frequency does not exceed 3 doses.
Usually, for adults, administer 240 mg of nivolumab (genetical recombination) every 2 weeks or 480 mg every 4 weeks as intravenous infusion.
In combination therapy with cabozantinib, usually, for adults, administer 240 mg of nivolumab (genetical recombination) every 2 weeks or 480 mg every 4 weeks as intravenous infusion. In combination therapy with ipilimumab (genetical recombination) for unresectable or metastatic renal cell carcinoma previously untreated with chemotherapy, usually, for adults, administer 240 mg of nivolumab (genetical recombination) as intravenous infusion every 3 weeks for 4 doses. After that, administer 240 mg of nivolumab (genetical recombination) every 2 weeks or 480 mg every 4 weeks as intravenous infusion.
Usually, for adults, administer 240 mg of nivolumab (genetical recombination) every 2 weeks or 480 mg every 4 weeks as intravenous infusion.
Usually, for pediatrics, administer 3 mg/kg (body weight) of nivolumab (genetical recombination) every 2 weeks as intravenous infusion. For pediatrics weighing 40 kg (body weight) or more, nivolumab (genetical recombination) can be administered at 240 mg every 2 weeks or 480 mg every 4 weeks as intravenous infusion.
Usually, for adults, administer 240 mg of nivolumab (genetical recombination) every 2 weeks or 480 mg every 4 weeks as intravenous infusion.
Usually, for adults, administer 240 mg of nivolumab (genetical recombination) every 2 weeks or 480 mg every 4 weeks as intravenous infusion.
In combination therapy with ipilimumab (genetical recombination), usually, for adults, administer 240 mg of nivolumab (genetical recombination) every 2 weeks or 360 mg every 3 weeks as intravenous infusion.
Usually, for adults, administer 240 mg of nivolumab (genetical recombination) every 2 weeks or 480 mg every 4 weeks as intravenous infusion. In combination therapy with ipilimumab (genetical recombination), usually, for adults, administer 240 mg of nivolumab (genetical recombination) every 3 weeks for 4 doses as intravenous infusion. After that, administer 240 mg of nivolumab (genetical recombination) every 2 weeks or 480 mg every 4 weeks as intravenous infusion.
In monotherapy with nivolumab (genetical recombination) for microsatellite instability-high (MSI-High) unresectable advanced or recurrent colorectal cancer that has progressed after chemotherapy, usually, for adults, administer 240 mg of nivolumab (genetical recombination) every 2 weeks or 480 mg every 4 weeks as intravenous infusion.
Usually, for adults, administer 240 mg of nivolumab (genetical recombination) every 2 weeks or 480 mg every 4 weeks as intravenous infusion.
In combination therapy with other anti-tumor drugs, usually, for adults, administer 240 mg of nivolumab (genetical recombination) every 2 weeks, 360 mg every 3 weeks, or 480 mg every 4 weeks as intravenous infusion.
Usually, for adults, administer 240 mg of nivolumab (genetical recombination) every 2 weeks or 480 mg every 4 weeks as intravenous infusion. The administration period does not exceed 12 months.
In combination with gemcitabine hydrochloride and platinum-containing anti-tumor drugs, usually, for adults, administer 360 mg of nivolumab (genetical recombination) every 3 weeks for 6 doses as intravenous infusion. After that, administer 240 mg of nivolumab (genetical recombination) every 2 weeks or 480 mg every 4 weeks as intravenous infusion.
In combination therapy with ipilimumab (genetical recombination), usually, for adults, administer 80 mg of nivolumab (genetical recombination) every 3 weeks for 4 doses as intravenous infusion. After that, administer 240 mg of nivolumab (genetical recombination) every 2 weeks or 480 mg every 4 weeks as intravenous infusion.
Manufacturer/distributor: Ono Pharmaceutical Co., Ltd.
Co-promotion: Bristol-Myers Squibb K.K.
* Note: Underlined parts show the revised ones according to this approval.
Overview of Yervoy® Injection
Product name: Yervoy® Injection 20 mg, 50 mg
Generic name (JAN): Ipilimumab (Genetical recombination)
Indication
• Unresectable melanoma
• Unresectable or metastatic renal cell carcinoma
• Microsatellite instability high (MSI-High) unresectable advanced or recurrent colorectal cancer that has progressed after chemotherapy
• Unresectable, advanced or recurrent non-small cell lung cancer
• Unresectable advanced or recurrent malignant pleural mesothelioma
• Unresectable advanced or recurrent esophageal cancer
• Unresectable hepatocellular carcinoma
Dosage
Usually, for adults, administer 3 mg/kg (body weight) of ipilimumab (genetical recombination) every 3 weeks for 4 doses as intravenous infusion. In combination therapy with other anti-cancer drugs, nivolumab (genetical recombination) should be co-administered.
In combination therapy with nivolumab (genetical recombination), usually, for adults, administer 1 mg/kg (body weight) of ipilimumab (genetical recombination) every 3 weeks for 4 doses as intravenous infusion.
In combination therapy with other anti-cancer drugs, usually, for adults, administer 1 mg/kg (body weight) of ipilimumab (genetical recombination) every 6 weeks as intravenous infusion.
In combination therapy with nivolumab (genetical recombination), usually, for adults, administer 1 mg/kg (body weight) of ipilimumab (genetical recombination) every 6 weeks as intravenous infusion.
In combination therapy with nivolumab (genetical recombination), usually, for adults, administer 3 mg/kg of ipilimumab (genetical recombination) every 3 weeks for 4 doses as intravenous infusion.
Manufacturer/distributor: Bristol-Myers Squibb K.K.
Co-promotion: Ono Pharmaceutical Co., Ltd.
* Note: Underlined parts show the revised ones according to this approval.
About Opdivo
Opdivo is a programmed death-1 (PD-1) immune checkpoint inhibitor that is designed to uniquely harness the body’s own immune system to help restore anti-tumor immune response by blocking the interaction between PD-1 and its ligands. By harnessing the body’s own immune system to fight cancer, Opdivo has become an important treatment option across multiple cancers since the approval for the treatment of melanoma in Japan in July 2014. Opdivo is currently approved in more than 65 countries, including Japan, South Korea, Taiwan, the US and European Union.
In Japan, Ono launched Opdivo for the treatment of unresectable melanoma in September 2014. Thereafter, Opdivo received an approval for additional indications of unresectable advanced or recurrent non-small cell lung cancer in December 2015, unresectable or metastatic renal cell carcinoma in August 2016, relapsed or refractory classical Hodgkin lymphoma in December 2016, recurrent or metastatic head and neck cancer in March 2017, unresectable advanced or recurrent gastric cancer which has progressed after chemotherapy in September 2017, unresectable advanced or recurrent malignant pleural mesothelioma that has progressed after chemotherapy in August 2018, microsatellite instability high (MSI-High) unresectable advanced or recurrent colorectal cancer that has progressed following chemotherapy and unresectable advanced or recurrent esophageal cancer that has progressed following chemotherapy in February 2020, cancer of unknown primary in December 2021, adjuvant therapy of urothelial carcinoma in March 2022, malignant mesothelioma (excluding malignant pleural mesothelioma) in November 2023, unresectable advanced or recurrent malignant epithelial tumors in February 2024, unresectable urothelial carcinoma in December 2024, and unresectable hepatocellular carcinoma in June 2025.
About Yervoy
Yervoy is a recombinant, human monoclonal antibody, and binds to the cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4). CTLA-4 is a negative regulator of T-cell activation. Yervoy binds to CTLA-4 and blocks the interaction of CTLA-4 with its ligands, CD80/CD86. Blockade of CTLA-4 has been shown to augment T-cell activation and proliferation, including the activation and proliferation of tumor infiltrating T-effector cells. Inhibition of CTLA-4 signaling can also reduce T-regulatory cell function, which may contribute to a general increase in T-cell responsiveness, including anti-tumor immune response. On March 25, 2011, the U.S. Food and Drug Administration (FDA) approved Yervoy 3 mg/kg monotherapy for patients with unresectable or metastatic melanoma. Yervoy is now approved in more than 50 countries. There is a broad, ongoing development program in place for Yervoy spanning multiple tumor types. In Japan, Yervoy was approved for the indication of unresectable malignant melanoma in July 2015.
About the Ono and Bristol Myers Squibb Collaboration
In 2011, through a collaboration agreement with Bristol Myers Squibb (BMS) (bms.com), Ono (ono-pharma.com) granted BMS its territorial rights to develop and commercialize Opdivo globally except in Japan, South Korea, and Taiwan, where Ono had retained all rights to Opdivo except the US at the time. In July 2014, Ono and BMS further expanded the companies’ strategic collaboration agreement to jointly develop and commercialize multiple immunotherapies as single agent and combination regimens for patients with cancer in Japan, South Korea, and Taiwan.
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