Mar.27.2023
R & D

ONO Receives Supplemental Approval of Opdivo in Combination with Chemotherapy for Neoadjuvant Treatment of Non-Small Cell Lung Cancer in Japan

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 Ono Pharmaceutical Co., Ltd. (Osaka, Japan; President and CEO: Gyo Sagara; “ONO”) and Bristol-Myers Squibb K.K. (Tokyo, Japan; President: Steve Sugino) today announced that ONO has received a supplemental approval of Opdivo® (generic name: nivolumab) Intravenous Infusion (“Opdivo”), a human anti-human PD-1 monoclonal antibody in Japan for the neoadjuvant treatment of non-small cell lung cancer in combination with chemotherapy, for a partial change in approved items of the manufacturing and marketing approval.

 This approval is based on the results from a global multi-center, randomized, open-label Phase 3 clinical trial, CheckMate -816 trial (ONO-4538-55), evaluating Opdivo in combination with chemotherapy compared to chemotherapy alone as a neoadjuvant treatment in patients with resectable non-small cell lung cancer (NSCLC). In this trial, three cycles of Opdivo in combination with chemotherapy demonstrated a statistically significant and clinically meaningful improvement in event-free survival (EFS) as assessed by Blinded Independent Central Review (BICR) and pathologic complete response (pCR) as assessed by Blinded Independent Pathology Review (BIPR) versus chemotherapy alone when given before surgery. The safety profile of Opdivo in combination with chemotherapy in this trial was consistent with previously reported trials in patients with NSCLC.

About CheckMate -816 Trial (ONO-4538-55)

 CheckMate -816 is a global multi-center, randomized, open-label Phase 3 clinical trial, evaluating Opdivo with chemotherapy compared to chemotherapy alone as neoadjuvant treatment in patients with resectable stage IB - IIIA non-small cell lung cancer (per the 7th edition American Joint Committee on Cancer/Union for International Cancer Control staging criteria), regardless of PD-L1 expression. Patients were randomized to receive either Opdivo 360 mg plus histology-based platinum doublet chemotherapy every three weeks for three cycles, or platinum doublet chemotherapy every three weeks for three cycles, followed by surgery. The primary endpoints of the trial are event-free survival (EFS) as assessed by Blinded Independent Central Review (BICR) and pathologic complete response (pCR) as assessed by Blinded Independent Pathology Review (BIPR). Secondary endpoints include overall survival (OS), major pathologic response (MPR), and time to death or distant metastases.

About Lung Cancer

 Lung cancer is a form of malignant tumor that arises from cells in the trachea, bronchi and alveoli. Lung cancer is divided into two types, small cell lung cancer and non-small cell lung cancer (NSCLC), depending on the broad histological subtypes. NSCLC is the most common type of lung cancer, accounting for about 80 - 85% of lung cancer1). NSCLC is further classified into mainly adenocarcinoma (about 40% of lung cancer), squamous cell carcinoma (about 25%) and large cell carcinoma (about 10%) 2). Lung cancer is the most common type of cancer with an estimated 138,000 new diagnoses per year in Japan3) (about 2,200,000 cases worldwide4)). It is estimated that approximately 82,000 deaths per year result from the disease in Japan3) (approximately 1,790,000 worldwide4)), representing the leading cause of cancer-related deaths in both cases3, 4). Curative surgery is performed in patients with stages I - IIIA and some patients with stage IIIB NSCLC. However, even if surgery is performed, 30 - 55% of NSCLC patients relapse and die of the disease5). Survival rates vary depending on the stage and type of the cancer when diagnosed.

  1. American Cancer Society; What Is Non-Small Cell Lung Cancer?：
    https://www.cancer.org/content/cancer/en/cancer/lung-cancer/about/what-is.html
  2. Non-Small Cell Lung Cancer Treatment (PDQ®)–Health Professional Version, National Cancer Institute: https://www.cancer.gov/types/lung/hp/non-small-cell-lung-treatment-pdq#_12_toc
  3. Globocan 2020: Japan. World Health Organization. Available at:
    https://gco.iarc.fr/today/data/factsheets/populations/392-japan-fact-sheets.pdf
  4. Globocan 2020: World. World Health Organization. Available at:
    https://gco.iarc.fr/today/data/factsheets/populations/900-world-fact-sheets.pdf
  5. Uramoto H, Tanaka F. Recurrence after surgery in patients with NSCLC. Transl Lung Cancer Res. 2014;3:242-9.
Overview of Opdivo® Intravenous Infusion
Product name Opdivo® Intravenous Infusion 20mg, 100mg, 120mg and 240mg
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
  • 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
Dosage and administration

<Melanoma>

Usually, for adults, administer at 240 mg of nivolumab every 2 weeks or 480 mg every 4 weeks as intravenous infusion. In the adjuvant treatment of melanoma, the administration period does not exceed 12 months.
In combination therapy with ipilimumab for unresectable melanoma, usually, for adults, administer 80 mg of nivolumab every 3 weeks for 4 doses. After that, administer 240 mg of nivolumab every 2 weeks or 480 mg every 4 weeks as intravenous infusion.

<Unresectable, advanced or recurrent non-small cell lung cancer, and unresectable advanced or recurrent gastric cancer>

Usually, for adults, administer at 240 mg of nivolumab 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 every 2 weeks or 360 mg every 3 weeks as intravenous infusion.

<Neoadjuvant treatment of non-small cell lung cancer>

In combination therapy with other anti-tumor drugs, usually, for adults, administer 360 mg of nivolumab every 3 weeks as intravenous infusion. The administration frequency does not exceed 3 doses.

<Unresectable or metastatic renal cell carcinoma>

Usually, for adults, administer 240 mg of nivolumab every 2 weeks or 480 mg every 4 weeks as intravenous infusion.
In combination with cabozantinib, usually, for adults, administer 240 mg of nivolumab every 2 weeks or 480 mg every 4 weeks as intravenous infusion.
In combination therapy with ipilimumab for unresectable or metastatic renal cell carcinoma previously untreated with chemotherapy, usually, for adults, administer 240 mg of nivolumab as intravenous infusion every 3 weeks for 4 doses. After that, administer 240 mg of nivolumab every 2 weeks or 480 mg every 4 weeks as intravenous infusion.

<Recurrent or refractory classical Hodgkin lymphoma>

Usually, for adults, administer 240 mg of nivolumab every 2 weeks or 480 mg every 4 weeks as intravenous infusion.
Usually for pediatrics, administer 3 mg/kg (body weight) of nivolumab every 2 weeks as intravenous infusion. For pediatrics weighing 40 kg (body weight) or more, nivolumab can be administered at 240 mg every 2 weeks or 480 mg every 4 weeks as intravenous infusion.

<Recurrent or metastatic head and neck cancer, and cancer of unknown primary>

Usually, for adults, administer 240 mg of nivolumab every 2 weeks or 480 mg every 4 weeks as intravenous infusion.

<Unresectable advanced or recurrent malignant pleural mesothelioma>

Usually, for adults, administer 240 mg of nivolumab every 2 weeks or 480 mg every 4 weeks as intravenous infusion.
In combination therapy with ipilimumab, usually, for adults, administer 240 mg of nivolumab every 2 weeks or 360 mg every 3 weeks as intravenous infusion.

<Microsatellite instability high (MSI-High) unresectable advanced or recurrent colorectal cancer that has progressed after chemotherapy>

Usually, for adults, administer at 240 mg of nivolumab every 2 weeks or 480 mg every 4 weeks as intravenous infusion.
In combination therapy with ipilimumab, usually, for adults, administer 240 mg of nivolumab as intravenous infusion every 3 weeks for 4 doses. After that, administer 240 mg of nivolumab every 2 weeks or 480 mg every 4 weeks as intravenous infusion.

<Unresectable advanced or recurrent esophageal cancer>

Usually, for adults, administer 240 mg of nivolumab 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 every 2 weeks, 360 mg every 3 weeks or 480 mg every 4 weeks as intravenous infusion.

<Adjuvant treatment of esophageal cancer, and adjuvant treatment of urothelial carcinoma>

Usually, for adults, administer 240 mg of nivolumab every 2 weeks or 480 mg every 4 weeks as intravenous infusion. The administration period does not exceed 12 months.
Manufacturer/
distributor		 Ono Pharmaceutical Co., Ltd.
Co-promotion Bristol-Myers Squibb K.K.

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, China, 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 which 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, and adjuvant treatment of urothelial carcinoma in March 2022.
 In addition, ONO is conducting clinical development program including hepatocellular carcinoma, ovarian cancer, prostate cancer, etc.

About the ONO and Bristol Myers Squibb Collaboration

 In 2011, through a collaboration agreement with Bristol Myers Squibb (BMS), ONO 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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