Bristol Myers Squibb Submits New Indication Applications for Opdivo and Yervoy in China

On December 3, the latest public notice on the website of the Center for Drug Evaluation (CDE) under China’s National Medical Products Administration indicated that the new indication marketing application for the immune checkpoint inhibitors nivolumab (Opdivo) and ipilimumab (Yervoy), submitted by Bristol-Myers Squibb (BMS), has been accepted (see table below for details). Notably, just one week prior, the combination therapy of these two drugs was proposed for inclusion in the priority review program as a “drug eligible for conditional approval,” intended for the treatment of adult patients with previously untreated, unresectable, non-epithelioid malignant pleural mesothelioma.

Nivolumab is a PD-1 inhibitor that helps restore the body’s anti-tumor immune response by harnessing its own immune system. Currently, this product has been approved globally for the treatment of more than ten indications, including advanced melanoma, lung cancer, renal cell carcinoma, and Hodgkin lymphoma. In China, nivolumab was first approved for marketing in 2018, and its currently approved indications in China include non-small cell lung cancer, head and neck squamous cell carcinoma, and gastric/gastroesophageal junction adenocarcinoma.

Ipilimumab is a CTLA-4 inhibitor. As one of the primary negative regulators of T-cell responses, CTLA-4 antibodies enhance tumor-killing capacity by boosting T-cell activity. The product was approved by the U.S. FDA in 2011 for the treatment of advanced melanoma, becoming the first CTLA-4 antibody drug approved globally. In China, ipilimumab submitted a New Drug Application (NDA) at the end of 2019, and the application is currently under review and approval.

Bristol-Myers Squibb (BMS) has simultaneously submitted marketing applications for these two new drugs, suggesting that they may be intended for use in combination therapy. This dual checkpoint inhibitor combination is believed to have a potential synergistic mechanism of action: ipilimumab helps activate and proliferate T cells, while nivolumab assists existing T cells in recognizing tumors. Certain T cells activated by ipilimumab can differentiate into memory T cells, thereby potentially enabling long-term immune responses.

Source of screenshot: China Drug Clinical Trial Registration and Information Publicity Platform

According to the Chinese Drug Clinical Trial Registration and Information Publicity Platform, Bristol-Myers Squibb (BMS) is currently conducting multiple clinical trials in China on the combination therapy of nivolumab and ipilimumab. The indications include advanced hepatocellular carcinoma (HCC), non-small cell lung cancer (NSCLC), urothelial carcinoma, renal cell carcinoma, esophageal squamous cell carcinoma, and malignant pleural mesothelioma (MPM).

Notably, one week ago, the indication for the combination of nivolumab and ipilimumab for the treatment of adult patients with previously untreated, unresectable, non-epithelioid malignant pleural mesothelioma was proposed by the Center for Drug Evaluation (CDE) for priority review as a “drug eligible for conditional approval.” This combination therapy had previously demonstrated in the CheckMate-743 study that, compared with chemotherapy, it provides significant and durable overall survival benefits in the first-line setting for patients with all histological subtypes of malignant pleural mesothelioma. According to public information, this represents the first pharmacological therapy approved for mesothelioma in 16 years.

In patients with advanced renal cell carcinoma, results from the Phase 3 CheckMate-214 clinical trial demonstrated that Opdivo plus Yervoy significantly improved overall survival (OS) benefit compared to current standard therapy, reducing the risk of death by 37%. Furthermore, OS benefit was observed regardless of PD-L1 expression levels. Meanwhile, the combination therapy provided durable responses and a higher objective response rate (41.6% vs. 26.5%).

In patients with hepatocellular carcinoma (HCC), results from the Phase 1/2 CheckMate-040 clinical study showed that among HCC patients previously treated with sorafenib, 33% achieved an objective response and 8% achieved a complete response (CR) after a minimum follow-up of 28 months. The duration of response (DOR) ranged from 4.6 to 30.5+ months, with 88% of responses lasting at least six months and 56% lasting at least 12 months.

In patients with non-small cell lung cancer (NSCLC), results from the randomized, open-label, Phase 3 CheckMate-227 clinical trial demonstrated that Opdivo plus Yervoy significantly improved overall survival (17.6 months vs. 14.9 months) and other efficacy endpoints compared with chemotherapy. With a median follow-up duration exceeding three years, the combination therapy provided sustained survival benefits, yielding a 3-year overall survival rate of 33% (vs. 22%) and a 3-year progression-free survival rate of 18% (vs. 4%).

According to a press release previously issued by Bristol-Myers Squibb (BMS), the dual checkpoint inhibitor combination therapy of Opdivo plus Yervoy was approved in October 2015 as the first immuno-oncology combination therapy to receive regulatory approval globally. It has since been approved in more than 50 countries and regions worldwide for six tumor types, with indications covering melanoma, advanced renal cell carcinoma, previously treated MSI-H/dMMR metastatic colorectal cancer, hepatocellular carcinoma, metastatic non-small cell lung cancer, and malignant pleural mesothelioma.

References:

[1] Center for Drug Evaluation (CDE), National Medical Products Administration of China. Retrieved Dec 3, 2020, from http://www.cde.org.cn/news.do?method=changePage&pageName=service&frameStr=21#

[2] New Breakthrough! Immune “Twin Stars” Gain FDA Approval for First-Line Treatment of Malignant Pleural Mesothelioma. Retrieved Oct 9, 2020, from https://mp.weixin.qq.com/s/hPySrBIQsPCWj9kWSNsk9w

[3] U.S. Food and Drug Administration Approves Opdivo® (nivolumab) + Yervoy® (ipilimumab) for Patients with Hepatocellular Carcinoma (HCC) Previously Treated with Sorafenib. Retrieved 2020-03-11, from https://news.bms.com/press-release/corporatefinancial-news/us-food-and-drug-administration-approves-opdivo-nivolumab-ye-0

[4] FDA approves nivolumab plus ipilimumab for first-line mNSCLC (PD-L1 tumor expression ≥1%). Retrieved May 15, 2020, from https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-nivolumab-plus-ipilimumab-first-line-mnsclc-pd-l1-tumor-expression-1

Source: Pharma Perspective

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