Opdivo Set to Gain Second Indication in China for Second-Line Treatment of Esophageal Cancer

Original: Cai Cai

Recently, there has been good news regarding the popular target PD-1. Opdivo (O drug) is about to be approved in China for its second indication, which will be used for the second-line treatment of esophageal cancer.

According to the NMPA website, the status of the new indication marketing application (Acceptance No.: JXSS1900001/02) for Bristol-Myers Squibb’s (BMS) PD-1 monoclonal antibody Opdivo has been updated to “Under Review.” The new indication is highly likely to be approved in October.

(Source: NMPA official website)

The First PD-1 Monoclonal Antibody Approved in China

On June 15, 2018, nivolumab (generic name: Nivolumab; brand name: Opdivo/Oudiyuo) was approved by the National Medical Products Administration (NMPA) for marketing in China (application numbers: JXSS1700015/16). It is indicated for the second-line treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) who are negative for epidermal growth factor receptor (EGFR) gene mutations and anaplastic lymphoma kinase (ALK), and whose disease has progressed after or who are intolerant to prior platinum-based chemotherapy. Opdivo is the first PD-1/L1 monoclonal antibody approved for marketing in China.

Specific Information on Opdivo Approval

(Source: FDA, NMPA)

Esophageal Cancer Specifically for Chinese Patients

As shown in the table above, Opdivo has not been approved for esophageal cancer in the United States. This is primarily due to significant differences in disease spectra between China and Western countries, with digestive system tumors being a distinctive feature in China.

Digestive system tumors are highly prevalent in China, with gastric cancer, esophageal cancer, and liver cancer ranking second to fourth in incidence rates, respectively. The combined annual number of patients with these three major tumor types in China reaches 1.62 million, and they are relatively sensitive to PD-1/L1 antibody therapy, with reported objective response rates (ORR) generally ranging between 15% and 20%.

Incidence of Digestive System Tumors in China

(Source: CA Cancer J Clin 2016)

Based on factors such as patient population, penetration rate, relative survival benefits for patients, and economic considerations, some securities analysts have estimated that the combined market size for gastric cancer, liver cancer, and esophageal cancer is approximately RMB 12.2 billion.

The "OK" Controversy

In the first half of 2019, Opdivo’s sales amounted to $3.6 billion, while Keytruda (K drug) reached $4.9 billion. Since losing its indication for first-line treatment of non-small cell lung cancer (NSCLC), Opdivo (O drug) has been overtaken by Keytruda, and the gap between the two is likely to widen in the future.

Opdivo and Keytruda are like the relationship described in the phrase "Since Yu was born, why was Liang also born?"

Opdivo’s Indications Expanded Aggressively in the Early Post-Launch Phase, Outpacing Keytruda: In 2014, both Opdivo and Keytruda were approved with melanoma as their initial indication. In 2015, both drugs secured approvals for non-small cell lung cancer (NSCLC). Subsequently, Opdivo gained additional indications including renal cell carcinoma, classical Hodgkin lymphoma, and head and neck squamous cell carcinoma, while Keytruda had only three indications at that time.

Keytruda Overtakes Opdivo with Approval for First-Line NSCLC Therapy, Launching Its Comeback: In 2017, Keytruda secured approvals for five major indications, including gastric cancer, as well as a landmark first-line therapy for non-small cell lung cancer (NSCLC), driving accelerated sales growth and ultimately surpassing Opdivo in Q2 2018. Meanwhile, Opdivo announced the failure of its first-line NSCLC therapy in Q3 2018, ceding this patient population to Keytruda. From Q4 2017 to Q2 2019, the quarter-over-quarter compound annual growth rates (CAGR) were 14.5% for Keytruda and 6% for Opdivo. It is anticipated that Opdivo will struggle to compete with Keytruda after missing out on the first-line NSCLC indication.

FDA-Approved Indications for Opdivo and Keytruda

(Source: FDA)

In June 2018, Opdivo was approved for marketing in China, becoming the first PD-1/PD-L1 inhibitor approved in the country. It is indicated for the second-line treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) who are negative for epidermal growth factor receptor (EGFR) gene mutations and anaplastic lymphoma kinase (ALK), and whose disease has progressed after or who are intolerant to prior platinum-based chemotherapy. In July 2018, Keytruda received its first indication approval in China for the second-line treatment of patients with locally advanced or metastatic melanoma whose disease has progressed. In April 2019, Keytruda’s second indication was approved for use in combination with pemetrexed and cisplatin as first-line treatment for EGFR- and ALK-negative metastatic non-squamous NSCLC.

It is worth mentioning that Keytruda also has new indications pending approval, as referenced in the article “Keytruda Is About to Gain Approval for Its Third Indication in China: First-Line Treatment for PD-L1-Positive Non-Small Cell Lung Cancer》。

Industry analysis indicates that lung cancer represents the largest market for PD-1 inhibitors. Leveraging a series of precisely designed clinical trials, Merck & Co. first entered the monotherapy first-line lung cancer market, starting with patients exhibiting high PD-L1 expression. Currently, the standard of care is Keytruda monotherapy for patients with high PD-L1 expression and a Keytruda/chemotherapy combination for those with low PD-L1 expression.

PD-1/PD-L1 Monoclonal Antibodies Marketed and Under Review for Approval in China

Currently, there are 2 imported and 3 domestically produced PD-1 monoclonal antibodies approved in China.

PD-1/PD-L1 Monoclonal Antibodies Marketed and Under Regulatory Review in China

(Source: CDE)