Merck's Keytruda Nears Third China Approval for First-Line Treatment of PD-L1-Positive NSCLC

Original: Cai Cai

Recently, another major development has emerged in the pharmaceutical industry: Keytruda (K drug) is set to receive approval in China for its third indication, as a first-line treatment for PD-L1-positive non-small cell lung cancer (NSCLC).

According to the NMPA website, the status of Merck & Co., Inc.’s new indication application for its PD-1 monoclonal antibody (Acceptance No.: JXSS1800029) has been updated to “Under Review.” This new indication is highly likely to be approved in October.

(Data source: NMPA official website)

Keytruda has already received approval for two indications in China.

On July 26, 2018, pembrolizumab (brand name: Keytruda/KeRuiDa) was approved by the NMPA for marketing (Application No.: JXSS1800002) for second-line treatment of patients with locally advanced or metastatic melanoma who have experienced disease progression;

On April 2, 2019, the second indication application for Keytruda (acceptance number: JXSS1800018) was approved, for the first-line treatment of EGFR- and ALK-negative metastatic non-squamous non-small cell lung cancer (NSCLC) in combination with pemetrexed and cisplatin.

Keytruda is the first PD-1/PD-L1 monoclonal antibody approved for first-line treatment in China. Currently, only MSD’s Keytruda and Roche’s Tecentriq have been approved globally as first-line therapies for NSCLC, with the latter still undergoing registration application in China.

Keytruda Approved in the US for First-Line Treatment of NSCLC Patients with High and Low PD-L1 Expression

On October 24, 2016, the FDA approved Keytruda for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) who have strong PD-L1 expression (Tumor Proportion Score [TPS] ≥50%) and are negative for both EGFR and ALK mutations.

This approval is based on the "KEYNOTE-024" study, a Phase III randomized trial that enrolled patients with PD-L1 expression ≥50% and compared pembrolizumab with platinum-based doublet chemotherapy.

OS Results from the KEYNOTE-024 Study

(Source: The Lancet)

The results showed that Keytruda significantly outperformed chemotherapy in terms of both PFS and OS, with mPFS of 10.3 vs. 6.0 months and mOS of 30.0 vs. 14.2 months. These data indicate that, for patients with advanced NSCLC who are strongly PD-L1 positive, treatment with Keytruda can significantly prolong PFS and overall survival compared to standard platinum-based chemotherapy.

On April 11, 2019, the FDA approved Keytruda as a monotherapy for first-line treatment of patients with stage III or metastatic non-small cell lung cancer (NSCLC) whose tumors express PD-L1 (TPS ≥1%) and lack EGFR and ALK mutations.

This approval is based on the KEYNOTE-042 study, a global, randomized, open-label Phase III trial that enrolled 1,274 patients with advanced non-small cell lung cancer (NSCLC), including both non-squamous and squamous histologies, whose tumors expressed PD-L1 with a Tumor Proportion Score (TPS) of ≥1%. Among these patients, 47% had a PD-L1 TPS ≥50%, and 64% had a PD-L1 TPS ≥20%. The study evaluated the efficacy and safety of Keytruda as a monotherapy for first-line treatment compared with platinum-based chemotherapy. Enrolled patients had no EGFR or ALK tumor genomic aberrations and had not previously received systemic therapy for advanced disease. The primary endpoint was overall survival (OS) in populations with different levels of PD-L1 expression (TPS ≥50%, TPS ≥20%, and TPS ≥1%), assessed sequentially according to PD-L1 expression stratification. The secondary endpoints were progression-free survival (PFS) and objective response rate (ORR), which were also assessed sequentially by PD-L1 expression stratification.

In terms of the primary endpoint OS, the specific results are as follows:

(Source: The Lancet)

(Source: The Lancet)

Which type of PD-L1-positive NSCLC was actually approved in China this time—high expression or low expression? Those with insights are welcome to leave comments and discuss.

Keytruda Conducts Multiple Clinical Trials in China

In addition to melanoma and NSCLC, Keytruda has also conducted multiple clinical trials in China for gastric cancer, esophageal cancer, and breast cancer.

(Source: Drug Clinical Trial Registration and Information Publicity Platform)

Price of Keytruda in China

On September 20, 2018, Keytruda was officially launched for sale in China, priced at RMB 17,918 per 100 mg. (Keytruda’s indication for malignant melanoma was included in the Shenzhen Medical Insurance program in November 2018, and its indication for lung cancer was incorporated into the Zhuhai Supplementary Medical Insurance scheme in May 2019.)

Indication Development Pathway for Keytruda

Since receiving its first approval for melanoma in 2014, Keytruda (K drug) has gained indications in 11 tumor types within five years. Based on current clinical development progress, it is expected that Keytruda will continue to achieve breakthroughs in indications such as triple-negative breast cancer and renal cell carcinoma over the next one to two years. According to Merck Sharp & Dohme’s development plan, Keytruda is ultimately projected to secure approvals in more than 15 tumor types, gradually expanding from high-incidence cancers to rare and orphan tumors.

Development Pathway for Keytruda Indications

(Source: MSD Official Website)

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

In June 2018, BMS’s Opdivo (commonly known as “O Drug”) received approval from the NMPA, becoming the first PD-1/PD-L1 monoclonal antibody marketed in China and ushering in the era of immunotherapy in the country.

In August 2018, Keytruda was approved; in December, Junshi Biosciences’ toripalimab and Innovent Biologics’ sintilimab also received approval. In May 2019, Hengrui Medicine’s camrelizumab was approved. From the second half of 2018 to early 2019, AstraZeneca’s durvalumab, BeiGene’s tislelizumab, and Roche’s atezolizumab sequentially submitted marketing applications.

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

(Source: CDE)