Merck's Keytruda Nears Sixth China Approval for First-Line Monotherapy in PD-L1-Positive Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma

Text: Dopine

Recently, the status of the new indication application for Merck’s PD-1 monoclonal antibody pembrolizumab injection (related acceptance number: JXSS2000010) with the NMPA has changed to “Under Review.” This indicates that the new indication for pembrolizumab as a first-line monotherapy for metastatic or unresectable recurrent head and neck squamous cell carcinoma (HNSCC) with tumor expression of PD-L1 [Combined Positive Score (CPS) ≥ 20] is imminent for approval in China. This will be its sixth indication approved in the country.

Head and neck malignancies rank seventh among all cancers worldwide, with approximately 600,000 new cases reported annually. In China, head and neck malignancies account for approximately 3% of all systemic malignancies. The most common histological subtype is squamous cell carcinoma, and more than 60% of patients with head and neck squamous cell carcinoma (HNSCC) present with locally advanced or metastatic disease at diagnosis. Statistics indicate that there are over 135,000 new cases of head and neck cancer annually in China, with approximately 70,000 deaths, figures that significantly exceed those of other countries and regions and continue to rise year by year. Furthermore, approximately 50% of patients with HNSCC experience recurrence, mostly within two years. For patients with recurrent or metastatic disease who have failed first-line therapy, the five-year survival rate is only 3.6%.

For decades, platinum-based chemotherapy alone has been the standard first-line regimen for recurrent/metastatic head and neck squamous cell carcinoma (HNSCC), yet survival outcomes have remained suboptimal. It was not until September 2019 that the National Medical Products Administration (NMPA) approved Bristol-Myers Squibb’s PD-1 monoclonal antibody, nivolumab, for the treatment of recurrent or metastatic HNSCC in patients who experienced disease progression during or after platinum-based therapy and whose tumors expressed PD-L1 (TPS ≥1%). This approval marked the dawn of a new era of immunotherapy for HNSCC in China. Furthermore, it is worth noting that this March, Merck’s EGFR-targeted drug cetuximab was approved in China for use in combination with platinum-based chemotherapy and fluorouracil as a first-line treatment for recurrent/metastatic HNSCC. This regimen has also received a Category I expert recommendation (Level of Evidence 1A) in the 2020 updated “CSCO Guidelines for the Diagnosis and Treatment of Head and Neck Tumors.”

Pembrolizumab (commonly known as Keytruda) is currently a PD-1 monoclonal antibody with substantial global sales, reaching $11.084 billion in 2019. Since its market launch, the drug has been approved for numerous indications, including more than 20 oncology indications such as melanoma, non-small cell lung cancer, lymphoma, and urothelial carcinoma. Recently, it was approved by the FDA for the treatment of triple-negative breast cancer. Additionally, the drug has received approval for two tumor-agnostic therapies.

In China, pembrolizumab has been approved for five indications: locally advanced or metastatic melanoma after failure of first-line therapy (July 2018); metastatic non-squamous non-small cell lung cancer (NSCLC) without EGFR/ALK mutations as first-line treatment (March 2019); monotherapy as first-line treatment for locally advanced or metastatic NSCLC with PD-L1 tumor proportion score (TPS) ≥1% and negative for EGFR gene mutations and ALK (September 2019); metastatic squamous NSCLC as first-line treatment (November 2019); and esophageal squamous cell carcinoma (June 2020).

Pembrolizumab is poised to receive approval in China for the first-line treatment of head and neck squamous cell carcinoma (HNSCC), based on the results of the pivotal Phase III randomized controlled KEYNOTE-048 trial: 1) In patients with PD-L1 expression positivity (CPS ≥20), pembrolizumab extended median overall survival (OS) from 10.8 months with the EXTREME regimen (chemotherapy plus an EGFR-targeted agent) to 14.9 months, reducing the risk of death by 39% while significantly lowering the incidence of severe adverse events; 2) In the overall population, pembrolizumab combined with chemotherapy extended OS from 10.7 months with the EXTREME regimen to 13.0 months, reducing the risk of death by 29%, with a comparable safety profile; 3) The incidence of significant adverse events was as high as 69.3% in the control group (EXTREME regimen), compared to only 17% in the pembrolizumab group.

In overseas markets, Keytruda was approved by the FDA in 2019 as a first-line treatment for head and neck squamous cell carcinoma (HNSCC). Furthermore, at the 2020 European Society for Medical Oncology (ESMO) Annual Meeting held this September, researchers presented long-term follow-up data on 4-year survival rates from the KEYNOTE-048 study. The results showed that the 2-year survival rate was 19.7% for patients receiving conventional standard therapy, compared to 35.3% for those receiving immunotherapy; the 4-year survival rate was 8.0% for the conventional standard therapy group, versus 21.6% for the immunotherapy group. We look forward to the approval of Keytruda as a first-line treatment for HNSCC in China, thereby benefiting patients nationwide.

The Domestic PD-1 Monoclonal Antibody War Begins: New Indications Are Being Approved in Succession

As of now, six PD-1 monoclonal antibodies have been approved in China, including two imported and four domestically produced ones, as detailed in the table below. Among these six PD-1 monoclonal antibodies, only Sintilimab from Innovent Biologics was included in the 2019 National Reimbursement Drug List.

As shown in the table above, pembrolizumab and camrelizumab (developed by Hengrui Medicine) currently have the largest number of approved indications. However, according to the Insight database, these PD-1 monoclonal antibodies have successively filed applications for new indications up to the present date; see the table below for details. In addition, three new domestically produced PD-1 monoclonal antibodies have been submitted for marketing approval: zimberelimab (Yuheng Biopharma), genolimzumab (Jiahua Biologics), and penpulimab (Akeso/Chia Tai Tianqing). Based on the submission timelines, these marketing applications are primarily concentrated in the current year, and the approval times for the new indications are also expected to be relatively clustered.

According to company financial reports, these four domestically produced PD-1 monoclonal antibodies should not be underestimated. In the first three quarters of 2020, the sales revenues for sintilimab, toripalimab, tislelizumab, and camrelizumab were RMB 1.5 billion, over RMB 700 million, RMB 662 million, and approximately RMB 3 billion, respectively (the RMB 3 billion figure for camrelizumab is an industry estimate, as specific sales figures for Q2 and Q3 were not disclosed). Notably, tislelizumab was officially launched for commercial sale in March of this year, making its sales revenue of RMB 662 million quite substantial.

Furthermore, it is worth noting that all five PD-1 monoclonal antibodies approved in China (excluding sintilimab) and two PD-L1 monoclonal antibodies (namely, durvalumab and atezolizumab) have been included in the 2020 preliminary review list for the National Reimbursement Drug List (NRDL). However, based on current NRDL policies, key determinants for the inclusion of these novel immunotherapies—such as efficacy, price, scope of indications, and the availability of alternative treatment regimens—remain critical. The NRDL has now entered the final review stage, and the ultimate outcomes await official announcement. In the meantime, pharmaceutical companies are striving to secure reimbursement status. For instance, Hengrui Medicine launched a significant promotional campaign in the fourth quarter, offering camrelizumab at an annual cost of RMB 39,600, whereas the previous annual expense, even with patient assistance programs providing free medication, amounted to approximately RMB 120,000.