The New Landscape of Checkpoint Inhibitors in China

On June 15, 2018, the first checkpoint inhibitor (CPI) was approved by the CFDA and will be commercially available in China by fall. It is anticipated more CPIs will be approved in the near future. In contrast, six CPIs have been approved in the U.S. for various diseases and stages since 2014. Consequently, PD-1/PD-L1 clinical trials have become the most active area of clinical research in China.

Using ClinicalTrials.gov with the criteria of "recruiting/active/interventional", I analyzed opened trials in China; I compiled data and cross-checked with domestic public domain information in China (http://www.chictr.org.cn/). As of July 8, 2018, a total of 134 protocols were identified in PD-1 (112 as China sites [CN], 22 as multi-regional clinical trials [MRCT]), 36 protocols in PD-L1 (9 CN, 27 MRCT) and 13 protocols in anti-CTLA-4 (ipilimumab) (4 CN, 9 MRCT) categories covering both malignant hematology and solid tumors over 20 different disease types. Trials of FDA approved agents in China include nivolumab (n=21), atezolizumab (19), pembrolizumab (12), Durvalumab (10), avelumab (2) and ipilimumab (13). They are predominantly MRCT and in combination with chemotherapy, second CPI or a targeted agent. Trials of domestic PD-1 agents are essentially conducted only in China, with exception of SHR-1210 and BGB-A317 which are also registered for ex-china trials. The majority of early phase trials (>95%) are conducted by a short list of centers in Beijing, Shanghai, and Guangdong, and Zhejiang.

Among domestic PD-1 trials, 36 combine PD-1 with various cell therapy technologies, including CAR-T, DC, PD-1 knockout T cells, or CSR T cells; this indicates such combinations are an area of active investigation. The number of registered trials for each PD-1 biologic agent are SHR-1210 (n=34), JS001 (15), BGB-A317 (8), GB226 (2) and IBI308 (1).

PD-L1 trials have essentially the same broad disease indications as PD-1 agents, and are open for advanced solid tumors. The number of PD-L1 trials is fewer than for PD-1 agents, including Atezolizumab (n=19), Durvalumab (10), Avelumab (2), KN035 (2), CS1001 (2), and SHR-1316 (1).

While majority of CPI trials in China are designed for a single category of cancer, 30% of PD-1 trials, 20% of PD-L1 trials and 7% of ipilimumab trials are opened to advanced solid tumors including lymphoma. In addition, there are more than 20 PD-(L) 1 inhibitors that are in various stages of clinical development in China.

In reality, patients in China have been obtaining CPI agents for cancer treatment outside of clinical trials from overseas. Patients who meet clinical trial eligibility criteria might not represent real world population for efficacy and adverse events. After the first CFDA approved nivolumab, which has a very specific label indication (advanced stage lung cancer after failing platin-based regimen) and other CPIs to be approved soon, the off-label use of these CPI agents could be widespread for various advanced stage cancers.

Judging from the multiple FDA-approved indications of CPIs, the potential demand in China could reach millions of cases. Currently, there are policies to limit total formulary drug expense in public hospitals, so with the high cost of these medications, hospitals may not be able to provide timely treatment to necessary patients, which could create wait list issue.

For care providers, the complexity of managing immune-related adverse events (irAE) and recognizing phenomenon such as pseudo-progression, poses critical need for systemic training and education for physicians, nurses, and patients as well.

It is crucial for policy makers, medical societies, and hospitals to implement policies, and treatment guidelines for all immuno-oncology drugs according to the best evidence-based practice to meet potential demand and safe guard societal and patient benefits.

In collaboration with Massachusetts General Hospital (Boston, USA), the Cancer Center of Jiahui International Hospital (Shanghai, China) has developed comprehensive clinical pathways and practice guidelines locally in China in order to deliver safe, effective and patient-centered care. We have implemented telemedicine to support multidisciplinary care models to manage treatment criteria and treatment complications. Going forward, post-market clinical studies will be conducted for data collection and in collaboration with pharmaceutical companies.