Ongoing clinical trials of PD-1 and PD-L1 inhibitors for lung cancer in China

Immunotherapy is revolutionizing the treatment of multiple cancer types and provides promising clinical responses, durable disease control, and fewer adverse events among patients with advanced melanoma, non-small cell lung cancer (NSCLC), and other tumor types [1]. Programmed cell death protein-1 (PD-1) is an important immune checkpoint protein that is expressing on the surface of T cells. When PD-1 binds to its ligands, such as programmed cell death protein ligand 1 (PD-L1) and programmed cell death protein ligand 2, T cell activity and cytokine production is greatly downregulated at the tumor site. This effect contrasts with the biological characteristics of treatments targeting cytotoxic T lymphocyte-associated protein 4 (CTLA-4), and PD-1/PD-L1 blockage is now considered a “tumor site immune modulation therapy” [2, 3]. Blocking the PD-1 pathway using monoclonal antibodies to PD-1 or PD-L1 can stimulate the patient’s immune system to kill tumor cells, and this approach has provided remarkable anti-tumor efficacy, compared to standard first-line and second-line chemotherapy for advanced NSCLC [4‐8]. By the end of December 2016, the US Food and Drug Administration had approved PD-1 pathway blockade treatments using nivolumab, pembrolizumab, and atezolizumab [9].

In China, no PD-1 or PD-L1 inhibitors have received marketing approval from the Chinese Food and Drug Administration (CFDA). However, various clinical trials are actively investigating international and domestic drugs. Between January 1, 2013 and April 6, 2017, ClinicalTrials.gov registered 270 international clinical trials using PD-1/PD-L1 therapies for NSCLC (e.g., nivolumab, pembrolizumab, atezolizumab, and durvalumab). These 270 trials included 61 studies that involved East Asian sites and 14 studies that involved Chinese sites (12 multinational trials and 2 trials that only evaluated Chinese patients). Thus, research regarding immune checkpoint inhibitors in China is several years behind research in other areas of the world. This review evaluates the ongoing international and domestic clinical trials using PD-1 or PD-L1 inhibitors, and we hope this review will provide detailed information regarding how to perform immunotherapy clinical trials in China.

Chinese participation in international multicenter clinical trials using PD-1/PD-L1 inhibitors has greatly increased during the last 3 years. Based on our research, Chinese sites were involved in 14 global clinical trials by April 6, 2017. These trials included six first-line trials (NCT02220894 [KEYNOTE 042], NCT03003962, NCT02542293 [NEPTUNE], NCT02763579 [IMpower133], NCT02657434 [IMpower132], and NCT02409342 [IMpower110]), four second-line trials (NCT02864394 [MK-3475-033], NCT02613507 [CheckMate078], NCT02481830 [CheckMate331], and NCT02813785 [IMpower210]), two adjuvant therapy trials (NCT02486718 [IMpower010] and NCT02273375 [BR.31]), and two trials that only evaluated Chinese patients (NCT02835690 [KEYNOTE 032] and NCT02978482) (Fig. 1).

Significant efforts by the Chinese government during the last 2 years have led to improvements in the overall clinical research environment [14]. Now the CFDA is actively reforming the regulatory framework for the approval of novel agents, which has introduced a “four-color light” strategy and will likely further adjust its policies to reflect advances in large international clinical trials of immunotherapy [15]. Chinese pharmaceutical companies had developed eight anti-PD-1/PD-L1 inhibitors by January 7, 2017, and four drugs (JS001, SHR-1210, IBI308, and BGB-A317) have been approved by the CFDA for phase I trials among patients with advanced solid tumors and NSCLC. Another four drugs (Jirnuo monoclonal antibodies, GLS-010, KN035, and WBP3155) are now being considered by the CFDA for clinical trial approval (Fig. 2). In November 2016, the PD-1 inhibitor KN035, ​that is administered by subcutaneous injection, received approval from the American Food and Drug Administration for clinical trial conduction.

Immunotherapy using PD-1 or PD-L1 inhibitors provides durable clinical regression, good tolerance, and relatively few adverse events among patients with malignant tumors. However, Chinese patients have limited access to these promising immune-checkpoint inhibitors, such as antibodies to PD-1 and PD-L1. Furthermore, the ongoing international and domestic clinical trials have duplicated the designs of previous trials for PD-1 and PD-L1 antibodies, which have revealed promising results, but rarely consider the characteristics of the Chinese or Asian populations.

The characteristics of Chinese patients are important considerations in trial designs, as the Chinese population has relatively high rates of hepatitis B virus infection and traditional medicine use [16]. Thus, many Chinese patients are ineligible for clinical trials of the antibodies to PD-1 or PD-L1. Furthermore, Chinese and international researchers have revealed that Chinese patients with NSCLC may have more driver gene mutations, different gene profiles, better clinical responses to chemotherapy, and different toxicity profiles [17‐20]. However, the relevance of these characteristics remains unclear for immunotherapy with blockade of the PD-1 pathway, and data from Chinese patients remain scarce.

At the 14th Lung Cancer Summit, Chinese scientists introduced several proposals for immunotherapy using PD-1 or PD-L1 inhibitors. First, the much higher proportion of EGFR mutation should be considered when designing Chinese immunotherapy trials, as the prevalence of EGFR mutations is approximately 50% among Chinese patients with NSCLC [21, 22]. Second, the introduction of four FDA-approved immunohistochemistry biomarker assays, and the development of domestic reagents, may allow for the development of PD-1 immunohistochemistry assays in China. A phase II single-arm study of SHR-1210 as a second-line NSCLC treatment is aiming to determine an optimal PD-L1 cut-off value for Chinese patients.

Global researchers remain faced with unanswered questions regarding PD-1 and PD-L1 inhibitors. First, the relationships between PD-L1 expression and other factors (e.g., mutational burden, smoking index, and neoantigen quantity) are very complicated [23, 24], and further research is needed. Second, it would be useful to develop combined biomarkers and complementary assays that could improve the overall specificity (58%) and sensitivity (72%) of PD-1 expression [1, 25]. Third, it is possible that combining immunotherapy with chemotherapy, targeted therapy, and radiotherapy could provide superior results, compared to immunotherapy alone. Fourth, although we have known that antibodies to PD-L1 have relatively low pulmonary toxicity, it remains unclear whether antibodies to PD-1 or PD-L1 provide a better clinical response. Fifth, the conventional Response Evaluation Criteria In Solid Tumors are not appropriate for evaluating PFS after immunotherapy and pseudo-progression, and additional research is needed to improve the utility of immune-related response criteria [26].

Chinese clinical trials using PD-1 or PD-L1 inhibitors remain in their early stages, and further efforts are needed to improve the design of future clinical trials. In addition, China must take steps to help translate the results of clinical trials into clinical practice. For example, it will be useful to simplify phase I study designs and speed up late-stage clinical development.