Recently, the ODAC meeting on Innovent/Lilly PD-1 mAb held by the FDA has attracted much attention from the pharmaceutical industry in China and even around the world. This conference not only let us see the courage and style of Chinese innovative pharmaceutical companies on the international stage, but also let us see the efforts and attempts made by Chinese innovative pharmaceutical companies to solve the huge unsolved clinical needs of human beings around the world. .

It is worth affirming that the meeting did not question the safety and efficacy of tumor drug research. As the first "path-finding" meeting, we saw international regulatory agencies' opinions on overall survival (OS), international multi-center clinical (MRCT) focus on other factors. The journey of exploring the internationalization of China's innovative drugs has already begun, and the future is full of opportunities and challenges. If you want to successfully go overseas, you must also stand up to the review of overseas regulatory authorities. On the road to knocking on the door of overseas supervision, the design of clinical trial endpoints, surrogate endpoints and effective communication with regulatory authorities will become important factors for Chinese innovative pharmaceutical companies to carefully consider.

SELECTION AND PROGRESS OF THE PRIMARY ENDPOINT

Knocked on the door of transformation in tumor treatment

Whether a new drug can be successfully approved requires phased clinical trials to confirm its clinical benefits, including assessing the degree of tumor-related symptoms reduction, the improvement of patient survival, whether the quality of life has been improved, and the status of physical recovery. The selection of appropriate and reliable clinical endpoints is crucial for early identification of patients' clinical benefit.

However, in order to better verify the safety and effectiveness of new drugs for human use, clinical trials have also become an important factor in the time-consuming and high cost of new drug development. In order to save the cost and time of new drug research and development, accelerate the review of new drugs, and improve the accessibility of drugs to patients, the FDA added accelerated approval (accelerated approval) as early as 1992. Approval or Marketing Approval Process for Drug Products Based on Clinical Endpoints Affecting Survival, Irreversible Morbidity". As a result, progression-free survival (PFS) as an effective indicator to measure clinical outcomes and reduce clinical observation time has gradually been recognized by regulatory agencies such as FDA and NMPA, and has been actively promoted as a surrogate endpoint for application in drug review.

With the widespread application of primary research endpoints such as OS and PFS in new drug development and review procedures, more and more innovative drugs have been approved for marketing in advance for the treatment of patients suffering from various serious diseases. Taking only PD-(L)1 mAbs as an example, since the FDA approved two PD-1 mAbs, nivolumab and pembrolizumab in 2014, PD-(L)1 The representative tumor immunotherapy has enabled patients with advanced tumors to obtain actual clinical benefits and successfully led the transformation of tumor treatment.

So far, 12 PD-(L)1 drugs have been successfully approved for marketing in China alone, including 8 PD-1 mAbs and 4 PD-L1 mAbs. NMPA has approved 4 PD-(L)1 drugs for the market in 2021, two of which are for classic Hodgkin lymphoma (r/r cHL), and one is the first domestic nanomab for the treatment of MSI -H or dMMR advanced solid tumors, and a fully human full-length anti-PD-L1 monoclonal antibody approved as the first domestically for the treatment of metastatic squamous and non-squamous non-small cell lung cancer (NSCLC).

The incidence of lung cancer continues to increase globally and is the leading cause of cancer-related death worldwide. According to relevant statistics, there will be 2.21 million new cases of lung cancer in the world in 2020, of which NSCLC accounts for about 85%, and about 66% of the patients are diagnosed with stage III/IV NSCLC. Lung cancer also ranks first in my country. According to the latest global cancer burden data released by the World Health Organization’s International Agency for Research on Cancer (IARC) in 2020, the number of new lung cancer cases in China is about 820,000, of which NSCLC is newly diagnosed every year. 656,000 to 697,000 people, and about 459,200 to 557,600 people with locally advanced (stage III) and distant metastases (stage IV).

Faced with such a huge unmet medical need, the goal of first-line treatment for advanced lung cancer is to maximize the long-term survival benefit of patients and delay disease progression. We have seen that CStone's sugelimab (Zejimet®) has been approved for marketing in China on December 21, 2021, for use in combination with pemetrexed and carboplatin for the epidermal growth factor receptor (EGFR) gene First-line treatment of mutation-negative and anaplastic lymphoma kinase (ALK)-negative metastatic non-squamous NSCLC, and combination paclitaxel and carboplatin for first-line treatment of patients with metastatic squamous NSCLC. At the same time, sugalimab, as CStone's third new drug approved for marketing in China in 2021, is also the world's first PD-L1 antibody approved in combination with chemotherapy for the first-line treatment of patients with metastatic squamous and non-squamous NSCLC.

Significant benefits for both preset OS and PFS

Sugalimab is expected to reshape the front-line treatment landscape of lung cancer

In January 2022, the research results of GEMSTONE-301, a registration clinical study of sugalimab in the treatment of stage III NSCLC, and GEMSTONE-302, a randomized double-blind registration clinical study of first-line treatment of stage IV NSCLC, have been published in the top international oncology journals respectively. ——On "The Lancet Oncology" (The Lancet Oncology), and received comments from top experts in the global medical academic field, which means that international colleagues recognize the excellent clinical efficacy of sugelimab and the strong R&D strength of CStone Pharmaceuticals .

It is worth mentioning that it is not only the excellent clinical data obtained by sugelimab that is encouraging. Looking back at CStone's initial design of various clinical studies, it is not difficult to see that each clinical study is pre-set for OS. analyze. It is believed that CStone is well aware that advanced tumors are currently incurable malignant diseases, and the overall survival period from randomization to the death of patients due to various reasons as the end point of clinical trials is the most reliable evaluation to test the efficacy of an anti-tumor drug. It is also the gold standard that can best reflect the clinical benefit of patients. Only in this way can the ultimate goal of prolonging the survival time of patients be truly achieved.

In January 2022, the research results of GEMSTONE-301, a registration clinical study of sugalimab in the treatment of stage III NSCLC, and GEMSTONE-302, a randomized double-blind registration clinical study of first-line treatment of stage IV NSCLC, have been published in the top international oncology journals respectively. ——On "The Lancet Oncology" (The Lancet Oncology), and received comments from top experts in the global medical academic field, which means that international colleagues recognize the excellent clinical efficacy of sugelimab and the strong R&D strength of CStone Pharmaceuticals .

It is worth mentioning that it is not only the excellent clinical data obtained by sugelimab that is encouraging. Looking back at CStone's initial design of various clinical studies, it is not difficult to see that each clinical study is pre-set for OS. analyze. It is believed that CStone is well aware that advanced tumors are currently incurable malignant diseases, and the overall survival period from randomization to the death of patients due to various reasons as the end point of clinical trials is the most reliable evaluation to test the efficacy of an anti-tumor drug. It is also the gold standard that can best reflect the clinical benefit of patients. Only in this way can the ultimate goal of prolonging the survival time of patients be truly achieved.

Reached the prespecified OS endpoint and significantly prolonged the overall survival of patients

GEMSTONE-302 is the world's first multi-center, randomized, double-blind phase III clinical trial of PD-L1 inhibitor combined with chemotherapy covering both stage IV squamous and non-squamous first-line metastatic NSCLC, which greatly reduces the cost of resources and time , resulting in both clinical and commercial success. Compared with the published data of several other PD-(L)1 mAbs, the GEMSTONE-302 study not only covers a wider population, but its therapeutic effect can also fully compete with other PD-(L)1. Among them, in patients with squamous cell carcinoma, sugalimab combined with chemotherapy reduced the risk of disease progression or death by 66%, significantly enhancing the clinical benefit of patients.

In July 2021, the final PFS analysis of the GEMSTONE-302 study showed that sugalimab combined with chemotherapy further enhanced the PFS benefit, with a 52% reduction in the risk of disease progression or death in patients, and showed a trend towards a clear OS benefit. Results of the analysis through 2021 at a median follow-up of 17.8 months showed a median PFS of 9.0 months for sugalimab plus chemotherapy and a median PFS of 4.9 months for placebo, with a hazard ratio (HR) of 0.48. The results of the PFS subgroup analysis showed that both squamous and non-squamous NSCLC patients showed significant clinical benefit. In addition, in patients with PD-L1 expression <1%, the HR was 0.56, and the benefit was more pronounced in patients with PD-L1 expression ≥1%.

On January 19, 2022, GEMSTONE-302 reached the prespecified OS endpoint, further demonstrating the important clinical value of sugelimab in the first-line treatment of NSCLC. As introduced by Dr. Jianxin Yang, Chief Medical Officer of CStone Pharmaceuticals: "GEMSTONE-302 demonstrated in this OS analysis that sugalimab combined with chemotherapy significantly improved the overall survival of patients, even with a higher proportion of patients in the chemotherapy control group. Received subsequent PD-1/PD-L1 inhibitor therapy after disease progression, including crossover based on protocol design."

Professor Zhou Caicun, the principal investigator of GEMSTONE-302 and director of the Department of Oncology, Shanghai Pulmonary Hospital, also said that combined chemotherapy further prolongs the PFS of patients with stage IV untreated NSCLC. Compared with chemotherapy alone, it will bring more lasting survival to patients. beneficial. At the same time, sugelimab has a unique dual mechanism of action, which can mobilize the "two forces" of T cells and macrophages in the human body to annihilate tumor cells, coupled with its lower immunogenicity and related toxicity risks, It is expected to change the first-line treatment pattern of advanced NSCLC and become the first-choice tumor immunotherapy drug for advanced NSCLC.

Concurrent chemoradiotherapy extended to sequential chemoradiotherapy significantly improved PFS benefit

For stage III NSCLC patients, there is a high chance that patients with stage IIIA can undergo neoadjuvant chemotherapy and then undergo surgery to obtain a radical cure. However, patients with stage IIIA-N2, IIIB and IIIC are inoperable locally advanced lung cancer, and concurrent chemoradiotherapy is the preferred treatment. In case of poor physical fitness, sequential chemoradiotherapy is used to reduce toxic and side effects and increase patient tolerance. According to public data, less than 30% of Chinese patients are suitable for concurrent chemoradiotherapy, and the rest are sequential chemoradiotherapy patients. The GEMSTONE-301 study is the first to provide a therapeutic basis for the consolidation of immunosuppressive therapy after sequential chemoradiotherapy.

GEMSTONE-301 is the world's first multicenter, randomized, double-blind study to show clinical benefit in patients with stage III NSCLC after concurrent or sequential chemoradiotherapy. Bringing the great significance of PD-(L)1 antibody therapy. According to the results of the GEMSTONE-301 study, compared with the placebo group, sugelimab can significantly improve the PFS of patients, the median PFS was 9.0 months vs 5.8 months, and the HR was 0.64, the difference was statistically significant and clinical significance. The OS data has not yet reached the formal analysis time preset by the protocol, but a trend of overall survival benefit has been observed, and the overall survival follow-up is still ongoing. Therefore, sugalimab immune maintenance therapy will also become another new treatment option for patients with stage III NSCLC after radiotherapy and chemotherapy.

Multi-indication expansion and international cooperation

Give CStone more room for imagination

As a best-in-class PD-L1 monoclonal antibody, sugelimab has fully demonstrated encouraging and excellent clinical data. It is important to discover a good product, but how to maximize its potential value is also the development direction that innovative pharmaceutical companies consider to benefit more patients. As a result, we have seen that CStone has carefully designed different clinical studies of sugelimab and actively expanded more indications. Today, a number of studies have respectively achieved preset study endpoints including OS or related important research nodes, which greatly endows sugelimab with unlimited imagination in solving various huge unsolved clinical needs. .

Relapsed or refractory extranodal natural killer/T-cell lymphoma (R/R ENKTL)

ENKTL belongs to a subtype of mature T-cell and NK-cell lymphoma, with high degree of malignancy and strong invasiveness, dangerous disease, rapid progression and very short survival. It is reported that the 1-year survival rate of R/R ENKTL patients is usually less than 20%. Patients with ENKTL develop disease progression after receiving standard asparaginase-based regimens, lack effective salvage therapy, and generally do not respond well to conventional therapy. Patients who have failed first-line regimens have significant unmet therapeutic needs.

Sugalimab has already been granted orphan drug designation (ODD) by the FDA for the treatment of T-cell lymphoma and breakthrough therapy designation for the treatment of adults with relapsed or refractory extranodal NK/T-cell lymphoma (R/ R ENKTL). It has also been included in the "Breakthrough Therapy Drug" by the China National Medical Products Administration Evaluation Center for the treatment of R/R ENKTL.

According to CStone's official website, GEMSTONE-201, a registrational clinical study on the use of sugalimab in the treatment of R/R ENKTL, reached its primary endpoint on January 13, 2022. Compared to historical controls, the objective response rate (ORR) was significantly improved, and the safety profile was favorable, with no new safety signals identified. The new drug marketing application of sugalimab for R/R ENKTL indications will also be submitted to NMPA in the near future. So far, no PD-1 or PD-L1 antibody has been approved for the treatment of R/R ENKTL. The world's first approved immunosuppressant for R/R ENKTL indications is expected to be born. It is worth mentioning that GEMSTONE-201, a clinical study of sugalimab in the treatment of R/R ENKTL, is currently being carried out simultaneously in China and the United States.

Gastric and esophageal cancer

According to GLOBOCAN 2020 data, there will be more than 1 million new cases of gastric cancer and 769,000 deaths worldwide in 2020, ranking the fifth most common cancer in the world and the fourth leading cause of cancer death; esophageal cancer is the sixth most common cancer in the world It ranks sixth in the cause of death from cancer, with over 600,000 new cases and 544,000 deaths.

In addition, up to 90% of gastric malignant tumors will develop gastric adenocarcinoma, and the incidence of gastroesophageal junction adenocarcinoma has also been on the rise in recent years. Statistics show that about 90% of esophageal cancer patients in China are esophageal squamous cell carcinoma, and most patients with esophageal squamous cell carcinoma are in the advanced stage at the time of diagnosis and lose the chance of radical treatment. Consequently, such a huge unmet therapeutic need for the vast majority of patients continues to be addressed.

The good news is that sugalimab combined with chemotherapy in the first-line treatment of unresectable locally advanced or metastatic gastric/gastric