Search

Abstract Introduction Restrictive eligibility criteria in cancer drug trials result in low enrollment rates and limited population diversity. Relaxed eligibility criteria (REC) based on solid evidence is becoming necessary for stakeholders worldwide. However, the absence of high‐quality, favorable evidence remains a major challenge. This study presents a protocol to quantitatively evaluate the impact of relaxing eligibility criteria in common non‐small cell lung cancer (NSCLC) protocols in China, on the risk–benefit profile. This involves a detailed explanation of the rationale, framework, and design of REC. Methods To evaluate our REC in NSCLC drug trials, we will first construct a structured, cross‐dimensional real‐world NSCLC database using deep learning methods. We will then establish randomized virtual cohorts and perform benefit–risk assessment using Monte Carlo simulation and propensity matching. Shapley value will be utilized to quantitatively measure the effect of the change of each eligibility criterion on patient volume, clinical efficacy and safety. Discussion This study is one of the few that focuses on the problem of overly stringent eligibility criteria cancer drug clinical trials, providing quantitative evaluation of the effect of relaxing each NSCLC eligibility criterion. This study will not only provide scientific evidence for the rational design of population inclusion in lung cancer clinical trials, but also establish a data governance system, as well as a REC evaluation framework that can be generalized to other cancer studies.

Tumor-associated macrophages (TAMs) exert integrated effects in all aspects of tumor progression, including tumor cell proliferation, angiogenesis, invasion, and metastasis. Recently, considerable preclinical and clinical trials have demonstrated that TAM-targeted therapy is an effective antitumor therapeutic approach, especially as a complementary strategy in combination with conventional chemotherapy, radiotherapy, or emerging immunotherapy. Here, we review all of the current clinical trials targeting TAMs worldwide up to May 2021 and highlight instances of the synergetic therapeutic efficacy of TAM-targeted combined therapeutic strategies. In total, 606 clinical trials were conducted, including 143 tested products. There has been explosive growth in macrophage-targeted therapy around the world during the past decade. Most trials were at early phase, and two-thirds used macrophage-targeting therapy as part of a combination approach. The most common combination is that of traditional chemotherapy with TAM-targeted therapy, followed by immune checkpoint inhibitors and targeted drugs. TAM-targeted therapeutic approaches are a newly emerging but rapidly developing area of anticancer therapy, especially as a combinatorial therapeutic approach. Further investigation of promising combination strategies will pave the way to more effective anticancer therapies.

Abstract The neoadjuvant and adjuvant anti-PD-1/PD-L1 treatment has been increasingly noticed. To summarize the global landscape of these clinical trials will provide essential data for all the stakeholders of drug development. Based on the Trialtrove database, a total of 668 clinical trials initiated by the end of 2020 were retrospectively analyzed. We found that a rising capability of global neoadjuvant and adjuvant anti-PD-1/PD-L1 clinical development has been achieved. High prevalent cancer types were extensively studied though the priorities in China and the United States were different. However, a lack of phase III trials and industry-sponsored trials was addressed. The confirmatory neoadjuvant trials were particularly insufficient, and the combination strategy mainly focused on chemotherapy. Thus, more public funding and accelerated regulatory strategies are needed in this field. Efforts should be made to confirm the benefit of neoadjuvant treatment and explore novel combination strategies.

Summary: Overall survival (OS) is considered the standard clinical endpoint to support effectiveness claims in new drug applications globally, particularly for lethal conditions such as cancer. However, the source and reliability of OS in the setting of clinical trials have seldom been doubted and discussed. This study first raised the common issue that data integrity and reliability are doubtful when we collect OS information or other time-to-event endpoints based solely on simple follow-up records by investigators without supporting material, especially since the 2019 COVID-19 pandemic. Then, two rounds of discussions with 30 Chinese experts were held and 12 potential source scenarios of three methods for obtaining the time of death of participants, including death certificate, death record and follow-up record, were sorted out and analysed. With a comprehensive assessment of the 12 scenarios by legitimacy, data reliability, data acquisition efficiency, difficulty of data acquisition, and coverage of participants, both short-term and long-term recommended sources, overall strategies and detailed measures for improving the integrity and reliability of death date are presented. In the short term, we suggest integrated sources such as public security systems made available to drug inspection centres appropriately as soon as possible to strengthen supervision. Death certificates provided by participants’ family members and detailed standard follow-up records are recommended to investigators as the two channels of mutual compensation, and the acquisition of supporting materials is encouraged as long as it is not prohibited legally. Moreover, we expect that the sharing of electronic medical records and the legal disclosure of death records in established health registries can be realized with the joint efforts of the whole industry in the long-term. The above proposed solutions are mainly based on the context of China and can also provide reference for other countries in the world.

Rare tumor has a huge unmet medical need without standard regimens, calling for novel therapeutic interventions. The National Cancer Center of China identified a threshold of incidence for rare tumor as 2.5/100,000, based on the characteristics of Chinese population. Molecular profiles for rare tumor patients in China further provided prospects for precise and individualized targeted treatment. An ongoing phase II clinical trial, the PLATFORM study, is the first trial tailored for rare solid tumors in China, featured by molecule‐guided therapeutics. With the promulgation of supportive policies to encourage the development of innovative drugs for rare tumors in China, opportunities will be provided for these patients and the gap will be filled in the treatment of rare tumors.

Objectives: To describe and compare the research and development (R&D) pipeline of cancer new drugs and newly approved drugs in China and the USA in 2020, thus to provide decision-making evidence for related stakeholders. Methods: Clinical trials and tested cancer new drugs information in China and the USA were respectively acquired from Information Disclosure Platform for Drug Clinical Studies and Trialtrove database. Drug approval was tracked from the official release. Subgroup comparison in terms of initiated trials and drugs were conducted between the two countries. Results: In 2020, 577 trials on 335 cancer new drugs were registered in China, accounting for 22.6% of all clinical drug trials, while in the USA, 916 trials on 678 cancer new drug trials were captured, accounting for 19.9% of the total. Relatively, a lower proportion of earlier phase (76.9% vs 87.4%), global (17.7% vs 39.0%), and top 20 pharmaceutics contribution (15.8% vs 43.2%) were found for cancer drug trials initiated in China. The fight against solid tumor took top billing in both countries, and the different distribution of cancer indications associated with cancer spectrum was also observed. Compared with the USA, more targeted agents (87.5% vs 77.0%, P

BackgroundIn recent years, significant progress has been made in immune checkpoint inhibitors (ICIs). However, accompanied by remarkable efficacy, a growing number of immune-related adverse events (irAEs) also arose. The mechanism of irAEs remains unclear. Previous studies indicated a positive association between specific human leukocyte antigen (HLA) variants and irAEs. Therefore, we planned and initiated a large cohort study aiming to uncover the relationship between irAEs and divergent HLA types.MethodsWe screened all patients who have been treated in the clinical research ward, Cancer Hospital of the Chinese Academy of Medical Sciences. All participants were diagnosed with malignant tumors with complete AE follow-up data in the original electronic medical records. Sequencing libraries were generated using a customized panel, and four-digit formatted HLA alleles were extracted for further analysis. Association analysis was performed between HLA variants and different irAEs. We introduced two external reference groups and a non-irAE control group within the study cohort to control the type I error. We also explored the relationship between the zygosity of HLA genes, the evolutionary divergence of HLA class I genotype (HED), and irAEs.Results530 participants received at least two doses of ICIs. The median follow-up time was 10.3 months. 97% of patients received anti-PD-1/PD-L1 treatment. The occurrence of overall irAEs showed no significant difference between the HLA homozygous group and the HLA heterozygous group. We did not find any significant association between irAEs and HED. We found that some HLA types are associated with irAEs of different organs and detected a significant association between HLA-DRB3*01:01 and thrombocytopenia (OR 3.48 (1.19,9.42), p = 0.011), HLA-DPB1*04:02 and hypokalemia/hyponatremia (OR 3.44 (1.24,9.1), p = 0.009), leukopenia (OR 2.1 (0.92,4.8), p = 0.037), anemia (OR 2.33 (1.0,5.41), p = 0.026), HLA-A*26:01 and bilirubin elevation (OR 2.67 (0.92,8.31), p = 0.037).ConclusionsIrAEs in specific organs and tissues may be associated with certain HLA types, while HLA heterogeneity has no significant influence on the happening of irAEs. More research is needed to explore the role of germline genetic changes in the risk assessment of irAEs.

Abstract Background Type I interferonopathies are a group of rare autoimmune diseases characterised by excessive activation of type I interferon that leads to disturbances in immune function. Three prime repair exonuclease 1 (TREX1) is an important exonuclease and plays an important role in DNA damage repair. TREX1 mutations are associated with many type I interferonopathies. Studies have been published on the effectiveness of tofacitinib in the treatment of type I interferonopathies. The aim of this study is to identify the pathogenic variation in a Chinese family with type I interferonopathies and to observe the therapeutic effects of tofacitinib. Methods A Chinese family with two members with type I interferonopathies was investigated. Whole exome sequencing and Sanger sequencing were applied for mutation screening using peripheral blood DNA of the patient and her family members. Sequencing results were analysed using bioinformatics software tools including VarCards and PolyPhen-2. Close clinical follow-up and observation were used to record changes in the disease before and after treatment with tofacitinib. Results Compound heterozygous variants of TREX1 were observed in the patient’s genome. One was a missense variant (NM_016381; c.C227T; p.Ala76Val) from the patient’s father, and the other was a frameshift variant (NM_016381; c.458dupA; p.Gln153Glnfs*3) from the patient’s mother. One of the proband’s elder brothers with similar skin lesions also carried these two variants. This brother of the proband had more serious cutaneous involvement with the comorbidity of cerebral palsy. These TREX1 variants have not been reported in previous studies and are predicted to be highly pathogenic. The proband was given tofacitinib that led to a marked improvement. Conclusions We identified two novel complex heterozygous variants in the TREX1 gene, which may underlie the molecular pathogenesis of the type I interferonopathies observed in members of this family. Tofacitinib could be an alternative treatment for this disease.

KRAS is the most commonly mutated oncogene in human cancers. Targeted therapy and immunotherapy for this gene have made remarkable progress in recent years. However, comprehensive molecular landscape analysis of KRAS in rare tumors is lacking. Retrospective analysis was performed on clinical samples from patients with rare tumors collected between September 2015 and September 2021, using hybrid-capture-based next-generation sequencing for genomic profiling and immunohistochemistry assay for PD-L1. Of the 3,453 patients included in analysis, KRAS mutations were identified in 8.7% patients in overall; mutation rate and mutation subtypes varied widely across tumor systems and subtypes. KRAS mutations included 21 missense mutations, of which G12D (29.2%), G12V (24.6%), and G13D (10.8%) were most common. Interestingly, KRAS G12C was observed in 0.6% patients overall, and in 5.7% of sarcomatoid carcinoma of the lung and 5.4% of clear cell ovarian cancer tumors, but none in small-bowel cancer tumors. 31.8% KRAS mutations and 36.4% KRAS G12C mutations co-occurred with other targetable alterations. No significant correlation was observed between TMB-H, MSI-H, PD-L1 status, and KRAS mutation status, which may be related to the high proportion of G12D. This study is the first KRAS mutation landscape study in rare tumors of large sample size in China and worldwide. Our results suggest that targeted therapy and immunotherapy are both feasible, albeit complex, in these patients. This information may have significant impact on the operation of clinical trials for rare tumor patients with KRAS mutations in China.

Abstract Background Erdheim-Chester Disease (ECD) is a rare type of non-Langerhans histiocytosis. Skeletal structures are affected in over 95% ECD patients. Due to the lack of proper imaging assessment tools, the alteration of bone microarchitecture in ECD has not been well studied. High-resolution peripheral quantitative computed tomography (HR-pQCT) is a newly developed assessment of bone mineral density and bone microarchitecture. Methods We performed a cross-sectional study with 13 patients diagnosed with ECD in Peking Union Medical College Hospital between October 2018 and June 2019. The diagnosis of ECD was based on typical pathological findings in the context of appropriate clinical and radiological manifestations. Bone geometry, volumetric bone mineral density and bone microarchitecture of those ECD patients were assessed using HR-pQCT at the non-dominant distal radius and distal tibia. Those HR-pQCT parameters were then compared to an ongoing population-based database of HR-pQCT for Mainland Chinese. Results As a result, remarkable heterogeneity of osteosclerosis in the HR-pQCT images was found in ECD patients, ranging from apparent normal structure, scattered thickening of trabecula, to homogenous consolidation. In terms of quantitative measurements, total volumetric BMD (383.50 mg/cm3, 1.352 times of normal mean, p = 0.023) of the tibia differed significantly in ECD patients, due to the increased trabecular volumetric BMD (291 mg/cm3, 2.058 times of normal mean, p = 0.003). The increased trabecular volumetric BMD of tibia was associated with remarkably increased number of trabecula (1.7/mm, 1.455 times of normal mean, p = 0.002) and increased thickness of trabecula (0.37 mm, 1.466 times of normal mean, p = 0.003). These differences could be due to the existence of dense bone interposed in the trabecula. Conclusion This study is the first to assess the volumetric bone mineral density and bone microstructure with HR-pQCT in a cohort of ECD patients and indicated that the application of HR-pQCT may help to reveal the nature of bone lesions in the disease.

Abstract Bispecific antibodies (bsAb) that target two independent epitopes or antigens have been extensively explored in translational and clinical studies since they were first developed in the 1960s. Many bsAbs are being tested in clinical trials for treating a variety of diseases, mostly cancer. Here, we provide an overview of various types of bsAbs in clinical studies and discuss their targets, safety profiles, and efficacy. We also highlight the current challenges, potential solutions, and future directions of bsAb development for cancer treatment.

Background: mRNA-based cancer vaccines have been considered a promising anticancer therapeutic approach against various cancers, yet their efficacy for malignant mesothelioma (MESO) is still not clear. The present study is designed to identify MESO antigens that have the potential for mRNA vaccine development, and to determine the immune subtypes for the selection of suitable patients. Methods: A total of 87 MESO datasets were used for the retrieval of RNA sequencing and clinical data from The Cancer Genome Atlas (TCGA) databases. The possible antigens were identified by a survival and a genome analysis. The samples were divided into two immune subtypes by the application of a consensus clustering algorithm. The functional annotation was also carried out by using the DAVID program. Furthermore, the characterization of each immune subtype related to the immune microenvironment was integrated by an immunogenomic analysis. A protein–protein interaction network was established to categorize the hub genes. Results: The five tumor antigens were identified in MESO. FAM134B, ALDH3A2, SAV1, and RORC were correlated with superior prognoses and the infiltration of antigen-presenting cells (APCs), while FN1 was associated with poor survival and the infiltration of APCs. Two immune subtypes were identified; TM2 exhibited significantly improved survival and was more likely to benefit from vaccination compared with TM1. TM1 was associated with a relatively quiet microenvironment, high tumor mutation burden, and enriched DNA damage repair pathways. The immune checkpoints and immunogenic cell death modulators were also differentially expressed between two subtypes. Finally, FN1 was identified to be the hub gene. Conclusions: FAM134B, ALDH3A2, SAV1, RORC, and FN1 are considered as possible and effective mRNA anti-MESO antigens for the development of an mRNA vaccine, and TM2 patients are the most suitable for vaccination.