Immunotherapy in the treatment of chemoresistant gestational trophoblastic neoplasia - systematic review with a presentation of the first 4 Brazilian cases

Abstract Objective To evaluate the efficacy of immunotherapy for GTN treatment after methotrexate-resistance or in cases of multiresistant disease, through a systematic review, as well as to present the first 4 Brazilian cases of immunotherapy for GTN treatment. Methods Three independent researchers searched five electronic databases (EMBASE, LILACS, Medline, CENTRAL and Web of Science), for relevant articles up to February/2023 (PROSPERO CRD42023401453). The quality assessment was performed using the Newcastle Ottawa scale for case series and case reports. The primary outcome of this study was the occurrence of complete remission. The presentation of the case reports was approved by the Institutional Review Board. Results Of the 4 cases presented, the first was a low-risk GTN with methotrexate resistance unsuccessfully treated with avelumab, which achieved remission with sequential multiagent chemotherapy. The remaining 3 cases were high-risk multiagent-resistant GTN that were successfully treated with pembrolizumab, among which there were two subsequent gestations, one of them with normal pregnancy and healthy conceptus. Regarding the systematic review, 12 studies were included, only one of them on avelumab, showing a 46.7% complete remission rate. The remaining 11 studies were on pembrolizumab, showing an 86.7% complete remission rate, regardless of tumor histology. Both immunotherapies showed good tolerability, with two healthy pregnancies being recorded: one after avelumb and another after pembrolizumab. Conclusion Immunotherapy showed effectiveness for GTN treatment and may be especially useful in cases of high-risk disease, where pembrolizumab achieves a high therapeutic response, regardless of the histological type, and despite prior chemoresistance to multiple lines of treatment.

Research progress on the correlation between dermatological immune-related adverse events and clinical outcome of PD-1/PD-L1 inhibitors / 国际肿瘤学杂志

Immunotherapy represented by PD-1/PD-L1 inhibitors has become the main treatment of malignant tumors. However, the adverse events caused by immunotherapy can not be ignored. Among them, dermatological immune-related adverse events (irAEs) occur with the highest incidence. Most dermatological irAEs belong to grade Ⅰ-Ⅱ, which does not affect the application of PD-1/PD-L1 inhibitors. The pathogenesis of dermatological irAEs is not fully understood. The most common types of dermatological irAEs are rash, pruritus and vitiligo. The domestic PD-1 inhibitor camrelizumab has unique adverse reactions of reactive cutaneous capillary endothelia proliferation (RCCEP) . It is found that dermatological irAEs can predict the clinical efficacy of PD-1/PD-L1 inhibitors in patients with malignant melanoma and non-small cell lung cancer (NSCLC) , especially RCCEP can be used as a potential biomarker of the efficacy of camrelizumab in the treatment of NSCLC, hepatocarcinoma, and esophageal cancer.

Predictive Value of Tumor Mutation Burden for PD-1/PD-L1 Inhibitors Treatment on Non-small Cell Lung Cancer: A Meta-analysis / 肿瘤防治研究

Objective To investigate the relation between TMB and the efficiency of PD-1/PD-L1 inhibitors treatment for non-small-cell lung cancer. Methods Studies were searched from PubMed, Embase, Cochrane Library database, Chinese Biomedical Literature Database and Wanfang Database up to March 25, 2020. RevMan 5.3 software and STATA15.0 were used for analysis. Results Twelve literatures were involved, including 1209 patients. TMB significantly improved PFS (HR=0.54, 95%CI: 0.42-0.70, P < 0.001) but reduced the ORR (OR=4.41, 95%CI: 2.54-7.63, P < 0.001) of NSCLC patients treated with PD-1/PD-L1 inhibitors. The subgroup analyses showed that the predictive value of TMB was significant in non-small cell lung cancer treated by PD-1/PD-L1 inhibitors combined with anti-CTLA-4 therapy or chemotherapy. No significant publication bias was observed by the Begg's test and Egger's test. Conclusion High tumor mutation burden may predict the improved PFS of non-small cell lung cancer by PD-1/PD-L1 inhibitors treatment, but its predictive value for OS, ORR and long-term survival need more exploration.

Research Advances of PD-1/PD-L1 Inhibitors Combined with Angiogenesis Inhibitors in Treatment of Advanced Triple-negative Breast Cancer / 肿瘤防治研究

Advanced triple-negative breast cancer(TNBC) has less treatments, shorter survival time and poorer prognosis than other subtypes of breast cancer. The rapid development of immunotherapy in recent years is expected to prolong the survival time of advanced TNBC patients, but multiple clinical studies have suggested that PD-1/PD-L1 inhibitor monotherapy have a low efficiency in the treatment of advanced TNBC. Recent studies have shown that the treatment with angiogenesis inhibitors can not only normalize blood vessels and inhibit tumor growth, but also enhance the efficacy of immunotherapy. Angiogenesis inhibitors combined with PD-1/PD-L1 inhibitors have synergistic effects. This article analyzes the mechanism of PD-1/PD-L1 inhibitors and angiogenesis inhibitors, reviews the preclinical and clinical studies on the combination of two types of drugs in the treatment of advanced TNBC and summarizes their efficacy and safety, to provide new perspectives and ideas for the treatment strategy of advanced TNBC.

Research Progress of Adverse Events Related to PD-1/PD-L1 Inhibitors Based Combination Therapy / 中国肺癌杂志

The development of immune checkpoint inhibitors (ICIs) has significantly improved the prognosis of cancer patients, but a large population of patients are still ineffective to ICIs treatment or develop aquired drug resistance. In order to improve the clinical benefits, a number of studies on ICIs based combination therapy have been actively explored, and have achieved satisfactory results. With the application of ICIs based combination therapy in clinical practice, increasing attention has been paid to the safety of combination therapy and the management of treatment-related adverse events. In this review, the characteristics of adverse events related to ICIs based combination therapies, especially programmed cell death protein 1/protein ligand 1 (PD-1/PD-L1) inhibitors are discussed, in order to provide profound thoughts for toxicity evaluation and individualized treatment decision in future clinical practice.
.

Systematic Analysis of Economic Evaluation of Listed PD- 1/PD-L1 Inhibitors in China / 中国药房

OBJECTIVE：To provide reference for the selection of more economical programmed death- 1（PD-1）/programmed death-ligand 1（PD-L1）inhibitors for National Medical Insurance List and the quality improvement of related economic evaluation. METHODS：Retrieved from CNKI ，VIP，Wanfang database ，PubMed，Web of Science and Ovid Embase ，economic evaluation studies including listed PD- 1/PD-L1 inhibitors of China were collected during the inception to Oct. 2020. CHEERS checklist was used to evaluate the quality of the included literatures ，and the methodological characteristics and economic evaluation results of the included studies were analyzed systematically. RESULTS ：A total of 14 literatures were included ，all of which were model-based and with moderate or high quality. However ，there were still some deficiencies in the included literatures ，mainly manifesting as the insufficient reports on the reasons for setting or selecting model parameters ，as well as the great uncertainty of clinical effect data and utility value. Only 3 of the 8 PD-1/PD-L1 inhibitors listed in China were involved in the included literatures. Compared with chemotherapy or targeted therapy plan ，9 literatures（64.29％）showed that the therapy plan containing PD- 1/PD-L1 inhibitors was not cost-effective. CONCLUSIONS ：The economic evidence of domestic PD- 1/PD-L1 inhibitors is lacking ，the higher price of imported PD- 1/PD-L1 inhibitors lead to poor economic performance. The existing economic evaluations has some shortcomings in methodological application and parameter selection. Pharmaceutical enterprises should fill in the data gaps and adjust the pricing strategy，researchers should improve the standardization of research ，and medical insurance decision-making departments should improve the judgment on the quality of economic evidences ，so as to promote more economical drugs to be included in the National Medical Insurance List.

Incidence and Risk of PD-1/PD-L1 Inhibitor-associated Pneumonia in Advance Cancer Patients: A Meta-analysis / 中国肺癌杂志

BACKGROUND@#Immune checkpoint inhibitors (ICIs) have good efficacy on most advanced tumors, which brings new hope to patients with advanced tumors. However, the immune system activated by ICIs may attack human normal tissues and organs, resulting in corresponding immunotoxicity, such as checkpoint inhibitor pneumonitis. This article carried out a meta-analysis on the incidence and risk of programmed cell death protein 1 (PD-1) and programmed cell death protein ligand 1 (PD-L1) inhibitor-associated pneumonia in advanced tumors patients.@*METHODS@#The computer retrieval of PubMed, Cochrane Library, EMbase and CNKI was performed, and the studies on the occurrence rate of PD-1/PD-L1 inhibitor-associated pneumonia in terminal cancer patients were collected, with the retrieval time limit of January 2000 to January 2020. Statistical analysis was conducted by using Revman 5.3 and R 3.6.2 software to compare the occurrence rate of pneumonia under different circumstances.@*RESULTS@#15 studies were included, involving 8,642 patients, of which those with PD-1/PD-L1 inhibitor were treatment group, and those with chemotherapy were control group. The odds radio of all grades of immune pneumonia was 6.63, and that of high grade was 4.87. The occurrence rate of all grades of pneumonia in the ICI group with non-small cell lung cancer (NSCLC) was 1.658 times than other tumors, and that of high grade was 2.299 times. The occurrence rate of all grades of pneumonia in second-line or more treatment with ICI was 0.489 times than that in first-line, and that of high grade was 0.449 times than that in first-line or more treatment with ICI.@*CONCLUSIONS@#Compared with chemotherapy, the risk of immune-associated pneumonia is higher in PD-1 and PD-L1 inhibitors, and its occurrence risk is high in the ICI group with NSCLC and the first-line treatment with ICI. This paper provides guidance for clinic treatment of terminal cancers and prevention of complications.

Recommendation of Diagnosis and Management for the Infections Related to Immune Checkpoint Inhibitors / 中国肺癌杂志

Immune checkpoint inhibitors (ICIs) have been widely used in management of malignant tumor. Programmed death ligand 1 (PD-1)/programmed death ligand 1 (PD-L1) inhibitors have been introduced to treat non-small cell lung cancer (NSCLC) in recent years. Currently, PD-1/PD-L1 inhibitors are considered to have minor side effects and do not independently increase the risk of infection. However, they may cause immune-related adverse events (irAEs) that can require immunosuppressive therapy with corticosteroids and/or immunosuppressants, leading to opportunistic infections. Furthermore, there were reports about reactivation of chronic/latent infections without irAEs. Thus, immune checkpoint inhibitor related infections have drawn more and more attention in the world. In this paper, we described the potential mechanism, available clinical data and recommendation of diagnosis and management for PD-1/PD-L1 inhibitor related infections.

Advances in the Influence of EGFR Mutation on the PD-L1 Expression in Non-small Cell Lung Cancer / 中国肺癌杂志

Researches on the inhibitors of programmed death-1 (PD-1) and programmed death-1 ligand (PD-L1) enjoy considerable breakthroughs in recent years, which has brought relative changes in the therapeutic model of non-small cell lung cancer (NSCLC) at an unexpected speed. However, it seems that PD-1/PD-L1 inhibitors are less effective in patients with epidermal growth factor receptor (EGFR) mutation than those without. Previous studies have shown that the expression rate of PD-L1 on tumor cells is correlated with the therapeutic effect of PD-1/PD-L1 inhibitors. Yet, there is no complete agreement on the effect of EGFR mutation on PD-L1 expression. In this review, relevant studies will be summarized with an expectation of making some contributions to basic researches and to the clinical treatment.

Research progress of PD-1/PD-L 1 inhibitors for colorectal cancer / 中国肿瘤临床

Although the overall survival rate of colorectal cancer has been significantly improved over the last decade, advanced colorectal cancer remains one of the main causes of death from malignant tumors globally.Chemotherapeutic drugs and biological agents are the main therapeutic methods for colorectal cancer.The recent success in the discovery of programmed cell death protein1 (PD-1)inhibitors in metastatic colorectal cancer patients with mismatch repair deficiency has generated overwhelming enthusiasm for its use in immunotherapy against the disease.In recent years,the efficacy of PD-1 inhibitors in colorectal cancer has become a hot top-ic.This review presents our current understanding of the immunophenotype and molecular changes in colorectal cancer and a novel combination therapy using inhibitors of the immune check-point.

Research progress on PD-1/PD-L1 inhibitors in prostate cancer immunotherapy / 中国肿瘤临床

The annual incidence of prostate cancer (PCa) continually increases. New PCa immune therapy has become the fourth line antitumor treatment following surgery, radiotherapy and chemotherapy. As the most promising research direction in cancer immunotherapy,immune checkpoint inhibitors, such as programmed cell death-1 and programmed cell death-ligand 1 (PD-1/PD-L1) inhibitors, block PD-1 and its ligand PD-L1 and then terminate the negative control signal to the T cell, thereby facilitating T cell recovery and reversal of tumor immune-escaping mechanism. These processes restore the capability of T cells for immune response and inhibit and kill tumor cells. This review summarizes the progress on the current application of PD-1/PD-L1 inhibitors in PCa clinical trials.