Clinical observation on skin adverse reactions after treatment of programmed cell death protein-1 inhibitors

This meta-analysis was performed to compare the efficacy and safety of a triple therapy, involving transcatheter arterial chemoembolization (TACE) + apatinib combined with a programmed-cell death protein-1 (PD-1) inhibitor versus TACE + apatinib, a dual therapy with apatinib and PD-1 inhibitor, and TACE alone for the treatment of advanced primary hepatocellular carcinoma (HCC). A computerized systematic search of databases, such as PubMed, Embase, the Cochrane Library, CNKI, Wanfang Data, and VIP e-Journals was performed to retrieve studies comparing TACE + apatinib combined with a PD-1 inhibitor versus a non-triple therapy for the treatment of advanced primary HCC. The literature search, quality assessment, and data extraction were performed independently by two researchers. Stata 16.0 software was employed to analyze the data. Heterogeneity was assessed utilizing the I2 statistic and p-value, followed by conducting sensitivity analysis. A total of 2,352 patients were enrolled from 8 studies, including 900 patients in the triple therapy group of TACE + apatinib combined with a PD-1 inhibitor, 877 patients in the TACE + apatinib group, 52 patients in the apatinib + a PD-1 inhibitor group, and 112 patients in the TACE group. The results revealed that the objective response rate (ORR) was significantly higher in the triple therapy group of TACE + apatinib combined with a PD-1 inhibitor than that in the non-triple therapy group [odds ratio (OR)=2.47, 95% confidence interval (95%CI): 1.61-3.78]. Besides, disease control rate (DCR) was greater in the triple therapy group of TACE + apatinib combined with a PD-1 inhibitor than that in the non-triple therapy group (OR=1.87, 95%CI: 1.44-2.44). Patients in the triple therapy group experienced a significant extension of overall survival (OS) (HR=0.42, 95%CI: 0.36-0.49). In addition, there was no significant difference in the overall rate of adverse events (AEs) between the two groups (OR=1.05, 95%CI: 0.89-1.22). Compared with the non-triple therapy group, the triple therapy group of TACE + apatinib combined with a PD-1 inhibitor outperformed in terms of tumor response and long-term survival with manageable AEs.

Background: Programmed cell death protein-1 inhibitors combined withlenvatinib have become a popular treatment option for patients with unresectablehepatocellular carcinoma. Transarterial chemoembolization combined withprogrammed cell death protein-1 inhibitors and lenvatinib has also shownpreliminary efficacy in the unresectable hepatocellular carcinoma. We conductedthis observational, retrospective, cohort study to compare the clinical outcomesand safety of transarterial chemoembolization combined with programmed celldeath protein-1 inhibitors plus lenvatinib versus programmed cell deathprotein-1 inhibitors plus lenvatinib in patients with unresectablehepatocellular carcinoma. Methods: Between November 2019 andNovember 2021, patients who were diagnosed with unresectable hepatocellularcarcinoma and received transarterial chemoembolization combined with programmedcell death protein-1 inhibitors plus lenvatinib or programmed cell deathprotein-1 inhibitors plus lenvatinib treatment were reviewed for eligibility.The primary endpoints included objective response rate, overall survival, andprogression-free survival. The secondary endpoint was the frequency of keyadverse events. Results: In total, 105 patients were eligible forthe present study, and they were divided into the transarterialchemoembolization combined with programmed cell death protein-1 inhibitors pluslenvatinib group (n = 46) and the programmed cell death protein-1 inhibitorsplus lenvatinib group (n = 59). The patient cohort after a one-to-one propensityscore matching (n = 86) was also analyzed. The transarterial chemoembolizationcombined with programmed cell death protein-1 inhibitors plus lenvatinib grouphad a higher objective response rate both in the patient cohort beforepropensity score matching (54.3% vs 25.4%, P = .002) and afterpropensity score matching (55.8% vs 30.2%, P = .017). Thepatients in the transarterial chemoembolization combined with programmed celldeath protein-1 inhibitors plus lenvatinib group had prolonged overall survival(median, 20.5 vs 12.6 months, P = .015) and progression-freesurvival (median, 10.2 vs 7.4 months, P = .035). For patientcohort- propensity score matching, the overall survival (20.5 vs 12.8 months,P = .013) and progression-free survival (12.1 vs 7.8months, P = .030) were also significantly better in thetransarterial chemoembolization combined with programmed cell death protein-1inhibitors plus lenvatinib group than in the programmed cell death protein-1inhibitors plus lenvatinib group. There were no significant differences betweenthe 2 groups concerning adverse reactions caused by immunotherapy andlenvatinib. The adverse reactions caused by transarterial chemoembolization weretransient and were quickly reversed. Conclusions: Compared toprogrammed cell death protein-1 inhibitors plus lenvatinib, transarterialchemoembolization combined with programmed cell death protein-1 inhibitors pluslenvatinib may provide better treatment response and survival benefits forpatients with unresectable hepatocellular carcinoma, and the adverse events weremanageable.

Formation of eruptive cutaneous squamous cell carcinomas after programmed cell death protein-1 blockade

6070 Background: PD-1 (programmed cell death protein-1) inhibitors combination with chemotherapy has a significant efficacy and approved indications in the first-line treatment of head and neck squamous cell carcinoma (HNSCC), but the efficacy of these combination therapies in locally advanced hypopharyngeal squamous cell carcinoma (HPSCC) remains unexplored. We conducted a single-arm, phase II trial to assess the efficacy and safety of toripalimab (a novel PD-1 inhibitor) combined with chemotherapy as induction treatment in locally advanced HPSCC. Methods: Patients with locally advanced HPSCC (cT1N+M0 or T2-4NanyM0, AJCC 8.0) were eligible. All patients received 2 cycles of intravenous docetaxel (75mg/m2), cisplatin (75mg/m2) and toripalimab (240mg) on day 1 every 21 days, followed by radical surgery or concurrent chemoradiotherapy (CCRT) with cisplatin (100mg/m2, q21d). The primary endpoint was objective response rate (ORR) assessed by investigators per RECIST v1.1. Secondary endpoints were major pathologic response (MPR), 2 year disease-free survival (DFS) rate in patients received surgery, 2 year progression-free survival (PFS) rate in patients received CCRT and 2 year overall survival (OS) rate in all patients. Results: From July 2020 to January 2023, 34 patients (median age: 59, range: 46-72, male: 100%, stag IV: 100%) were enrolled. Patients with stage IVA an IVB disease were 19 (19/34, 55.9%) and 15 (15/34, 44.1%), respectively. 33 patients completed 2 cycles induction treatment and efficacy evaluation (1 patient dropped out). The evaluated ORR was 54.5%, including 3 pts achieving complete response and 15 achieving partial response. PD-L1 status (combined positive score, CPS) were known in 8 patients, ORR were 80% (4/5) and 66.7% (4/6) in patients with CPS≥20 and CPS≥1, respectively, 2 patients with CPS＜1 had stable disease. Treatment-related grade 3-4 adverse events occurred in 45.5% (15/33) of patients, leukopenia (42.4%) and neutropenia (3.1%). Immune-related AEs were acceptable, 1 patient (1/33, 3.0%) experienced grade 2 interstitial pneumonia and 2 patients (2/33, 6.1%) experienced grade 1 rash. In the following treatment, 27 patients (27/33, 81.8%) performed CCRT. 4 patients (4/33, 12.1%) underwent surgery followed by CCRT and 2 patients (2/33, 6.1%) refused further treatment. Among these 17 patients finished CCRT and radiological assessment, 9 patients (9/17, 52.9%) had complete response, 7 patients (7/17, 41.2%) had partial response and 1 patient (1/17, 5.9%) had progressive disease. Survival data are not mature by cut-off date. Conclusions: Induction therapy of toripalimab combined with docetaxel and cisplatin was well tolerated and highly efficient for locally advanced HPSCC. Clinical trial information: NCT04296747 .

BackgroundLenvatinib combined with programmed cell death protein-1 inhibitor has achieved good survival results in the treatment of hepatocellular carcinoma with portal vein tumor thrombus. Transarterial chemoembolization (TACE) or hepatic arterial infusion chemotherapy (HAIC) has attracted attention because of its high response rate and favorable survival rate in patients with liver cancer and portal vein tumor thrombus. This study aimed to compare the efficacy and safety of Lenvatinib combined with programmed cell death protein-1 inhibitor plus transarterial chemoembolization or hepatic arterial infusion chemotherapy in patients with hepatocellular carcinoma with portal vein tumor thrombus.MethodWe searched PubMed, Embase and the Cochrane Library for studies. These included randomized controlled trials or clinical trials of Lenvatinib plus programmed cell death protein-1 inhibitor plus transarterial chemoembolization or hepatic arterial infusion chemotherapy (intervention group) versus Lenvatinib plus programmed cell death protein-1 inhibitor or Lenvatinib plus transarterial chemoembolization/hepatic arterial infusion chemotherapy or Lenvatinib alone (control group) in liver cancer with portal vein tumor thrombus The primary outcomes were overall survival and progression-free time, and the secondary outcomes were response rate and the rate of adverse events. According to the heterogeneity among different studies, Revman5.4 was used to conduct fixed effect or random effect model analysis.ResultsFive clinical trials were included, including 311 cases in the intervention group and 309 cases in the control group. In terms of efficacy, compared with the control group, the overall survival (HR=1.88, 95%CI: 1.57-2.25, P < 0.00001) and progression-free survival (HR=1.62, 95%CI: 1.41-1.86, P < 0.00001), better efficacy, and better disease response than the control group. In terms of safety, the risk of treatment-related adverse events in the intervention group was higher than that in the control group, and White Blood cell count decreased (RR=0.72, 95%CI: 0.38-1.37, P=0.32), Platelet count decreased (RR=0.99, 95%CI: 0.65-1.51, P=0.96) and Total bilirubin increased (RR=0.86, 95%CI: Increased) 0.88-1.28, P=0.46) were lower than those in the control group, and the rest were higher than those in the control group, and the differences in some results were statistically significant.ConclusionsTransarterial chemoembolization or hepatic arterial infusion chemotherapy combined with Lenvatinib plus programmed cell death protein-1 inhibitor can effectively delay the progression, prolong the survival period and improve the quality of life of liver cancer patients with portal vein tumor thrombus.

Programmed-cell death protein 1 (PD-1) inhibitors have emerged as a standard of care treatment among advanced-stage or metastatic cutaneous squamous cell carcinoma (cSCC). Immune-compromised patients and particularly solid organ transplant recipients (SOTRs) are considered at high risk for cSCC. When treated with PD-1 inhibitors, the possibility of organ rejection, autoimmune flare, or insufficient response to treatment is feared. As these patients were excluded from past prospective clinical trials, we aim to describe our institute's experience regarding these patients. A retrospective analysis was conducted on cSCC patients treated with PD-1 inhibitors. Comparisons were made between immune-compromised and immune-competent groups, with a subgroup analysis of SOTR. The study cohort comprised of 133 patients, including 97.8% receiving Cemiplimab with a mean age of 77.2 ± 11.7 years. Immune-compromised patients constituted 26.9% (n = 35) of the cohort, including 10 SOTR (all kidney transplant recipients). Objective response rates (ORRs) and disease control rates (DCR) were comparable between immunocompetent and immunosuppressed patients receiving Cemiplimab (ORR: 76.8% vs 62.9%, P = .12; DCR: 81.1% vs 68.6%, P = .13). SOTR demonstrated an 80% ORR and DCR. Progression-free survival was comparable across all groups. Toxicity rates were similar between immunosuppressed and immunocompetent subgroups (68.6% vs 62.1%, P = .5). Two OTRs (20%) experienced acute graft rejection. PD-1 inhibitors demonstrate efficacy and safety in immunosuppressed cSCC patients. While effective in SOTR, treatment requires multidisciplinary management due to the potential risk of organ rejection. These findings provide valuable insights into this understudied population and support the use of PD-1 inhibitors in immunosuppressed patients with advanced cSCC.

Our aim was to assess the efficacy of adjuvant programmed cell death protein-1 (PD-1) inhibitors and compare the other adjuvant treatments in patients with surgically resected stage III or IV acral melanoma. This study is a multicenter, retrospective analysis. We included 114 patients with stage III or IV acral malignant melanoma who underwent surgery within the past 10 years. We analyzed the effect of adjuvant programmed cell death protein-1 inhibitors on disease-free survival (DFS). The mean follow-up was 40 months, during which 69 (59.5%) patients experienced recurrence. Among the participants, 64 (56.1%) received systemic adjuvant therapy. Specifically, 48.4% received anti-PD-1 therapy, 29.7% received interferon, 14.1% received tezozolomide, and 7.8% received B-Raf proto-oncogene/mitogen-activated protein kinase inhibitors. Patients who received adjuvant therapy had a median DFS of 24 (10.9-37.2) months, whereas those who did not receive adjuvant therapy had a median DFS of 15 (9.8-20.2) months. Multivariate analysis for DFS revealed that the receipt of adjuvant therapy and lymph node metastasis stage were independent significant parameters ( P = 0.021, P = 0.018, respectively). No statistically significant difference was observed for DFS between programmed cell death protein-1 inhibitor treatment and other adjuvant treatments. Regarding overall survival (OS), patients who received adjuvant treatment had a median OS of 71 (30.4-111.7) months, whereas those who did not receive adjuvant treatment had a median OS of 38 (16.7-59.3; P = 0.023) months. In addition, there were no significant differences in OS observed between various adjuvant treatment agents ( P = 0.122). In our study, we have shown that adjuvant therapy had a positive effect on both DFS and OS in patients with stages III-IV acral melanoma who underwent curative intent surgery. Notably, we found no significant differences between anti-PD-1 therapy and other adjuvant therapies.

BackgroundHigh medication literacy is the basis of rational medication application and is essential for the management of severe adverse drug reactions. The objective of the present study was to assess the level of medication literacy and determine the association between medication literacy and skin adverse drug reactions in non-small-cell lung cancer (NSCLC) patients undergoing targeted epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) therapy.MethodsThis is a cross-sectional study conducted from May to September 2020. In total, 296 NSCLC patients undergoing targeted EGFR-TKI therapy were recruited from hospitals in Henan, China. Structured questionnaires were used to evaluate skin adverse drug reactions and medication literacy. Pearson correlation analysis and binary logistic regression analysis were carried out to identify the correlations between medication literacy and the severity of skin adverse drug reactions in the recruited patients.ResultsThe research sample consisted of 296 patients with a response rate of 92.5%. The mean score of skin adverse drug reactions and the mean score of medication literacy were 1.83 ± 0.91 and 6.54 ± 2.78, respectively. In total, 188 patients (63.5%) were considered to have moderate medication literacy. According to the binary logistic regression analysis, the following factors were associated with severe skin adverse drug reactions: age (B = − 3.929, P = 0.000), sex (B = -4.062, P = 0.000), educational level (B = 2.712, P = 0.002), comorbidity (B = 3.297, P = 0.001), eczema history (B = 2.996, P = 0.001), nutritional status (B = -4.891, P = 0.000), blood interleukin-6 level (B = -2.143, P = 0.013), blood high-sensitivity C-reactive protein level (B = -4.015, P = 0.000), combination of drugs (B = -3.183, P = 0.048) and medication literacy (B = − 1.503, P = 0.000). Subgroup analysis showed that in addition to medication literacy, some other factors including education level, comorbidity, nutritional status, blood interleukin-6 level and combined drug application were common factors that contributed to various adverse skin drug reactions in NSCLC patients under targeted EGFR-TKI therapy.ConclusionThe low medication literacy of the investigated NSCLC patients undergoing targeted EGFR-TKI therapy was correlated with a high proportion of severe skin adverse drug reactions. In addition, factors other than medication literacy including education level, comorbidity, nutritional status, blood interleukin-6 level and the combinatorial application of drugs were also related to the severity of various adverse skin drug reactions. A comprehensive and targeted intervention may be beneficial to improve medication literacy and control severe skin adverse drug reactions in NSCLC patients.

Immune checkpoint inhibitors are associated with peripheral artery disease in cancer patients.

Pembrolizumab is an immune checkpoint inhibitor that is gaining widespread use as an immunotherapy for various cancers. With its growing application, a range of immune-related adverse events are being more frequently recognized. Pruritus, lichenoid reaction and eczema are known dermatological adverse effects of pembrolizumab, but bullous pemphigoid (BP) is a rare adverse effect of the drug. We present the case of a 59-year-old male who developed BP after being treated with pembrolizumab for renal cell carcinoma. It has been established that triggering of BP with programmed cell death protein-1 inhibitors like pembrolizumab correlates well with tumor suppression. Hence, there is a line of thought that programmed cell death protein-1 inhibitors may be continued and BP be managed with immunomodulatory therapy. Our patient responded well to monthly intravenous immunoglobulin injections while continuing pembrolizumab.

BACKGROUNDChimeric antigen receptor T cell (CART) therapy has benefited many refractory lymphoma patients, but some patients experience poor effects. Previous studies have shown that programmed cell death protein-1 (PD-1) inhibitors can improve and prolong the therapeutic effect of CAR-T cell treatment.CASE SUMMARYA 61-year-old male presented with 15-d history of diarrhea and lower-limb edema. A large mass was detected in the pelvis, and pathology indicated non-Hodgkin diffuse large B-cell lymphoma. After three cycles of the R-CHOP chemotherapeutic regimen, the patient showed three subcutaneous nodules under the left armpit and both sides of the cervical spine. Pathological examination of the nodules indicated DLBCL again. The patient was diagnosed with relapsed and refractory diffuse large B-cell lymphoma. We recommended CAR-T cell treatment. Before treatment, the patient’s T cell function and expression of immune detection points were tested. Expression of PD-1 was obviously increased (52.7%) on cluster of differentiation (CD)3+ T cells. The PD-1 inhibitor (3 mg/kg) was infused prior to lymphodepleting chemotherapy with fludarabine and cyclophosphamide. CAR-CD19 T cells of 3 × 106/kg and CAR-CD22 T cells 1 × 106/kg were infused, respectively. The therapeutic effect was significant, and the deoxyribonucleic acid copy numbers of CAR-CD19 T cells and CAR-CD22 T cells were stable. Presently, the patient has been disease-free for more than 12 mo.CONCLUSIONThis case suggests that the combination of PD-1 inhibitors and CAR-T cells improved therapeutic efficacy in B-cell lymphoma.

Reports of immune-related adverse events caused by programmed cell death protein-1 inhibitor are becoming increasingly frequent. Herein, we report the first case of pemphigus herpetiformis-type drug reaction presented after the treatment of tislelizumab (6 cycles) in a primary non-small cell lung carcinoma patient. A 56-year-old Chinese man was referred to our department for pruritic annulare erythema and blister for two weeks. Histological finding revealed blister formation in the epidermis and eosinophilic infiltration in the blister fluid. Direct immunofluorescence showed intercellular deposition of IgG and C3 within the lower part of epidermis. Serum anti-intercellular antibodies were positive at 1:100 dilution. Based on history and clinicopathological correlation, herpetiformis-type drug-induced pemphigus was diagnosed, which was possibly be induced by tislelizumab. To the best to our knowledge, there is no report of pemphigus herpetiformis-type drug-induced reaction associated with programmed cell death protein-1 inhibitor treatment.

IntroductionHere, we provide a feasible, well-designed protocol of a randomised controlled trial for the assessment of the effects of a home-based multidisciplinary intervention on the severity of skin adverse drug...

Tumor of the digestive system is a common malignancy with high morbidity and mortality. Although programmed cell death-1 (PD-1) inhibitors have become an effective treatment strategies for many kinds of tumors, there is still some uncertainty in digestive tumors, including: (I) therapeutic effects of PD-1 inhibitors are relatively limited; (II) responses of digestive system tumors to immunotherapies are highly heterogeneous. In the present study, we investigated the outcomes of PD-1 inhibitors for digestive system tumors in Chinese patients to analyze factors that may affect the effects of immunotherapies in digestive system tumors. Data were obtained from the Hospital Information System (HIS) of the Department of Digestive Oncology (Henan Cancer Hospital) between January 2019 and December 2019. Inclusion criteria included patients receiving the same PD-1 inhibitor continuously for advanced or recurrent/metastatic digestive system tumors. Indicators including age, sex, clinical diagnosis, height, weight, gene status, PD-1 inhibitors, treatment regimen, medication cycle, efficacy evaluation results, and adverse reactions were analyzed retrospectively. The clinical outcomes were progression-free survival (PFS) and safety. A total of 2,767 patients were discharged from HIS, of which 64 (37 male/27 female) were included in this study. Thirty-eight (59.4%) of the patients were aged <60 years. Tumors included esophageal, gastric, liver, colorectal, and pancreatic cancer. Up until 30 June 2020, 51 patients were followed up to median progression-free survival (PFS), which was 5 months; the longest PFS was 18.5 months. There was no statistical significance in grouping according to sex, age and body mass index. Nevertheless, the median PFS differed statistically between monotherapy (9.4 months) versus combined therapy (4.7 months), and Cox regression analysis suggested that patients might benefit more from monotherapy than combined therapy. The incidence of adverse reactions was 47.7%, with thyroid dysfunction the most common adverse reaction. The incidence of grade 3-4 adverse reactions was 9.2% and mainly included pulmonary infection, immune-associated hepatitis, and severe oral ulcers. In digestive tumors, especially for second-line treatment and beyond, PD-1 monotherapy might be more beneficial than combined therapy. However, this might be related to the patient's tolerance. Large-sample prospective studies are needed for confirmation.

e16210 Background: Hepatocellular carcinoma (HCC) stands as a predominant form of liver cancer, characterized by its aggressive nature and poor prognosis. Current treatment modalities, including systemic therapies, often yield suboptimal outcomes; therefore, the exploration of novel therapeutic strategies is warranted. Donafenib, a relatively new pharmacological agent, has garnered attention for its potential in enhancing the efficacy of established treatments such as programmed cell death protein-1 (PD-1) inhibitors and hepatic arterial intervention (HAIC). This study aimed to evaluate the efficacy and safety of donafenib as a first-line therapy in patients with HCC. Methods: A retrospective analysis was conducted involving 145 patients diagnosed with HCC, who underwent treatment with donafenib in conjunction with PD-1 inhibitors and either transarterial therapy (TACE or HAIC) from 2022 to 2024 at the Department of Hepatobiliary Surgery, the First Affiliated Hospital of Guangxi Medical University. Following strict inclusion criteria, 40 cases were excluded, primarily due to insufficient imaging or lack of efficacy assessment. Efficacy was evaluated using objective response rates based on RECIST1.1 and mRECIST criteria, while safety data focused on the incidence of grade 3-4 adverse events. Results: 105 patients were enrolled, with the media age of 53, 94 (89.5%) of 105 participants were male. The tumor stage of BCLC A/B/C were 22.9%/20%/57.1%, respectively. The objective response rates within the treated cohort were recorded at 61% and 64% according to RECIST1.1 and mRECIST criteria, with the same complete response rate of 18.1%.. The median follow-up duration was 14.2 months, revealing a median progression-free survival (mPFS) of 11.7 months, with the median overall survival (mOS) yet to be established, and 1 year OS rate was 89.9%. Notably, the study recorded an overall incidence of grade 3-4 adverse events at 77.1%, with liver enzyme elevations (ALT at 32.4% and AST at 43.8%) and lymphocyte count reductions (53.3%) dominating the safety profile. Conclusions: The preliminary findings of this single-center real-world study suggest that donafenib exhibits commendable efficacy and an acceptable safety profile as a new targeted agent in the management of hepatocellular carcinoma. Future investigations should aim to further elucidate its role in combination therapies and establish comprehensive protocols to optimize treatment outcomes for patients with HCC.