Efficacy And Safety Of PD-1/PD-L1 Inhibitors In Advanced Solid Tumors

PART Ⅰ:To explore the efficacy and safety of perioperative chemotherapy with LP002,an anti-PD-L1 antibody,in locally advanced,resectable gastric and gastroesophageal junction cancers:a prospective phase 1 trialBackground:In recent years,the monoclonal antibodies against programmed cell death protein-1(PD-l)have shown promising results,either alone or in combination with chemotherapy,in advanced or metastatic gastric or gastroesophageal junction(G/GEJ)cancers through a number of prospective clinical trails.Furthermore,several clinical studies of anti-PD-1 antibody combined with chemotherapy in the perioperative treatment for resectable G/GEJ cancer are ongoing.Referring to the efficacy of anti-PD-1 antibody in G/GEJ cancer,it can be speculated that anti-programmed cell death-ligand 1(PD-L1)monoclonal antibody which targeting the same signaling pathway would have a promising future,especially its clinical effects has already been proved in different tumor types such as lung cancer and hepatocellular carcinoma.However,the research progress of anti-PD-L1 antibodies in the treatment of gastric cancer is slow and no results in patients with resectable disease have been reported particularly.We report the safety and clinical response of G/GEJ cancer patients receiving LP002,an anti-PD-L1 antibody,plus cisplatin and 5-fluorouracil as perioperative treatment in a open-label,phase 1 trial.Methods:We enrolled patients with previously untreated,PD-L1 positive,resectable(cT2-4a,any N,M0)G/GEJ cancer.Eligible patients received three preoperative and six postoperative 2-week cycles of intravenous LP002,cisplatin and 5-fluorouracil.The standard surgery was scheduled 4-6 weeks after completion of 3 cycles of preoperative treatment.The primary endpoint was safety.Secondary objectives of the study included proportion of patients with R0 resection and pathological complete response(pCR),relapse-free survival.With pre-and post-treatment samples,we also characterized genomic changes in tumor tissue with next generation sequencing(NGS),and alterations in the tumor immune microenvironment(TIME)using multiplex immunofluorescence staining.Results:From September 2,2020 to July 16,2021,30 patients were enrolled into this study.The median age was 64.5 years(range,50-74).Most primary tumors were in the GEJ(N=28,93.3%),the other 2 cases were in the stomach.29 patients(96.7%)had adenocarcinoma,and 1 had small cell neuroendocrine tumor.The median follow-up duration was 7.9 months(range:5.1-10.6)as of data cut-off(November 1,2021).All patients completed the planned preoperative treatment,and 27 patients(90.0%)proceeded to surgery.1 patient with metastatic disease and 2 cases with patient request didn’t undergo surgery.24 patients had R0 resection,while 3 underwent R1 resection.1 patient achieved pCR(TRG 1 per the Mandard’s tumor regression grading system)and 5 patients(18.5%)reached TRG 2-3.Treatment related adverse events(TRAEs)were observed in 27 patients during perioperative treatment.Most of the TRAEs were of grade 1 to 2.The most common grade 3 toxicities were nausea(23.3%),neutrophil count decreased(16.7%)and anorexia(6.7%).11 patients had immune-related AEs,the most common toxicities(>5%)were hyperthyroidism(16.7%),subclinical hyperthyroidism(6.7%),paroxysmal atrial tachycardia(6.7%),hypothyroidism(3.3%).No treatment-related death occurred.NGS analysis of 43 samples originating form 24 patients revealed that the pre-treatment tumor mutation burden(TMB)levels is not associated with pathological response.However,alterations in negative predictor mutations were more common in TRG4-5 group.Paired pre-and post-treatment samples from 27 patients were analyzed by multiplex fluorescence immunohistochemistry which indicated that the density of PD-L1/CD68 double-positive macrophages may be a potential predictor of the efficacy of neoadjuvant ICI with chemotherapy.Conclusions:LP002 plus cisplatin and 5-fluorouracil was safe and effective in patients with locally advanced,resectable G/GEJ cancer,and could be a new perioperative treatment option.The density of PD-L1/CD68 double positive cells may be a promising predictive biomarker.PART Ⅱ:The clinical observation on adrenocortical function in patients following anti-PD-1 antibody,SHR-1210 therapy in advanced unresectable or metastatic solid tumorsBackground:Immune-related adverse events following immunotherapy can be induced in multiple systems including endocrine systems in which thyroid,adrenal and pituitary are the most affected endocrine organs.We intend to highlight the potentially fatal endocrine irAEs,especially life-threatening adrenal crisis after hypopituitarism induced by immune-related hypophysitis.We investigate the adrenocortical function changes of patients with advanced solid tumors who received the anti-programmed cell death protein-1(PD-1)antibody,SHR-1210 therapy.Methods:The clinical data of 98 patients with advanced solid tumors who were enrolled in a prospective phase I trial of SHR-1210 therapy at our institution between April 27,2016 and June 8,2017 were collected.The levels of plasma adrenocorticotropic hormone(ACTH)and cortisol were evaluated in 96 patients.The clinical manifestations,laboratory tests and radiologic data were collected to define the immune-related adrenal insufficiency.Results:Until June 1,2020,no SHR-1210 related primary adrenal insufficiency occurred,and the incidence of immune-related secondary adrenal insufficiency was 1.0%among the 96 patients,which was identified as grade 2.No patient developed grade 3-4 adrenal insufficiency.The main clinical manifestations of the patient who was diagnosed as secondary adrenal insufficiency were grade 2 fatigue,anorexia and headache.The patient developed fatigue and anorexia at the 267th day after receiving the first dose of SHR-1210,the hypocortisolism occurred on the 279th day,and the headache emerged on the 291th day.The anorexia of patient who treated by physiological replacement doses of glucocorticoid since the 457th day was attenuated.The patient whose cortisol level was still below the normal limit continued to accept the hormone replacement therapy up to 776 days after the initial administration of SHR-1210.Conclusions:The incidence of SHR-1210 related adrenal insufficiency of patients with advanced solid tumors is low,and the symptoms can be effectively ameliorated by hormone replacement therapy.The potential adverse outcome of adrenal insufficiency following immunotherapy should be noticed by clinicians to avoid the occurrence of adrenal crisis.