Programmed Death Receptor-1 Inhibitor Research Articles

Contrary to expectation: Preserved renal function after using PD-1 Inhibitor Cemiplimab-rwlc in a kidney transplant recipient

The use of immune checkpoint inhibitors in transplant recipients with malignancy is associated with the risk of graft failure due to acute rejection. There is limited literature regarding the use of Cemiplimab-rwlc (Libtayo) in kidney transplant patients. Here we present a case of using Cemiplimab-rwlc (Libtayo), a Programmed Death receptor-1 (PD-1) blocking antibody for locally advanced and metastatic Cutaneous Squamous Cell Carcinoma (CSCC), in a kidney transplant recipient.

Aptamer-siRNA chimera and gold nanoparticle modified collagen membrane for the treatment of malignant pleural effusion.

Malignant pleural effusion is one of the most common complications of advanced lung cancer and there is no effective clinical treatment at present. Here, we constructed an aptamer-siRNA chimeras/PEI/PEG/gold nanoparticle (AuNP)/collagen membrane that can progressively activate T cells by layer by layer assembly. Electron microscope showed this collagen membrane could be divided into 10 layers with a total thickness of 50–80μm, and AuNPs could be observed. Aptamer-siRNA chimeras could bind specifically to OX40+ cells and silencing programmed death receptor-1 (PD-1) gene. In vitro experiments demonstrated that chimeras/PEI/PEG/AuNPs gradually activated T cells to continuously kill lung adenocarcinoma cells in malignant pleural effusion. Animal experiments showed that chimeras/PEI/PEG/AuNP/collagen membrane effectively treated malignant pleural effusion. Compared with PD-1 inhibitor group, the number of cancer cells, ki-67 proliferation index and CD44 expression in the pleural effusion was significantly decreased and the lymphocyte/cancer cell ratio was significantly increased in the chimeras/AuNP-CM group. Flow cytometry showed that compared with PD-1 inhibitor group, T cell number in the chimeras/AuNP-CM group was significantly increased, while the proportion of PD-1+ T cells was markedly decreased. In conclusion, we constructed an chimeras/PEI/PEG/AuNP/collagen membrane, which was more effective in the treatment of malignant pleural effusion, and had less side effects than PD-1 inhibitors.

PD-1 inhibitor-associated type 1 diabetes: A case report and systematic review

ObjectiveThis study aimed to summarize the clinical characteristics of programmed death receptor 1 (PD-1) inhibitor-associated type 1 diabetes so as to improve the ability of clinicians to correctly diagnose and treat it.MethodsWe reported a case of a 70-year-old woman with gastric cancer who developed hyperosmolar hyperglycemic coma during camrelizumab (a PD-1 inhibitor) treatment and was diagnosed with PD-1 inhibitor-associated type 1 diabetes. We conducted a systematic review of 74 case reports of type 1 diabetes associated with PD-1 inhibitor therapy published before June 2022.ResultsThe patient developed type 1 diabetes with hyperosmolar hyperglycemic coma after receiving camrelizumab chemotherapy for 6 months (9 cycles). We searched 69 English articles comprising 75 patients, all of whom had been treated with a PD-1 inhibitor (nivolumab or pembrolizumab) and progressed to diabetes after an average of 6.11 (1–28) cycles. Nivolumab combined with ipilimumab (a cytotoxic T lymphocyte-associated protein 4 inhibitor) had the shortest onset (4.47 cycles on average). A total of 76% (57/75) of patients developed diabetic ketoacidosis (DKA) at onset, and 50.67% (38/75) of patients had C-peptide <0.1 ng/mL. Most of the patients were tested for insulin autoantibodies, with a positive rate of 33.33% (23/69); of these, 86.96% (20/23) were tested for glutamate decarboxylase antibody and 46.67% (35/75) were tested for human leukocyte antigen (HLA). HLA-DR4 was the most common type.ConclusionsThe progression of type 1 diabetes induced by PD-1 inhibitors is relatively rapid. Islet failure often occurs when detected, seriously endangering patients' lives. Patients treated with PD-1 inhibitors should closely monitor their plasma glucose level during treatment to detect, diagnose, and treat diabetes on time.

RWD80 Gastrointestinal Adverse Events in Lung Cancer Patients Treated with Ipilimumab and Nivolumab Using Real-World Data

Evidence shows that programmed death receptor-1 (PD-1)-blocking and human cytotoxic T-lymphocyte antigen 4 (CTLA-4)-blocking antibodies display apparent benefits in lung cancer therapy. Further, lung cancer patients who receive nivolumab (PD-1 inhibitor) plus ipilimumab (CLTA-4 inhibitor) in combination have higher overall survival rate than those treated with ipilimumab alone. However, adverse events (AE) are still a concern, especially gastrointestinal (GI) AEs. Since GI AE is one of the most common reasons for patients stopping immunotherapy, we utilized real-world data to gain insight in the incidence and severity of GI AEs among lung cancer patients treated with nivolumab and ipilimumab.

Short-term outcomes of neoadjuvant sintilimab with chemotherapy in stage III non-small cell lung cancer: a case series.

BackgroundNeoadjuvant chemoimmunotherapy seems to be a promising treatment option for stage III non-small cell lung cancer (NSCLC). Sintilimab, as a programmed death receptor-1 inhibitor, has exhibited a fine performance in treating NSCLC. However, the efficiency of sintilimab combined with chemotherapy for stage IIIA/IIIB NSCLC remains inconclusive. The purpose of this study was to share our experience on sintilimab in neoadjuvant chemoimmunotherapy for stage III NSCLC.MethodsThis study retrospectively reviewed patients who received surgical resection following 1–3 cycles of neoadjuvant sintilimab (200 mg) with chemotherapy for stage III NSCLC between June 2020 and March 2022 in our center. Patients characteristics, surgical factors, surgery-related complications 30 days postoperatively, and treatment-related adverse events (TRAEs) before surgery were recorded through reviewing medical record data and telephone follow-up.ResultsA total of eight patients were enrolled, including six cases of squamous cell carcinoma and two cases of adenocarcinoma. All of the patients received 1–3 cycles of neoadjuvant therapy. There were no treatment-related surgical delays. All patients underwent lobectomy, among which two underwent sleeve lobectomy and one received bronchoplasty. Five patients underwent open thoracotomy. Fibrosis of the primary tumor and lymph nodes was observed in all the cases. There were no surgery-related complications > grade 2 at 30 days postoperatively. According to the radiographic findings, one patient had stable disease and all of the others achieved a partial response. The median of maximum standardized uptake value change from baseline was a 52.75% reduction (range, 37.2–68.8%). Five patients achieved a major pathological response. R0 resection was achieved in all eight cases. One grade 4 event was observed. Neutropenia was the most common TRAE > grade 2 (3/8). There were no cases of treatment discontinuation or dose reduction due to TRAEs.ConclusionsThe current study found that neoadjuvant sintilimab plus chemotherapy bring a high rate of major pathological response and acceptable TRAEs. Even though it increased the difficulties of surgery, there is still no evidence suggesting that it will brings additional surgical death. We believe that neoadjuvant sintilimab plus chemotherapy might be feasible for stage III NSCLC.

Clinical activity of PD-1 inhibition in the treatment of locally advanced or metastatic basal cell carcinoma

BackgroundBasal cell carcinoma (BCC) is the most common malignancy worldwide, yet the management of patients with advanced or metastatic disease is challenging, with limited treatment options. Recently, programmed death receptor...

Hepatitis B virus infection does not affect the clinical outcome of anti-programmed death receptor-1 therapy in advanced solid malignancies: Real-world evidence from a retrospective study using propensity score matching.

This study aimed to investigate the impact of hepatitis B virus (HBV) infection on the outcome of patients with advanced solid malignancies treated with programmed death receptor-1 (PD-1) inhibitors.We retrospectively included patients treated with PD-1 inhibitors between August 2018 and April 2020. Propensity score matching (PSM) was performed to match the characteristics of the HBV and non-HBV groups. Objective response rate (ORR) and disease control rate (DCR) were compared between HBV and non-HBV groups using χ2 or Fisher exact tests. Kaplan-Meier and log-rank tests were used to analyze overall survival (OS) and progression-free survival (PFS).A total of 120 patients, including 43 (35.8%) with HBV and 77 (64.2%) without HBV, were enrolled. Cases of HBV reactivation were not observed. In the entire study population, ORR and DCR did not significantly differ between both groups. After PSM, the study population comprised 39 patients, 15 with and 24 without HBV. The HBV group had an ORR of 55.6%, whereas the ORR in the non-HBV group was 36.8% (P = .35). Similarly, the DCR was 77.8% in the HBV group, as compared to 68.4% in the non-HBV group (P = .61). Additionally, HBV infection did not significantly affect OS (P = .54) and PFS (P = .64) in the unmatched cohort. Moreover, statistically significant differences regarding OS (P = .15) and PFS (P = .23) were also not detected after PSM.In conclusion, the HBV infection status did not impact the therapy response or prognosis of patients treated with PD-1 inhibitors. Further prospective studies are needed to corroborate these findings.

Efficacy and Safety of Fruquintinib Plus PD-1 Inhibitors Versus Regorafenib Plus PD-1 Inhibitors in Refractory Microsatellite Stable Metastatic Colorectal Cancer.

BackgroundMicrosatellite stability (MSS) or mismatch repair proficient (pMMR) metastatic colorectal cancer (mCRC) is resistant to immune checkpoint inhibitors. Studies have shown that antiangiogenic drugs combined with programmed death receptor-1 (PD-1) inhibitors can improve immunosuppression. The purpose of this study was to compare the efficacy of fruquintinib combined with PD-1 inhibitor (FP) and regorafenib combined with PD-1 inhibitor (RP) in the treatment of advanced mCRC with MSS or pMMR.Materials and MethodsWe retrospectively collected advanced MSS or pMMR mCRC patient data from The Second Affiliated Hospital of Nanchang, China, from June 2019 to March 2021. Then, we analyzed and compared the efficacy and safety of FP and RP.ResultsA total of 51 patients who met the criteria were divided into FP (n = 28) and RP groups (n = 23). The overall response rate of the FP and RP groups was 7.1% and 8.7% and the disease control rate was 89.3% and 56.5%, respectively. The median progression-free survival (PFS) time was higher in the FP group than in the RP group (6.4 vs. 3.9 months, respectively; P = 0.0209). Patients with no liver metastasis, KRAS wild type, and left colon tumor may benefit from FP. Eight patients (15.7%) had grade 3 toxicity related to treatment. Cox multivariate regression analysis showed that the treatment method was an independent risk factor for median PFS time.ConclusionOur study indicates that FP could improve PFS time of patients with advanced mCRC compared with RP.

Application and prospect of PD-1 or PD-L1 inhibitor in advanced hepatocellular carcinoma

Hepatocellular carcinoma(HCC) is one of the most common malignant tumors of the digestive system in the clinic. In recent years, the proposal and development of immunotherapy have set off a worldwide anticancer upsurge. In particular, programmed death receptor 1(PD-1) and programmed death receptor ligand 1(PD-L1) inhibitor have been used in a wide variety of tumor diseases and achieved good curative effect. However, the application of PD-1 or PD-L1 inhibitors in HCC is mostly still at the stage of clinical trials, and some clinical trials have shown gratifying results in patients with advanced HCC and postoperative recurrence. More studies have shown that PD-1 or PD-L1 inhibitors combined with radiofrequency, chemoradiotherapy, and molecular targeted drugs can bring greater benefits to patients.

Ingle-Institutional Experience with the Use of PD-1 Inhibitors for the Treatment of Richter's Syndrome

BACKGROUNDRichter's syndrome (RS), an aggressive lymphoma in a chronic lymphocytic leukemia (CLL) patient, has a poor prognosis and new therapies are needed. Recently, a clinical trial of the programmed death receptor-1 (PD-1) blocking antibody, pembrolizumab, in relapsed CLL and RS reported responses in RS. Two PD-1 inhibitors, nivolumab and pembrolizumab, are approved by the US FDA for other cancers. Based on reported responses in RS with pembrolizumab and the favorable toxicity profile of these agents we have prescribed them for RS outside of clinical trials. We reviewed our institutional experience. METHODSMedical records of all patients with a diagnosis of RS treated outside of a clinical trial with at least 1 dose of either pembrolizumab or nivolumab at the Ohio State University (OSU) were reviewed. Baseline characteristics, CLL and RS disease features, and treatment were abstracted from medical records. Treatment failure was defined as disease progression documented by the treating physician, start of a new treatment for RS other than planned allogeneic stem cell transplant, or death while taking a PD-1 inhibitor. Time to treatment failure was calculated from initiation of a PD-1 inhibitor. Patient and disease characteristics were described using summary statistics and time to treatment failure and overall survival were estimated using the method of Kaplan-Meier. RESULTSA total of 10 patients received PD-1 inhibitors for RS. The median age was 69 (range 52-79) and 4/10 (40%) were men. The median time from CLL diagnosis to biopsy demonstrating RS was 8.1 (range 1-14) years. The cohort was enriched for high-risk genetic features in the underlying CLL: 8/10 (80%) IGHV unmutated, 7/10 (70%) deletion 17p by FISH, and 5/10 (50%) complex CLL karyotype. Patients had a median of 3.5 (range 1-11) treatments for CLL prior to RS diagnosis and all 10 had prior BTK inhibitor exposure. All patients had biopsy proven RS with diffuse large B-cell lymphoma histology. The PD-1 inhibitor used was nivolumab in 7/10 (70%) patients and pembrolizumab in 3/10 (30%). The majority of patients (6/10, 60%) received a PD-1 inhibitor as an initial treatment for RS, and the median time from RS biopsy to first dose of PD-1 inhibitor was 27 (range 13-86) days. Three patients had 1 prior RS treatment: R-EPOCH, rituximab and high-dose methylprednisolone, or radiation therapy, respectively. One patient was more extensively pre-treated and had received hyper-CVAD, pulse dexamethasone, radiation therapy, and single-agent rituximab. For patients that received nivolumab the total number of doses was known for 6/7 (86%) and the median doses received was 2.5 (range 1-5). For patients treated with pembrolizumab the number of doses received was known for 2/3 (67%) patients with 1 patient receiving only 1 dose and 1 receiving 10 doses. One patient in each drug group received doses outside of OSU. In 4/10 (40%) cases a targeted therapy for CLL was given concurrently with the PD-1 inhibitor. This was single agent ibrutinib in 3 cases and combination ibrutinib and venetoclax in 1. Two of these patients were taking the targeted therapy at the time of developing RS and the PD-1 inhibitor was added. Therapy outcome was known for all 10 patients. The majority of patients (9/10, 90%) had treatment failure: 3 had disease progression, 2 started a new therapy due to lack of response, and 4 died prior to documentation of response. Median time to treatment failure from the first dose of PD-1 inhibitor was 36 days (95% CI: 4-56 days) (Figure 1). Only 1 patient received a sustained course of a PD-1 inhibitor (pembrolizumab) and underwent allogeneic stem cell transplant without experiencing RS relapse. That patient had disease features distinct from the rest of the cohort in that the only site of RS was brain parenchyma and they had a complete resection at time of diagnosis. Median overall-survival for the cohort from RS biopsy was 123 (95% CI: 33-not reached) days with median follow-up of 125 days and 4/10 (40%) of patients were alive at last follow-up. CONCLUSIONSReview of our institutional experience with the use of PD-1 inhibitors for the treatment of RS demonstrates poor efficacy with a very short time to treatment failure. This may be due to the aggressive nature of RS or a highly enriched population of patients already on immune modulatory therapy with ibrutinib. Our data do not support the use of monotherapy PD-1 inhibitors outside of clinical trials for RS. [Display omitted] DisclosuresByrd:Genentech: Research Funding; Janssen: Research Funding; Acerta Pharma: Research Funding; Pharmacyclics: Research Funding; The Ohio State University: Patents & Royalties: OSU-2S.

Comparative efficacy of treatments for previously treated patients with advanced esophageal and esophagogastric junction cancer: A network meta-analysis.

It remains unclear which treatment is the most effective for previously treated patients with advanced esophageal and esophagogastric junction (EGJ) cancer. We conducted a network meta-analysis to address this important issue. PubMed, Embase, Cochrane Library, and Web of Science databases were searched for relevant phase II and III randomized controlled trials (RCTs). Overall survival (OS) was the primary outcome of interest, which was reported as hazard ratio (HR) and 95% confidence intervals (CIs). Sixteen RCTs involving 3372 patients and evaluating 15 treatments were included in this network meta-analysis. Ramucirumab+chemotherapy (CT) (HR = 0.52, 95% CI: 0.35-0.77) and use of programmed death receptor 1 (PD-1) inhibitors, including camrelizumab (HR = 0.71, 95% CI: 0.57-0.88), sintilimab (HR = 0.70, 95% CI: 0.50-0.98), nivolumab (HR = 0.76, 95% CI: 0.62-0.94), and pembrolizumab (HR = 0.84, 95% CI: 0.72-0.98), conferred better OS than CT; however, this OS benefit was not observed for PD-L1 inhibitor (avelumab) and other target agents (trastuzumab, everolimus, gefitinib, and anlotinib). In subgroup analysis, ramucirumab+CT and pembrolizumab showed significant improvement in OS, when compared to CT, in esophageal/EGJ adenocarcinoma (AC) cases; moreover, all PD-1 inhibitors had significant OS advantage over CT in treating esophageal squamous cell carcinoma (SCC). Based on treatment ranking in terms of OS, ramucirumab+CT and camrelizumab were ranked the best treatments for patients with AC and SCC, respectively. Ramucirumab+CT and PD-1 inhibitors were superior to CT for previously treated cases of advanced esophageal/EGJ cancer. Ramucirumab+CT seemed to be the most effective treatment in patients with esophageal/EGJ AC, while use of PD-1 inhibitors, especially camrelizumab, was likely to be the optimal treatment in patients with esophageal SCC.

Local Anti-PD-1 Delivery Prevents Progression of Premalignant Lesions in a 4NQO-Oral Carcinogenesis Mouse Model.

Although the principle of systemic treatment to prevent the progression of oral premalignant lesions (OPL) has been demonstrated, there remains a lack of consensus about an optimal approach that balances clinical efficacy with toxicity concerns. Recent advances in cancer therapy using approaches targeting the tumor immune microenvironment (TIME) including immune-checkpoint inhibitors indicate that these agents have significant clinically activity against different types of cancers, including oral cancer, and therefore they may provide an effective oral cancer prevention strategy for patients with OPLs. Our past work showed that systemic delivery of a monoclonal antibody to the programmed death receptor 1 (PD-1) immune checkpoint can inhibit the progression of OPLs to oral cancer in a syngeneic murine oral carcinogenesis model. Here we report a novel approach of local delivery of a PD-1 immune-checkpoint inhibitor loaded using a hydrogel, which significantly reduces the progression of OPLs to carcinomas. In addition, we detected a significant infiltration of regulatory T cells associated with oral lesions with p53 mutation, and a severe loss of expression of STING, which correlated with a decreased infiltration of dendritic cells in the oral lesions. However, a single local dose of PD-1 inhibitor was found to restore stimulator of interferon response cGAMP interactor 1 (STING) and CD11c expression and increase the infiltration of CD8+ T cells into the TIME irrespective of the p53 mutational status. Overall, we provide evidence for the potential clinical value of local delivery of biomaterials loaded with anti-PD-1 antibodies to prevent malignant progression of OPLs. PREVENTION RELEVANCE: Oral cancer is an aggressive disease, with an overall survival rate of 50%. Preinvasive histologic abnormalities such as tongue dysplasia represent an early stage of oral cancer; however, there are no treatments to prevent oral carcinoma progression. Here, we combined biomaterials loaded with an immunotherapeutic agent preventing oral cancer progression.

IMMU-26. DISEASE CONTROL IN A PEDIATRIC PATIENT WITH NEWLY DIAGNOSED GLIOBLASTOMA MULTIFORME (GBM) AND SOMATIC HIGH MICROSATELLITE INSTABILITY (MSI-H) WITH PD-1 INHIBITOR NIVOLUMAB (NIVO) ONLY AND NO FOCAL RADIOTHERAPY (RT)

Immune checkpoint inhibitors that target programmed death receptor-1 (PD-1) have recently been shown to be a promising option for the management of recurrent mismatch repair (MMR) deficient GBM following radiotherapy. We report a case of a 9-year-old boy who presented with a 6 week history of frontal headaches and was found to have a left frontal lobe mass. Pathology obtained from a gross total resection (GTR) was consistent with classic GBM, WHO Grade IV. Neuroimaging four weeks following initial resection was remarkable for local recurrence. The patient underwent another GTR of the tumor at our center. While pathology again confirmed GBM, GlioSequencing of tumor tissue from second resection showed MSI-H, NF2 mutation p.R338H, NF1 mutations p.R2450* and pI193Yfs*11, TP53 mutations p.R213* and p.R273C, EGFR mutation, and multiple variants of uncertain significance. Germline testing was negative for MMR deficiency or other deleterious mutations. Parents opted to defer radiotherapy and consented to monotherapy treatment with Nivolumab (Opdivo, BMS pharmaceuticals, USA), a PD-1 inhibitor, at a dose of 3 mg/kg administered every two weeks. Our patient is now 22 months post-second resection and continues to receive Nivolumab without evidence of recurrent disease or adverse autoimmune effects from PD-1 blockade. He has remained in school with good academic performance and has exhibited no regression of functional status during the entirety of his treatment course. This case provides evidence of possible efficacy of PD-1 blockade without focal radiotherapy in this child with GBM and somatic MSI instability.

S2017 Esophagitis in Metastatic Lung Adenocarcinoma Associated With Pembrolizumab

INTRODUCTION: Pembrolizumab, a monoclonal antibody against programmed death receptor 1 (PD-1), is a form of immunotherapy used in multiple malignancies. PD-1 inhibitors have been associated with numerous “immune-related adverse events” (irAEs) affecting most organs in the body. IrAEs in the lower gastrointestinal tract have been widely reported, with only few in the upper GI tract. We present a case of acute, grade 3 esophagitis in a patient on pembrolizumab. CASE DESCRIPTION/METHODS: Case report and literature review. We searched the words “esophagitis” “immune checkpoint inhibitors” “pembrolizumab” on PubMed. A 70-year-old male was admitted to the hospital with a 1-month history of progressive dysphagia and odynophagia. Medical history was notable for metastatic lung adenocarcinoma (stage T1cN3M1c) with a tumor proportion score of 95% positive PDL-1. Patient received 31 cycles of pembrolizumab 200mg IV prior to symptom onset. Physical exam demonstrated buccal mucosa swelling and oral candidiasis upon admission. With candida esophagitis as the primary differential, patient was started on IV fluconazole 200mg q24 hours with a 400mg loading dose. After 48 hours of IV fluconazole, symptoms did not improve; Gastroenterology was consulted. An esophagogastroduodenoscopy was performed which demonstrated linear furrows and esophagitis throughout the whole esophagus and no signs of candidal infection. Biopsy showed acute esophagitis with ulceration, reactive epithelial changes, and granulation tissue. Patient was started on IV methylprednisolone 60 mg for ICI-associated esophagitis. Dysphagia improved after two days of IV steroids. Oral prednisone was continued and pembrolizumab was held. Steroid dose was gradually tapered. Tumor progression was not observed four months after discontinuation of pembrolizumab and it was not reinitiated. DISCUSSION: Immune checkpoint inhibitor therapies are associated with a wide range of adverse events that can include the upper gastrointestinal system. Management includes initiation of corticosteroids and cessation of chemotherapy in severe cases. Early recognition and timely initiation of appropriate therapy are the keys to optimal outcomes. With the growing use of pembrolizumab in oncology, physicians must be aware of all potential irAEs. This case is one of the first to highlight acute esophagitis as one of its irAE. We conclude that close monitoring for manifestations of esophagitis is crucial when prescribing PD-1 inhibitors.Figure 1.: Linear furrows and esophagitis in the mid-esophagus.

1268P JASPER: Efficacy and safety of first-line (1L) niraparib plus a programmed death receptor 1 inhibitor (PD-1i) in patients with advanced non-small cell lung cancer (NSCLC)

1268P JASPER: Efficacy and safety of first-line (1L) niraparib plus a programmed death receptor 1 inhibitor (PD-1i) in patients with advanced non-small cell lung cancer (NSCLC)

Daratumumab With Cetrelimab, an Anti–PD-1 Monoclonal Antibody, in Relapsed/Refractory Multiple Myeloma

BackgroundDaratumumab is approved for relapsed or refractory multiple myeloma (RRMM) as monotherapy or in combination regimens. We evaluated daratumumab plus cetrelimab, a programmed death receptor-1 inhibitor, in RRMM. Patients and MethodsThis open-label, multiphase study enrolled adults with RRMM with ≥ 3 prior lines of therapy. Part 1 was a safety run-in phase examining dose-limiting toxicities of daratumumab (16 mg/kg intravenously weekly for cycles 1-2, biweekly for cycles 3-6, and monthly thereafter) plus cetrelimab (240 mg intravenously biweekly, all cycles). In Parts 2 and 3, patients were to be randomized to daratumumab with or without cetrelimab (same schedule as Part 1). Endpoints included safety, overall response rate, pharmacokinetics, and biomarker analyses. ResultsNine patients received daratumumab plus cetrelimab in the safety run-in, and 1 received daratumumab in Part 2 before administrative study termination following a data monitoring committee’s global recommendation to stop any trial including daratumumab combined with inhibitors of programmed death receptor-1 or its ligand (programmed death-ligand 1). The median follow-up times were 6.7 months (safety run-in) and 0.3 months (Part 2). No dose-limiting toxicities occurred. All 10 patients had ≥ 1 treatment-emergent adverse event; 7 patients had grade 3 to 4 treatment-emergent adverse events, and none led to treatment discontinuation or death. In the safety run-in, 7 (77.7%) patients had ≥ 1 infusion-related reaction (most grade 1-2), and 1 had a grade 2 immune-mediated reaction. Among safety run-in patients, the overall response rate was 44.4%. ConclusionsNo new safety concerns were identified for daratumumab plus cetrelimab in RRMM. The short study duration and small population limit complete analysis of this combination.

Baseline metabolic tumor volume as a strong predictive and prognostic biomarker in patients with non-small cell lung cancer treated with PD1 inhibitors: a prospective study.

BackgroundReliable predictive and prognostic markers are still lacking for patients treated with programmed death receptor 1 (PD1) inhibitors for non-small cell lung cancer (NSCLC). The purpose of this study was to investigate the prognostic and predictive values of different baseline metabolic parameters, including metabolic tumor volume (MTV), from 18F-fluorodeoxyglucose positron emission tomography–computed tomography (18F-FDG PET/CT) scans in patients with NSCLC treated with PD1 inhibitors.MethodsMaximum and peak standardized uptake values, MTV and total lesion glycolysis (TLG), as well as clinical and biological parameters, were recorded in 75 prospectively included patients with NSCLC treated with PD1 inhibitors. Associations between these parameters and overall survival (OS) were evaluated as well as their accuracy to predict early treatment discontinuation (ETD).ResultsA high MTV and a high TLG were significantly associated with a lower OS (p<0.001). The median OS in patients with MTV above the median (36.5 cm3) was 10.5 months (95% CI: 6.2 to upper limit: unreached), while the median OS in patients with MTV below the median was not reached. Patients with no prior chemotherapy had a poorer OS than patients who had received prior systemic treatment (p=0.04). MTV and TLG could reliably predict ETD (area under the receiver operating characteristic curve=0.76, 95% CI: 0.65 to 0.87 and 0.72, 95% CI: 0.62 to 0.84, respectively).ConclusionMTV is a strong prognostic and predictive factor in patients with NSCLC treated with PD1 inhibitors and can be easily determined from routine 18F-FDG PET/CT scans. MTV, could help to personalize immunotherapy and be used to stratify patients in future clinical studies.

SUN-183 Adrenalitis Induced by Nivolumab

Introduction: Tumor cells often express a programmed death-ligand 1 (PD-L1), which binds to the programmed death receptor-1 (PD-1) on activated T-cells to induce immune tolerance. Among the class of immune checkpoint inhibitors (ICI), Nivolumab is an anti-PD-1 antibody which blocks these tumor cell interactions. Although some endocrinopathies have been reported for other PD-1 inhibitors, the adverse event of adrenalitis with nivolumab has not been reported before. Clinical Case: A 65-year-old female presented to the hospital with complaints of nausea, vomiting, fatigue, and headache for five days. She was recently diagnosed with metastatic lung adenocarcinoma, complicated by cerebellar metastases, and the left cerebellar mass was resected. She was also started on Nivolumab. Her blood pressure was 98/65 mmHg on the presentation. Serum sodium was 122mEq/L (normal 135–145) and potassium was 5mEq/L (3.5–5). TSH, LH, and prolactin were all normal. Aldosterone was low: 23pmol/L (27.7–582.5) and renin was high: 11 ng/ml/h (0.167- 1.38). Morning cortisol levels were low: 2.2 ug/dl (5- 25) and concomitant ACTH was high: 78 pg/ml (7.2- 63.3). Upon standard high dose cosyntropin stimulation test, basal cortisol was 2.0 ug/dl (5- 25). Cortisol level 30 minutes post cosyntropin was 7.1 ug/dl, while Cortisol 60 minutes post cosyntropin was 12.2 ug/dl (normal >18 -20 ug/dl). Considering the low cortisol levels with high ACTH, and an inadequate rise in cortisol after the ACTH stimulation test, adrenal insufficiency was suspected as a result of adrenalitis due to Nivolumab. Hyponatremia along with low aldosterone and high renin levels also reinforced this clinical diagnosis. A computerized tomographic scan of the chest abdomen and pelvis only showed calcified uterine fibroids. She was initially resuscitated with intravenous fluids. Hydrocortisone 100 mg every 8 hours was started and then gradually tapered down to 60mg every 12 hours. Fludrocortisone was also initiated at 0.2mg daily. Symptoms began to improve, and sodium levels normalized to136 mEq/dl. She was discharged on 30mg of hydrocortisone and 0.1 mg of fludrocortisone daily and is stable since then. Conclusion: This is a rare case of Nivolumab-induced adrenalitis. It highlights the importance of checking for adrenal insufficiency in a patient who presents with symptoms of hypotension and hyponatremia while being on ICI drugs, as unidentified adrenal insufficiency and adrenal crisis can be fatal.

Anti-PD-1 blockade with nivolumab with and without therapeutic vaccination for virally suppressed chronic hepatitis B: A pilot study

To evaluate the hypothesis that increasing T cell frequency and activity may provide durable control of hepatitis B virus (HBV), we administered nivolumab, a programmed death receptor 1 (PD-1) inhibitor, with or without GS-4774, an HBV therapeutic vaccine, in virally suppressed patients with HBV e antigen (HBeAg)-negative chronic HBV. In a phase Ib study, patients received either a single dose of nivolumab at 0.1 mg/kg (n = 2) or 0.3 mg/kg (n = 12), or 40 yeast units of GS-4774 at baseline and week 4 and 0.3 mg/kg of nivolumab at week 4 (n = 10). The primary efficacy endpoint was mean change in HBV surface antigen (HBsAg) 12 weeks after nivolumab. Safety and immunologic changes were assessed through week 24. There were no grade 3 or 4 adverse events or serious adverse events. All assessed patients retained T cell PD-1 receptor occupancy 6-12 weeks post-infusion, with a mean total across 0.1 and 0.3 mg/kg cohorts of 76% (95% CI 75-77), and no significant differences were observed between cohorts (p = 0.839). Patients receiving 0.3 mg/kg nivolumab without and with GS-4774 had mean declines of -0.30 (95% CI -0.46 to -0.14) and -0.16 (95% CI -0.33 to 0.01) log10 IU/ml, respectively. Patients showed significant HBsAg declines from baseline (p = 0.035) with 3 patients experiencing declines of >0.5 log10 by the end of study. One patient, whose HBsAg went from baseline 1,173 IU/ml to undetectable at week 20, experienced an alanine aminotransferase flare (grade 3) at week 4 that resolved by week 8 and was accompanied by a significant increase in peripheral HBsAg-specific T cells at week 24. In virally suppressed HBeAg-negative patients, checkpoint blockade was well-tolerated and led to HBsAg decline in most patients and sustained HBsAg loss in 1 patient. Chronic hepatitis B virus infection (CHB) is characterized by a dysfunctional immune response. In patients with CHB, inhibitory receptors, such as programmed death receptor 1 (PD-1) are overexpressed on T cells, leading to an ineffective immune response in the liver. Herein, we show that the PD-1 inhibitor, nivolumab, is safe and effective for the treatment of virally suppressed patients with CHB. Australian New Zealand Clinical Trials Registry (http://www.anzctr.org.au/) number: ACTRN12615001133527.

Abstract 3212: Patient-level pharmacodynamics of response to combined ipilimumab and nivolumab for gastric cancer using a human autologous ex-vivo platform, CANscript

Abstract Background: Combined cancer immunotherapy is an emerging paradigm for the treatment of cancer. PD-L1, the cognate receptor for the programmed death receptor 1 (PD-1) is expressed in up to 40% of gastric/gastroesophageal junction (GEJ) tumors. Despite this, patients show modest responses to PD-1 inhibitors. A recent clinical trial, Checkmate-032, demonstrated superior efficacy when PD-1 inhibitor, Nivolumab, was combined with CTLA-4 inhibitor, Ipilimumab. Despite this, biomarkers that predict clinical response remain poorly understood. Methods: Here, with informed consent under IRB, fresh tumor biopsies were obtained from a randomly-selected cohort of gastric/GEJ patients (N=39). We then employed CANscriptTM, a clinically-validated human autologous ex-vivo tumor platform to interrogate the pharmacodynamics and prognostic efficacy (M-Score) of nivolumab +/- ipilimumab. PDL-1 status was determined for every patient by immunohistochemistry, flow cytometry was performed to analyze intratumor CD4+ and CD8+ T-cell profiles before and after treatment, and RNA seq. gene expression was performed to understand mechanistic changes under drug pressure. Results: We predicted, based on M-Score, that single agent nivolumab results in an overall response rate (ORR) of 10%, which closely matched previous single agent results from Checkmate-032 (10%). In contrast, we determined the combination of ipi+nivo resulted in a response rate of 20%, a finding consistent with reported clinical data (Checkmate-032; ORR 18%). Interestingly, we determined that only 28% of patients who responded to the ipi+nivo combination were predicted to respond to the monotherapy, suggesting the increased efficacy of the combination. RNA seq revealed unique features of adaptive immunity in the subset of patients who were predicted to respond to the combination immunotherapy, while PD-L1 status was a less-important biomarker to predict response. Conclusions: These results demonstrate the utility of the CANscript system to profile clinical response of immunotherapy. Our efforts may better inform clinical trial design and patient stratification before therapy to improve the potential for response. Citation Format: Vidushi Kapoor, Munisha Smalley, Nandini Pal Basak, Abhishek Basu, Manjusha Biswas, Manas Kumar Mandal, Pinaki Roy, Pradip K. Majumder, Aaron Goldman. Patient-level pharmacodynamics of response to combined ipilimumab and nivolumab for gastric cancer using a human autologous ex-vivo platform, CANscript [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3212.