Administration Of Pembrolizumab Research Articles

Scleroderma-like Lesions in a Patient Undergoing Combined Pembrolizumab and Routine Chemotherapy: A Case Report and Literature Review

Triple-negative breast cancer (TNBC) represents a challenging malignancy with limited treatment options and a poor prognosis. Adjuvant therapies, including chemotherapy and immune checkpoint inhibitors (ICI), are commonly employed following breast conservation surgery. However, these treatments can lead to various adverse effects, including cutaneous complications and connective tissue disorders. Here, we present the case of a 54-year-old woman with TNBC who developed morphea, a form of localized scleroderma, following adjuvant chemotherapy and pembrolizumab administration. This case highlights the rarity of drug-induced morphea and emphasizes the importance of recognizing and managing such adverse events in breast cancer patients. We discuss the clinical characteristics, diagnostic challenges, and treatment considerations associated with drug-induced scleroderma-like lesions, as well as the potential mechanisms underlying their development. Furthermore, we review the literature on the incidence, clinical features, and outcomes of scleroderma-like lesions induced by chemotherapy and ICIs. This case underscores the need for increased awareness of immune-related adverse events in patients receiving immunotherapy, as well as the importance of individualized treatment approaches to optimize patient care and outcomes.

Projected environmental and public health benefits of extended-interval dosing: an analysis of pembrolizumab use in a US national health system

Health care is a major source of greenhouse gas emissions, leading to climate change and public health harms. Changes are needed to improve the environmental sustainability of health-care practices, but such changes should not sacrifice patient outcomes or financial sustainability. Alternative dosing strategies that reduce the frequency with which specialty drugs are administered, without sacrificing patient outcomes, are an attractive possibility for improving environmental sustainability. We sought to inform environmentally sustainable cancer care by estimating and comparing the environmental and financial effects of alternative, clinically equivalent strategies for pembrolizumab administration. We conducted a retrospective analysis using a cohort of patients from the Veterans Health Administration (VHA) in the USA who received one or more pembrolizumab doses between May 1, 2020, and Sept 30, 2022. Using baseline, real-world administration of pembrolizumab, we generated simulated pembrolizumab use data under three near-equivalent counterfactual pembrolizumab administration strategies defined by combinations of weight-based dosing, pharmacy-level vial sharing and dose rounding, and extended-interval dosing (ie, every 6 weeks). For each counterfactual dosing strategy, we estimated greenhouse gas emissions related to pembrolizumab use across the VHA cohort using a deterministic environmental impact model that estimated greenhouse gas emissions due to patient travel, drug manufacture, and medical waste as the primary outcome measure. We identified 7813 veterans who received at least one dose of pembrolizumab-containing therapy in the VHA during the study period. 59 140 pembrolizumab administrations occurred in the study period, of which 46 255 (78·2%) were dosed at 200 mg every 3 weeks, 12 885 (21·8%) at 400 mg every 6 weeks, and 14 955 (25·3%) were coadministered with infusional chemotherapies. Adoption of weight-based, extended-interval pembrolizumab dosing (4 mg/kg every 6 weeks) and pharmacy-level stewardship strategies (ie, dose rounding and vial sharing) for all pembrolizumab infusions would have resulted in 24·7% fewer administration events than baseline dosing (44 533 events vs 59 140 events) and an estimated 200 metric tons less CO2 emitted per year as a result of pembrolizumab use within the VHA (650 tons vs 850 tons of CO2, a relative reduction of 24%), largely due to reductions in distance travelled by patients to receive treatment. Similar results were observed when weight-based and extended-interval dosing were applied only to pembrolizumab monotherapy and pembrolizumab in combination with oral therapies. Alternative pembrolizumab administration strategies might have environmental advantages over the current dosing and compounding paradigms. Specialty medication dosing can be optimised for health-care spending and environmental sustainability without sacrificing clinical outcomes. None.

Intravesical local administration of pembrolizumab for treatment of bladder cancer: A novel strategy to minimize toxicity.

e14687 Background: A major hallmark of bladder cancer (BCa) is a higher treatment success rate than prostate cancer following stimulation of innate anti-tumor immune response either by intravesical BCG or to FDA approved intravenous anti-PD1 checkpoint antibody (pembrolizumab) approved for BCG resistant BCa since 2021. However, injected pembrolizumab is characterized by a markedly higher incidence (66%) of serious adverse events than the median duration of complete response of ~40% for non-muscle invasive BCa (NMIBC) and 15-20% for invasive BCa. Since the toxicity (fatigue, Pneumonitis and diarrhea) of injected pembrolizumab is linked to systemic breakdown of T-cell mediated immune surveillance we enquired whether analogous to BCG, pembrolizumab can be administered intravesically to safely induce a localized anti-tumor response in mouse model of BCa. Methods: Six weeks old female mice of B6D2F1 strain (n=10) were ad libitum fed carcinogen, N-butyl-N-4-hydroxybutyl nitrosamine (BBN) in drinking water (0.05% w/v) for 12 weeks. The presence of BBN evoked tumor was ascertained by unenhanced T2 weighted MRI at week 11 prior to single intravesical dosing by 24G transurethral catheter under isoflurane anesthesia of 0.1mL vehicle (sterile water) with or without 0.3mg of Pembrolizumab (Lipella Pharmaceuticals). 6 weeks later, T2 weighted MRI was repeated together with T1 mapping by ICE-MRI prior to organ harvest. Results: BBN feeding evoked multiclonal tumors (red*) of comparable size on T2 weighted MRI at week 11 but repeat MRI 7 weeks after treatment revealed that tumor progression and perivesical invasion noted in vehicle group was arrested in pembrolizumab group. Longest dimension of BBN tumor in vehicle treated mice was ≥ 1mm longer (p<0.05) than in pembrolizumab treated mice. T1 mapping revealed thickened bladder wall missed by T2 MRI. Conclusions: These findings on single intravesical dose of pembrolizumab (10mg/kg) in mice are consistent with human study on multiple intravesical dosing of BCG plus pembrolizumab (1-2mg/kg) in BCG resistant NMIBC patients. Intravesical pembrolizumab mirrors the limited systemic uptake of radiolabelled antibodies together with substantially higher ingress into tumor foci. The tumor selective ingress for BCa immunotherapy without any toxicity will be enhanced with Lipella Pharmaceutical’s liposomal delivery of Pembrolizumab.

Calcium pyrophosphate crystal arthritis associated with immune checkpoint inhibitor successfully treated with intra-articular glucocorticoid: A case report.

Immune checkpoint inhibitors (ICIs) sometimes induce immune-related adverse events (irAEs), and arthritis is one of the irAE symptoms. Recently, crystal-induced arthritis, such as calcium pyrophosphate (CPP) crystal deposition disease and gout, has been reported to occur after ICI administration. However, the distinction between ICI-associated crystal arthritis and ICI-induced non-crystal arthritis is difficult because their symptoms are similar. Besides, optimal treatment for ICI-associated crystal arthritis has not been established. Here, we report a patient who developed CPP crystal arthritis twice after pembrolizumab (ICI) administration and was successfully treated with intra-articular glucocorticoid injection. He suffered arthritis and acute interstitial nephritis simultaneously after ICI administration. Musculoskeletal ultrasound of his affected joint suggests that his arthritis was crystal-induced arthritis, and arthrocentesis detected CPP crystal in synovial fluid. Thus, we diagnosed his arthritis as ICI-associated cystal arthritis. Therefore, our case encourages the use of musculoskeletal ultrasound in patients with arthritis after treatment with ICI because it may distinguish between ICI-associated crystal arthritis and ICI-induced non-crystal arthritis. Besides, ICI-associated crystal arthritis could be treatable by intra-articular glucocorticoid injection.

Optimization of immune checkpoint inhibitor treatment planning for relapsed or refractory extranodal NK/T cell lymphoma.

Pembrolizumab (anti-programmed cell death-ligand 1 inhibitor) is a promising salvage therapeutic option for relapsed/refractory extranodal NK/T-cell lymphoma (R/R ENKTL). However, the appropriate duration of pembrolizumab use in R/R ENKTL patients and the optimal timing for administering pembrolizumab remain undetermined. We collected and analyzed clinical information on R/R ENKTL 58 patients who received pembrolizumab to evaluate the optimal treatment durations and clinical information for considering treatment interruption. Treatment outcomes were assessed by 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) and Epstein Barr virus DNA (EBV DNA) every 3months. Nineteen (32.8%) patients had been treated with more than three chemotherapies before pembrolizumab administration. The best response rate towards the first try of pembrolizumab was 38.9% (31.5% complete response rate (CR), 7.4% partial response (PR)). During the 41.8-month median follow-up duration, the median progression-free survival (PFS) was 3.1months, and the median overall survival (OS) was 7.1months. The failure group, which was characterized by Deaville score (DS) 3-4 and circulating EBV detection, or DS 5 with/without EBV detection, had the worst PFS (p < 0.001) and OS (p < 0.001), followed by the high (DS 1-2 and EBV detection, or DS 3-4 and EBV not detected) and low-risk groups (DS 1-2 and EBV not detected). Among the 21 patients who achieved the best response at the first pembolizumab try, the patients who received planned 24 cycles presented better PFS than those who received incomplete cycles (57.6 months vs 20.9 months, P-value = 0.012). Among 13 patients who received avelumab or pembrolizumab in advance, a few who responded to the second trial of pembrolizumab administration had over one year of chemotherapy vacation. Determining the discontinuation or continuation of pembrolizumab would be considered in selected cases assessed by PET-CT and EBV monitoring. Disruption of pembrolizumab treatment may be advisable for the low-risk group(DS 1-2 and EBV not detected), whereas continuation could be warranted for the high-risk group (DS 1-2 and EBV detection, or DS 3-4 and EBV not detected). Moreover, it might be critical to maintain over 24 cycles to improve the survival outcome of R/R ENKTL.

Pembrolizumab-Induced Pancytopenia: A Case Report

Introduction: Immunotherapy is increasingly acknowledged as an effective treatment for metastatic melanoma. Hematological immune-mediated adverse events are rarely reported. In this article, we report a case of a patient who developed pancytopenia following administration of pembrolizumab. Case Report: A 63 -year-old woman, followed for a scalp melanoma with pulmonary metastasis developed severe pancytopenia after receiving 4 cycles of pembrolizumab. Outcome and Management: Following the appearance of the adverse effect, Pembrolizumab was stopped. A series of blood tests were performed in order to get the reasons of this event. The patient received high-dose of corticosteroids with tapering the dose over 6 weeks, and blood transfusion was required. Discussion: Checkpoint inhibitors (ICI) stimulate both humoral and cellular immune responses against tumor antigens, potentially resulting in immune-related adverse effects, including hematological issues like pancytopenia. Due to the substantial morbidity and mortality linked to ICI-induced pancytopenia, further data is essential to formulate evidence-based management guidelines.

Endocrine system-related adverse events associated with PD-1/PD-L1 inhibitors: data mining from the FDA adverse event reporting system.

Various immune checkpoint inhibitors, such as programmed cell death protein-1 (PD-1) and its ligand (PD-L1), have been approved for use, but they have side effects on the endocrine glands. Adverse event reports related to PD-1/PD-L1 inhibitors from the FDA Adverse Event Reporting System (FAERS) from the first quarter of 2019 to the first quarter of 2023 were extracted, and the reported Odds ratio methods (ROR method) and comprehensive standard methods (MHRA methods) were used for data mining and analysis. A total of 5,322 reports (accounts for 6.68% of the total reports)of AEs in endocrine system were collected, including 1852 of pabolizumab (34.80%), 2,326 of navuliumab (43.71%), 54 of cimipriliumab (1.01%), 800 of atilizumab (15.03%), 222 of duvariumab (4.17%) and 68 of averumab (1.28%). Endocrine system-related AEs were mainly present in men (excluding those treated with pembrolizumab) aged ≥65 years. The ratio of AEs components in the endocrine system for the six drugs was approximately 3-8%. The main endocrine glands involved in AEs were the thyroid (pembrolizumab), pituitary and adrenal (nivolumab), adrenal (cemiplimab, atezolizumab, and avelumab), and thyroid (durvalumab). Most patients experienced AEs between 30 and 365 (mean, 117) days,the median time was 61d. AEs resulted in prolonged hospitalization in >40% and death in >10% of cases after administration of pembrolizumab, nivolumab, or durvalumab. Men aged ≥65 years should be concerned about endocrine-related AEs. There was a lengthy interval between the use of PD-1/PD-L1 inhibitors and endocrine system-related AEs, but the outcome was serious. Special attention should be given to endocrine system-related AEs when using pembrolizumab, nivolumab, or durvalumab.

Comparison of the efficacy of enfortumab vedotin between patients with metastatic urothelial carcinoma who were treated with avelumab or pembrolizumab: real-world data from a multi-institutional study in Japan

ObjectivesEnfortumab vedotin (EV) is a novel antibody–drug conjugate approved for metastatic urothelial carcinoma (UC) refractory to prior treatment with immune checkpoint inhibitors (ICIs). However, the difference in efficacy of EV after each ICIs and prognostic factors are not well known. We aimed to compare the efficacy of EV in patients with metastatic UC who were treated with avelumab or pembrolizumab and to identify the prognostic factors.MethodsThe records of 100 patients with advanced metastatic UC who received EV after the administration of either avelumab or pembrolizumab were retrospectively collected from five academic hospitals in Japan.ResultsThe median follow-up period was 6.7 months. The median overall survival (OS) and progression-free survival (PFS) in the EV after avelumab/pembrolizumab group were not reached/14.7 months (p = 0.17) and 10.4/5.2 months (p = 0.039), respectively. The objective response rates (ORR) were 66.6% and 46.8% in EV after avelumab and EV after pembrolizumab groups, respectively (p = 0.14). Multivariate analysis identified histological variants, liver metastasis, low serum albumin levels, and high serum CRP level as significant poor prognostic factors. The median OS and PFS of cachexia patients with both low serum albumin levels and high serum CRP levels were 6.0 months and 0.93 months, respectively.ConclusionPFS was superior in patients treated with EV after avelumab to EV after pembrolizumab. However, OS showed no significant difference between the two groups. Because the prognosis of patients with cachexia is extremely poor, the initiation of EV should be discussed in these patients.

Acute pancreatitis associated with pembrolizumab-induced hypertriglyceridemia.

Acute pancreatitis (AP) following drug-induced hypertriglyceridemia is a rare clinical phenomenon. Immune checkpoint inhibitors have revolutionized treatment for a variety of solid organ and hematological malignancies. Pembrolizumab is a programmed cell death receptor-1 (PD-1) inhibitor that has shown promising responses in many advanced cancers. However, a constellation of immune-related adverse events has also been described. There are reports of pembrolizumab-induced hypertriglyceridemia, but AP as a result of this side effect remains an exceedingly rare clinical sequela. We delineate a case of a patient with stage IVB non-small-cell lung cancer who developed progressive abdominal pain and nausea following administration of pembrolizumab for four months. Laboratory studies revealed increased serum lipase and triglyceride levels at 12,562 IU/L and 16,901 mg/dL, respectively. The diagnosis of AP was made based on the revised Atlanta classification criteria. After ruling out alternative causes, pembrolizumab-induced hypertriglyceridemia was considered the likely etiology of AP. The patient was transferred to the medical intensive care unit for close monitoring. Treatment was initiated with intravenous fluids, pain medications, and an insulin infusion. However, her hypertriglyceridemia levels remained persistently elevated, necessitating therapeutic apheresis. She recovered well with no complications after triglyceride apheresis. AP following pembrolizumab-associated hypertriglyceridemia remains a rare clinicopathologic entity. Given the widespread clinical use of immune checkpoint inhibitors, knowledge of such rare adverse events is crucial. Evaluation of serum triglyceride levels before and after initiating pembrolizumab therapy may be mandated, especially in patients with metabolic comorbidities.

An autopsy case of lung adenocarcinoma with immune checkpoint inhibitor-induced pneumonia and fulminant myocarditis following pembrolizumab administration: a case report.

Immune checkpoint inhibitors (ICIs) are the current standard of care for non-small-cell lung cancer (NSCLC). Myocarditis is a rare but serious immune-related adverse event (irAE) associated with ICI therapy. We present a patient who received a single dose of pembrolizumab for NSCLC and developed ICI-associated pneumonia. Although pneumonia improved with corticosteroid therapy, the patient subsequently developed ICI-associated fulminant myocarditis. Despite high-dose corticosteroid therapy, the patient died on day 30 after pembrolizumab initiation. Even if an observed irAE was effectively treated, clinicians should remain vigilant for other irAEs, especially those that are difficult to control with low-dose corticosteroids.

A case of postoperative pancreatitis in patients with renal cell carcinoma with an inferior vena cava tumor thrombus treated by presurgical lenvatinib plus pembrolizumab.

Pancreatic injury is a rare, but noted complication of nephrectomy. We report a case involving a 56-year-old man who presented with cT3bN0M0 left locally advanced renal cell carcinoma with an inferior vena cava thrombus. Nephrectomy with thrombectomy was performed given the remarkable shrinkage of the primary tumor and thrombus following lenvatinib plus pembrolizumab administration. The patient developed postoperative pancreatitis associated with unrecognized minor pancreatic injury, which was treated conservatively. To our knowledge, this has been the first case that underwent nephrectomy for RCC with an IVC thrombus after presurgical lenvatinib plus pembrolizumab and received conservative treatment for postoperative pancreatitis.

Abstract PR07: Intratumoral injection of mRNA-2752 and anti-PD-1 results in rapid regression of HER2 positive and or Hormone Receptor Negative DCIS: Phase 1 study results

Abstract Background: High-grade DCIS with immune infiltrates may be contained by the immune system, but are at risk for progression to invasive disease. Spatial proximity of CD8+/PD-1+ T cells and PD-L1+ cells predict response to chemotherapy and PD-1 inhibitors in hormone negative (HR-) invasive tumors. DCIS with high-risk features (such as HR- and or Her2+) often have T cell infiltrates. We hypothesized that intratumoral (ITu) administration of pembrolizumab (ITu-P) could potentiate the immune response and avoid systemic toxicities. We also explored whether the addition of mRNA-2752 (Moderna), an mRNA based therapeutic encoding T cell co-stimulator OX40L and proinflammatory cytokines IL-23 and IL-36g, would synergize adaptive anti-cancer immune responses of immune checkpoint injection alone. Since mortality for DCIS is extremely low, we proposed ITu treatment to avoid systemic adverse effects. In a phase 1 dose escalation study of single agent ITu-P we found 2 doses of 8 mg, administered 2-3 wks apart, was tolerable, induced immunological changes within the DCIS lesions, but had little clinical benefit. Herein, we expanded the number of injections to 4 and also tested a combination with ITu mRNA-2752 (ITu-M), to determine if we could find a dose that was both tolerable and elicited anti-tumor responses. Methods: This study evaluated ITu-P monotherapy (8mg, q2-3 wks x 4 doses; n=5) and combination ITu-P (8, 4, or 2mg) + ITu-M (4, 2, or 1mg) (n=10). DCIS with &amp;gt;2 high-risk features were eligible: age&amp;lt;45; high grade, extensive comedo necrosis; palpable mass; HR-; HER2+; size &amp;gt;5 cm, or microinvasion (&amp;lt;10% of lesion with invasive cancer). Dose was reduced based on AEs. Patients (pts) had MRI before and after 2 injections. Core biopsy/surgery was conducted after the last MRI. Baseline and biopsy/surgery breast tissue specimens were analyzed for immune infiltrates by multiplex immunofluorescence (mIF) staining. Results: In the ITu-P monotherapy expanded cohort, T cell density increased except when there was a paucity of T cells pre-treatment. Only 1 pt demonstrated a reduction in lesion size (clinically and on MRI); no side effects were seen. Of 10 pts enrolled in the combination (ITu-P + ITu-M) cohort, 80% responded: 2 non responders had &amp;lt;5% T cells and the 8 responders had &amp;gt; 6% T cell infiltrates at baseline. In 4 pts, all DCIS (3-8 cm) resolved completely (pCR) and 4 pts had a PR. Two CRs had post-therapy core biopsies only and remain NED with &amp;gt;1 yr follow-up (MRI). Pts experienced Gr1/2 fever, myalgias, and fatigue, enlargement of regional nodes, and erythema and induration of the breast lasting 4-20 days. No AEs &amp;gt; grade 2 were noted. The tolerable dose was 1mg ITu-M + 4mg ITu-P. Conclusion: The combination of ITu-P + ITu-M demonstrated modulation of the tumor immune microenvironment and robust antitumor activity in high-risk DCIS (typically HR- or HER2+) with pre-existing T cell infiltrates. mIF analyses suggest that the degree of immune infiltrate at baseline is associated with complete response. A study evaluating monotherapy ITu-M is in progress. Citation Format: Laura J. Esserman, Kirithiga Ramalingam, Rachel Woody, Alexa Glencer, Christopher Schwartz, Hidetoshi Mori, Jasmine Wong, Gillian Hirst, Jennifer Rosenbluth, Nola Hylton, Natsuko Onishi, Alexander D. Borowsky, Michael J. Campbell. Intratumoral injection of mRNA-2752 and anti-PD-1 results in rapid regression of HER2 positive and or Hormone Receptor Negative DCIS: Phase 1 study results [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr PR07.

Clinical characteristics and the course of hepatobiliary and pancreatic malignant tumors with high microsatellite instability after pembrolizumab administration: A multicenter observational study.

459 Background: The Keynote-158 trial have resulted in an expanded approval for pembrolizumab (Pem) in solid tumors with high microsatellite instability (MSI-H). In the trial, Pem was administered to patients with MSI-H solid tumors, excluding colorectal cancer, and the overall response rate (ORR) was 34%. However, the ORR for pancreatic (PANC) and biliary tract (BT) cancer were 19% (4/22 cases) and 41% (9/22 cases), respectively, suggesting the possibility of varying treatment efficacy by the primary tumor site. In this study, we aimed to clarify the clinical characteristics of patients with MSI-H and the efficacy of Pem administration in hepatobiliary and pancreatic (HBP) cancers. Methods: A multicenter observational study of patients with HBP cancer with MSI-H was conducted from March 2020 to March 2023. This study consists of prospective and retrospective cohorts. We evaluated the efficacy of PEM administration in patients with PANC and BT, respectively. Results: We enrolled 51 patients, including 32 in the prospective cohort; males comprised 51% of the patients. The BT, PANC, and liver were the primary sites in 26, 24, and 1 patients, respectively. MSI-H diagnostic methods were the MSI kit (FALCO) and comprehensive genome profile in 43 (84%) and 8 (16%) patients, respectively. Intrahepatic cholangiocarcinoma (ICC) was the most common cancer in BT tumor; ICC was observed 13 (50%) patients, followed by perihilar, gallbladder, and distal bile duct (including ampullary cancer) cancers in 6, 4, and 3 patients, respectively. Some rare histological types were observed, two patients had neuroendocrine carcinoma and one had hepatoid carcinoma in PANC. One had an undifferentiated carcinoma in BT. Five and six patients with PANC and BT tumors, respectively, had one or more first-degree relatives with lynch syndrome-related disease. Pem was administered to 96% and 88% of the patients with PANC and BT tumors, respectively. The ORR was 30% in PANC and 73% in BT tumors (p=0.003). In BT tumor, three patients demonstrated complete response as follows: two with ICC and one with perihilar cholangiocarcinoma. The median progression-free survival was 3.2 months (95% confidence interval [CI], 1.3–14.4) and 16.3 months (95% CI, 8.7 to not reached) in patients PANC and BT tumors (p=0.08), respectively. Grade 3/4 immune-related adverse events occurred in 13% and 29% of the patients with PANC and BT tumors, respectively. Conclusions: ICC was the most common BT cancer with MSI-H. Pem was significantly more effective in BT tumors than in PANC tumors, with higher ORR. Clinical trial information: UMIN000040591 .

C-reactive Protein Is a Prognostic Factor for Survival in Metastatic Upper Tract Urothelial Carcinoma Patients Receiving Pembrolizumab.

The number of available treatment options for urothelial carcinoma has increased recently. Upper tract urothelial carcinoma (UTUC) is relatively rare compared with bladder cancer. There are few reports on the efficacy of immune checkpoint inhibitors (ICIs) for metastatic UTUC, and ICIs may occasionally show less efficacy and cause severe side effects. Therefore, it is important to predict the treatment response and change the treatment strategy as appropriate. We investigated the prognostic factors for treatment response in patients with metastatic UTUC treated with pembrolizumab at our hospital. Patients who received pembrolizumab for UTUC between January 2018 and June 2023 were analyzed. Patients who presented with bladder cancer complications at initial diagnosis were excluded. The primary endpoints assessed were overall survival (OS) and progression-free survival (PFS). Statistical analyses were conducted using laboratory values obtained before and after pembrolizumab administration. The relationship between cancer and inflammation is important. Therefore, we analyzed this relationship using prognostic factors for urothelial carcinoma as previously reported. Specifically, pretreatment C-reactive protein (CRP) level, neutrophil-to-lymphocyte ratio (NLR), and NLR/albumin values were examined. Forty-seven patients were analyzed. The median PFS was 66 days (24-107 days), and the median OS was 164 days (13-314 days). A CRP level <1 before the first cycle was a useful factor in the multivariate analysis for both OS and PFS [OS: p=0.004, hazard ratio (HR)=3.244, 95% confidence interval (CI)=1.464-7.104; PFS: p=0.003, HR=2.998, 95%CI=1.444-6.225]. CRP level is a prognostic factor for pembrolizumab treatment response in patients with UTUC.

Early Experience With Pembrolizumab in Bacillus Calmette-Guérin Unresponsive Non–Muscle-Invasive Bladder Cancer

Purpose: Radical cystectomy (RC) is recommended for patients with non–muscle-invasive bladder cancer (NMIBC) who are unresponsive to intravesical bacillus Calmette-Guérin (BCG) instillation. However, RC is a very risky treatment, and some patients cannot undergo RC due to old age, patient preference, and comorbidities. In this study, we investigated the efficacy of pembrolizumab, a programmed cell death protein 1 inhibitor, in patients with NMIBC unresponsive to intravesical BCG instillation.Materials and Methods: Between December 2016 and February 2023, 24 patients who experienced recurrence after BCG treatment and subsequently received pembrolizumab were enrolled. We evaluated the patients’ response to pembrolizumab therapy using urine cytology, cystoscopic examination (with/without biopsy), and/or computed tomography imaging. The primary endpoint was the complete response (CR) rate 3 months after the first dose of pembrolizumab. Patients were followed up every 3 months for the first 2 years and every 6 months thereafter. Kaplan-Meier survival analysis was used to illustrate CR and the individual treatment course was demonstrated.Results: The median follow-up period was 16 months (range, 2–68 months) and the median number of pembrolizumab administrations was 5 times (range, 3–39 times). Thirteen of the 18 patients (54.2%) with BCG-unresponsive NMIBC achieved CR at 3 months. The median duration of CR maintenance was 15 months (range, 5–47 months). Five patients (20.8%) showed no recurrence for 12 months after pembrolizumab administration. Seven patients underwent RC, and pathological reports showed T2 stage in 3 patients. To date, 1 patient (4.2%) has died.Conclusions: Our early experience with pembrolizumab treatment for BCG-unresponsive NMIBC showed better results than those of the KEYNOTE-057 trial, which reported a CR rate of 40% at 3 months. However, long-term data and more cases are required to establish pembrolizumab therapy in patients with BCG-unresponsive NMIBC in a real-world setting.

Abstract 15756: To Close or Not to Close: A Case of Multisystem Immune Checkpoint Inhibitor Toxicity and PFO

Introduction: Recent emergence of immune checkpoint inhibitors (ICIs) in oncologic treatments has led to increasing research on their side effect profile. Myocarditis occurs in roughly 0.04-1.14% of patients treated with ICIs and is associated with up to 50% mortality. We present a case of multisystem ICI toxicity requiring comprehensive evaluation to ultimately reveal a PFO shunt as the cause of persistent hypoxemia. Case: A 67-year-old male with Stage IIIC cutaneous melanoma presented with non-radiating pleuritic chest pain, diplopia, dyspnea and syncope. ECG showed high grade AV block and right bundle branch block. Labs showed elevated troponin, creatinine kinase and inflammatory markers. An echocardiogram showed edematous myocardium, a small pericardial effusion, and akinetic apical/inferior septal segments. Despite diuresis, 5g of methylprednisolone, IV immunoglobulin plus mycophenolate and resolution of AV block, the patient had hypoxemia on 100% FiO2. He underwent a CTA (which ruled out PE and ICI-induced pneumonitis) and fluoroscopic sniff test (revealing bilateral moderate diaphragm paresis). A recent cardiac catheterization on prior admission showed no obstructive coronary disease. Arterial blood gas showed pO2 120 mmHg without hypercapnia on 100% FiO2. We suspected a shunt as the underlying cause and obtained a bubble study disclosing a large (&gt; 25 bubble) PFO with right-to-left shunt. Results: Given the timing of symptoms, it was determined that pembrolizumab administration caused myocarditis and myositis with diaphragmatic paresis. In patients with pulmonary disease or diaphragmatic paresis, elevated intrathoracic and pulmonary artery pressures have been a proposed mechanism of acute worsening of right-to-left shunt resulting in hypoxemia. The patient underwent right heart catheterization and PFO closure using Gore Cardioform septal occluder with resolution of hypoxemia. A repeat echocardiogram obtained 1 month later was normal. Conclusion: All concerning clinical symptoms in the setting of ICI use require a thorough evaluation. In this case, persistent hypoxemia despite treatment for ICI toxicity unmasked a large PFO requiring closure. A multisystem approach should be used to assess suspected ICI myocarditis.

Pituitary-Related Adverse Events and Onset Patterns Caused by Immune Checkpoint Inhibitors: Analysis Using the Japanese Adverse Drug Event Report Database.

Background and Objectives: One type of immune-related adverse event caused by immune checkpoint inhibitors (ICIs) is pituitary-related adverse events. The management of pituitary-related adverse events is important because they can be fatal if not treated promptly. Therefore, this study was conducted to investigate the onset of pituitary-related adverse events using the Japanese Adverse Drug Report (JADER) database. Materials and Methods: Cases registered in the JADER database from 2004 to 2019 were used. The target drugs were ipilimumab, nivolumab, pembrolizumab, avelumab, atezolizumab, and durvalumab, and the target adverse events were the high-level terms "Anterior pituitary hypofunction," "Anterior pituitary hyperfunction," "Posterior pituitary disorder," and "Pituitary neoplasm" in the Medical Dictionary for Regulatory Activities, Japanese version (MedDRA/J). The information component (IC) was used for signal detection and IC delta (ICΔ) was used for women-related signals. Onset timing and patterns were analyzed using the Weibull distribution. Results: Signals were detected with ipilimumab, nivolumab, pembrolizumab, and atezolizumab in "Anterior pituitary hypofunction," with ICs and 95% credible intervals (95%CrI) of 5.53 (5.30-5.69), 4.96 (4.79-5.08), 4.04 (3.76-4.25), and 2.40 (1.53-3.00). Significant signals were detected in women, except for atezolizumab. Additionally, the time of onset was classified as the wear-out failure type. Inverse signals were detected with ipilimumab and nivolumab in "Posterior pituitary disorder," with ICs (95%CrI) of -1.24 (-2.80--0.26), and -0.89 (-1.64--0.37). Conclusions: Anterior pituitary hypofunction is likely to occur with the long-term administration of ipilimumab, nivolumab, and pembrolizumab. Further investigation is needed to determine the differences in the tendencies to detect signals in the anterior and posterior pituitaries between ipilimumab and nivolumab.

A Phase Ⅱ Study of Ubenimex Combined With Pembrolizumab, Nab-Paclitaxel, and Carboplatin for Previously Untreated Advanced Squamous Non–Small-Cell Lung Cancer: TORG2241 (UBE-Q)

BackgroundAccording to the results of the KEYNOTE-407 trial, pembrolizumab plus platinum-based chemotherapy is the standard of care for patients with previously untreated advanced squamous non–small-cell lung cancer (NSCLC). Ubenimex, a potent aminopeptidase inhibitor, is an oral drug with immunostimulatory and antitumor activities. We aim to assess the safety and efficacy of ubenimex in combination with pembrolizumab, nab-paclitaxel, and carboplatin in patients with previously untreated advanced squamous NSCLC. Patients and MethodsThis prospective, single-arm, multicenter, phase II clinical trial is conducted to confirm the tolerability and efficacy of the tested drugs. Patients with previously untreated advanced squamous NSCLC will receive a predetermined daily dose of ubenimex orally plus 4 cycles of pembrolizumab, nab-paclitaxel, and carboplatin, followed by continuous administration of ubenimex and pembrolizumab for a maximum of 2 years. To confirm tolerability, the daily dose of ubenimex will begin at level 1 (30 mg), which will be increased to levels 2 (60 mg) and 3 (120 mg) according to the escalation criteria, with a standard 3 + 3 design for achieving the target dose-limiting toxicity rate of 33%. The efficacy, safety, and tolerability of ubenimex at the determined dose level will be analyzed. The primary endpoint of the efficacy evaluation will be the objective response rate assessed by an independent review committee. ConclusionsThis is the first study to evaluate the efficacy and safety of ubenimex combined with pembrolizumab, nab-paclitaxel, and carboplatin in patients with previously untreated advanced squamous NSCLC. The results will help devise future treatment strategies.

253P Is 6-weekly administration of pembrolizumab in combination with chemotherapy for early triple-negative breast cancer safe? A real-world early comparison of q6w versus q3w administration of pembrolizumab in two large cancer centres in the UK

253P Is 6-weekly administration of pembrolizumab in combination with chemotherapy for early triple-negative breast cancer safe? A real-world early comparison of q6w versus q3w administration of pembrolizumab in two large cancer centres in the UK

Early Phase Persistent Changes in the White Blood Cell Fraction in Patients With Advanced Urothelial Carcinoma Treated With Pembrolizumab: A Multicenter Retrospective Study.

The association of clinical outcomes with posttreatment persistent changes in eosinophils and other white blood cell (WBC) subtypes in patients with advanced urothelial cancer (UC) treated with pembrolizumab after the failure of platinum-based chemotherapy is unclear. We retrospectively analyzed 87 patients with advanced UC who received pembrolizumab after the failure of platinum-based chemotherapy. The changes in WBC subtypes from pretreatment were evaluated three and six weeks after pembrolizumab administration. The association between the changes in the WBC subtypes and clinical outcomes was then evaluated using the Kaplan-Meier method and a Cox regression model. Among WBC subtypes, significant changes in the absolute (AEC) and relative eosinophil count (REC) and the neutrophil-to-eosinophil ratio (NER) were observed at three and six weeks compared with pretreatment (p<0.001). Multivariable Cox regression analyses revealed that a persistent decrease in AEC and REC and a persistent increase in NER were associated with poor overall survival. Persistent increase in AEC and REC and decrease in NER in the early phase after pembrolizumab may be significant early predictive markers of improved clinical outcomes in patients with advanced UC receiving pembrolizumab.