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Immunological checkpoint inhibitors are now part of the oncological therapeutic arsenal in many solid cancers and malignant blood diseases, at the cost of immuno-mediated toxicities, of which dermatological disorders are among the most frequent. The most common, following treatment with anti-PD1 or anti-CTLA4, are maculopapular erythema, pruritus, vitiligo, or lichenoid lesions, but other more atypical conditions may lead to the internist being called upon. Here, we present a case series of these less common dermatological manifestations including fasciitis, dermatomyositis, scleroderma, granulomatosis and immune-induced vasculitis. Some manifestations appear similar to the primary forms or seem to correspond to paraneoplastic syndromes, but some diagnostic and therapeutic particularities are specific to ICI toxicity that the internist must be aware of., (Copyright © 2024 Société Nationale Française de Médecine Interne (SNFMI). Published by Elsevier Masson SAS. All rights reserved.)

Glioblastoma (GBM), the most common and aggressive primary central nervous system (CNS) tumor in adults, continues to have a dismal prognosis. Across hundreds of clinical trials, few novel approaches have translated to clinical practice while survival has improved by only a few months over the past three decades. Randomized controlled trials of immune checkpoint inhibitors (ICIs), which have seen impressive success for advanced or metastatic extracranial solid tumors, have so far failed to demonstrate a clinical benefit for patients with GBM. This has been secondary to GBM heterogeneity, the unique immunosuppressive CNS microenvironment, immune-evasive strategies by cancer cells, and the rapid evolution of tumor on therapy. This review aims to summarize findings from major clinical trials of ICIs for GBM, review historic failures, and describe currently promising avenues of investigation. We explore the biological mechanisms driving ICI responses, focusing on the role of the tumor microenvironment, immune evasion, and molecular biomarkers. Beyond conventional monotherapy approaches targeting PD-1, PD-L1, CTLA-4, we describe emerging approaches for GBM, such as dual-agent ICIs, and combination of ICIs with oncolytic virotherapy, antigenic peptide vaccines, chimeric antigenic receptor (CAR) T-cell therapy, along with nanoparticle-based delivery systems to enhance ICI efficacy. We highlight potential strategies for improving patient selection and treatment personalization, along with real-time, longitudinal monitoring of therapeutic responses through advanced imaging and liquid biopsy techniques. Integrated radiomics, tissue, and plasma-based analyses, may potentially uncover immunotherapeutic response signatures, enabling early, adaptive therapeutic adjustments. By specifically targeting current therapeutic challenges, outcomes for GBM patients may potentially be improved., Competing Interests: Declarations. Competing interests: Manmeet Singh Ahluwalia: Grants from Seagen and NIH. Consultation fees from Bayer, Kiyatec, Insightec, GSK, Xoft, Nuvation, SDP Oncology, Apollomics, Prelude, Janssen, Voyager Therapeutics, Viewray, CarisLifesciences, Pyramid Biosciences, Varian Medical Systems, Cairn Therapeutics, AnheartTherapeutics, Theraguix, MenariniRicerche, Sumitomo Pharma Oncology, Autem therapeutics, GT Medical Technologies, Allovir, EquilliumBio., QV Bioelectronics. Scientific Advisory Boardmemberships in Modifibiosciences., Bugworks. DSMC membership for VBI Vaccines. Stockshareholder in: Mimivax, Cytodyn, MedInnovateAdvisors LLC, TrisalusLifesciences. Graeme Woodworth: Grants from Focused Ultrasound Foundation, NIH, Maryland StemCenter Research Foundation. Clinical Trial Support from Insightec and Keep PunchingFoundation. Mustafa Khasraw: Grants or contracts from BMS, AbbVie, BioNTech, CNS Pharmaceuticals, Daiichi Sankyo, Inc., Immorna Therapeutics, Immvira Therapeutics, JAX lab for genomic research, and Personalis, Inc.; received consulting fees from AnHeart Therapeutics, George Clinical, Manarini Stemline, and Servier; received honoraria from GSK; and is on a data safety monitoring board for BPG Bio. All other authors have no disclosures., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Pembrolizumab monotherapy significantly extends progression-free and overall survival compared to platinum-based chemotherapy for advanced non-small cell lung cancer (NSCLC), but also has a significant impact on medical costs., Aim: To clarify the health economic evidence for selecting the first-line treatment for patients with stage IV advanced NSCLC with a programmed cell death ligand 1 tumor proportion score of 50% or greater in Japan, we assessed the cost-effectiveness of pembrolizumab monotherapy compared with that of platinum-based chemotherapy., Method: Using a Markov model, the study simulated three health states for patients, based on clinical data and utility values from KEYNOTE-024. Transition probabilities were estimated exponentially. Direct medical costs were calculated according to the 2022 National Health Insurance Medical Fee Points and Drug Price Standards. The outcomes measured included life years, quality-adjusted life years, and incremental cost-effectiveness ratio, with sensitivity analysis performed to evaluate the effect of uncertainties., Results: Pembrolizumab led to an additional 1.58 life years and 1.23 quality-adjusted life years at an additional cost of 7,009,888 Japanese yen (48,448 U.S. dollars [USD]), resulting in incremental cost-effectiveness ratio of 4,436,638 Japanese yen (30,663 USD) per life year and 5,699,096 Japanese yen (39,388 USD) per quality-adjusted life year. Pembrolizumab was deemed cost-effective under a threshold of 7.5 million Japanese yen (51,835 USD) per quality-adjusted life year., Conclusion: Pembrolizumab monotherapy is a cost-effective option for the first-line treatment of advanced NSCLC with high programmed cell death ligand 1 expression in Japan, providing valuable health economic evidence for treatment selection., Competing Interests: Conflicts of interest: The authors have no conflicts of interest to declare., (© 2024. The Author(s).)

Background: There are currently limited real-world data on the effectiveness and safety of first-line pembrolizumab combined with chemotherapy in patients with advanced/recurrent or metastatic esophageal squamous cell carcinoma (ESCC) in China. This study was conducted to address this knowledge gap., Methods: This multicenter retrospective cohort study was conducted at 17 hospitals in China and included adults (⩾18 years) with stage IV primary ESCC, or recurring 6 months after radical radiotherapy/surgery-based combination therapy, who had received first-line pembrolizumab plus chemotherapy. Data were collected from electronic medical records. Endpoints included objective response rate (ORR), disease control rate (DCR) progression-free survival (PFS), overall survival (OS), and safety. Subgroup analyses were conducted to identify patient characteristics and treatment patterns associated with treatment response., Results: In total, 202 patients who had received treatment from 2018 to 2023 were included: 125 (61.9%) newly diagnosed and 77 (38.1%) with recurrence, 181 (89.1%) were male. Pembrolizumab was most commonly combined with paclitaxel + platinum (69.8%) or fluorouracil + platinum (19.3%). After a median follow-up of 22.6 months (95% confidence interval (CI) 20.1-25.4), the ORR and DCR were 60.9% and 87.6% and the median PFS and OS were 10.8 months (95% CI 9.1-13.5) and 17.3 months (95% CI 14.9-19.9), respectively. OS was similar in patients with treatment-naïve and recurrent disease. Among the combination chemotherapy regimens, paclitaxel + platinum was associated with the longest median OS (18.2 months, 95% CI 16.1-22.5). Favorable survival outcomes were observed in patients with oligometastases. No new safety signals were observed., Conclusion: These real-world data indicate that the first-line treatment with pembrolizumab plus chemotherapy is effective and safe in Chinese patients with advanced ESCC and show that paclitaxel + platinum is the most commonly used and most effective partner chemotherapy in China., Competing Interests: The authors declare that there is no conflict of interest., (© The Author(s), 2024.)

The success of modern biopharmaceutical products depends on enhancing the stability of protein therapeutics. Freezing and thawing, which are common thermal stresses encountered throughout the lifecycle of drug substances, spanning protein production, formulation design, manufacturing, storage, and shipping, can impact this stability. Understanding the physicochemical and molecular behaviors of components in biological drug products at temperatures relevant to manufacturing and shipping is essential for assessing stability risks and determining appropriate storage conditions. This study focuses on the stability of high-concentration monoclonal antibody (mAb) pembrolizumab, the drug substance of Keytruda (Merck & Co., Inc., Rahway, NJ, United States), and its excipients in a frozen solution. By leveraging dynamic nuclear polarization (DNP), we achieve more than 100-fold signal enhancements in solid-state NMR (ssNMR), enabling efficient low-temperature (LT) analysis of pembrolizumab without isotopic enrichment. Through both ex situ and in situ ssNMR experiments conducted across a temperature range of 297 to 77 K, we provide insights into the stability of crystalline pembrolizumab under frozen conditions. Importantly, utilizing LT magic-angle spinning (MAS) probes allows us to study molecular dynamics in pembrolizumab from room temperature down to liquid nitrogen temperatures (<100 K). Our results demonstrate that valuable insights into protein conformation and dynamics, crystallinity, and the phase transformations of excipients during the freezing of the formulation matrix can be readily obtained for biological drug products. This study underscores the potential of LT-MAS ssNMR and DNP techniques for analyzing protein therapeutics and vaccines in frozen solutions.

Background: Immunotherapy has emerged as a standard treatment for deficient mismatch repair (dMMR) metastatic colorectal cancer (mCRC). Pembrolizumab became widely available as a first-line (1L) option in Australia following the Pharmaceutical Benefits Scheme (PBS) listing in August 2021. The uptake of new treatment options can be lengthy., Methods: The Treatment of Recurrent and Advanced Colorectal Cancer mCRC registry data at participating Australian sites was analysed from January 2015 (when MMR testing became routine). 1L treatment of dMMR cancers was compared with pre- and post-PBS funding., Results: Out of 2819 patients, 2344 (83%) had known MMR status. Of these, 162 (7%) were dMMR, which was associated with older age (median age 69 vs 63 years, P = 0.001), a right-side primary (68% vs 31%, P < 0.001) and a BRAF V600E mutation (49% vs 11%, P < 0.001). Prior to August 2021, 85 out of 117 (73%) patients with dMMR received 1L treatment: 63 out of 85 (74%) chemotherapy and 20 out of 85 (24%) immunotherapy. Following approval, 39 out of 45 (87%) received 1L treatment and 39 out of 39 (100%) pembrolizumab. Of the patients 75 years and older, a significantly higher proportion of patients were treated with any 1L therapy post-PBS listing (89% vs 60%, P = 0.036)., Conclusion: Previously reported associations of dMMR were observed. The higher-than-expected proportion of patients with dMMR is likely driven by the inclusion of older patients in this real-world study. Many patients were able to access immunotherapy prior to PBS listing, potentially through trials or access programs. Early uptake of pembrolizumab following PBS listing has been high, and this effective and well-tolerated option has increased the proportion of elderly patients receiving active therapy., (© 2024 Royal Australasian College of Physicians.)

Introduction: Recently, immunotherapy has offered new hope for treating biliary tract cancer (BTC). However, several issues are to be considered, including the lack of validated predictive biomarkers that could help to identify patient groups which are most likely to benefit from such therapeutic approaches., Areas Covered: In the current article, we will provide an overview of recent results and ongoing and future research directions of immunotherapy in BTC, with a special focus on recently published, practice-changing data, and ongoing active and recruiting clinical trials., Expert Opinion: At this moment, dozens of clinical trials in phases I to III are evaluating the role of cancer immunotherapy in this setting, with the hope of adding more therapeutic options for BTC patients. Future research must focus on the development of novel agents and combinations, but the validation of biomarkers remains an urgent need. As more research results emerge, novel combinatorial strategies are destined to further transform the treatment paradigm for this heterogeneous and aggressive tumor type.

Pembrolizumab-containing regimens are the standard first-line treatment for recurrent/metastatic squamous cell carcinoma of the head and neck (R/M HNSCC). The neutrophil-to-lymphocyte ratio (NLR) and C-reactive protein-to-albumin ratio (CAR) have been reported to be important prognostic factors in a variety of carcinomas, but none have been investigated in combination with pembrolizumab and chemotherapy or in first-line treatment. Seventy-four patients with R/M HNSCC received pembrolizumab-containing regimens at Tohoku University Hospital, Sendai, Japan, from April 2020 to March 2023. Patient characteristics, tumor response, overall survival (OS), progression-free survival (PFS), and laboratory findings were reviewed. Associations between NLR, CAR, and survival outcomes were analyzed. The 1-year OS and 1-year PFS rates were 60.4% and 18.1%, respectively. The disease control rate was 66.2%. In multivariate analysis, low NLR (< 5) was significantly associated with better OS and PFS. NLR may be a predictive factor for OS and PFS in patients with R/M HNSCC treated with a pembrolizumab-containing regimen., Competing Interests: Declarations Competing interests The authors declare no competing interests. Ethics approval This study was approved by the Ethics Committee of the Faculty of Medicine of the Tohoku University School of Medicine (Approval No.2021-1-351) and performed in line with the ethical standards described in the Declaration of Helsinki. Patient consent statement Patient consent for this study was obtained with the opt-out method., (© 2024. The Author(s).)

Background: In 2017, the Food and Drug Administration approved pembrolizumab for treatment of any mismatch repair-deficient (dMMR) tumor making MMR immunohistochemistry (IHC) testing beneficial for all tumor types. For the first time, MMR IHC was not performed exclusively to screen for Lynch syndrome (LS)., Methods: In this study, all MMR IHC reports issued between 2017 and 2021 at an academic hospital were reviewed and completion of genetic testing was determined through chart review. Colorectal cancers (CRCs), endometrial cancers (ECs), and noncancerous lesions were excluded., Results: Between 2017 and 2021, MMR IHC was completed in 1939 patients with a malignancy other than CRC or EC. Absent or weak staining for at least one MMR protein was detected in 115 (5.9%) patients and 59 (51%) of those completed germline genetic testing. Overall, the identification rate of LS in this cohort was 0.72%, which is similar to the rate in our previously reported CRC and EC universal screening cohort. A diagnosis of LS was most commonly made in patients with dMMR brain (18.75%) and small intestinal cancers (10.20%). Five additional patients were found to carry a pathogenic variant in a non-LS gene., Conclusions: Pan-cancer MMR testing for pembrolizumab consideration can identify LS cases at a rate similar to universal CRC and EC screening programs. A persistent challenge is subsequent uptake of genetic testing. MMR testing should be prioritized in brain and small intestinal tumors, and multigene panel testing is recommended in patients with dMMR, as unexpected pathogenic variants in non-LS genes were found as frequently as LS gene variants., (© 2024 American Cancer Society.)

Introduction: In general, platelet counts fluctuate in cancer patients receiving anticancer therapy. It may include thrombocytopenia caused by bone marrow suppression due to cytotoxic anticancer agents and thrombocytosis due to rebound during recovery. This should not be the case in the case of administration of immune checkpoint inhibitors, given their mechanism of action., Case Presentation: However, we have experienced a case of thrombocytosis in a patient treated with an immune checkpoint inhibitor. We present a platelet count pattern in patient with bladder cancer underwent Gemcitabine and Cisplatin (GC) therapy and pembrolizumab monotherapy., Conclusion: This case underscores the need for a diverse perspective on platelet behavior in clinical settings., Competing Interests: The Department of Hospital Pharmaceutics, School of Pharmacy, Showa University, received funds from Ono for a contract research project in accordance with a collaborative research agreement. As potential conflicts of interest, Hospital Pharmaceutics received research grants from Daiichi Sankyo, Mochida, Shionogi, Ono, Taiho, Nippon-Kayaku, and Bayer. TN received an honorarium fee for presentations from Sanofi. KM received an honorarium from AbbVie, Eisai, Sawai, and Nippon-Kayaku for his presentation. The other authors declare no conflicts of interest associated with this manuscript., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Immune checkpoint inhibitors (ICIs), such as pembrolizumab (PEM), are widely recognized for their antitumor efficacy, but they can also lead to various cutaneous adverse events (CAEs). While most CAEs can be managed with topical corticosteroids, severe cases may necessitate halting immunotherapy. The incidence of severe CAEs is notably higher in combination therapies involving ICIs than in monotherapies, emphasizing the need for stringent, long-term management strategies. This includes potential modifications or discontinuations of the combination therapy. PEM, when added to the conventional paclitaxel + cisplatin (or carboplatin) ± bevacizumab regimen, has shown significant improvements in overall and progression-free survival for patients with Stage IVB metastatic or locally uncontrolled recurrent cervical cancer. This case series retrospectively examined the incidence and management of CAEs in 19 female patients treated with this combination therapy between October 2022 and May 2023. Four patients exhibiting CTCAE grade 3 were identified. The four cases of severe CAEs involved erythema multiforme after the initial course of PEM combination chemotherapy. Notably, three patients experienced immediate hypersensitivity reactions, including anaphylaxis, during subsequent treatments. This observation underscores the necessity for rigorous dermatological monitoring of patients undergoing PEM combination chemotherapy. Such vigilance is crucial for early detection of adverse reactions and timely adjustment of treatment regimens, thereby enhancing patient safety., (© 2024 The Author(s). The Journal of Dermatology published by John Wiley & Sons Australia, Ltd on behalf of Japanese Dermatological Association.)

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system caused by JC virus (JCV) infection. Although recognized as an AIDS complication in the 1980s, PML has emerged as a serious adverse event of immunosuppressive therapies since 2005, particularly disease-modifying drugs (DMDs) for multiple sclerosis (MS). PML can also occur in patients with collagenous diseases receiving steroid therapy or with age-related immunosuppression. In some cases, the etiology of immunosuppression remains unclear. These cases often present with early manifestations of PML, which, while common, are less well recognized, as PML was identified at more advanced stages in AIDS-related cases. Early diagnosis poses difficulty due to unfamiliar magnetic resonance (MR) images and low viral loads in cerebrospinal fluid (CSF), and brain biopsy may be conducted. This review summarizes the PML pathology identified through biopsy. Early cytopathological changes of JCV-infected cells, with the importance of dot-shaped inclusions associated with promyelocytic leukemia nuclear bodies (PML-NBs), are described. The variability of host immune responses, including PML immune reconstitution inflammatory syndrome (PML-IRIS), is addressed. The potential role of immune checkpoint inhibitors (ICIs), such as pembrolizumab, is also explored. Understanding the pathology of early PML helps to optimize diagnostic strategies and therapeutic interventions, ultimately improving prognosis., (© 2024 The Author(s). Pathology International published by Japanese Society of Pathology and John Wiley & Sons Australia, Ltd.)

Background: Poly (ADP-ribose) inhibitors, including olaparib, upregulate programmed cell death ligand 1 (PD-L1), which may increase efficacy of anti-PD-(L)1 therapies., Methods: In the phase 3 KEYLYNK-006 trial (NCT03976323), eligible adults with previously untreated metastatic nonsquamous NSCLC without targetable genetic alterations who had complete response (CR), partial response (PR), or stable disease (SD) following induction therapy with 4 cycles of pembrolizumab 200 mg Q3W, pemetrexed 500 mg/m 2 , and carboplatin AUC5 or cisplatin 75 mg/m 2 were randomized 1:1 to olaparib 300 mg orally twice daily or pemetrexed Q3W, both given with ≤31 cycles of pembrolizumab Q3W. Dual primary endpoints were progression-free survival (PFS) and overall survival (OS). PFS was tested at interim analysis 2 (IA2; ie, final PFS analysis), OS at final analysis (FA)., Results: Of 1003 patients who received induction therapy, 672 (67.0%) were randomized to pembrolizumab plus olaparib (n=337) or pembrolizumab plus pemetrexed (n=335) in the intention-to-treat population. Median follow-up at FA was 39.9 (range, 28.1-51.5) months. At IA2, median (95% CI) PFS was 7.1 (5.6-8.7) months versus 8.3 (6.9-11.5) months in the olaparib versus pemetrexed groups (HR, 1.12; 95% CI, 0.92-1.36; P=0.87). At FA, median (95% CI) OS was 20.7 (18.0-24.8) months versus 23.0 (19.0-26.4) months (HR, 1.04; 95% CI, 0.87-1.25; P=0.6649). Grade 3-5 maintenance treatment-related AEs occurred in 26.1% versus 30.1% patients., Conclusion: Pembrolizumab plus maintenance olaparib did not improve PFS or OS versus pembrolizumab plus pemetrexed in previously untreated metastatic nonsquamous NSCLC without targetable genetic alterations., (Copyright © 2024. Published by Elsevier Inc.)

Purpose: The activity of targeted and immunotherapy for the management of advanced bladder cancer is reviewed., Summary: Platinum-based chemotherapy is standard first-line treatment for advanced bladder cancer. Pembrolizumab is approved alone as first-line therapy for patients who are ineligible for any platinum-based chemotherapy and with enfortumab for patients ineligible for cisplatin-based chemotherapy. Avelumab is approved for maintenance therapy in patients who have not progressed with first-line platinum-containing therapy. Pembrolizumab, avelumab, and nivolumab are approved second-line therapy in patients who experience progression during or after platinum-containing chemotherapy. Erdafitinib is indicated for advanced disease that has susceptible FGFR2 or FGFR3 genetic alterations and has progressed during or after treatment with at least one line of platinum-containing chemotherapy. Enfortumab vedotin and sacituzumab govitecan are antibody-drug conjugates. They are both approved for patients who have received anti-PD-L1 or anti-PD-1 therapy and treatment with platinum-containing chemotherapy. Enfortumab is also indicated for patients who are ineligible to receive cisplatin-based therapy and have received one or more prior lines of therapy., Conclusion: Six targeted and immunotherapeutic agents have been approved for patients with advanced urothelial bladder cancer. They all have demonstrated activity in patients for whom disease has progressed during or after platinum-based therapy. Pembrolizumab, with and without enfortumab, has demonstrated first-line activity, and avelumab is a key maintenance therapy after first-line treatment. The results of additional clinical trials should provide evidence to establish the exact role in therapy of each agent in patients with advanced disease., (© American Society of Health-System Pharmacists 2024. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Introduction: First-line treatment of persistent, recurrent, or metastatic (advanced) cervical cancer in patients who have a combined positive score (CPS) ≥ 1 with pembrolizumab + chemotherapy versus standard-of-care chemotherapy provides meaningful improvements in overall survival. We conducted a cost-effectiveness analysis from a US payer perspective. A societal perspective scenario was also considered, including productivity gains., Methods: The cost-effectiveness of pembrolizumab + chemotherapy versus chemotherapy was assessed using a state-transition model comprising the health states "pre-progression," "post-progression," and "death," with a 1-week cycle length and 50-year time horizon. Patient-level KEYNOTE-826 data informed the efficacy, safety, and health-related quality of life of pembrolizumab + chemotherapy versus chemotherapy at first-line and subsequent treatments. Real-world data were sought to cost subsequent treatments according to US clinical practice. Transition probabilities were derived from parametric survival models fit to time-to-progression, progression-free survival, and post-progression survival patient-level KEYNOTE-826 data. Sensitivity analyses explored the impact on outcomes from variables such as bevacizumab use., Results: According to the state-transition model, pembrolizumab + chemotherapy extended mean life expectancy versus chemotherapy from 1.8 to 6.7 life-years. The mean gain of 4.9 life-years/patient was mostly caused by pembrolizumab delaying progression. Total discounted quality-adjusted life-years (QALY) were 5.0 and 1.3 per patient for pembrolizumab + chemotherapy and chemotherapy, respectively (mean gain: 3.7 QALY/patient). Pembrolizumab + chemotherapy had comparable safety outcomes to chemotherapy alone. Total costs incurred were US $320,247 (pembrolizumab + chemotherapy) versus US $105,446 (chemotherapy; mean incremental costs: US $214,801/patient). The incremental cost-effectiveness ratio of pembrolizumab + chemotherapy versus chemotherapy was US $58,446/QALY. Sensitivity analyses showed results were insensitive to bevacizumab use. Including productivity gains led to an incremental cost-effectiveness ratio of US $58,385 per QALY., Conclusions: Our model-based analysis suggests that first-line treatment of pembrolizumab + chemotherapy in advanced cervical cancer with a CPS ≥ 1 offers a substantial clinical benefit over standard-of-care chemotherapy alone and is cost-effective at a willingness-to-pay threshold of US $150,000. The approximate doubling of life-years and QALYs associated with pembrolizumab + chemotherapy represents a step improvement in the treatment of advanced cervical cancer., Trial Registration: ClinicalTrials.gov Identification Number: NCT03635567., (© 2024. Merck & Co., Inc., Rahway, NJ, USA and its affiliates & Bradley J Monk.)

Immune checkpoint inhibitor drugs can trigger autoimmune endocrine reactions as a known side effect. Several cases of immunotherapy-induced autoimmune endocrinopathies have been described, but multiple sequential endocrine toxicities are a rare occurrence. A 39-year-old patient with metastatic melanoma started adjuvant therapy with pembrolizumab. One month later he presented with asymptomatic thyrotoxicosis and, within several weeks, overt hypothyroidism, for which he started levothyroxine therapy. Subsequently the patient developed central adrenal insufficiency due to probable hypophysitis, and steroid replacement therapy was started. Pembrolizumab therapy was then discontinued. After a few months, a full recovery of pituitary function was observed, but primary adrenal insufficiency occurred, requiring additional fludrocortisone therapy. The described clinical case is a very uncommon case of triple endocrinological toxicity from immunotherapy. The clinical and biochemical manifestations of immunotherapy-induced endocrinopathies can be variable and atypical; therefore, it is necessary to pay special attention to any clue of hormonal dysfunction., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Patients with advanced gastric and colorectal cancers have limited treatment options. Since mesothelin is highly expressed in these tumour types, we evaluated the therapeutic benefits of anti-mesothelin hYP218 CAR T cells alone, and in combination with anti-PD1 antibody, pembrolizumab. GEPIA analysis was performed using human gastric (n = 408) and colon cancer tumours (n = 275) in TCGA database, to evaluate mRNA expression of mesothelin, compared to normal tissues. Mesothelin expression in gastric and colorectal cancer cell-lines (n = 5) was analysed using flow cytometry. In vitro efficacy by hYP218 CAR T cells was tested by cytotoxicity and cytokine release assays. In vivo anti-tumour efficacy of hYP218 CAR T cells alone, and in combination with pembrolizumab, was evaluated in NSG mice bearing human gastric (HGC27) and colorectal (SW48) tumour xenografts. Additionally, hYP218 CAR-T cell persistence, activation and exhaustion marker-expression were studied. Mesothelin expression was significantly higher in gastric and colon cancer biopsies compared to normal tissues (p < .005). Mesothelin expression in gastric and colon cancer cell lines ranged from 10 000 to 70 000 molecules per cell. hYP218 CAR T cells demonstrated strong cytotoxic activity at low effector to target ratio, ranging from 0.24 to 1.0. In NSG mouse-models, hYP218 CAR T cells demonstrated anti-tumour efficacy and persisted in the tumour microenvironment in a functional state at day 40 posttreatment with expression of activation markers CD39 and CD69, increased production of IFN-γ and TNF-α and ability to kill tumour cells in vitro when isolated from tumours. There was increased PD1 expression. In combination with pembrolizumab, hYP218 CAR T cells led to slower tumour growth in NSG mice bearing large but not small HGC27 tumours. Anti-tumour efficacy of hYP218 CAR T cells is due to increased accumulation of activated CAR T cells in the tumour and combination with pembrolizumab resulted in improvement in anti-tumour activity of large established tumours. HIGHLIGHTS: Mesothelin expression is significantly higher in gastric and colorectal cancers than normal tissues. hYP218 CAR T cells demonstrate strong anti-tumour activity against mesothelin-positive gastric and colorectal carcinomas. Activated hYP218 CAR T cells persist in the tumour microenvironment and retain their cytotoxic activity. Addition of pembrolizumab in larger tumours enhance CAR T cell efficacy., (Published 2024. This article is a U.S. Government work and is in the public domain in the USA. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

Background: Levels of C-reactive protein (CRP) and alpha-fetoprotein (AFP) in immunotherapy (CRAFITY) scores are associated with the prognosis of patients with hepatocellular carcinoma (HCC). This study aimed to explore the efficacy of lenvatinib and pembrolizumab (Len-P) based on the CRAFITY score., Methods: In this study, 228 patients with HCC who received Len-P in Sun Yat-sen University Cancer Center were included. CRAFITY 0 score was defined as AFP level below 100 ng/ml, CRP level below 1 mg/dl, CRAFITY 1 score was defined as AFP level at least 100 ng/ml or CRP level at least 1 mg/dl. CRAFITY 2 scores were defined as AFP levels exceeding 100 ng/ml and CRP levels exceeding 100 ng/ml. The primary outcome was overall survival (OS). The second outcome was tumor response rate., Results: The survival time of CRAFITY 0 is significantly longer than that of CRAFITY 1 and CRAFITY 2 (p =.044). Univariate analysis showed that largest tumor size (HR = 2.149; 95% CI 1.129 - 4.091; p =.02), lymph node metastasis (HR = 2.012; 95% CI 1.132- 3.579; p = .017), and CRAFITY (HR = 0.372; 95% CI 0.168-0.824; p = .015) were important risk determinants of OS in all patients. The results of multivariate analysis show that CRAFITY score is an independent risk factors for OS (HR = 0.719; 95% CI 0.377-1.374; p =.048). The ORR of CRAFITY 0, 1 and 2 scores were 36.4%, 32% and 27.4%, respectively ( p = .556). The ORR of intrahepatic lesions by CRAFITY 0, 1 and 2 were 37.9%, 35%, 30.6% ( p = .688)., Conclusion: CRAFITY score is a good predictor of prognosis in HCC patients receiving Len-P., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Wu, Yang, Zou, Long, Zhou, Zhang, Chen and Hu.)

This case study describes a female patient in her late 70s who developed autoimmune cholangitis a year after finishing 35 cycles of pembrolizumab for the treatment of her non-small cell lung cancer. The diagnosis was initially missed and delayed; the patient's agoraphobia and the COVID-19 pandemic were noted as contributing factors., Competing Interests: The authors declare no conflict of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Institute of Radiology.)

Background: PERLA (NCT04581824) compared efficacy and safety of dostarlimab (DCT) or pembrolizumab (PCT) plus chemotherapy as first-line treatment for metastatic non-small cell lung cancer. Here, we report patient-reported outcomes (PROs; exploratory analysis) from PERLA., Methods: Patients were randomized 1:1 to receive DCT or PCT every 3 weeks (Q3W) for ≤ 35 cycles [C]. PROs (EORTC QLQ-C30 and QLQ-LC13, PRO-CTCAE, FACT-GP5) were collected at baseline, Q3W until C4, Q9W until C16, Q12W until end of treatment and at 30-day safety follow-up. Change from baseline and time to deterioration (TTD) in QLQ-C30 and QLQ-LC13 were analyzed using longitudinal mixed models and Kaplan-Meier estimators, respectively., Results: The PRO (DCT/PCT) datasets included 102/99 patients for QLQ-C30, 96/90 for QLQ-LC13, 96/88 for PRO-CTCAE, and 95/87 for FACT-GP5. Completion rates were > 80 % to C4, then decreased in both arms. For QLQ-C30 and QLQ-LC13, most patients reported stable/improved responses at C13 (∼ 9 months on treatment), with similar responses between arms except more patients reported improvements in dyspnea (QLQ-C30: 36.4 % vs 13.0 %; QLQ-LC13: 40.6 % vs 25.0 %) and chest pain (QLQ-LC13: 34.4 % vs 10.0 %) with DCT vs PCT. TTD per QLQ-C30 and QLQ-LC13 were similar between arms, although TTD in dyspnea was longer with DCT vs PCT (QLQ-LC13: 4.24 vs 1.54 months; p = 0.0168). Most patients in both arms reported that adverse events occurred occasionally/rarely/never with moderate/mild severity. Overall, patients reported little/no bother from treatment side effects., Conclusions: DCT maintained health-related quality of life similarly to PCT and was well tolerated, supporting the PERLA primary results and dostarlimab use in future regimens., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Martin Reck has had an advisory role for Amgen, AstraZeneca, Beigene, BMS, Boehringer Ingelheim, Daiichi-Sankyo, GSK, Lilly, Merck, MSD, Novartis, Pfizer, Regeneron, Roche, Samsun Bioepsis, and Sanofi. Ana Laura Ortega Granados is an employee of the Servicio Andaluz de Salud and has had an advisory role for Roche, Bristol Myers Squibb, and Merck Sharp Dohme. Filippo de Marinis has had an advisory role for AstraZeneca, Roche, Novartis, Merck, BMS, and MSD. Oren Meyers is an employee of and holds financial equities in GSK. Qin Shen is an employee of and holds financial equities in GSK. Lillian Cho is an employee of and holds financial equities in GSK. Neda Stjepanovic is an employee of and holds financial equities in GSK. Susan Boklage is an employee of and holds financial equities in GSK., (Copyright © 2024. Published by Elsevier Ltd.)

Objective: There is no consensus on whether platinum doublet chemotherapy or lenvatinib and pembrolizumab (LEN/PEM) is superior for advanced or recurrent endometrial cancer. Thus, this study aimed to compare the prognosis and adverse events in patients with advanced or recurrent endometrial cancer treated with platinum doublet chemotherapy or LEN/PEM., Methods: We retrospectively reviewed the medical records of patients who received platinum doublet chemotherapy or LEN/PEM at our institution for advanced or recurrent endometrial cancer and had a history of platinum-based chemotherapy between January 2013 and August 2023., Results: During the study period, 11 regimens were identified in the platinum doublet chemotherapy group, and 11 regimens were identified in the LEN/PEM group. The objective response rates of the platinum doublet chemotherapy and LEN/ PEM groups were 36.4% and 54.5% (P=0.67), respectively. The 6-month progression-free survival (PFS) rates of the platinum doublet chemotherapy and LEN/PEM groups were 27.3% (95% confidence interval [CI], 13.8%-40.7%) and 70.0% (95% CI, 55.5%-84.5%), respectively. The differences were significant between the two groups. Multivariate analyses of histology, prior lines of chemotherapy, platinum-free intervals, and regimens revealed that the LEN/PEM group had significantly better PFS rates., Conclusion: Treatment with LEN/PEM resulted in significantly longer PFS than that of treatment with platinum doublet chemotherapy in patients with advanced and recurrent endometrial cancer. However, further large-scale studies are required to validate these findings.

In the previously reported primary analyses of this phase 3 trial, 12 months of adjuvant pembrolizumab resulted in significantly longer recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) than placebo in patients with resected high risk stage III melanoma. Stability of these benefits when the median follow-up was 3.5 and 5 years was published. Here we report results with a longer follow-up., Methods: We randomized 1019 patients to receive pembrolizumab 200 mg or placebo, intravenously every 3 weeks for a total of 18 doses. RFS in the overall population and in the subgroup of patients with melanoma positive for the PD-1 ligand (PD-L1) were co-primary endpoints. DMFS in these two populations was a secondary and progression/recurrence-free survival 2 (PRFS2) an exploratory endpoint., Results: The median follow-up was 6.9 years. In the overall intention-to-treat population, RFS was longer in the pembrolizumab group than in the placebo group (HR 0.63, 95 % CI 0.53 to 0.74). RFS at 7 years was 50 % (95 % CI 46 % to 55 %) in the pembrolizumab and 36 % (95 % CI 32 % to 41 %) in the placebo group. Positive effects were present both for loco-regional recurrences and distant metastases, and across substages IIIA-IIIB-IIIC, and PD-L1 positive and PD-L1 negative as well as for BRAF mutant and BRAF wild type populations. DMFS was longer in the pembrolizumab group than in the placebo group (HR 0.64, 95 % CI 0.54 to 0.76). DMFS at 7 years was 54 % (95 % CI 50 % to 59 %) in the pembrolizumab and 42 % (95 % CI 37 % to 46 %) in the placebo group. PRFS2 was longer in the pembrolizumab group than in the placebo group (HR 0.69, 95 % CI 0.57 to 0.84). PRFS2 at 7 years was 61 % (95 % CI 57 % to 66 %) in the pembrolizumab and 53 % (95 % CI 49 % to 57 %) in the placebo group., Conclusions: The 7-year analysis of adjuvant therapy with pembrolizumab demonstrated a sustained improvement in the long-term RFS, DMFS and PRFS2 compared with placebo in patients with resected stage III melanoma., Competing Interests: Declaration of Competing Interest Alexander MM Eggermont is an Editor-in-Chief for European Journal of Cancer and was not involved in the editorial review or the decision to publish this article. Susana Puig is an Editor for European Journal of Cancer Skin Cancer and was not involved in the editorial review or the decision to publish this article. Dirk Schadendorf is an Editor-in-Chief European Journal of Cancer Skin Cancer and was not involved in the editorial review or the decision to publish this article. The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Alexander C.J. van Akkooi: advisory board/consultancy honoraria from 4SC AG, Amgen, Bristol-Myers Squibb, Merck Serono-Pfizer, MSD-Merck, Neracare, Novartis, Pierre Fabre, Sanofi, Sirius Medical, SkylineDX; research grants from Amgen, Merck Serono-Pfizer, SkylineDX. Paolo A. Ascierto: a consultant/advisory role for Bristol Myers Squibb, Roche-Genentech, Merck Sharp & Dohme, Novartis, Merck Serono, Pierre-Fabre, Sun Pharma, Sanofi, Sandoz, Immunocore, Italfarmaco, Boehringer-Ingelheim, Regeneron, Pfizer, Nouscom, Lunaphore, Medicenna, Bio-Al Health, ValoTX, Replimmune, Bayer, Erasca, Philogen, Biontech, Anaveon; research funding from Bristol Myers Squibb, Roche-Genentech, Pfizer, Sanofi; travel support by Pfizer, Bio-Al Health, Replimmune, MSD, Pierre Fabre, Philogen. Victoria Atkinson: advisory board for and speeches fees from BMS, MSD, Novartis, Immunocore; travel support by Pierre Fabre. Christian U Blank: advisory role for BMS, MSD, Roche, Novartis, GSK, AZ, Pfizer, Lilly, GenMab, Pierre Fabre, Third Rock Ventures, Sandoz; research funding from BMS, Novartis, NanoString, 4SC; stock ownership of Flindr Therapeutics, Signature Oncology. Matteo Carlino: advisory boards or a consultant for Amgen, BMS, Eisai, Ideaya, MSD, Nektar, Novartis, Oncosec, Pierre-Fabre, Qbiotics, Regeneron, Roche, Merck, and Sanofi; honoraria from BMS, MSD, and Novartis. Stéphane Dalle: research grants to institution from MSD, BMS, Pierre Fabre; advisory board paid to institution by MSD and BMS; spouse employment Sanofi. Alexander MM Eggermont: honoraria for scientific advisory board or data monitoring committee activities from Agenus, Bioinvent, BioNTech, Boehringer Ingelheim, Brenus, CatalYm, Eurobio, GenOway, Imcheck, IO Biotech, Ipsen, IQVIA, ISA Pharmaceuticals, Merck KGA, Merck&Co/MSD, Pfizer, Pierre Fabre, QBiotics, Regeneron, Replimune, Sairopa BV, ScanCell, Scorpion Pharmaceuticals, Secarna, Sellas, SkylineDX BV, TigaTX, Thermosome, Trained Immunotherapeutics Discovery. Stock: IO Biotech, Sairopa BV, SkylineDX. Anna Maria Di Giacomo: advisor/board member for Merck, Roche, Bristol Myers Squibb, Incyte, Pierre Fabre, Sanofi, GlaxoSmithKline, SunPharma, Immunocore; honoraria from Merck, Bristol Myers Squibb, Sanofi, Pierre Fabre, GlaxoSmithKline, SunPharma. Immunocore. Dmitri Grebennik: employee of Merck & Co. Jean-Jacques Grob: advisory boards for Novartis, BMS, MSD, Philogen, Pierre Fabr, Sanofi, Roche, Amgen. Ralf Gutzmer: honoraria for lectures and advice from BristolMyers Squibb, MerckSharpDohme, Novartis, Merck-Serono, Amgen, Almirall Hermal, Pierre-Fabre, Sun Pharma, Immunocore, 4SC, Delcath, Sanofi/Regeneron; support for participation in meetings from SUN Pharma, Boehringer Ingelheim and PierreFabre; research support (to institution) from Sanofi/Regeneron, Merck Serono, Amgen, SUN Pharma, KyowaKirin, Almirall Hermal, Recordati. Andrew Haydon: advisory board member for BMS, MSD and Novartis. Rahima Jamal: honoraria for presentation and advisory board with Merck. PI in Merck-sponsored trials. Adnan Khattak: speaker honoraria, advisory board, and travel sponsorship from MSD. Michal Kicinski: research funding from MSD, BMS, Pierre Fabre, Immunocore, and JnJ. Clemens Kreplere: employee and shareholder of Merck & Co. James Larkin: relationships with the following companies: iOnctura, Apple Tree, Merck, BMS, MSD, Telix, Novartis, Philogen, Pfizer, Incyte, Eisai, Debipharm, GCO, TouchIME, Immatics, Insighter, Agence Unik, VJOncology, Royal College of General Practioners, Cambridge Healthcare Research, Royal College of Physicians, TouchExperts. Georgina V Long: consultant advisor for Agenus, Amgen, Array Biopharma, AstraZeneca, Bayer, BioNTech, Boehringer Ingelheim, Bristol Myers Squibb, Evaxion, GI Innovation, Hexal AG (Sandoz Company), Highlight Therapeutics S.L., IOBiotech, Immunocore, Innovent Biologics USA, MSD, Novartis, PHMR Ltd, Pierre Fabre, Regeneron, Scancell, SkylineDX B.V. Paul Lorigan: support for travel from MSD; research funding from Pierre Fabre and BMS; speakers bureau/consultancy for BMS and Pierre Fabre. Mario Mandala: advisory board and lectures for: MSD, BMS, Novartis, Pierre Fabre, Sanofi, Sun Pharma; research grant from Novartis. Susana Puig: speaker for Almirall, BMS, Cantabria, ISDIN, La Roche Posay, Leo Pharma, MSD, Novartis, Pfizer, Roche, Regeneron, Sanofi, Sunpharma; advisory board of Almirall, BMS, ISDIN, La Roche Posay, Regeneron, Roche, Sanofi, Sun Pharma; involvement in research and trials of Abbvie, Almirall, Amgen, BMS, Biofrontera, Canfield, Cantabria, Fotofinder, GSK, ISDIN, La Roche Posay, Leo Pharma, MSD, MEDA, Novartis, Polychem, Roche, Sun Pharma; husband has relationship with Almirall, Amgen, BMS, Biofrontera, Canfield, Cantabria, Fotofinder, GSK, ISDIN, La Roche Posay, Leo, Mavig, Nevisence, Novartis, Polychem, Roche, Sun Pharma. Educational activities for Abbie, Lilly, and ISD; ownership of Athena Tech & Dermavision Solutions. Caroline Robert: consultant/advisory board of Pierre Fabre, Sanofi, BMS, MSD, Novaris, Merck, Roche, Pfizer, Sun Pharma, Ultimovacs, Regeneron, Egle, Philogen, Maat Pharma; consultant steering committee for Novartis, Regeneron, Pfizer, IO Biotech; consultant IDMC for Ultimovacs; speaker for Pierre Fabre, Sanofi, BMS, MSD, Novaris; travel by Pierre Fabre. Piotr Rutkowski: honoraria for lectures and advisory boards from MSD, BMS, Novartis, Pierre Fabre, Genesis Pharma, Medison Pharma. Shahneen Sandhu: research funding from Novartis/AAA, AstraZeneca, Merck Sharp and Dohme, Amgen, Genentech, Senwha, Bristol-Myers Squibb, Merck Healthcare and Pfizer; participation on advisory boards for Merck Sharp and Dohme, AstraZeneca, Novartis, SkylineDx and Abbvie (fees for attending go to research funds at the institution); honoraria from AstraZeneca, Bristol-Myers Squibb, Merck Sharp & Dohme and Janssen (all paid to the institution); chair of DSMB for 2 Novartis/AAA sponsored Phase III trials (no fee accepted for chair role). Dirk Schadendorf: a member of the advisory board, consultant or received speakers´ honoraria from: Astra Zeneca, BMS, CureVac, Daiichi Sankyo, Erasca, Haystack, Immatics, Immunocore, InFlarX, Lapcorp, Merck-Serono, MSD, Neracare, Novartis, Novogenix, PamGene, Philogen, Pierre Fabre, Pfizer, Regeneron, Replimune, Sanofi, Seagen, Sun Pharma, UltraVacs; research funding from BMS, Roche, MSD, Amgen & Novartis. Stefan Suciu: DSMB member of the NADINA study. Alfonsus JM van den Eertwegh: study grant from Bristol-Myers Squibb, Idera; travel expenses by Ipsen; advisory board of Bristol-Myers Squibb, MSD Oncology, Ipsen, Pierre Fabre, Janssen Cilag BV. The remaining authors declare no conflicts of interest., (Copyright © 2024. Published by Elsevier Ltd.)

Mucosal malignant melanoma (MMM) is a rare subtype of malignant melanoma with a more aggressive biological behavior than cutaneous melanoma (CM). Owing to its rarity, it is necessary to accumulate information on treatments, especially in Asians, in whom MMM occurs more frequently than in Caucasians. In this study, we investigated the efficacy and adverse events (AEs) of nivolumab plus ipilimumab therapy (NIVO+IPI) versus immune checkpoint inhibitor (ICI) monotherapy (PD-1) in Japanese patients with MMM. We reviewed patients with advanced or recurrent MMM who received ICIs as first-line systematic therapy between February 2012 and February 2024 at the Shizuoka Cancer Center. We enrolled a total of 57 patients: 10 (17.5%) were treated with NIVO+IPI, and 47 (82.5%) were treated with PD-1 as first-line systemic therapy. Objective response rates (ORR) did not differ significantly between the NIVO+IPI and PD-1 groups (40.0% vs 27.7%; p = 0.176). There was also no statistically significant difference in progression-free survival (PFS) (median PFS time: 4.3 months vs 9.9 months, log-rank test, p = 0.578) or overall survival (OS) (median OS time: 33.1 months vs. 22.8 months, log-rank test, p = 0.697) between the two groups. However, regarding AEs, grade ≥3 AEs leading to discontinuation of first-line treatment occurred in 80% of patients in the NIVO+IPI group and in 22.6% of patients in the PD-1 group (p = 0.002). No difference was found in the efficacy of NIVO+IPI therapy and anti-PD-1 antibody monotherapy as the first-line treatment for MMM in Japanese patients, but an increase in AEs was observed with combination therapy. This study suggests that patients with MMM may receive less benefit from NIVO+IPI than from PD-1., (© 2024 The Author(s). The Journal of Dermatology published by John Wiley & Sons Australia, Ltd on behalf of Japanese Dermatological Association.)

Cutaneous squamous cell carcinoma (cSCC) arising from radiation dermatitis has a higher risk of metastasis than conventional cSCC. Immunosuppression is another risk factor for cSCC, suggesting that mycosis fungoides (MF) could be a risk factor for cSCC. Here we report a case of radiation-induced cSCC with a high level of tumor-mutation burden that developed in a patient with MF who was successfully treated with pembrolizumab. The present case suggests that pembrolizumab might be an optimal therapy for radiation-induced cSCC, even at advanced stages., (© 2024 Japanese Dermatological Association.)

Definitive chemoradiotherapy (DCRT) is administered as standard treatment for patients with cT4 and/or M1Lym esophageal squamous cell carcinoma (ESCC); however, its long-term result is inadequate. Although several studies have reported that conversion surgery can improve the survival of these patients, none have identified significantly better long-term survival than that achieved by DCRT. Thus, enhancing DCRT seems important to improve the survival of these patients. A strategy of shrinking tumor volume before DCRT and providing consolidation chemotherapy for systemic control is expected to improve the survival of these patients. Pembrolizumab plus cisplatin and fluorouracil has demonstrated good local control and significant improvement in the survival of patients with advanced esophageal cancer. Based on these results, the following strategy is proposed: This protocol should be applied as induction for these patients; then, DCRT should be provided depending on the initial response; and finally, adjuvant chemotherapy with an immune checkpoint inhibitor should be given to all responders., (© 2024. The Author(s).)

Background: The therapeutic benefit of immuno-oncology (IO) therapy for patients with advanced non-clear-cell renal cell carcinoma (nccRCC) remains unclear., Patients and Methods: We reviewed clinical data from 93 patients with advanced nccRCC who received first-line systemic therapy including IO combination therapy and tyrosine kinase inhibitor (TKI) monotherapy at our affiliated institutions. Patients were divided based on the period when the treatment was implemented as the standard of care into the IO and TKI eras. Survival and tumor response outcomes were compared between the IO and TKI eras., Results: Of the 93 patients, 50 (54%) and 43 (46%) were categorized as IO era and TKI era groups, respectively. Progression-free survival (PFS) and overall survival (OS) were significantly longer in the IO era than in the TKI era (median PFS: 8.97 vs. 4.96 months, p = 0.0152; median OS: 38.4 vs. 13.5 months, p = 0.0001). After the adjustment using other covariates, the treatment era was an independent factor for PFS (hazard ratio: 0.59, p = 0.0235) and OS (hazard ratio: 0.27, p < 0.0001). Objective response and disease control rates was not significantly different between the treatment eras (26% vs. 16.3%, p = 0.268; 62% vs. 62.8%, p = 0.594)., Conclusion: The implementation of IO therapy was significantly associated with longer survival in the nccRCC population. Further studies are needed to establish a more effective treatment strategy in this population using multiple regimens of IO combination therapy., (© 2024. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

Parathyroid cancer (PC) is extremely resistant to chemotherapy and radiotherapy (RT), but hormonally functional by producing excessive parathyroid hormone (PTH), causing remarkable hypercalcemia even in biochemical disease recurrence. Accordingly, management of hypercalcemia by calcimimetics and bisphosphonates has been main treatment for unresectable PC. Here, we report a case of unresectable tumor mutational burden (TMB)-high recurrent PC that has been effectively controlled by pembrolizumab (PEM) with RT. A 48-year-old male patient, with previous history of left single parathyroidectomy for primary hyperparathyroidism, underwent surgeries for recurrent hyperparathyroidism at 47 and 48 years of age, and was pathologically diagnosed with PC. He was referred to our hospital due to persistent hypercalcemia and elevated PTH. The recurrent tumors were identified in the superior mediastinum and radically resected, then the hyperparathyroidism was improved. A FoundationOne ® CDx of the specimen called TMB-high. He demonstrated recurrent hyperparathyroidism at 49 years of age, and underwent a gross curative resection. However, hyperparathyroidism achieved only insufficient improvement, indicating biochemical residual cancer cells. PEM treatment was initiated in combination with RT to the left central-lateral neck and superior mediastinum. He successfully achieved evocalcet and zoledronate withdrawal, and the PTH level improvement was continuously observed for 8 months at present, with only grade 2 subclinical hypothyroidism. Interestingly, leukocyte fraction ratios were reversed corresponding to disease improvement. A combination of PEM and RT is a promising treatment of unresectable TMB-high PC. Recent evidence on the immunomodulatory effect of RT provides the rationale for the combination of RT and PEM.

Objective: To assess the cost-effectiveness of pembrolizumab in combination with chemotherapy compared to chemotherapy alone, based on the results of the NRG-GY018 trial, in patients with advanced or recurrent endometrial cancer (EC), stratified by mismatch repair-deficient (dMMR) and mismatch repair-proficient (pMMR) subgroups., Methods: A Markov model was used to simulate patients receiving either pembrolizumab plus chemotherapy or chemotherapy alone. Lifetime costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio (ICER) were calculated using a willingness-to-pay (WTP) threshold of $150,000/QALY. Univariate and probabilistic sensitivity analyses were conducted to assess the robustness of our findings., Results: The addition of pembrolizumab to chemotherapy led to an incremental gain of 4.05 QALYs at an additional cost of $167,224, resulting in an ICER of $41,305.09/QALY compared to chemotherapy alone in dMMR EC. Additionally, there were 0.93 additional QALYs at an additional cost of $83,661, which resulted in an ICER of $90,284.80/QALY in pMMR EC. Sensitivity analyses indicated that the cost of pembrolizumab, utility of progressed disease, and utility of progression-free survival had the greatest impact on the results. Probabilistic sensitivity analysis showed that pembrolizumab was considered cost-effective at a 100% probability at a WTP threshold of $150,000 per QALY., Conclusion: Pembrolizumab, when combined with chemotherapy, was found to be cost-effective compared to chemotherapy alone both for patients with advanced or recurrent dMMR and pMMR EC from the perspective of a payer in the United States., Competing Interests: No potential conflict of interest relevant to this article was reported., (© 2024. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology, and Japan Society of Gynecologic Oncology.)

Objective: The efficacy of pembrolizumab in patients with microsatellite instability (MSI)-high cancers has been reported; however, the differences in efficacy according to the subtypes of MSI-high endometrial cancers (ECs) remain unclear. MSI-high ECs are classified into at least 3 groups based on their molecular characteristics: MLH1 hypermethylated, Lynch-like syndrome (LLS)-associated, and Lynch syndrome (LS)-associated cancers. This study aimed to investigate whether the efficacy of pembrolizumab differs among these 3 groups, and if so, whether EPM2AIP1 immunohistochemistry (IHC), which correlates with MLH1 promoter methylation, can be used to rule out MLH1 methylation cases., Methods: This study included 12 patients with MSI-high EC who received pembrolizumab treatment. Patients were categorized into 3 groups based on MLH1 methylation analysis and the Amsterdam Criteria: MLH1 hypermethylated (sporadic [SP]), LLS-associated, and LS-associated. Patients' medical records were retrospectively reviewed, and the efficacy of treatment was evaluated based on the response rate using the Response Evaluation Criteria in Solid Tumors version 1.1., Results: The overall response rate was 75% (3/4) in the SP group, while it was 100% including one complete response patient in the LLS-associated and the LS-associated group, respectively. The sensitivity and positive predictive value of EPM2AIP1 IHC for MLH1 methylation were 100% and 66.7%, respectively., Conclusion: Pembrolizumab may be more effective in LLS and LS-associated groups. EPM2AIP1 IHC was less predictive than MLH1 methylation analysis; however, it may be useful for ruling out MLH1 methylation cases due to its high sensitivity. Further studies are needed to determine whether EPM2AIP1 IHC can predict pembrolizumab efficacy., Competing Interests: Tadaaki Nishikawa reports receiving Grants to his institution from Daiichi-Sankyo, and AstraZeneca. He also reports receiving honoraria for speakers' bureaus and manuscript writing from AstraZeneca, Chugai, Takeda, MSD, Eisai, Taiho, Roche Diagnostics and Sanofi., (© 2024. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology, and Japan Society of Gynecologic Oncology.)

Background: Recent studies have underscored the potential of innovative administration methods to mitigate the capacity burden on healthcare systems, without compromising the quality of care. This study assessed and compared the resource utilization and associated costs of two distinct administration modes of immune checkpoint inhibitors: the innovative elastomeric pump and conventional intravenous infusion. This comparison can inform sustainable healthcare practices and healthcare decision-making to optimize treatment efficiency in an era of escalating healthcare demands., Methods: In this micro-costing study, data on resource use and time allocation for drug preparation and administration were collected using an observational, non-interventional study design. Data were registered at the oncology daycare unit and hospital pharmacy. Cost categories included drug acquisition, disposable materials, healthcare professional time for drug administration, drug preparation, and patient time spent at the oncology day care unit., Results: Drug administration through the elastomeric pump resulted in substantially lower healthcare costs when compared to conventional infusion, particularly due to reduced labor and chair time. The elastomeric pump reduced the total chair time by 78% and nurse time by 55%. Total average costs (excluding drug costs) were €103,47 and €77.99 for conventional infusion and the elastomeric pump, respectively, showcasing potential savings of €25.48 (P < 0.001) per administration., Conclusions: This study demonstrated that the elastomeric pump not only offers substantial cost savings but also enhances the treatment capacity of the oncology day care unit. These findings support the adoption of the elastomeric pump in clinical settings as a cost-saving and efficient alternative to conventional infusion., Trial Registration: This study has been registered in the National Trial Register (NTR), with the reference number NTR NL9473. Registration date: 05-05-2021., (© 2024. The Author(s).)

Background/objectives: The landscape of advanced melanoma treatments has shifted dramatically in recent years. Target therapy and immunotherapy have changed the management of patients with both metastatic (stage IV according to AJCC 8th ed.) and nodal (stage IIB/C and III) disease. As the use of novel agents has increased, so have the cutaneous toxicities associated with these medications. While most skin reactions are low-grade and can be managed conservatively with topical therapies, high-grade or life-threatening drug reactions can arise during therapy, requiring prompt dermatologic recognition and treatment. Given the survival benefit attributed to these new agents, treating skin toxicity and maintaining a patient's quality of life is of paramount importance., Methods: We undertook a prospective, monocentric, and descriptive study in Bologna, Italy, including patients referred to the Oncologic Dermatology Unit of IRCCS AOU of Bologna who developed biopsy-proven cutaneous adverse events (AE) under treatment with immunotherapy for cutaneous melanoma with nodal (stage IIB/C, III) and metastatic (stage IV) disease from January 2016 to April 2024., Results: In 202 identified patients, 75 (37.5%) developed skin AEs. Ipilimumab was causal for 48.1% of skin AEs, followed by nivolumab (37%) and pembrolizumab (31.4%). Recorded types of skin AEs included erythematous rash, vitiligo, alopecia, lichenoid, maculopapular, acneiform, urticarial, psoriasiform, granulomatous, eczematous, and severe cutaneous AEs, such as Erythema multiforme/Stevens-Johnson syndrome and bullous autoimmune dermatoses. Most AEs were low-grade [CTCAE 1-2] (97%) and typically occurred after 10 weeks of treatment., Conclusions: This study comprehensively describes skin AEs occurring during systemic treatment with ICIs for cutaneous melanoma at a single center.

Background: Combined treatment with lenvatinib and pembrolizumab is currently regarded as one of the standard first-line therapies for advanced renal cell carcinoma (aRCC) patients. The objective of this study was to assess the efficacy and safety of this combined regimen in treatment-naïve Japanese aRCC patients., Methods: This study included a total of 50 consecutive aRCC patients receiving combined lenvatinib plus pembrolizumab in routine clinical practice in Japan, and comprehensively analyzed clinical outcomes of this treatment., Results: Of these 50, 7 (14.0%), 23 (46.0%) and 20 (40.0%) were classified into favorable, intermediate and poor risk groups, respectively, according to the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) system. Responses to this combined therapy in the 50 patients were as follows: complete response, 7 (14.0%); partial response, 26 (52.0%); stable disease, 15 (30%) and progressive disease, 2 (4%); thus, the objective response rate (ORR) was 66%. ORRs in favorable, intermediate and poor risk groups were 57.1, 69.6 and 65.0%, respectively. During the observation period, disease progression and death occurred in 14 (28.0%) and 6 (12.0%) patients, respectively, and neither the median PFS nor OS was reached. Adverse events and those corresponding to grade ≥ 3 were observed in all (100%) and 33 (66.0%) patients, respectively., Conclusions: To our knowledge, this is the first study focusing on real-world outcomes of lenvatinib and pembrolizumab for treatment-naïve aRCC patients, showing that the efficacy and safety of this combined regimen are similar to those noted in randomized clinical trial., (© 2024. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

Introduction: The phase 3 KEYNOTE-361 trial of first-line pembrolizumab with or without chemotherapy versus chemotherapy alone in patients with locally advanced or metastatic urothelial carcinoma (la/mUC) completed enrollment before the approval of postchemotherapy maintenance avelumab for patients without progressive disease. This post hoc analysis evaluated the outcomes of patients who received chemotherapy alone in KEYNOTE-361 by retrospective eligibility for subsequent maintenance therapy., Patients and Methods: Patients in the chemotherapy alone arm were retrospectively categorized as maintenance eligible (received ≥4 cycles of chemotherapy and did not die or experience disease progression within 10 weeks of chemotherapy completion), maintenance ineligible (received <4 cycles of chemotherapy or had progressive disease or died within 0-10 weeks after completion of ≥4 cycles of chemotherapy), and indeterminate eligibility for maintenance therapy (if neither maintenance eligible or ineligible). End points included progression-free survival per Response Evaluation Criteria in Solid Tumors version 1.1 by blinded independent central review and overall survival from randomization (start of chemotherapy)., Results: Median follow-up was 31.7 months (range, 22.0-42.3). Among 342 patients who received chemotherapy alone, 172 (50.3%) were maintenance eligible, 108 (31.6%) were maintenance ineligible, and 62 (18.1%) had indeterminate eligibility for maintenance therapy. The median progression-free survival was 9.0 months (95% CI 8.4-10.4) in maintenance-eligible patients, 5.1 months (4.2-6.0) in maintenance-ineligible patients, and 2.3 months (1.9-3.8) in the indeterminate group; median overall survival was 23.3 months (95% CI 19.4-26.1), 10.2 months (9.1-11.6), and 5.5 months (3.7-8.5), respectively., Conclusion: This post hoc analysis suggests that a majority of patients with untreated la/mUC who initiated chemotherapy in a clinical trial may have been considered eligible for maintenance therapy and had favorable survival outcomes compared with those considered maintenance ineligible., Competing Interests: Disclosure R. Mamtani reports research grants or contracts to his institution from Astellas and MSD and consulting fees from Astellas, Bristol Myers Squibb, Merck & Co, Inc, and Seagen outside the submitted work. N. Matsubara reports research grants or contracts to his institution from AbbVie, Amgen, Astellas, AstraZeneca, Bayer, Chugai, Eisai, Eli Lilly, Janssen, MSD, Pfizer, PRA Health Science, Roche, Taiho, Takeda, and Seagen; personal payment or honoraria from Sanofi; and support for attending meetings and/or travel from Pfizer outside the submitted work. A. Montesa Pino reports consulting fees from Advanced Accelerator Applications, Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Ipsen, Janssen, Merck & Co, Inc, MSD, Novartis, and Pfizer; support for attending meetings and/or travel from Bayer, Ipsen, Merck & Co, Inc, and Pfizer; and participation on a data safety monitoring board or advisory board of Advanced Accelerator Applications, Ipsen, and Merck & Co, Inc outside the submitted work. U. Anido Herranz reports payments for lectures from Ipsen and Merck & Co, Inc outside the submitted work. M. A. N. Şendur reports consulting fees and payments or honoraria from Astellas, AstraZeneca, Bristol Myers Squibb, Gilead, Janssen, Lilly, MSD, Novartis, Pfizer, Roche, and Takeda. G. Gravis reports research grants or contracts to his institution from Bristol Myers Squibb and Janssen; payments or honoraria to his institution for lectures, presentations, speaker's bureaus, manuscript writing, or educational events from Advanced Accelerator Applications, Alliance Merck-Pfizer, Amgen, Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Eisai, Ipsen, Janssen, MSD, Pfizer, and Sanofi; support for attending meetings and/or travel from AstraZeneca, Bayer, Bristol Myers Squibb, Ipsen, Janssen, MSD, and Pfizer; and participation on a data safety monitoring board or advisory board of Advanced Accelerator Applications, Alliance Merck-Pfizer, AstraZeneca, Bayer, Bristol Myers Squibb, Eisai, Ipsen, Janssen, and Pfizer outside the submitted work. O. Huillard reports payments or honoraria to his institution for lectures, presentations, speaker's bureaus, manuscript writing or educational events from Advanced Accelerator Applications, Bristol Myers Squibb, Eisai, Ipsen, Janssen, MSD, Novartis, Pfizer, and Sanofi; and support for attending meetings and/or travel from Advanced Accelerator Applications and Ipsen outside the submitted work. R. Gafanov reports funding for the present manuscript from MSD; research grants or contracts to him and his institution from Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Ipsen, Jannsen, Pfizer, and Roche; payments or honoraria to him and his institution for lectures, presentations, speaker's bureaus, manuscript writing or educational events from Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Ipsen, Jannsen, Pfizer, and Roche; support for attending meetings and/or travel from Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Ipsen, Jannsen, Pfizer, and Roche; and participation on a data safety monitoring board or advisory board of Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Ipsen, Jannsen, Pfizer, and Roche outside the submitted work. F. Joly reports grants or contracts to her institution for ISS protocol from Ipsen; consulting fees paid to her for membership of scientific board of Esai Co, Ltd., Ipsen, and Pfizer; payment for lectures from Ipsen and Pfizer; and support for congress attendance from Esai Co, Ltd. and Ipsen. J. Bedke reports receiving medical writing support and local principal investigator payments to his institution for the present manuscript from MSD; local principal investigator payments to his institution from Astellas, AstraZeneca, Bristol Myers Squibb, Eisai, Ipsen, MSD, Nektar, Novartis, Pfizer, Roche, and Seagen; consulting fees from Apogepha, Astellas, AstraZeneca, Bristol Myers Squibb, Eisai, Ipsen, Janssen, Merck Serono, MSD, Pfizer, and Roche; payment or honoraria to him and his institution for lectures, presentations, speaker's bureaus, manuscript writing or educational events from Astellas, Bristol Myers Squibb, Ipsen, Merck Serono, MSD, Pfizer, Roche, and Seagen; support for attending meetings and/or travel from Ipsen and Merck & Co, Inc; payments to his institution for participation on a steering committee of Bristol Myers Squibb, MSD, and Seagen and participation on a data safety monitoring board or advisory board of MSD and Pfizer, outside the submitted work. K. Imai, B. Homet Moreno, and J. Z. Xu are employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc, Rahway, NJ, USA, and have stock in Merck & Co, Inc, Rahway, NJ, USA. A. Alva reports funding to his institution for the present manuscript from MSD and research grants or contracts to his institution from MSD. T. Powles reports grants or contracts from Astellas, AstraZeneca, Bristol Myers Squibb, Eisai, Exelixis, Gilead, Ipsen, Johnson & Johnson, Merck Serono, MSD, Novartis, Pfizer, Seattle Genetics, and Roche; consulting fees from Astellas, AstraZeneca, Bristol Myers Squibb, Eisai, Exelixis, Incyte, Ipsen, Johnson & Johnson, Mashup, Merck Serono, MSD, Novartis, Pfizer, Roche, and Seattle Genetics; and payment or honoraria for lectures, presentations, speaker's bureaus, manuscript writing or educational events from Astellas, AstraZeneca, Bristol Myers Squibb, Eisai, Exelixis, Incyte, Ipsen, Johnson & Johnson, Mashup, Merck Serono, MSD, Novartis, Pfizer, Roche, and Seattle Genetics; support for attending meetings and/or travel from Astellas, AstraZeneca, Gilead, Ipsen, MSD, Pfizer, and Roche; participation on a data safety monitoring board or advisory board of Astellas, AstraZeneca, Bristol Myers Squibb, Eisai, Exelixis, Ipsen, Johnson & Johnson, Merck Serono, MSD, Novartis, Pfizer, Roche, and Seattle Genetics; and other financial or nonfinancial interests as principal investigator for AstraZeneca, Eisai, MSD, Novartis, Pfizer, and Roche/Genentech, outside the submitted work. H. J. Lee, A. Sella, and Y.-H. Chang declare no competing interests., (Copyright © 2024. Published by Elsevier Inc.)

Background: PARP inhibitors can upregulate PD-L1 expression and promote immune-mediated responses, and may improve efficacy of first-line anti‒PD-1‒based therapies in patients with metastatic squamous NSCLC., Methods: In this randomized, double-blind, phase 3 trial (NCT03976362), adults with previously untreated stage IV squamous NSCLC received 4 cycles of induction therapy (pembrolizumab 200 mg Q3W plus carboplatin and paclitaxel or nab-paclitaxel). Patients with disease control were randomized to 31 cycles of pembrolizumab 200 mg Q3W plus olaparib 300 mg orally twice-daily or placebo. Dual primary endpoints were progression-free survival (PFS) and overall survival (OS). PFS was tested at interim analysis 2 (IA2; the final PFS analysis); OS was tested at final analysis., Results: 851 patients received induction treatment; 296 were randomized to pembrolizumab plus olaparib and 295 to pembrolizumab plus placebo. At IA2, with median follow-up of 27.1 months, median (95% CI) PFS was 8.3 (6.7‒9.7) in the pembrolizumab plus olaparib group and 5.4 (4.1‒5.6) months in the pembrolizumab plus placebo group (HR, 0.77 [95% CI, 0.63‒0.93]; P=0.0040 [not significant at a 1-sided at superiority boundary of P=0.003). At final analysis, with median follow-up of 33.4 months, median (95% CI) OS was 19.1 (15.9‒22.2) and 18.6 (16.0‒21.6) months, respectively (HR, 1.01 [95% CI, 0.83‒1.24]; P=0.5481). Treatment-related adverse events occurred in 76.5% and 65.1% of patients, respectively., Conclusion: Adding olaparib to pembrolizumab as maintenance therapy for metastatic squamous NSCLC did not significantly improve PFS versus pembrolizumab plus placebo, neither PFS nor OS met the prespecified statistical significance boundary. No new safety signals were identified., (Copyright © 2024. Published by Elsevier Inc.)

Background: First-line pembrolizumab monotherapy is a standard of care for platinum-ineligible patients with advanced urothelial carcinoma (UC). No global standardized definition of platinum ineligibility exists. This study aimed to evaluate the efficacy and safety of pembrolizumab monotherapy in patients with UC who met various criteria for platinum ineligibility., Methods: Patients from KEYNOTE-052 and LEAP-011 deemed potentially platinum ineligible were pooled for this post hoc exploratory analysis as follows: group 1: Eastern Cooperative Oncology Group performance status (ECOG PS) 2; group 2: ECOG PS 2 and age ≥80 years, renal dysfunction, or visceral disease; and group 3: any two other factors regardless of ECOG PS. Patients received pembrolizumab 200 mg intravenously every 3 weeks. End points included objective response rate (ORR), progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors, version 1.1, by blinded independent central review, overall survival (OS), and safety., Results: A total of 612 patients treated with pembrolizumab from KEYNOTE-052 (n = 370) and LEAP-011 (n = 242) were included; the median (range) follow-up was 56.3 months (51.2-65.3 months) and 12.8 months (0.2-25.1 months), respectively. For group 1, ORR was 26.2%, median PFS was 2.7 months, and median OS was 10.1 months. For group 2, ORR ranged from 23.5% to 33.3%, median PFS ranged from 2.1 to 4.4 months, and median OS ranged from 9.1 to 10.1 months. For group 3, ORR ranged from 25.7% to 27.9%, median PFS ranged from 2.1 to 2.8 months, and median OS ranged from 9.0 to 10.6 months. Treatment-related adverse event rates were consistent across groups., Conclusions: Frontline pembrolizumab has consistent antitumor activity and safety in patients with advanced UC categorized as potentially ineligible for platinum-based chemotherapy, regardless of the variable definitions of platinum ineligibility used., (© 2024 The Author(s). Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

A glioblastoma (GBM) patient with a high tumor mutation burden (TMB-high) and mismatch repair deficiency (dMMR) exhibited a significant response to pembrolizumab, an immune checkpoint inhibitor (ICI), despite prior treatment with temozolomide (TMZ), known to induce hypermutation and potential resistance to ICIs. The rapid disease progression, indicated by 80% Ki67 positivity, was markedly countered by the positive outcome of pembrolizumab treatment. This case challenges traditional GBM treatment paradigms, demonstrating the potential of precision oncology in patients with significant TMB and dMMR, and underscores the importance of comprehensive genomic profiling in guiding clinical decisions in GBM management., (© 2024 The Author(s). Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Introduction: Immune-check-point inhibitors (ICIs) are established in the treatment of many malignancies. Many immune-related adverse events (irAEs) are well described; however, there is less information about opportunistic infections in cancer patients receiving ICIs., Case Presentation: We describe the case of a 62-year-old woman with non-small cell lung cancer, who relapsed after surgical resection and chemotherapy. She received 13 months of pembrolizumab, achieving stable disease, before presenting with suspected pneumonitis 2 weeks prior to departure for an international vacation. She was treated with high-dose corticosteroids and, shortly thereafter, developed severe nocardiosis, requiring venovenous extracorporeal membrane oxygenation and lengthy hospitalization., Conclusion: To our knowledge, this represents the second known case of pulmonary nocardiosis in a patient on pembrolizumab. Moreover, this is a rarely reported instance of opportunistic bacterial infection following steroid treatment for ICI pneumonitis. This case report emphasizes the risk of bacterial infection associated with ICI pneumonitis, both due to the difficulty of excluding underlying infection at presentation, and the immunosuppression caused by irAE treatment. As such, we suggest that clinicians maintain a high suspicion for potential infection in ICI pneumonitis, and strongly consider initiating infectious workup with regular follow-ups for monitoring. Prophylactic antibiotics could be considered when such monitoring is not possible., Competing Interests: The authors have no conflicts of interest to declare., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Since their initial approval as single agent therapy for multiply relapsed/refractory Hodgkin lymphoma (HL), the PD-1 inhibitors nivolumab and pembrolizumab have been incorporated into second-line salvage regimens, and they are being investigated in upfront therapy of newly diagnosed patients. As second-line therapy in combination with brentuximab vedotin or multi-agent chemotherapy, nivolumab and pembrolizumab provide high complete remission rates and durable progression-free survival after consolidative autologous stem cell transplant. Incorporation of these agents into frontline chemotherapy regimens is feasible, and early results from a Phase III trial of nivolumab-AVD compare favorably with the existing standard for advanced stage HL, brentuximab vedotin plus AVD. As nivolumab and pembrolizumab move into earlier lines of HL therapy, open research questions include the efficacy of checkpoint inhibitor regimens in patients who relapse after frontline exposure to nivolumab or pembrolizumab; the selection of patients with relapsed HL who can achieve durable remissions without autologous stem cell transplant; and the efficacy of the PD-1 inhibitors in the frontline therapy of patients with early stage Hodgkin lymphoma., Competing Interests: The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Cashen.)

Background: This study aimed to determine if the neoadjuvant (NAT) KEYNOTE-522 regimen was associated with higher rates of pathologic complete response (pCR), corresponding to higher rates of breast conservation therapy (BCT) in early-stage triple-negative breast cancer (TNBC) patients., Patients and Methods: Stage II-III TNBC patients diagnosed between 2019 and 2022 who underwent NAT were analyzed retrospectively. NAT with KEYNOTE-522 versus control NAT were compared for rates of BCT, axillary node dissection (ALND), pCR, and survival outcomes. The prevalence of immune-related adverse events (irAE) from chemoimmunotherapy was recorded., Results: Of 240 patients identified: 86 received KEYNOTE-522 and 154 received control. The frequency of pCR was significantly higher in KEYNOTE versus the control cohort, 59.3% and 33.1%, respectively (p = 0.001). There was no significant difference in the rate of BCT between the control (33.1%) and the KEYNOTE-522 (32.1%) groups (p = 0.47). Rates of ALND were significantly lower with KEYNOTE-522 (25.6%) as compared with control (39.6%); p = 0.03. The rate of development of grade 2 or higher irAEs was 34.9%. At a median follow-up of 2.4 years, there was no difference in survival outcomes. BRCA1 patients had high rates of pCR regardless of treatment group, KEYNOTE-522: 80.0% (4/5) and control: 75% (9/12), (p = 1)., Conclusion: This real-world evidence supports the use of the KEYNOTE-522 regimen in patients with early-stage TNBC given the higher pCR rate and corresponding decrease in the rate of ALND. The majority of patients in both NAT cohorts became BCT eligible, but the rate of BCT did not differ between the two groups., (© 2024. Society of Surgical Oncology.)

Background: Immune checkpoint inhibitor (ICI) therapy is becoming the standard of care for the treatment of advanced non-small-cell lung cancer. However, T-cell activation by ICIs frequently induces a flare-up of preexisting autoimmune diseases such as rheumatoid arthritis (RA). Janus kinase (JAK) inhibitors are increasingly used in the treatment of RA, but they could interfere with the efficacy of ICIs by inhibiting interferon signaling. Case Report: Here, we describe a case in which upadacitinib, a JAK1-selective inhibitor, was used to manage a severe RA flare-up occurring during ICI therapy with pembrolizumab, an anti-programmed cell death protein-1 antibody. A 54-year-old man with RA was diagnosed with grade IV lung squamous cell carcinoma. The patient had maintained RA remission for 4 years at the time of lung cancer diagnosis. After seven cycles of pembrolizumab therapy, the size of the primary tumor was markedly reduced, but a severe RA flare-up and organizing pneumonia (OP)-like pulmonary lesions occurred. Considering the severity of the flare-up, pembrolizumab was discontinued. Upadacitinib induced swift recovery from the RA flare-up and OP. Eleven months after the last pembrolizumab use, almost all metastatic lesions in the body had disappeared. We did not observe recurrence of lung cancer for more than 1 year during upadacitinib therapy. Conclusions: Upadacitinib could be a safe and effective option to treat severe RA flare-ups occurring during anti-PD-1 ICI therapy.

Disclaimer: In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time., Purpose: There is currently limited data on cross-sensitivity between immunotherapy agents. In this case study, we report a case of severe anaphylaxis to both pembrolizumab and cemiplimab., Summary: Pembrolizumab (Keytruda) and cemiplimab (Libtayo) are both approved for the treatment of metastatic cutaneous squamous cell carcinoma. Infusion reactions occur rarely with immunotherapy agents. However, if infusion reactions are severe, the treatment should be discontinued, and there is no guidance as to whether another immunotherapy agent may be used. An 87-year-old-male was diagnosed with metastatic cutaneous squamous cell carcinoma expressing a PD-L1 combined positive score of 81%-90%. He was treated with pembrolizumab and, 15 minutes after completion of the first infusion, developed swelling of the eyelids, ears, and tongue in addition to a whole-body rash without pruritus. Due to the severity of the reaction, pembrolizumab was permanently discontinued and the patient was then started on cemiplimab. The patient received a high-dose corticosteroid as premedication before the first infusion of cemiplimab and tolerated the treatment without any adverse effects. However, when the corticosteroid premedication dose was decreased before the second cycle, the patient had a severe infusion reaction to cemiplimab requiring discontinuation., Conclusion: A patient with metastatic cutaneous squamous cell carcinoma developed a severe hypersensitivity reaction to pembrolizumab and subsequently to cemiplimab, despite premedication., (© American Society of Health-System Pharmacists 2024. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Pembrolizumab, a PD-1 inhibitor, has become a cornerstone in the treatment of various cancers, including breast cancer. However, its use is associated with immune-related adverse effects (irAEs), particularly those involving the endocrine system. This case report presents a rare instance of pembrolizumab-induced Addison's disease leading to severe hyponatremia. The case is supported by detailed laboratory findings and evaluated using the Naranjo adverse drug reaction probability scale. A 53-year-old female with a history of breast cancer presented with dizziness and fatigue while on a cruise. Initial laboratory tests revealed severe hyponatremia (serum sodium 117 mEq/L). Further evaluation revealed low cortisol (1.7 µg/dL) and elevated adrenocorticotropic hormone (ACTH) (452 pg/mL), indicative of adrenal insufficiency. Although thyroid function was normal, low IGF-1 levels suggested secondary adrenal insufficiency. The administration of hydrocortisone resulted in rapid symptom improvement, and the patient was discharged with a prescription for ongoing corticosteroid therapy. The Naranjo scale score of 4 indicated a possible relationship between pembrolizumab and the development of Addison's disease. This case underscores the critical need for awareness of irAEs in patients undergoing treatment with immune checkpoint inhibitors. The application of the Naranjo scale provided a quantitative assessment of the likelihood that pembrolizumab induced adrenal insufficiency. Emergency department protocols should incorporate endocrine evaluations for patients presenting with non-specific symptoms while undergoing immunotherapy. Pembrolizumab can lead to severe endocrine disorders, such as Addison's disease, which can result in life-threatening conditions like severe hyponatremia. Emergency clinicians must remain vigilant in recognizing and treating these adverse effects to optimize patient outcomes., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Aydin et al.)

Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality worldwide. Immunotherapy has emerged as a promising treatment option due to its favorable toxicity profile. However, selecting the most appropriate immunotherapeutic agent for neoadjuvant use-aimed at curative intent in early-stage NSCLC-based on efficacy and safety remains a critical question. This review aims to compare the efficacy and safety profiles of nivolumab and pembrolizumab when used as neoadjuvant treatments in NSCLC. A systematic review was conducted across PubMed, Scopus, Wiley Online Library, ProQuest Dissertations and Theses Global, and Google Scholar, utilizing the search terms "Nivolumab OR Pembrolizumab AND Neoadjuvant Immunotherapy AND non-small cell lung cancer." Out of 1444 retrieved studies, 4 retrospective studies met the inclusion criteria by providing comparative data on nivolumab and pembrolizumab within the same study cohorts. Despite the critical risk of bias and the evidence quality ranging from moderate to very low across these studies, both nivolumab and pembrolizumab demonstrated efficacy rates exceeding 30% and maintained favorable safety profiles. There is no observed superiority between nivolumab and pembrolizumab in terms of efficacy and safety for the neoadjuvant treatment of early-stage NSCLC.

A 75-year-old man diagnosed with esophageal cancer and lung metastasis received a combination of fluorouracil, cisplatin, and pembrolizumab. During pembrolizumab maintenance therapy, lymphoproliferative lesions at the lips and mouth and multiple lymph node swellings appeared. Histologically, Epstein-Barr virus (EBV)-encoded RNA was positive, and EBV-DNA was detected in the blood. The patient was diagnosed with other iatrogenic immunodeficiency-associated lymph proliferative disorders (OIIA-LPDs) related to EBV activation induced by pembrolizumab. Rituximab was administered, resulting in the improvement of the OIIA-LPD. The emergence of an OIIA-LPD merits close attention in patients receiving immune checkpoint inhibitors.

Background: Immune checkpoint inhibitors (ICIs) have been successfully used in the previous decade for the treatment of a variety of malignancies. Adverse events (AEs) can cause many symptoms, most notably cardiac. We analyzed the frequency of these adverse events, comparing pembrolizumab and other ICIs., Methods: Using the Food and Drug Administration (FDA) adverse event reporting database (FAERS), we searched for all adverse events of interest reported for every ICI included in this study. After obtaining the data, we conducted a disproportionality analysis using the reporting odds ratio (ROR) and the information component (IC)., Results: A total of 6719 ICI-related cardiac adverse events of interest were reported in the database. Serious outcomes were reported in 100% of the cases, with 34.3% of the cases ending fatally. Compared with all other medications in the database, pembrolizumab use was more frequently associated with myocarditis, pericardial disease, heart failure, and atrial fibrillation. No difference was found in cardiotoxicity between different ICIs., Conclusions: Although infrequent, cardiac AEs in pembrolizumab use are associated with serious outcomes and high mortality. Prospective studies are needed to further research the connection between ICI use and cardiotoxicity.

Background and Objective: Metastatic urothelial carcinoma (mUCa) ranks as the costliest cancer to treat per patient due to frequent interventions and expensive follow-ups. Investigating first-line therapies, combinations such as enfortumab vedotin + pembrolizumab (EV + P) and gemcitabine/cisplatin + nivolumab exhibit significant overall survival benefits compared with the standard treatment (SoC; gemcitabine/cisplatin). Here, we conducted a cost-effectiveness analysis for mUCa., Methods: We developed a Markov model from a payer perspective, filtering clinical data from the phase 3 Checkmate-901 and EV302/Keynote-A39 trials. Monte Carlo simulation was used to identify the optimal treatment from a socioeconomic perspective in Germany and the USA. Finally, we compared the incremental cost-effectiveness ratio (ICER) of each modality at different willingness-to-pay (WTP) thresholds., Key Findings and Limitations: At a lifetime horizon, SoC, gemcitabine/cisplatin + nivolumab, and EV + P were associated with average costs of €163 424 (USA: $458 006), €206 853 (USA: $597 802), and €401 170 (USA: $1 228 455), and gained quality-adjusted life years (QALYs) of 1.21, 1.71, and 2.31, respectively. The ICERs of the newer strategies were €87 340 (USA: $281 142; gemcitabine/cisplatin + nivolumab) and €216 140 (USA: $700 448; EV + P). At a commonly used WTP threshold of €/$100 000, gemcitabine/cisplatin + nivolumab would be the optimal strategy in Germany, while EV + P would require a price reduction of 46% (USA: 82%) to be cost effective., Conclusions and Clinical Implications: QALYs nearly double with EV + P compared with the current SoC; yet, current costs may not be justified from a strict socioeconomic perspective. Despite its lower oncological benefit, gemcitabine/cisplatin + nivolumab should be considered for first-line therapy due to favorable cost effectiveness, especially in Europe. Establishing individual risk factors is essential for optimizing therapeutic response and treatment costs in the future., Patient Summary: This report presents a cost-effectiveness analysis of emerging treatment options for metastatic urothelial carcinoma. The combination of enfortumab vedotin + pembrolizumab emerged as the most effective treatment; however, it also proved to be the costliest. From a purely socioeconomic standpoint, the combination of gemcitabine/cisplatin and nivolumab represents a cost-effective alternative at least in Germany., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: This meta-analysis aimed to evaluate the efficacy and safety of combining pemetrexed and platinum with or without pembrolizumab for the treatment of advanced non-small-cell lung cancer (NSCLC)., Methods: A systematic search of PubMed, Embase, Cochrane Library, and Web Of Science databases was conducted to identify studies comparing pemetrexed and platinum with or without pembrolizumab in advanced NSCLC. Raw data were extracted from eligible studies to calculate Hazard Ratios (HR) for Progression-Free Survival (PFS) and Overall Survival (OS), as well as rates of adverse events of all grades and those of Grade 3 or higher., Results: Eight studies with 1639 patients occurred advanced NSCLC included. The group receiving pembrolizumab in combination with pemetrexed and platinum showed significant benefits in terms of OS (HR 0.63; 95% CI 0.54-0.73; p < 0.00001) and PFS (HR:0.64; 95% CI 0.48-0.85; p = 0.002) compared to the group receiving pemetrexed and platinum alone. However, this benefit was accompanied by a higher incidence of Grade 3 or higher adverse events (OR: 1.55; 95% CI 1.24-1.95; p = 0.0001)., Conclusion: The combination of pemetrexed and platinum with pembrolizumab is recommended as a first-line treatment option for advanced NSCLC due to its significant efficacy benefits. However, the increased risk of Grade 3 or higher adverse events suggests the need for careful consideration and assessment when considering this regimen for second-line or subsequent therapy., (© 2024. The Author(s), under exclusive licence to Federación de Sociedades Españolas de Oncología (FESEO).)

A 72-year-old woman was diagnosed with unresectable pancreatic body-tail cancer (cT4N1M1, cStage IV) with para-aortic lymph node metastasis. She underwent six courses of gemcitabine + nab-paclitaxel as first-line chemotherapy, 12 courses of oxaliplatin + irinotecan + levofolinate + fluorouracil as second-line chemotherapy, and five courses of albumin-suspended irinotecan + levofolinate + fluorouracil as third-line chemotherapy. After each chemotherapy regimen, the disease was determined to be progressive. Analyses of endoscopic ultrasound-fine needle aspiration specimens and peripheral blood samples revealed microsatellite-instability (MSI)-high pancreatic cancer. The patient underwent 19 courses of pembrolizumab and achieved a partial response. She then underwent conversion surgery, including distal pancreatectomy, lymph node dissection, local gastrectomy and partial mesenteric resection of transverse colon. She is currently alive without recurrence at 18 months postoperatively. It is extremely rare for patients with unresectable and MSI-high pancreatic cancer to successfully undergo conversion surgery after pembrolizumab treatment., (© 2024. Japanese Society of Gastroenterology.)

Gestational trophoblastic neoplasia (GTN) are rare diseases that are typically chemo-responsive. While the majority of patients are cured with chemotherapy alone, a small portion of cases are fatal due to chemotherapy resistance. Risk factors for treatment failure are liver and brain metastases, extensive disease, and chemo-refractory disease. Gastrointestinal (GI) metastases are extremely rare and indicate a poor prognosis. Treatment with immunotherapy has been studied and included in treatment guidelines for high-risk and chemotherapy-resistant GTN. This case reports on the early use of programmed cell death protein 1 (PD-1) inhibitor in combination with systemic chemotherapy in a patient with ultra-high risk GTN with GI metastases., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier Inc.)