Immune Checkpoint Inhibitor Drugs Research Articles

Updated estimates of eligibility and response: Immune checkpoint inhibitors.

e14613 Background: Immune checkpoint inhibitors (ICIs) have notably changed the landscape of systemic treatment of advanced and metastatic cancers in the last decade. We previously estimated the eligibility for and responses to ICIs, but since then, there have been multiple approvals for additional indications. As such, we have updated these estimates to include all approvals, as of December 2023. Methods: For eligibility, we used death data from the American Cancer Society’s Cancer Facts and Figures. Deaths was used as a stand-in for eligibility because these therapies are often given in later lines. Data from the peer-reviewed literature was used to further refine specific tumor type estimates (e.g., the percentage of lung cancers that are non-small cell and small cell lung cancer). For each tumor type, we multiplied the response rates reported in the FDA’s package insert by the number of deaths for each respective tumor type. When multiple drugs were approved for the same indication, we used the highest response rate. Results: Eleven ICI drugs were approved for 88 different indication approvals in the advanced/metastatic setting between 2015 and 2023. These approvals were for 20 general tumor types. The estimated eligibility for ICIs increased from 1.54% in 2011 to 55.47% in 2023. The tumor types with the highest eligibility in 2023 were non-small cell lung cancer with PDL1 status of 50% (13.28%) or less and PDL1 status >50% (4.42%), solid tumors TMB-h (6.81%), and hepatocellular (4.82%). The estimated response to ICIs increased from 0.14% in 2011 to 19.60% in 2023. The tumor types with the highest contribution to response estimates in 2023 were non-small cell lung cancer with PDL1 status of 50% (4.78%) or less and PDL1 status >50% (1.99%), solid tumors TMB-h (2.72%), and renal cell carcinoma (1.95%). Conclusions: We find that the estimated eligibility for and response to ICIs has increased since their introduction in 2011. Our estimates are an upper bound since many people are not eligible due to contraindications or healthcare coverage. Both the response and eligibility were driven by certain tumor types, including non-small cell lung cancer (either PDL1 high or PDL1 low). Patients with these types of tumors made up about one-third of the estimated response and eligibility. Solid tumors TMB-h, hepatocellular and renal cell carcinoma were other tumors with high eligibility and response, but other tumor types had low eligibility and response. While many patients have benefited from ICIs, half of patients with advanced or metastatic cancers are either not eligible or likely do not respond. [Table: see text]

The survival benefits and the risk of severe renal injury of immune checkpoint inhibitors in patients with cancer: The real-world evidence from the National Clinical Cohort Collaborative (N3C).

e24142 Background: The survival benefits and the risks of severe immune-related adverse events (sirAEs) of Immune checkpoint inhibitors (ICI) vary dramatically among cancer patients. Among sirAEs, acute kidney injury (AKI) incidences are rising, often cause sustained renal damage, and are responsible for the deterioration of patients’ overall health and quality of life. There is an urgent need to support oncologists and nephrologists in choosing the right ICI drugs for the right patients. We aim to comprehensively scrutinize the tradeoff between the survival benefits and the severe AKI risk for ICI patients by leveraging the national electronic medical records (EMR) from the National Clinical Cohort Collaborative (N3C) registry. Our work provides real-world evidence for clinical decisions on ICI use. Methods: Cancer patients treated with ICI are followed up for at least 6 months using N3C data (01/01/2018 - 01/19/2024). Primary outcomes included severe AKI within 6 months of initiation or mortality up to the last follow-up. We fit multivariable Cox proportional hazards models to evaluate the effect of various ICI types, adjusting for age, gender, race, cancer types, smoking status, and comorbidities. Results: Our study cohort included 55,767 patients who received an ICI, with 25,197 deaths and 6,458 severe AKI events. The most common ICI used were PD-1 inhibitors (74.3%), PD-L1 inhibitors (16.6%), CTLA-4 inhibitors (0.3%), and combination treatments of PD-1 and CTLA-4 inhibitors (8.8%). Observed long-term severe AKI incidences exceeded prior reports, with 96%, 92%, 88%, and 71% at 1, 3, 6, and 36 months. Survival benefits of PD-1, CTLA-4 and their combinations versus PD-L1 inhibitors were comparable (HR: 0.94 [95%CI: 0.91–0.97]; HR: 0.81 [95%CI: 0.63–1.02]; HR: 1.09 [95%CI: 1.04–1.15]). Severe AKI risks were higher with CTLA-4 and combination therapy (HR: 1.48 [95%CI: 0.96–2.28]; HR: 1.96 [95%CI: 1.78–2.16]) compared to PD-L1 inhibitors, with PD-1 inhibitors also showing increased risk (HR: 1.15 [95%CI: 1.07–1.23]). We also scrutinize risk factors associated with significant AKI risk, including a history of AKI, congestive heart failure, dementia, complicated diabetes, hypertension, liver disease, other immunocompromised diseases, and cancers of the gynecologic type, prostate cancer, and gastrointestinal cancers, and being of Black race. Conclusions: Our work provides up-to-date and comprehensive real-world evidence of the survival benefits and severe renal injury risks for clinical decisions of ICI therapy. PD-L1 inhibitors are associated with a lower risk of severe AKI compared to PD-1, CTLA-4 inhibitors, and their combination. Future research should focus on identifying patient subgroups that may benefit from specific ICI therapies while minimizing adverse outcomes.

Treatment options for immune-related adverse events associated with immune checkpoint inhibitors.

The immunotherapy revolution with the use of immune checkpoint inhibitors (ICIs) started with the clinical use of the first ICI, ipilimumab, in 2011. Since then, the field of ICI therapy has rapidly expanded - with the FDA approval of 10 different ICI drugs so far and their incorporation into the therapeutic regimens of a range of malignancies. While ICIs have shown high anti-cancer efficacy, they also have characteristic side effects, termed immune-related adverse events (irAEs). These side effects hinder the therapeutic potential of ICIs and, therefore, finding ways to prevent and treat them is of paramount importance. The current protocols to manage irAEs follow an empirical route of steroid administration and, in more severe cases, ICI withdrawal. However, this approach is not optimal in many cases, as there are often steroid-refractory irAEs, and there is a potential for corticosteroid use to promote tumour progression. This review surveys the current alternative approaches to the treatments for irAEs, with the goal of summarizing and highlighting the best attempts to treat irAEs, without compromising anti-tumour immunity and allowing for rechallenge with ICIs after resolution of the irAEs.

Follow-up biopsies in gastrointestinal immune checkpoint inhibitor toxicity may show markedly different inflammatory patterns than initial injury

Colitis is a common manifestation of immune checkpoint inhibitor (ICI) toxicity and can present with varied histologic patterns of inflammation, some of which have been shown to be associated with specific ICI drug types. Although the histologic features of ICI colitis seen at the time of diagnosis have been described, there have been few reports following these patients over time. We evaluated initial and follow-up biopsies in 30 patients with ICI colitis and found that 37% of patients developed a different pattern of injury on follow-up biopsy compared to the initial biopsy. Patients with a different inflammatory pattern were more likely to have restarted ICI therapy before their follow-up biopsy (64%) compared to those without a change in inflammatory pattern (11%; P < 0.01). The majority of these patients had changed ICI drug types (86%). Additionally, many cases changed to an inflammatory bowel disease (IBD)-like pattern (36%), raising a question of de novo IBD. However, all of our patients with an IBD-like pattern experienced sustained resolution of symptoms without steroids or other immunosuppressive medications following discontinuation of ICI therapy, consistent with a diagnosis of ICI toxicity. Our findings suggest that follow-up biopsies in patients with ICI colitis may show a different histology and that this does not necessarily warrant a change in the histologic diagnosis to another disease.

Prognostic value of pretreatment neutrophil-to-lymphocyte ratio in advanced gastrointestinal cancer immunotherapy: evidence from published studies and a Chinese single center cohort

BackgroundIdentification of prognostic biomarkers for outcomes in gastrointestinal (GI) cancer with immunotherapy is important. This study investigated the relationship between the prognostic biomarker, pretreatment neutrophil-to-lymphocyte ratio (preNLR), and immunotherapeutic outcomes in patients with advanced GI cancer.MethodsWe searched the PubMed, Embase, and Cochrane Library databases for studies reporting predictive values for preNLR in patients with advanced GI cancer treated with immune checkpoint inhibitor (ICI). The primary outcomes considered were progression-free survival (PFS) and overall survival (OS). Hazard ratios (HRs) with 95% confidence intervals (CIs) for PFS and OS were pooled using a random effects model. We then validated the results observed in an in-house cohort of patients treated with ICIs for advanced GI cancers. Other prognostic factors for PFS and OS were explored using Cox proportional hazard analyses.ResultsOverall, 27 observational studies involving 3,610 patients with advanced GI cancer were included. Patients with higher preNLR were associated with poorer PFS (HR 1.70, 95% CI 1.50–1.92) and OS (HR 2.35, 95% CI 1.82–3.03) with ICI treatment. Subgroup analyses based on NLR cut-off value, research center, sample size, and ICI drugs used were consistent with the primary results. A retrospective analysis of the in-house patient cohort validated these results (PFS: HR 3.173, 95% CI 2.314–4.351; OS: HR 3.004, 95% CI 1.837–4.912). Multivariable Cox regression analysis of 174 patients showed that higher preNLR and negative programmed death ligand-1 (PD-L1) expression were independently, significantly, and unfavorably associated with PFS and OS.ConclusionPreNLR might be an effective prognostic biomarker for patients with advanced GI cancer treated with ICIs.

Evaluation of tumor response to immune checkpoint inhibitors by a 3D immunotumoroid model.

Only 20 percent of renal and bladder cancer patients will show a significant response to immune checkpoint inhibitor (ICI) therapy, and no test currently available accurately predicts ICI response. We developed an "immunotumoroid" cell model system that recapitulates the tumor, its microenvironment, and necessary immune system components in patient-derived spheroids to enable ex vivo assessment of tumor response to ICI therapy. Immunotumoroids were developed from surgically resected renal cell carcinomas and bladder carcinomas selected for high tumor-infiltrating lymphocytes (TILs) and survived more than a month without media exchange. Immunohistochemistry was used to detect immune and non-immune cells in cryopreserved source tumors and the resulting immunotumoroids. Immunotumoroid response to ICIs (nivolumab, pembrolizumab, and durvalumab) and chemotherapy (cisplatin, gemcitabine, and paclitaxel) was monitored in real-time with Cytotox Red staining in an Incucyte device, and the immunotumoroid response was compared to retrospective clinical drug responses. Six of the 13 cases tested grew viable immunotumoroid models, with failed cases attributed to extensive tumor tissue necrosis or excess lymphocytes preventing spheroid formation. One successfully cultured case was excluded from the study due to low TIL infiltration (<5%) in the primary tumor sample. The five remaining models contained immune cells (CD4+ and CD8+ T cells, and macrophages), non-immune cells (fibroblasts), and tumor cells. Chemotherapy and ICI drugs were tested in immunotumoroids from 5 cases and compared to clinical outcomes where data was available. Four/five models showed cell killing in response to chemotherapy and two/five showed sensitivity to ICI. In three cases, the immunotumoroid model accurately predicted the patient's clinical response or non-response to ICIs or chemotherapy. Our immunotumoroid model replicated the multicellular nature of the tumor microenvironment sufficiently for preclinical ICI screening. This model could enable valuable insights into the complex interactions between cancer cells, the immune system, and the microenvironment. This is a feasibility study on a small number of cases, and additional studies with larger case numbers are required including correlation with clinical response.

Comparison of efficacy and safety between PD-1 inhibitors and PD-L1 inhibitors plus platinum-etoposide as first-line treatment for extensive-stage small-cell lung cancer: a multicenter, real-world analysis

BackgroundImmunotherapy in combination with platinum-etoposide (EP) chemotherapy has been approved as a first-line treatment for extensive-stage small cell lung cancer (ES-SCLC). However, real-world (RW) data regarding the use of immune checkpoint inhibitors (ICIs) in ES-SCLC are lacking. We aimed to assess the differences between programmed death protein 1 (PD-1) inhibitors and programmed death ligand 1 (PD-L1) inhibitors, both in conjunction with EP chemotherapy, as first-line treatment for ES SCLC.MethodsWe conducted a real-world, multicenter, retrospective cohort, controlled study to compare the prognosis, efficacy, and safety of PD-1 and PD-L1 inhibitors in ES-SCLC patients when used along with chemotherapy. Each patient received up to six cycles of etoposide, carboplatin, or cisplatin combined with ICI drugs, including PD-1 and PD-L1 inhibitors. The primary endpoints were investigator-assessed progression-free survival (PFS) and overall survival (OS). The secondary endpoints were the investigator-assessed objective response rate (ORR) and disease control rate (DCR) according to the Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1).ResultsBetween January 2017 and December 2021, 194 patients with ES-SCLC from three clinical centers in a PLA general hospital were included in our study, including 93 patients in the PD-1 group and 101 patients in the PD-L1 group. At the time of data cutoff, progression-free survival in the PD-1 group (median PFS, 6.8 months; 95% CI, 5.3–8.1) was similar to that in the PD-L1 group (median PFS, 6.4 months; 95% CI, 5.5–7.5); the stratified hazard ratio for PFS was 1.12 (95% CI, 0.83–1.53; P = 0.452). The median OS was similar in the PD-1 and PD-L1 groups (15.8 m vs. 17.7 m, P = 0.566); the hazard ratio was 0.90 (95% CI, 0.62–1.30, P = 0.566). The two groups had comparable investigator-assessed confirmed objective response rates (ORR) (76.3% vs. 76.2%). Adverse effect (AE)-related discontinuation occurred in 4 (4.3%) patients in the PD-1 group and 2 (2.0%) patients in the PD-L1 group. Deaths due to AEs of any cause occurred in 2 (2.2%) patients in the PD-1 inhibitor group and 1 (1.0%) patient in the PD-L1 inhibitor group.ConclusionsOur research revealed that there were no significant differences in efficacy or prognosis between PD-1 inhibitor + EP chemotherapy and PD-L1 inhibitor + EP chemotherapy. The two groups seemed to have comparable safety profiles, but the number of discontinuation or death events was too small to draw a firm conclusion.

Pembrolizumab related osteonecrosis of the jaw

Medication related osteonecrosis of the jaw (MRONJ) is a serious complication with potential implications on patients’ ongoing medical care. This case report describes a case of MRONJ from pembrolizumab; a novel immune checkpoint inhibitor drug.

Immunoediting of KEAP1-NRF2 mutant tumours is required to circumvent NRF2-mediated immune surveillance

In human cancer, activating mutations in the KEAP1-NRF2 pathway are frequently observed, and positively selected for, as they confer the cytoprotective functions of the transcription factor NRF2 on the cancer cells. This results in the development of aggressive tumours which are resistant to treatment with chemotherapeutic compounds. Recent clinical developments have also revealed that NRF2-activated cancers are similarly resistant to immune checkpoint inhibitor drugs. As the mechanism of action of these immune modulating therapies is tangential to the classical cytoprotective function of NRF2, it is unclear how aberrant NRF2 activity could impact the anti-cancer functionality of the immune system. In this context, we found that in human cancer, NRF2-activated cells are highly immunoedited, which allows the cancer cells to escape immune surveillance and develop into malignant tumours. This immunoediting takes the form of reduced antigen presentation by the MHC-I complex, coupled with reduced expression of activating ligands for NK cells. Together, these modifications to the immunogenicity of NRF2-activated cancers inhibit immune effector cell infiltration and engagement, and contribute to the formation of the immunologically cold tumour microenvironment which is a characteristic feature of NRF2-activated cancers.

Research progress on PD-1 and PD-L1 inhibitors in the treatment of metastatic urothelial carcinoma.

Urothelial carcinoma (UC) is a very common malignant tumor. In the past few decades, platinum-based chemotherapy has been regarded as the standard recommended regimen for patients with metastatic urothelial carcinoma (mUC) who can receive either cisplatin or carboplatin. The emergence of immune checkpoint inhibitors (ICIs) brought some hope for possible treatments for mUC patients who were unfit for platinum therapy. ICIs drugs have emerged as new potential weapons to overcome UC in our lifetime. ICIs block the binding of programmed death-1 (PD-1) to programmed death-ligand 1 (PD-L1), leading to enhancement of the immune function of antitumor T cells. In the treatment of UC, ICIs show an apparent ascendancy and effectively enhance survival rates. With good tolerability and remarkable effects, ICIs have given thousands of patients hope. This article mainly shows the application of PD-1 and PD-L1 inhibitors in mUC.

Immune checkpoint inhibition in advanced colorectal cancer with inherited and acquired microsatellite instability: Current state and future directions.

This paper reviews comprehensively the most relevant data on single-agent and combination therapies for advanced colorectal cancer with inherited and acquired microsatellite instability (MSI). We performed a systematic search on PubMed and MEDLINE articles published from inception to December 2022. We have also searched independent websites including U.S. Food and Drug Administration and ClinicalTrials.gov. Performing microsatellite stability testing, tumor mutational burden (TMB), and germline mutation analysis could identify patients with metastatic colorectal cancer that benefit from immune checkpoint inhibitor (ICI) therapy. Single-agent pembrolizumab has proven superiority over traditional chemotherapy in these patients. The nivolumab-ipilimumab is the only combination ICI therapy approved in this space. Recently, the anti-PD-1 antibody dostarlimab was granted Food and Drug Administration approval in refractory tissue-agnostic advanced solid cancers with deficient mismatch repair (dMMR). ICIs are also being studied in the adjuvant/neoadjuvant setting in colon cancer patients with dMMR. Newer agents are being scrutinized in this space as well. More solid data on biomarkers predicting responses in patients with MSI-high or TMB-H to various therapies are needed. Given its both clinical and financial toxicity, it is imperative to determine the optimal duration of ICI therapy in individual patients. Overall, the outlook in advanced colorectal cancer patients with MSI appears optimistic as new and efficacious ICI drugs and combinations are being added to the existing therapeutic armamentarium.

Indoleamine 2,3-dioxygenase 1 in circumventing checkpoint inhibitor responses: Updated.

Metabolic alterations occur commonly in tumor cells as a way to adapt available energetic sources for their proliferation, survival and resistance. Indoleamine 2,3-dioxygenase 1 (IDO1) is an intracellular enzyme catalyzing tryptophan degradation into kynurenine. IDO1 expression shows a rise in the stroma of many types of human cancers, and it provides a negative feedback mechanism for cancer evasion from immunosurveillance. Upregulation of IDO1 correlates with cancer aggression, poor prognosis and shortened patient survival. The increased activity of this endogenous checkpoint impairs effector T cell function, increases regulatory T cell (Treg) population and induces immune tolerance, so its inhibition potentiates anti-tumor immune responses and reshapes immunogenic state of tumor microenvironment (TME) presumably through normalizing effector T cell activity. A point is that the expression of this immunoregulatory marker is upregulated after immune checkpoint inhibitor (ICI) therapy, and that it has inducible effect on expression of other checkpoints. These are indicative of the importance of IDO1 as an attractive immunotherapeutic target and rationalizing combination of IDO1 inhibitors with ICI drugs in patients with advanced solid cancers. In this review, we aimed to discuss about the impact of IDO1 on tumor immune ecosystem, and the IDO1-mediated bypass of ICI therapy. The efficacy of IDO1 inhibitor therapy in combination with ICIs in advanced/metastatic solid tumors is also a focus of this paper.

Abstract 6352: Combination treatment with recombinant murine IL-12 and anti-PD-1 antibody enhanced anti-tumor efficacy through the activation of cytotoxic T cell response

Abstract Introduction: Immune checkpoint inhibitors (ICIs) are widely used in cancer therapy. Among them, anti-PD-1 antibodies are the most used and have been approved by FDA for the treatment of many types of cancer (1). In our previous studies, combination of anti-PD-1 antibody with IL-12 demonstrated significant synergistic effect on tumor growth inhibition. The elevation of IFN-γ mRNA expression suggested the potential roles of CD8 T cells and NK cells in this process. In this study, we used two syngeneic mice tumor models to investigate the mechanisms of synergistic effect by the combination of IL-12 and anti-PD-1 antibody. Methods: We used syngeneic mice tumor models with mice cancer cell lines CT-26 and MC-38. The mice inoculated with tumor cells and were treated until tumors grew to 100 mm3. The mice were divided into three groups to receive the treatment, including rmIL-12 alone, anti-PD1-antibody alone, and the combination of rmIL-12 and anti-PD1-antibody (BIW x 3 weeks). At the end of the study, the mice were sacrificed and tumor resection and splenectomy were performed. The tumor infiltrating lymphocyte subpopulations within the tumor microenvironment were analyzed by flow cytometry and gene expression profile by RNA Seq. Results: The combination of rmIL-12 and anti-PD-1 antibody significantly inhibited tumor growth compared to the treatment with rmIL-12 and anti-PD-1 antibody alone. The combination group demonstrated more CD8+ T cell in the tumor microenvironment via flow cytometry. In addition, RNA Seq showed the combination group increased CD8+ T cells, NK cells, and Th1 populations. The levels of cytotoxicity related genes (IFN-γ, Granzyme B, Perforin) were also higher in combination group. Conclusion: Combination of rmIL-12 and anti-PD-1 antibody increased immune cells infiltration in the tumor microenvironment and enhanced anti-tumor response suggesting the potential of this combination for cancer treatment. Citation:(1). Watson, G.A. et al. (2020) “Novel strategies in immune checkpoint inhibitor drug development: How far are we from the paradigm shift?,” British Journal of Clinical Pharmacology, 86(9), pp. 1753-1768. https://doi.org/10.1111/bcp.14355. Citation Format: Yeng-Jey Yang, Pei-Yi Tsou, Shiuh-Dih Chou, Meng-Na Lee, San-Chi Chen. Combination treatment with recombinant murine IL-12 and anti-PD-1 antibody enhanced anti-tumor efficacy through the activation of cytotoxic T cell response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6352.

Correction of endocrine complications of oncoimmunotherapy

Over the years, immunotherapy with immune checkpoint inhibitors (ICI) has become an effective treatment for malignant neoplasms. However, checkpoints play a crucial role in immunological tolerance and prevention of autoimmune diseases. Interfering with this mechanism can cause immune-related adverse events (IRAEs) that affect multiple organs in the body. Endocrinopathies are among the most common IRAES associated with ICI therapy. Given the unique nature of adverse events caused by the use of ICI drugs, a multidisciplinary team approach is required to effectively manage patients, minimize complications associated with drug toxicity, and fully realize the therapeutic potential of this treatment method. Taking into account the difficulty of detecting nonspecific symptoms, the importance of follow-up and timely intervention in case of toxicity detection, regular clinical and laboratory monitoring is necessary, as well as informing patients and doctors about the variants of endocrine adverse events and their treatment. While non-endocrine IRAES often require discontinuation of immunotherapy and are usually resolved by immunosuppressive therapy with high doses of glucocorticoids, endocrine IRAES usually do not need discontinuation of ICI treatment and rarely require immunosuppressive therapy, but seldomly regress and therefore demand a long-term treatment.

Neoadjuvant immunotherapy in colorectal cancer beyond immune checkpoint inhibitors: emerging from bench to bedside.

Colorectal cancer (CRC) is the second most frequent cancer in both men and women, and of concern increasing in the younger population. Despite the progress in treatment, still up to half of CRC patients will develop metastasis. Immunotherapy consists of an arsenal of different managements that in many aspects has revolutionized cancer therapy. Monoclonal antibodies, chimeric antigen receptor (CAR) T-cell receptor gene modified T-cells and immunization and/or vaccination are different immunotherapies used in cancer treatment. Large trials in metastatic CRC, such as CheckMate 142 and KEYNOTE-177, have proven the efficacy of immune checkpoint inhibitors (ICI). The ICI drugs, targeting the cytotoxic T-lymphocyte associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) are now part of first-line treatment of dMMR/MSI-H metastatic CRC. However, ICIs are gaining a novel role in management of primary operable CRC after preliminary results from early-phase clinical studies in both colon and rectal cancer. Neoadjuvant ICI in operable colon and rectal cancer is hence becoming a clinical reality, while not quite yet adopted as a routine use. However, with some answers comes more questions and challenges. In this review article we aim to give an overview over different modes of immunotherapy to treat cancer with an emphasis on ICIs and their relevance to CRC, describe some of the progresses made in immunotherapy overall, with potential mechanisms, some of the concerns and, some highlight for the way forward.

Hepatotoxicity of immune checkpoint inhibitors: What is Currently Known

This systematic review and network meta-analysis aimed to provide a complete hepatotoxicity profile, hepatotoxicity spectrum, and safety ranking of immune checkpoint inhibitor drugs for cancer treatment. PubMed, Embase, Scopus, CINAHL, Web of Science, psycINFO, Cochrane Library, and ClinicalTrials.gov. websites were searched, and a manual search of relevant reviews and trials up to January 1, 2022, was undertaken. Head-to-head III randomized controlled trials comparing any 2 or 3 of the following treatments or different doses of the same immune checkpoint inhibitor drug were included: programmed death 1 (PD-1), programmed death ligand 1, and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitors and conventional therapy. We included 106 randomized trials (n=164,782) containing 17 treatment arms. The overall incidence of hepatotoxicity was 4.06%. The rate of fatal liver adverse events was 0.07%. The programmed death ligand 1 inhibitor+targeted therapy drug+chemotherapy group had the highest risk of treatment-related increases in all-grade alanine aminotransferase and aspartate aminotransferase levels, and the differences were significant. For immune-related hepatotoxicity, no significant difference was found between PD-1 and CTLA-4 inhibitors for all-grade hepatotoxicity; however, CTLA-4 inhibitors were associated with a higher risk of grade 3-5 hepatotoxicity than PD-1 inhibitors. The highest incidence of hepatotoxicity and fatality was observed with triple therapy. The overall incidence of hepatotoxicity was similar between different dual regimens. For immune checkpoint inhibitor monotherapy, the overall risk of immune-mediated hepatotoxicity related to CTLA-4 inhibitors did not differ significantly from that of PD-1 inhibitors. There was no direct relationship between the risk of liver injury and drug dose, whether monotherapy or combination therapy was used.

Development and validation of a GRGPI model for predicting the prognostic and treatment outcomes in head and neck squamous cell carcinoma.

Head and neck squamous cell carcinoma (HNSCC) is among the most lethal and most prevalent malignant tumors. Glycolysis affects tumor growth, invasion, chemotherapy resistance, and the tumor microenvironment. Therefore, we aimed at identifying a glycolysis-related prognostic model for HNSCC and to analyze its relationship with tumor immune cell infiltrations. The mRNA and clinical data were obtained from The Cancer Genome Atlas (TCGA), while glycolysis-related genes were obtained from the Molecular Signature Database (MSigDB). Bioinformatics analysis included Univariate cox and least absolute shrinkage and selection operator (LASSO) analyses to select optimal prognosis-related genes for constructing glycolysis-related gene prognostic index(GRGPI), as well as a nomogram for overall survival (OS) evaluation. GRGPI was validated using the Gene Expression Omnibus (GEO) database. A predictive nomogram was established based on the stepwise multivariate regression model. The immune status of GRGPI-defined subgroups was analyzed, and high and low immune groups were characterized. Prognostic effects of immune checkpoint inhibitor (ICI) treatment and chemotherapy were investigated by Tumor Immune Dysfunction and Exclusion (TIDE) scores and half inhibitory concentration (IC50) value. Reverse transcription-quantitative PCR (RT-qPCR) was utilized to validate the model by analyzing the mRNA expression levels of the prognostic glycolysis-related genes in HNSCC tissues and adjacent non-tumorous tissues. Five glycolysis-related genes were used to construct GRGPI. The GRGPI and the nomogram model exhibited robust validity in prognostic prediction. Clinical correlation analysis revealed positive correlations between the risk score used to construct the GRGPI model and the clinical stage. Immune checkpoint analysis revealed that the risk model was associated with immune checkpoint-related biomarkers. Immune microenvironment and immune status analysis exhibited a strong correlation between risk score and infiltrating immune cells. Gene set enrichment analysis (GSEA) pathway enrichment analysis showed typical immune pathways. Furthermore, the GRGPIdel showed excellent predictive performance in ICI treatment and drug sensitivity analysis. RT-qPCR showed that compared with adjacent non-tumorous tissues, the expressions of five genes were significantly up-regulated in HNSCC tissues. The model we constructed can not only be used as an important indicator for predicting the prognosis of patients but also had an important guiding role for clinical treatment.

Oral Immune-Related Adverse Events Associated with PD-1 Inhibitor Treatment: A Case Series

Introduction: Immune Checkpoint Inhibitor (ICI) drugs have led to a revolution in the treatment of different forms of cancer, shifting the target of action from cancer cells to the patient’s immune system, enhancing their responses against the tumor itself. On the other hand, this mechanism can lead to responses against oneself, with the appearance of immune-related adverse events. The aim of the present study was to examine the immune-related adverse events (irAEs) affecting the mucous membranes of the oral cavity and the possible correlation between these and skin toxicities, which are reported in the literature as the most common adverse events. Materials and methods: Thirteen patients treated with anti-Programmed Death (PD-1) drugs (pembrolizumab, nivolumab, and cemiplimab) were selected. The data collected include the general history of the patient and the type of anticancer treatment. The sample was then analyzed by recording the alterations found on the mucous membranes of the oral cavity and on the skin. Finally, the average time that elapsed between the start of immunotherapy and the onset of lesions was analyzed. Results: Patients often had multiple lesions at the same time. Hyperkeratosis was found in three patients, candidiasis (pseudomembranous and median rhomboid glossitis) in two patients, epithelial atrophy in four patients, and ulcerative areas in two patients. One patient reported xerostomia with dysphagia. The anatomical areas most involved were the dorsal tongue and palate. Skin irAEs included skin rash erythema (n = 7) with diffuse redness, the presence of small bubbles with a crusty outcome, and dryness of the skin in the affected areas. Discussion: In the literature, there are few studies that analyze how irAEs affect the mucous membranes of the oral cavity in patients treated with ICI drugs. The most frequently described lesions are lichenoid reactions and xerostomia. Moreover, the development of mucositis, generally of low grade, has been reported. The present study has confirmed the data from the literature and, in addition, reports two cases of candidiasis, an adverse event that has never been shown in the literature. Conclusions: irAEs have the potential to affect any organ. The only way to avoid the occurrence of serious events that is currently available is early interception, which is only possible through the knowledge of these manifestations. It is therefore considered necessary to deepen our knowledge of oral irAEs and their correlation with dermatological toxicities, allowing for a multidisciplinary classification of the patient and a timely diagnosis of any adverse event and avoiding progression to more advanced stages, which could lead to the temporary or permanent suspension of anticancer drugs.

Comparative risk of acute kidney injury among cancer patients treated with immune checkpoint inhibitors

With the development and introduction of immune checkpoint inhibitors (ICIs) in cancer patients, immune-related side effects have increasingly attracted attention. However, the risks of immune-related renal toxicity are poorly characterized. In this study, we performed a network meta-analysis (NMA) of ICI-related randomized clinical trials (RCTs) to elucidate the comparative risk of acute kidney injury (AKI) in cancer patients receiving different ICIs. We also sought to identify other factors potentially affecting the risk of AKI. PubMed and EMBASE were searched for peer-reviewed trial reports published between January 2000 and May 2021. Eligible studies were RCTs studying ICIs in cancer patients and reporting AKI data. We performed a frequentist NMA to evaluate the risk ratios for grade 1-5 and grade 3-5 AKI between the treatment groups. We also assessed the absolute incidence of AKI in the ICI-containing arm using traditional direct meta-analysis. Once significant heterogeneity was detected in a traditional direct meta-analysis, multivariable meta-regression analysis was applied to identify factors that significantly affected the absolute incidence of AKI. A total of 85 RCTs were included in this study. In the NMA for the risk of grade 1-5 and 3-5 AKI, ipilimumab showed a significantly higher risk than avelumab and durvalumab, whereas 1 mg/kg nivolumab plus 3 mg/kg ipilimumab (N1I3) showed a significantly higher risk than other groups. In terms of treatment ranking, durvalumab ± low-dose tremelimumab and avelumab were consistently among the top three safest treatments for grade 1-5 or 3-5 AKI, whereas N1I3, ipilimumab and tremelimumab were consistently among the top three treatments with the highest risk for grade 1-5 or 3-5 AKI. Compared with other cancers, renal cell carcinoma and urothelial carcinoma showed a significantly higher risk of AKI. The incidence of AKI was significantly higher with ICI+chemotherapy than with ICI monotherapy. In this NMA involving large-scale up-to-date ICI trials, we demonstrated the comparative safety of existing ICI drugs for grade 1-5 and grade 3-5 AKI. Based on data from the ICI arms of these trials, we also revealed several potential risk factors for immune-related AKI, including tumor type and treatment paradigm.

Duration of first-line immune checkpoint inhibitor treatment in U.S. patients with melanoma, non–small cell lung cancer, and renal cell carcinoma.

411 Background: By 2018, Immune Checkpoint Inhibitor (ICI) drugs had gained FDA approval for the treatment of several cancers including melanoma, non-small cell lung cancer (NSCLC), and renal cell carcinoma (RCC). Recommendations for treatment duration for ICI therapy varies and is often used until either progression of disease or intolerance from toxic effects. Blumenthal et al showed that there is a positive correlation between real-world time to discontinuation (rwTTD) and progression free survival. We report the rwTTD of ICI drug use in first-line of therapy (LOT1) among enrollees diagnosed with melanoma, NSCLC, and RCC between 2015 and 2018, as well as ICI utilization in second-line therapy. Methods: A cohort of patients treated for these 3 cancers between 2015 and 2018 was identified using de-identified data from the Optum Labs Data Warehouse and clinical information from the Optum Cancer Guidance Program’s electronic prior authorization (ePA) platform. De-identified administrative claims data were then linked to ePA information at the patient level to identify details of treatment received and duration of treatment. Eligible patients were enrolled in a commercial or Medicare Advantage (MA) plan and required to initiate treatment within 6 months of diagnosis, enrolled at least 6 months prior to diagnosis date (in order to ensure this was the LOT1) and at least thirty days after start of first identified treatment regimen (in order to identify the full treatment regimen). ICI regimens are defined as those with an ICI drug received within the first 30 days of the LOT1 start date. Duration of ICI use was defined as number of days from LOT1 start to date of last ICI administration in LOT1. We estimate rwTTD accounting for censoring via SAS PROC LIFETEST. Results: In this population, we identified 844 eligible patients with these 3 cancers who received LOT1 ICI therapy from 2015 - 2018. NSCLC is the most common cancer treated with an ICI (N = 598). Median rwTTD varied between 172 and 191 days across these 3 cancers. 68% of melanoma patients remained on LOT1 ICI treatment at 90 days decreasing to 30% at 1 year, while 74% of NSCLC remained on LOT1 ICI for at least 90 days and 40% of RCC patients for 1 year. We observed that of individuals who had an ICI in LOT1, 18% of those with NSCLC moved on to an ICI in LOT2, 39% of those with Melanoma, and 25% of those with RCC. Conclusions: Median rwTTD and the percent of patients remaining on ICI treatment at 90 and 180 days in LOT1 was similar among the three cancers. However, RCC patient are more likely to remain on LOT1 ICI (40%) than those being treated for Melanoma and NSCLC.[Table: see text]