Role Of Immune Checkpoint Inhibitors Research Articles

Progress in immunotherapy for neuroendocrine neoplasm of the digestive system.

Neuroendocrine neoplasms (NENs) are rare heterogeneous tumors that can develop in almost any organ, with the digestive organs, including the gastrointestinal tract and pancreas being the most commonly affected sites. Despite the fact that advances in initial therapies have progressed, there is presently no recognized effective treatment for advanced NEN. Immune checkpoint inhibitors (ICIs) have shown superior efficacy in treating several types of solid tumors. Despite their successful role in the treatment of partial NENs, such as small cell lung cancer, and Merkel cell carcinoma, the role of ICIs in most of the NENs remains limited. Nevertheless, due to their specific anti-tumor mechanisms and acceptable safety profile, ICIs are a promising avenue for further study in NENs therapy. Recent clinical trials have illustrated that combination therapy with ICI is more efficient than monotherapy, and multiple clinical trials are constantly ongoing to evaluate the efficacy and safety of these combination therapies. Therefore, the purpose of this review is to provide a comprehensive summary of the clinical progress of immunotherapy in NENs affecting the digestive system, with a specific emphasis on the application of programmed cell death protein 1/programmed death receptor ligand 1 inhibitor. Furthermore, this review has an exploration of the potential beneficiary population and the inherent value of utilizing immunotherapy in the management of NENs.

CTLA-4 Pathway Is Instrumental in Giant Cell Arteritis.

Giant cell arteritis (GCA) causes severe inflammation of the aorta and its branches and is characterized by intense effector T-cell infiltration. The roles that immune checkpoints play in the pathogenesis of GCA are still unclear. Our aim was to study the immune checkpoint interplay in GCA. First, we used VigiBase, the World Health Organization international pharmacovigilance database, to evaluate the relationship between GCA occurrence and immune checkpoint inhibitors treatments. We then further dissected the role of immune checkpoint inhibitors in the pathogenesis of GCA, using immunohistochemistry, immunofluorescence, transcriptomics, and flow cytometry on peripheral blood mononuclear cells and aortic tissues of GCA patients and appropriated controls. Using VigiBase, we identified GCA as a significant immune-related adverse event associated with anti-CTLA-4 (cytotoxic T-lymphocyte-associated protein-4) but not anti-PD-1/PD-L1 treatment. We further dissected a critical role for the CTLA-4 pathway in GCA by identification of the dysregulation of CTLA-4-derived gene pathways and proteins in CD4+ T cells (and specifically regulatory T cells) present in blood and aorta of GCA patients versus controls. While regulatory T cells were less abundant and activated/suppressive in blood and aorta of GCA versus controls, they still specifically upregulated CTLA-4. Activated and proliferating CTLA-4+ Ki-67+ regulatory T cells from GCA were more sensitive to anti-CTLA-4 (ipilimumab)-mediated in vitro depletion versus controls. We highlighted the instrumental role of CTLA-4 immune checkpoint in GCA, which provides a strong rationale for targeting this pathway.

Prolonged Survival of NUT Midline Carcinoma and Current Approaches to Treatment.

NUT midline carcinoma is a rare malignancy most commonly seen in adolescents and young adults. The disease presents most often in the lung or head and neck area but can be seen occasionally elsewhere. The diagnosis can be difficult and requires a high degree of suspicion with demonstration of the classic fusion rearrangement mutation of the NUTM1 gene with one of a variety of partners by immunohistochemistry, fluorescent in situ hybridization, or genomic analysis. Survival is usually only a number of months with few long-term survivors. Here we report one of the longest-known survivors of this disease treated with surgery and radiation without additional therapy. Systemic treatment approaches including the use of chemotherapy and BET and histone deacetylase inhibitors have yielded modest results. Further studies of these, as well as p300 and CDK9 inhibitors and combinations of BET inhibitors with chemotherapy or CDK 4/6 inhibitors, are being evaluated. Recent reports suggest there may be a role for immune checkpoint inhibitors, even in the absence of high tumor mutation burden or PD-L1 positivity. RNA sequencing of this patient's tumor demonstrated overexpression of multiple potentially targetable genes. Given the altered transcription that results from the causative mutation multi-omic evaluation of these tumors may uncover druggable targets for treatment.

Prognostic impact of intra- and peritumoral immune cell subpopulations in head and neck squamous cell carcinomas - comprehensive analysis of the TCGA-HNSC cohort and immunohistochemical validation on 101 patients.

Due to the expanding role of immune checkpoint inhibition in the treatment of head and neck squamous cell carcinoma, understanding immunological processes in the tumor microevironment (TME) has strong translational importance. Though analytical methods for a comprehensive analysis of the immunological TME have constantly improved and expanded over the past years the prognostic relevance of immune cell composition in head and neck cancer TME largely remains ambiguous with most studies focusing on one or a small subset of immune cells. The overall survival (OS) of the TCGA-HNSC patient cohort comprising 513 head and neck cancer patients was correlated with a total of 29 different immune metrics including a wide spectrum of immune cell subpopulations as well as immune checkpoint receptors and cytokines using RNAseq based immune deconvolution analyses. The most significant predictors of survival among these 29 immune metrics were validated on a separate HNSCC patient cohort (n=101) using immunohistochemistry: CD3, CD20+CXCR5, CD4+CXCR5, Foxp3 and CD68. Overall immune infiltration irrespective of immune cell composition showed no significant correlation with the patients' overall survival in the TCGA-HNSC cohort. However, when focusing on different immune cell subpopulations, naïve B cells (p=0.0006), follicular T-helper cells (p<0.0001), macrophages (p=0.0042), regulatory T cells (p=0.0306), lymphocytes (p=0.0001), and cytotoxic T cells (p=0.0242) were identified as highly significant predictors of improved patient survival. Using immunohistochemical detection of these immune cells in a second independent validation cohort of 101 HNSCC patients, we confirmed the prognostic relevance of follicular T helper cells, cytotoxic T cells and lymphocytes. In multivariable analysis, HPV negativity and advanced UICC stages were identified as additional prognostic biomarkers associated with poor outcome. Our study highlights the prognostic relevance of the immunological tumor environment in head and neck cancer and demonstrates that a more detailed analysis of immune cell composition and immune cell subtypes is necessary to accurately prognosticate. We observed the highest prognostic relevance for lymphocytes, cytotoxic T cells, and follicular T helper cells, suggesting further investigations focusing on these specific immune cell subpopulations not only as predictors of patient prognosis but also as promising targets of new immunotherapeutic strategies.

Highlights of the ASCO and ESMO annual meetings 2022: radiotherapy of head and neck cancer

At the 2022 annual meetings of the American Society of Clinical Oncology (ASCO) and the European Society for Medical Oncology (ESMO), several studies on radiation therapy for head and neck squamous cell carcinoma (HNSCC) were presented. Among the main topics were new concepts for treatment de-escalation with the goal of reducing side effects. Radiotherapy alone for nasopharyngeal carcinoma with an intermediate-risk profile was found to be noninferior to chemoradiotherapy with cisplatin while improving tolerability. In the phaseII DIREKHT trial for adjuvant radiotherapy, individualized deintensification concepts of radiation dose or volume were implemented. Overall, this treatment resulted in excellent levels of locoregional control with aminimal side effects profile. In subgroup analysis, however, an increased locoregional recurrence rate was observed for tumors of the oral cavity. In 2022, as in the previous year, there was acontinued focus on the role of immune checkpoint inhibitors in combination with platinum-based chemoradiotherapy in the first-line treatment of locally advanced HNSCC. In the HNSCC-15-132 trial, sequential application of the PD‑1 inhibitor pembrolizumab to chemoradiotherapy was not significantly, but numerically superior to concomitant application. The phaseIII KEYNOTE-412 trial evaluated the efficacy of concomitant and sequential additive pembrolizumab therapy compared to additive placebo in 804patients with locally advanced HNSCC. The observed benefit in terms of event-free survival in the pembrolizumab group marginally missed statistical significance, probably due to the particular study design. In addition, new 5‑year overall survival data from the phaseII trial of chemoradiotherapy in combination with the inhibitor of apoptosis proteins (IAP) antagonist xevinapant versus placebo were presented. The xevinapant group continued to demonstrate asignificant survival advantage and asustained response to treatment.

The role of immune checkpoint inhibitors (ICI) as adjuvant treatment in renal cell carcinoma (RCC): A systematic review and meta-analysis.

Pembrolizumab, a PD-1 ICI is approved for the adjuvant treatment of postnephrectomy patients with clear cell RCC in some countries worldwide. However, recent negative data from randomized clinical trials (RCT) with another ICIs makes the benefit of this treatment uncertain. A systematic review and study-level meta-analysis was performed to evaluate the benefit of disease-free survival (DFS) with adjuvant ICI treatment for patients with localized and/or metastatic resected RCC. Using the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement, a systematic search was performed in PUBMED/MEDLINE, Scopus and EMBASE up to September 15, 2022. The statistical analysis was performed by ProMeta 3 software in intention-to-treat (ITT) population and in predetermined subgroups. Four RCT totalizing 3407 patients were included in this analysis. Systemic immunotherapy was pembrolizumab, atezolizumab, nivolumab, and ipilimumab plus nivolumab in 496, 390, 404, and 405 patients, respectively. In the ITT population there was a nonstatistically significant DFS benefit with adjuvant ICI (HR: 0.85, 95% CI: 0.69-1.04). Regarding the subgroups, there was a DFS benefit for PD-L1 positive (HR: 0.72; 95% CI: 0.55-0.94), intermediate-high risk patients (HR: 0.77; 95% CI: 0.63-0.94), and patients with sarcomatoid component (HR: 0.66; 95% CI: 0.43-0.99). This meta-analysis did not demonstrate a statistically significant DFS benefit in overall population, however considering the heterogeneity between the RCTs the use of adjuvant ICI should be individualized.

Role of immune checkpoint inhibitors in PDL1-negative, low TMB, stable MSI metastatic solid tumours: Single centre study.

e14603 Background: Immune check point inhibitors clearly play a part in malignancies with elevated PDL1 expression, high TMB or unstable MSI. There is no information on PDL1 negative, low TMB/MSI stable metastatic solid tumours, however several treatment trials advise using immune check point inhibitors regardless of tissue agnostic indicators. Detailed subset analysis was not performed, though. This study examines the effectiveness of immunotherapy in metastatic solid tumours with PDL1 negative/TMB low/MSI stability. Methods: Study was carried out from Jan-2020 to Dec- 2022 (retrospective data from 2019 also included for analysis). Inclusion criteria: Metastatic solid tumours in patients who received immunotherapy. Exclusion criteria: PDL1&gt;1% ( Either TPS/ CPS &gt;1) by sp263 or 22c3 platforms, TMB&gt; 10, Unstable MSI by IHC or by genomics. Patients who were diagnosed with melanoma, hepatocellular cancer, renal cell carcinoma were also excluded from the study. Response was initially assessed after 3 to 6 cycles of immunotherapy, analysed by PET CT scan. Data were analysed using standard statistical method. Results: After carefully applying exclusion criteria, a total of 40 patients were enrolled in the research, with a male to female ratio of 1.5. Overall response rate in all tumours was 17.5% (7/ 40) Immune checkpoint inhibitors' ORRs at various tumour locations. Among the responders head and neck tumours 2/4 (50%) and lung cancers (37.5%) had higher ORR who also had greater depth of response, living more than 2 years from diagnosis. There is no response observed in gastroesophageal (0/8) gynaecological malignancies (clear cell ovary (0/2), endometrial and cervical (0/3). A patient with urothelial carcinoma who also had a BRCA mutation and was one out of seven responded to IO. Conclusions: Regardless of the presence of PDL1 expression, high TMB, or MSI, adding immune checkpoint inhibitors to the treatment regimen for metastatic head and neck malignancies and lung tumours that lack driver mutations is obviously advantageous. On the other hand, immunotherapy had no effect on gastrointestinal, gynaecological, or urothelial tumours. To validate these findings, more research with several centres and a sizable sample size is necessary. It's interesting that one patient responded to immunotherapy with positive BRCA mutation. Investigating immunotherapy in HRR deficient tumours may shed further insights. [Table: see text]

Heterogeneity of CD40 Expression in Different Types of High-Risk Endometrial Cancer Affects Discordant Prognostic Outcomes.

The role of immune checkpoint inhibitors in endometrial cancer is limited. At present, the anti-programmed cell death protein 1 (anti-PD-1) antibody is only used in patients with recurrence or metastasis. CD40 is an important immune checkpoint, which is expressed in tumor cells and immune cells, but its distribution characteristics in endometrial carcinoma have not been explored. Sixty-eight cases of primary endometrial carcinoma treated in Peking University People's Hospital from January 2010 to December 2020 were collected, including 28 cases of poorly differentiated endometrioid adenocarcinoma, 23 cases of serous carcinoma and 17 cases of clear cell carcinoma. The relationship of CD40 expression and PD-L1 expression with their prognosis was analyzed by immunohistochemistry. We found that CD40 had higher expression in non-endometrioid endometrial carcinoma, which lead to the worse prognosis. The effect of high expression of CD40 on the prognosis of endometrioid adenocarcinoma was not significantly different, and most patients with good prognosis. We found that the proportion of CD40 distribution in tumor cells and immune cells may be associated with this heterogeneity. The expression of CD40 in different endometrial cancers may indicate the difference prognosis, which may become a potential target for drug treatment of non-endometrioid endometrial carcinoma.

Role of immune checkpoint inhibitors in metastatic uveal melanoma: a single-center retrospective cohort study

Background Uveal melanoma is an orphan malignancy with very limited data on treatment options in metastatic setting. Methods In this single-center retrospective study, we describe real-world epidemiological and survival data on 121 metastatic uveal melanoma (MUM) patients registered in our institution. As a large tertiary referral center, almost 30% of all diagnoses in the Flemish region of Belgium were covered. Primarily, we determined whether introduction of immune checkpoint inhibitors (ICI) led to improved overall survival (OS) in MUM patients. Secondarily, response rates to ICI were assessed and we evaluated whether first-line ICI could be a valid alternative to liver-directed therapy (LDT) in liver-only disease. Results The initially perceived 10.8 months survival benefit from treatment with ICI disappeared after correction for immortality bias. By analyzing treatment type as time-varying covariate on OS, no significant benefit of ICI over other systemic therapies (HR = 0.771) or best supportive care (BSC) (HR = 0.780) was found. Also comparison of the pre-ICI versus ICI era showed no OS improvement after introduction of ICI in our center (p = 0.7994). Only liver-directed and local oligometastatic approaches were associated with a lower chance of mortality when compared to ICI (p = 0.0025), other systemic therapies (p = 0.0001) and BSC (p = 0.0003), yet without correction for selection bias. We reported overall response rates on ICI ranging from 8–15% and we found some support for neoadjuvant strategies with ICI resulting in remission or downsizing, allowing oligometastatic approaches later on. In first-line liver-only disease, median real-world progression-free survival and OS did not significantly differ between patients treated with LDT or ICI upfront (p = 0.2930 and p = 0.5461 respectively). Conclusion Although we documented responses to ICI, our analyses do not demonstrate an OS benefit of ICI over alternative treatment strategies for MUM. However, local treatment options, whether liver-directed or for oligometastatic disease, may be beneficial and should be considered.

Targeting Angiogenesis in the Era of Biliary Tract Cancer Immunotherapy: Biological Rationale, Clinical Implications, and Future Research Avenues.

Although biliary tract cancers are traditionally considered rare in Western countries, their incidence and mortality rates are rising worldwide. A better knowledge of the genomic landscape of these tumor types has broadened the number of molecular targeted therapies, including angiogenesis inhibitors. The role of immune checkpoint inhibitors (ICIs) could potentially change the first-line therapeutic approach, but monotherapy with ICIs has shown disappointing results in CCA. Several clinical trials are evaluating combination strategies that include immunotherapy together with other anticancer agents with a synergistic activity. The tumor microenvironment (TME) composition plays a pivotal role in the prognosis of BTC patients. The accumulation of immunosuppressive cell types, such as tumor-associated macrophages (TAMs) and regulatory T-cells, together with the poor infiltration of cytotoxic CD8+ T-cells, is known to predispose to a poor prognosis owing to the establishment of resistance mechanisms. Likewise, angiogenesis is recognized as a major player in modulating the TME in an immunosuppressive manner. This is the mechanistic rationale for combination treatment schemes blocking both immunity and angiogenesis. In this scenario, this review aims to provide an overview of the most recent completed or ongoing clinical trials combining immunotherapy and angiogenesis inhibitors with/without a chemotherapy backbone.

Cardiovascular Effects of Immune Checkpoint Inhibitors: More Than Just Myocarditis.

Immune checkpoint inhibitors have reshaped the treatment of cancer, but they are characterized by peculiar toxicity consisting of immune-related adverse events that may potentially affect any organ or system. In this review, we summarize data on clinical presentation, diagnosis, pathogenesis, and management of the main immune-related cardiovascular toxicities of immune checkpoint inhibitors. The most relevant immune-related cardiovascular toxicity is myocarditis, but other non-negligible reported events include non-inflammatory heart failure, conduction abnormalities, pericardial disease, and vasculitis. More recently, growing evidence suggests a role for immune checkpoint inhibitors in accelerating atherosclerosis and promoting plaque inflammation, thus leading to myocardial infarction. Immune checkpoint inhibitors are associated with several forms of cardiovascular toxicity; thus, an accurate cardiovascular baseline evaluation and periodical monitoring are required. Furthermore, the optimization of cardiovascular risk factors before, during, and after treatment may contribute to mitigating both short-term and long-term cardiovascular toxicity of these drugs.

Abstract 79: Study of tumor microenvironment of ovarian clear cell carcinoma

Abstract Background: Clear cell ovarian carcinoma (CCOC) is characterized by a distinct histologic and molecular profile, and associated with very poor responses to standard treatment consisting of surgery and carboplatin:taxol chemotherapy. CCOC is chemo-resistant at the time of diagnosis and response to chemotherapy in the recurrent setting is less than 10%. Literature suggests a potential role for immune checkpoint inhibitors (ICI). However, only a subgroup of patients (20%) responds to ICI and little is known about the mechanisms of response and resistance to therapy. We postulate that a better understanding of CCOC tumor microenvironment (TME) could help predict patients’ response to ICI. Objective: The aim of this study is to investigate the relationship between TME immune infiltrate and clinical/outcome in 22 CCOC cases and identify subsets of CCOC who may benefit from immunotherapy. Material &amp; Methods: We characterized the immune landscape of 11 early and 11 advanced CCOC through a multiplex IHC Discovery Platform. Spatial single-cell proteomics analyses (cyclic-IF) and spatially-resolved RNAseq in 10 CCOC cases using an OC tissue microarray (TMA) were performed. Results were corelated with clinical and treatment outcome. Results: The percent of CD8, CD4, CD20 B cells Tregs, PD1, PDL1, monocytes and M2 monocytes and myeloid cells was significantly higher in advanced than early-stage cancers. Recurrent cancers were more immunosuppressive than cases with no recurrence. Tumor infiltrate was dense in 4 cases. Four patients with early-stage disease had a high number of CD8 naïve cells and experienced no recurrence. TME analysis of single case of advanced CCOC (before and after chemotherapy), revealed that hot tumor changed to cold tumor, suggesting the resistance to treatment. Cyclic IF analyses identified 3 tumor phenotype groups in a subset of 10 CCOC present on the OC TMA. The majority of CCOC had high expression of CCNE and high PI3K-AKT-mTor activity, low expression of hormone receptors (AR, ERa, PRg) and low cell cycle activity. Some tumors were also high for HER2. The stromal compartment was enriched in collagen VI, aSMA and PDGFR. The immune monitoring of several of those samples also revealed an immunosuppressive microenvironment, including the presence of M2 macrophages and expression of immune checkpoint proteins PD-L1 and B7-H4. Conclusion: Our study shows that various phenotypes of CCOC are defined by the cancer cell profiles and TME content. Importantly, a strong immunosuppressive microenvironment was detected in many samples, suggesting a potential response to ICI. Furthermore, we detected the expression of several therapeutic targets (MAPK, CCNE, PI3K-AKT-mTOR, HSP90, HER2), including oncogenic signaling pathways (RTK, MAPK). Different tumor phenotypes identified across our CCOC samples suggest that clear cell carcinoma could be subclassified into subtypes that should be treated differently. Citation Format: Tanja Pejovic, Sonali Joshi, Shawn Campbell, Dhanir Tailor, Joanna Pucilowska, Benjamin Tate, Pierre-Valérien Abate, Korina Mouzakitis, Marilyne Labrie, Elizabeth Munro, Jenna Emerson, Sanjay V. Malhotra. Study of tumor microenvironment of ovarian clear cell carcinoma [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 79.

Immunotherapy in malignant peritoneal mesothelioma (Review).

Over the last decade, there has been a movement in cancer treatment away from cytotoxic therapies toward strategies that enhance the immune system against cancer. Immune checkpoint inhibitors (ICIs) have been incorporated into the treatment regimens for patients with various solid tumors. Mesothelioma trials revealed encouraging efficacy; however, patients with peritoneal mesothelioma are usually excluded, slowing the progress of improving the treatment of this aggressive cancer and compelling oncologist to rely on retrospective studies despite their flaws and limitations. Currently, there is no consensus on the role of ICIs in the treatment of malignant peritoneal mesothelioma (MPeM). The present review discusses data from clinical studies that examined immunotherapy in MPeM and evaluates what is known about the relevance of the tumor microenvironment and clinically validated biomarkers for ICIs efficacy. Furthermore, a proposed strategy for utilizing immunotherapy in treating MPeM is discussed.

Adjuvant immunotherapy for patients with renal cell carcinoma at increased risk of recurrence following resection: A National Cancer Database analysis.

649 Background: Radical nephrectomy is the standard management for locoregional renal cell carcinoma (RCC); however, patients with adverse pathological features are at increased risk of recurrence. IMmotion010 and KeyNote 564 trials investigated the adjuvant role of immune checkpoint inhibitors (ICI) for high-risk clear cell RCC (ccRCC) and have yielded conflicting results. We aimed to investigate real-world survival outcomes associated with the adjuvant use of ICI in high-risk ccRCC using the National Cancer Database Methods: In this nationwide contemporary cohort study, patients with newly diagnosed non-metastatic high-risk clear cell RCC undergoing radical nephrectomy between 2015-2019 were included. High-risk RCC was defined as cT2 with Fuhrman grade 4 or cT3a with Fuhrman grade 3/4 or cT3b/T3c/T4 with any grade, or TxN+ any grade. Patients receiving adjuvant ICI were classified as Group A and patients who did not receive adjuvant ICI were classified as Group B. Inverse probability weighting (IPW)-adjusted Kaplan Meier curves were utilized to compare overall survival (OS) between the groups and cox proportional hazard models were utilized to identify the predictors for OS. Results: Overall, 768 patients met the inclusion criteria; 270 patients in Group A and 498 patients in Group B. The mean age was 60.5(10.6) years, and 70.8% of patients were males (Table). The use of ICI in the adjuvant setting for high-risk RCC increased from 17.4% in 2015 to 61.8% in 2019. The unadjusted and IPW-adjusted Kaplan Meier 5-year overall survival was similar in the two groups [Unadjusted: 36.8% in Group A vs 50.1% in Group B, p=0.30 and adjusted: 39.5% in Group A vs 47.9% in Group B, p=0.17]. The use of adjuvant ICI did not appear to be an independent predictor for OS on multivariable cox regression analysis (HR=1.14, p=0.31) Conclusions: Adjuvant ICI therapy in non-metastatic high-risk ccRCC might not be associated with a benefit in overall survival. [Table: see text]

Predicting survival of NSCLC patients treated with immune checkpoint inhibitors: Impact and timing of immune-related adverse events and prior tyrosine kinase inhibitor therapy.

Immune checkpoint inhibitors (ICIs) produce a broad spectrum of immune-related adverse events (irAEs) affecting various organ systems. While ICIs are established as a therapeutic option in non-small cell lung cancer (NSCLC) treatment, most patients receiving ICI relapse. Additionally, the role of ICIs on survival in patients receiving prior targeted tyrosine kinase inhibitor (TKI) therapy has not been well-defined. To investigate the impact of irAEs, the relative time of occurrence, and prior TKI therapy to predict clinical outcomes in NSCLC patients treated with ICIs. A single center retrospective cohort study identified 354 adult patients with NSCLC receiving ICI therapy between 2014 and 2018. Survival analysis utilized overall survival (OS) and real-world progression free survival (rwPFS) outcomes. Model performance matrices for predicting 1-year OS and 6-month rwPFS using linear regression baseline, optimal, and machine learning modeling approaches. Patients experiencing an irAE were found to have a significantly longer OS and rwPFS compared to patients who did not (median OS 25.1 vs. 11.1 months; hazard ratio [HR] 0.51, confidence interval [CI] 0.39- 0.68, P-value <0.001, median rwPFS 5.7 months vs. 2.3; HR 0.52, CI 0.41- 0.66, P-value <0.001, respectively). Patients who received TKI therapy before initiation of ICI experienced significantly shorter OS than patients without prior TKI therapy (median OS 7.6 months vs. 18.5 months; P-value < 0.01). After adjusting for other variables, irAEs and prior TKI therapy significantly impacted OS and rwPFS. Lastly, the performances of models implementing logistic regression and machine learning approaches were comparable in predicting 1-year OS and 6-month rwPFS. The occurrence of irAEs, the timing of the events, and prior TKI therapy were significant predictors of survival in NSCLC patients on ICI therapy. Therefore, our study supports future prospective studies to investigate the impact of irAEs, and sequence of therapy on the survival of NSCLC patients taking ICIs.

Role of immune checkpoint inhibitors in non-extirpative treatment of high-grade upper tract urothelial carcinoma. Single referral center experience

Role of immune checkpoint inhibitors in non-extirpative treatment of high-grade upper tract urothelial carcinoma. Single referral center experience

The role of immune checkpoint inhibitors in patients with intracranial metastatic disease.

Intracranial metastatic disease (IMD) complicates the course of nearly 2-4% of patients with systemic cancer. The prevalence of IMD has been increasing over the past few decades. Historically, definitive treatment for brain metastases (BM) has been limited to radiation therapy or surgical resection. Chemotherapies have not typically proven valuable in the treatment of IMD, with the exception of highly chemotherapy-sensitive lesions. Recent data have supported a role for systemic targeted therapies and immune checkpoint inhibitors (ICIs) in the treatment of select patients with IMD. There remains, however, a clear clinical need for further investigation to delineate the role of ICIs in patients with BM. In this review, we outline and describe recent and current efforts to identify the efficacy of ICI therapy in patients with IMD.

A phase II biomarker-oriented study to evaluate paclitaxel, olaparib, and durvalumab combination in patients with advanced gastric cancer.

404 Background: DNA damage response (DDR) gene alterations are observed in 27% of gastric cancer (GC), therefore, targeting DDR might be an interesting strategy in GC. Olaparib plus paclitaxel showed numerically improved overall survival (OS) compared to paclitaxel in 2L GC patients (pts), even though it did not meet the endpoint. (Lancet Oncol 2017). Besides DNA damage repair, olaparib induces immune modulation. The role of immune checkpoint inhibitor (ICI) is established in 1L and 3L+ GC. The combination of cytotoxic chemotherapy, DDR acting agent and ICI might have synergistic effects in GC, which has not been tested in clinical studies. Here, we report biomarker-oriented phase II study of paclitaxel/olaparib/durvalumab combination in 2L GC. (NCT03579784). Methods: Advanced GC pts who have failed to 1L chemotherapy were enrolled. During 1st cycle, paclitaxel (80 mg/m2, D1, 8, 15 Q 4wk) and olaparib (150mg bid, D1-28) was administered. From 2nd cycle, durvalumab (1500 mg, D1 Q 4wk) was added on them. Tumor biopsy (pretreatment, after 1st cycle, at disease progression) and blood collection (every cycle) was mandatory. Primary endpoint was the disease control rate (DCR). Secondary endpoints included ORR, DoR, PFS, OS and safety. For biomarker study, multiplex IHC, NGS, ctDNA, and cytokines and angiogenic factors analysis were performed. Efficacy analysis set (ES) and safety analysis set (SS) were defined as pts who underwent at least one tumor assessment and all pts who received cycle1 day1 or more, respectively. Results: Fifty pts were enrolled (6 screening fail or withdrawal of consent, 44 in SS, 38 in ES) HER2+ GC were 13.2%. Among 38 in ES, DCR and ORR were 84.1% (95% CI, 72.5-95.7) and 39.5% (95% CI, 24.0-55.0) (1 CR, 14 PR and 17 SD). PFS, DoR and OS were 6.7 (95% CI, 4.5-10.3), 6.5 (95% CI, 5.1-10.7) and 11.4 (95% CI, 9.2-13.2) months. Homologous recombination repair (HRR) genetic alterations (9.6 vs. 5.9 in PFS, p=0.037), high CD8/CD3 ratio (8.8 vs. 3.7 in PFS, p=0.008), high PD-L1 (CPS≥10) (9.6 vs 5.1 in PFS, p=0.031), low ATM IHC (13.3 vs. 9.8 in OS, p=0.066), and low serum IL-6 (12.9 vs. 8.3 in OS, p=0.001) were associated with prolonged PFS or OS. In SS, most adverse events (AEs) were mild, and Gr 3/4 leukopenia and anemia were observed in 52.2% and 31.8%. There were no treatment related AEs resulted in study discontinuation. Conclusions: Paclitaxel/olaparib/durvalumab is a promising combination in 2L GC, and is worth to be further explored, especially in biomarker-enriched patients with HRR, specific T-cells subsets, high PD-L1, low ATM and IL-6. Clinical trial information: NCT03579784 .

Diagnostic and Therapeutic Pathway in Diffuse Malignant Peritoneal Mesothelioma.

Diffuse malignant peritoneal mesothelioma (DMPM) is a rare form of mesothelioma that carries a very poor prognosis. The 5-year overall survival is about 20% (±5.9). Survival is optimal for patients suitable for cytoreductive surgery (CRS) with Hyperthermic Intraperitoneal Chemotherapy (HIPEC), with a median OS ranging from 34 to 92 months. However, selecting patients for surgery remains a complex task and requires a careful preoperative workup, rational analysis of prognostic profiles, and risk prediction models. Systemic chemotherapy could be offered: (1) in the adjuvant setting for high-risk patients; (2) for patients not eligible for CRS; and (3) for those with recurrent disease. It mainly includes the combination of Platin compound with Pemetrexed or immunotherapy. The biology of DMPM is still largely unknown. However, progress has been made on some fronts, such as telomere maintenance mechanisms, deregulation of apoptosis, tyrosine kinase pathways, and mutation of BRCA1-associated protein 1 (BAP1). Future perspectives should include translational research to improve our understanding of the disease biology to identify druggable targets. We should also clear the role of immune checkpoint inhibitors and investigate new locoregional technologies, such as pressurized intraperitoneal aerosol chemotherapy (PIPAC) or normothermic intraperitoneal chemotherapy (NIPEC).

The Role of Immune Checkpoint Inhibitors in Cancer Therapy.

Over the years, immune checkpoint inhibitors (CPIs) have become a powerful treatment strategy in the field of cancer immunotherapy. In the last decade, the number of FDA-approved CPIs has been increasing prominently, opening new horizons for the treatment of a wide range of tumor types. Pointedly, three immune checkpoint molecules have been under extensive research, which include cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein-1 (PD-1) and its ligand-1 (PD-L1). Despite remarkable success, not all patients respond positively to therapy, which highlights the complexity of the tumor microenvironment (TME) and immune system. This has led to the identification of molecular biomarkers to predict response and toxicity. In addition, there has been an emerging focus on developing new delivery and targeting approaches for better drug efficacy and potency. In this review, we highlight the mechanism of action of major CPIs, their clinical impact, variation in effectiveness, response prediction, updated clinical indications, current challenges and limitations, promising novel approaches, and future directions.