Role Of Immune Checkpoint Inhibitors Research Articles

Beyond Platinum, ICIs in Metastatic Cervical Cancer: A Systematic Review

Cervical cancer (CC) constitutes the fourth most common tumor among the female population. Therapeutic approaches to advanced CC are limited, with dismal results in terms of survival, mainly after progression to platinum-based regimens. Immune checkpoint inhibitors (ICIs) are remodeling the therapeutic scenario of many solid tumors. The role of ICIs in CC should be addressed. Therefore, we systematically reviewed the latest clinical trials employing ICIs in advanced CC to assess which ICIs have been employed and how ICIs might meet the need for new therapeutic options in terms of efficacy and safety. The review was conducted following the PRISMA guidelines. The following efficacy outcomes were specifically collected: overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS); for safety: type, number, and grade of adverse events (AEs). A total of 17 studies were analyzed. Anti-PD1 (pembrolizumab, nivolumab, cemiplimab, balstilimab, and tislelizumab), anti-PD-L1 (atezolizumab), and anti-CTLA-4 (ipilimumab, zalifrelimab) agents were employed both as single agents or combinations. Overall ORR ranged from 0% to 65.9%. ORR ranged from 5.9% to 69.6% in PD-L1-positive patients and from 0% to 50% in PD-L1-negative patients. DCR was 30.6-94.1%. mPFS ranged from 2 to 10.4 months. mOS ranged from 8 months to not reached. PD-L1 status did not impact survival. A total of 33.9% to 100% of patients experienced AEs. Immunotherapy represents an appealing strategy for patients with advanced CC, as 2 out of 3 patients seem to respond to ICIs. PD-L1 status might be an indicator of response without impacting survival.

Assessing the Relationship between Thrombosis and Immune-Related Adverse Events in Patients with Lung Cancer Treated with Immune Checkpoint Inhibitors

Introduction: Venous thromboembolisms (VTE) frequently occur in cancer patients, and the role of immune checkpoint inhibitors on thrombotic risk has been a rising concern for clinicians. Identifying pro-thrombotic risk factors could guide primary prophylaxis strategies in patients receiving immunotherapy. Immune checkpoint blockade can induce inflammatory side effects known as immune-related Adverse Events (irAE). Inflammatory states are known to be associated with a hypercoagulable state. It is not established whether patients treated with immunotherapy experience a higher risk of thrombotic events during periods of increased inflammation surrounding irAE occurrence. Similarly, while immune checkpoint inhibitors have been shown to be associated with increased bleeding events, it is not clear whether irAE occurrence affects incidence of hemorrhage. Our primary objective was to determine the association between irAE and thrombosis in patients with non-small cell lung cancer treated with immune checkpoint inhibitors in order to better elucidate potential risk factors for thrombosis in patients on immunotherapy. Our secondary objective was to evaluate the association between irAE and clinically significant bleeding events. Methods: We identified all patients with non-small cell lung cancer treated with pembrolizumab at an academic medical center between 2016 and 2021. Outcomes of interest were VTE and clinically relevant bleeding (a composite of major bleeding and clinically-relevant non-major bleeds). We collected information regarding concurrent chemotherapy use with immunotherapy, frequency and type of irAE, steroid use for treatment for irAE, and use of anticoagulation or antiplatelet agents. We used logistic regression to calculate the odds ratios (OR) and 95% confidence intervals (CI) of VTE and clinically-relevant bleeding among patients who had an irAE prior to the outcome of interest compared to those who did not. We calculated the odds of VTE associated with use of concurrent chemotherapy (vs. no concurrent chemotherapy). Results: Of 102 patients included, 46.1% were female, and average age at diagnosis was 66.8 ± 10.5 years. Thirty-four patients were treated with pembrolizumab alone, with the remainder receiving concurrent chemotherapy and/or targeted therapy with pembrolizumab. Overall, 21 patients experienced thrombotic events (20.6%), 7 (6.9%) experienced clinically-relevant bleeding events, and 28 (27%) experienced an irAE. (Table 1). Overall, occurrence of irAE was not associated with increased odds of VTE (OR: 1.07, 95% CI: 0.37-3.11, P=0.90). (Figure 1). Similarly, among those with an irAE, steroid treatment was not associated with increased odds of VTE (OR: 1.14, 95% CI: 0.17-7.69, P=0.89). The combination of chemotherapy with pembrolizumab did not result in a statistically significant increase in odds of VTE (OR: 1.37, 95% CI: 0.52-3.60, P=0.53). The odds of clinically-relevant bleeding was not statistically higher among those with an irAE (OR: 2.10, 95% CI: 0.44-10.0, P=0.35). Conclusions: The development of irAE in patients with NSCLC treated with pembrolizumab does not appear to predict the development of VTE. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

The Role of Chemotherapy Plus Immune Checkpoint Inhibitors in Oncogenic-Driven NSCLC: A University of California Lung Cancer Consortium Retrospective Study

IntroductionThere is a paucity of data on immune checkpoint inhibitors (ICIs) plus doublet chemotherapy (C) in patients with advanced lung cancer whose tumor harbors an actionable mutation. We sought to provide insight into the role of this combination in relation to chemotherapy alone in this patient population. MethodsWe conducted a retrospective study at the five University of California National Cancer Institute–designated Comprehensive Cancer Centers. The primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS) and significant adverse events. Adverse events in patients who received a tyrosine kinase inhibitor (TKI) post-ICI were also captured. ResultsA total of 246 patients were identified, 170 treated with C plus ICI and 76 treated with C alone. Driver alterations included EGFR (54.9%), KRAS (32.9%), ALK (5.3%), HER2/ERBB2 (2.9%), ROS1 (1.2%), MET (1.2%), RET (0.8%), and BRAF non-V600 (0.8%). The overall PFS and OS hazard ratios were not significant at 1.12 (95% confidence interval 0.83–1.51; p = 0.472) and 0.86 (95% confidence interval: 0.60–1.24, p = 0.429), respectively. No significant differences in PFS or OS were observed in the mutational subgroups. Grade 3 or greater adverse events were lower in the C plus ICI group. The multivariate analysis for PFS and OS revealed a performance status (Eastern Cooperative Oncology Group) score of 2, and previous TKI treatment was associated with poorer outcomes with C plus ICI. ConclusionsOur study suggests that patients with oncogenic-driven NSCLC, primarily those with EGFR-driven tumors, treated with a TKI should not subsequently receive C plus ICI. Analysis from prospective clinical trials will provide additional information on the role of ICIs in this group of patients.

The Role of Immune Checkpoint Inhibitors in Pharyngolaryngeal Cancer: A Current Review

The Role of Immune Checkpoint Inhibitors in Pharyngolaryngeal Cancer: A Current Review

A Systematic Review and Meta-Analysis of the Role of Immune Checkpoint Inhibitors (ICI) as Adjuvant Treatment for Localized High-Risk Muscle-Invasive Urothelial Carcinoma (MIUC).

Nivolumab, a PD-1 ICI has been recently approved for the adjuvant treatment of high-risk MIUC patients. However, conflicting data from another randomized controlled trial (RCT) with atezolizumab makes the benefit of this treatment uncertain. We performed a systematic review and study-level meta-analysis to evaluate the benefit in terms of disease-free survival (DFS) with ICI adjuvant treatment for patients with high-risk MIUC. Considering the Preferred Reporting Items for Systematic Review statement, a systematic search was performed in PUBMED/MEDLINE, Scopus and EMBASE up to October 30, 2021. The statistical analysis was performed by RevMan 5.4 software in intention-to-treat (ITT) population and in predetermined subgroups. Two RCTRCT, with a total of 1518 patients, met the inclusion criteria. Systemic immunotherapy was atezolizumab for 406 patients and nivolumab for 353 patients. In the ITT population there was a nonsignificant benefit with the systemic adjuvant immunotherapy (HR:0.79, 95% CI 0.62-1.00; z=2.00) but with high heterogeneity (I2=65%). Regarding the subgroups, there was no benefit in PD-L1 negative (HR:0.81, 95% CI 0.70-1.00; z=1.96, I2=0%) and in non-neoadjuvant chemotherapy (HR:0.95, 95% CI 0.78-1.15; z=0.56, I2=0%). Adjuvant treatment with ICI to patients with high-risk MIUC reveals a nonsignificant impact in DFS. The lack of clinical benefit was demonstrated in all subgroups. These data reinforce the need for a careful selection of patients before offering this approach in daily practice.

Gastroenteropancreatic Neuroendocrine Neoplasms (GEP NENs): The Role of Checkpoint Inhibitors.

The treatment options for GEP-NENs include various drugs and are based on grading, morphology, and location of the primary. The aim of our work is to investigate the clinical impact of new immune checkpoint inhibitors in order to define a new possible strategy of use within GEP-NENs. A scientific literature search from 2015 to January 2020 was performed using PubMed and Embase: reviews and prospective or retrospective studies with a minimum of twenty patients were selected; conference proceedings were included. Several studies have been conducted to assess the role of immune checkpoint inhibitors in NENs, but nowadays, the current knowledge in this field is mainly based on phase I-II studies. Immunotherapy showed limited antitumor activity, but a higher response rate was reported in poor-differentiated neuroendocrine tumors. No specific biomarkers were identified for patient selection and response assessment. Immunotherapy appears as a powerful possibility to help our patients, but nowadays, we see many gaps in this field. We must balance therapeutic possibilities offered by precision oncology with an understanding of the limitations of the application of testing and treatment in clinical practice. Future efforts should focus on research of the best patients to a candidate for immunotherapy in terms of disease characteristics and previous treatments and how to select them with accurate biomarkers.

The role of immune checkpoint inhibitors in clinical practice: an analysis of the treatment patterns, survival and toxicity rates by sex

PurposeOur aim is to describe the role of immune checkpoint inhibitors (ICI) in clinical practice by providing the patient and tumor characteristics as well as survival and toxicity rates by sex.MethodsWe used electronic health records to identify patients treated at the Cancer Center of the University Hospital Bern, Switzerland between January 1, 2017 and June 16, 2021.ResultsWe identified 5109 patients, 689 of whom (13.5%) received at least one dose of ICI. The fraction of patients who were prescribed ICI increased from 8.6% in 2017 to 22.9% in 2021. ICI represented 13.2% of the anticancer treatments in 2017 and increased to 28.2% in 2021. The majority of patients were male (68.7%), who were older than the female patients (median age 67 vs. 61 years). Over time, adjuvant and first line treatments increased for both sexes. Lung cancer and melanoma were the most common cancer types in males and females. The incidence of irAEs was higher among females (38.4% vs. 28.1%) and lead more often to treatment discontination in females than in males (21.1% vs. 16.8%). Independent of sex, the occurrence of irAEs was associated with greater median overall survival (OS, not reached vs. 1.1 years). Female patients had a longer median OS than males (1.9 vs. 1.5 years).ConclusionsICI play an increasingly important role in oncology. irAEs are more frequent in female patients and are associated with a longer OS. More research is needed to understand the association between patient sex and toxicity and survival.

Evaluation of the Molecular Landscape in PD-L1 Positive Metastatic NSCLC: Data from Campania, Italy.

Background: Immune-checkpoint inhibitors (ICIs) have increased and improved the treatment options for patients with non-oncogene-addicted advanced stage non-small cell lung cancer (NSCLC). However, the role of ICIs in oncogene-addicted advanced stage NSCLC patients is still debated. In this study, in an attempt to fill in the informational gap on the effect of ICIs on other driver mutations, we set out to provide a molecular landscape of clinically relevant oncogenic drivers in programmed death-ligand 1 (PD-L1) positive NSCLC patients. Methods: We retrospectively reviewed data on 167 advanced stage NSCLC PD-L1 positive patients (≥1%) who were referred to our clinic for molecular evaluation of five driver oncogenes, namely, EGFR, KRAS, BRAF, ALK and ROS1. Results: Interestingly, n = 93 (55.7%) patients showed at least one genomic alteration within the tested genes. Furthermore, analyzing a subset of patients with PD-L1 tumor proportion score (TPS) ≥ 50% and concomitant gene alterations (n = 8), we found that n = 3 (37.5%) of these patients feature clinical benefit with ICIs administration, despite the presence of a concomitant KRAS gene alteration. Conclusions: In this study, we provide a molecular landscape of clinically relevant biomarkers in NSCLC PD-L1 positive patients, along with data evidencing the clinical benefit of ICIs in patient NSCLC PD-L1 positive alterations.

Recent Insights into PARP and Immuno-Checkpoint Inhibitors in Epithelial Ovarian Cancer.

Ovarian cancer is one of the most common gynecologic cancers and has the highest mortality rate of any other cancer of the female reproductive system. Epithelial ovarian cancer (EOC) accounts for approximately 90% of all ovarian malignancies. The standard therapeutic strategy includes cytoreductive surgery accompanied by pre- or postoperative platinum-based chemotherapy. Nevertheless, up to 80% of the patients relapse within the following 12–18 months from the completion of the treatment and then receive first-line chemotherapy depending on platinum sensitivity. Mutations in BRCA1/2 genes are the most significant molecular aberrations in EOC and serve as prognostic and predictive biomarkers. Poly ADP-ribose polymerase (PARP) inhibitors exploit defects in the DNA repair pathway through synthetic lethality. They have also been shown to trap PARP1 and PARP2 on DNA, leading to PARP-DNA complexes. Olaparib, rucaparib, and niraparib have all obtained Food and Drug Administration (FDA) and/or the European Medicine Agency (EMA) approval for the treatment of EOC in different settings. Immune checkpoint inhibitors (ICI) have improved the survival of several cancers and are under evaluation in EOC. However, despite the success of immunotherapy in other malignancies, the use of antibodies inhibiting the immune checkpoint programmed cell death (PD-1) or its ligand (PD-L1) obtained modest results in EOC so far, with median response rates of up to 10%. As such, ICI have not yet been approved for the treatment of EOC. We herein provided a comprehensive insight into the most recent progress in synthetic lethality PARP inhibitors, along with the mechanisms of resistance. We also summarised data regarding the role of immune checkpoint inhibitors, the use of vaccination therapy, and adoptive immunotherapy in treating epithelial ovarian cancer.

Enhanced stimulation of antigen-specific immune responses against nucleophosmin 1 mutated acute myeloid leukaemia by an anti-programmed death 1 antibody.

Nucleophosmin1 (NPM1) is one of the most commonly mutated genes in AML and is often associated with a favourable prognosis. Immune responses play an increasing role in AML treatment decisions; however, the role of immune checkpoint inhibition is still not clear. To address this, we investigated specific immune responses against NPM1, and three other leukaemia-associated antigens (LAA), PRAME, Wilms' tumour 1 and RHAMM in AML patients. We investigated T cell responses against leukaemic progenitor/stem cells (LPC/LSC) using colony-forming immunoassays and flow cytometry. We examined whether immune checkpoint inhibition with the anti-programmed death 1 antibody increases the immune response against stem cell-like cells, comparing cells from NPM1 mutated and NPM1 wild-type AML patients. We found that the anti-PD-1 antibody, nivolumab, increases LAA stimulated cytotoxic T lymphocytes and the cytotoxic effect against LPC/LSC. The effect was strongest against NPM1mut cells when the immunogenic epitope was derived from the mutated region of NPM1 and these effects were enhanced through the addition of anti-PD-1. The data suggest that patients with NPM1 mutated AML could be treated with the immune checkpoint inhibitor anti-PD-1 and that this treatment combined with NPM1-mutation specific directed immunotherapy could be even more effective for this unique group of patients.

Checkpoint Immunotherapy in Pediatrics: Here, Gone, and Back Again.

The role of immune checkpoint inhibitors (ICIs) in the treatment of pediatric cancers continues to evolve. Such therapies function by augmenting existing antitumor T-cell responses that have been rendered ineffective by inhibitory pathways. Although ICIs have proven highly effective for adult cancers, initial phase I/II clinical trials using single-agent ICIs against unselected pediatric cancers have been overall disappointing. With the exception of pediatric classic Hodgkin lymphoma, responses to ICIs have been infrequent, likely stemming from an inherent difference in the immunogenicity of childhood cancers, which, on average, have far fewer neoantigens than adult cancers. Recently, however, hope has reemerged that certain subsets of children with cancer may benefit from ICI therapies. In preliminary studies, patients with both pediatric hypermutated and SMARCB1-deficient cancers have had impressive responses to ICI therapies, likely as a result of underlying biologies that enhance neoantigen expression and tumoral inflammation. Dedicated trials are ongoing to fully evaluate the efficacy of ICIs for patients with these subsets of pediatric cancer.

Prolonging Survival in Advanced Esophageal Squamous Cell Carcinoma With Immune Checkpoint Inhibitors

Doki Y, Ajani A, Xu L, et al. Nivolumab combination therapy in advanced esophageal squamous-cell carcinoma. N Engl J Med 2022;386:449–462. Prognosis among patients with advanced esophageal squamous cell cancer (SCC) receiving chemotherapy is poor, with life expectancy averaging less than 1 year. Treatment with nivolumab, an anti–programmed death-1 monoclonal antibody, has been found to prolong survival compared with chemotherapy in previously treated advanced esophageal SCC. In other solid tumors, the combination of nivolumab with ipilimumab (an anti–cytotoxic T-lymphocyte antigen 4 antibody) has been found to improve survival compared with chemotherapy or nivolumab alone. Checkmate-648 was a global, randomized, open-label phase 3 trial that evaluated the efficacy of nivolumab combination therapies compared with chemotherapy alone in advanced, incurable esophageal SCC. The primary end point was overall and progression-free survival, with subset analyses performed in patients with programmed death ligand 1 (PD-L1) expression ≥1%. The trial randomized 970 patients to receive nivolumab plus chemotherapy (constituting cisplatin and fluorouracil, n = 321), nivolumab plus ipilimumab (n = 325), or chemotherapy alone (n = 324). At a 13-month minimum follow-up, overall survival was significantly longer with nivolumab plus chemotherapy compared with chemotherapy alone, in both patients with PD-L1 expression ≥1% (15.4 vs 9.1 months) and in the overall population (13.2 vs 10.7 months). Progression-free survival in patients with PD-L1 expression ≥1% was also longer with nivolumab plus chemotherapy compared with chemotherapy alone (6.9 vs 4.4 months). Similarly, the dual immune checkpoint inhibitor combination of nivolumab and ipilimumab improved survival compared with chemotherapy alone in both patients with PD-L1 expression ≥1% (13.7 vs 9.1 months) and in the overall population (12.7 vs 10.7 months), although there was no significant difference in progression-free survival. Treatment-related adverse events, leading to drug discontinuation, were higher with nivolumab plus chemotherapy (34%) than nivolumab plus ipilimumab (18%) and chemotherapy alone (19%). Health-related quality of life was maintained in all groups during the treatment period. In summary, first-line treatment with nivolumab-based regimens prolonged survival by 2.0–6.3 months in patients with advanced esophageal SCC compared with chemotherapy alone. However, the trial was not designed to examine differences between nivolumab plus chemotherapy vs nivolumab plus ipilimumab. Future studies should aim to address this, in addition to identifying key prognostic markers that will aid personalizing immunotherapy for patients with esophageal SCC. The results of ongoing studies evaluating the role of immune checkpoint inhibitors in the neoadjuvant setting of operable esophageal cancer are also awaited (ClinicalTrials.gov, Numbers: NCT03604991, NCT03399071, and NCT04592913).

Immune Checkpoint Inhibitors in the Treatment of Breast Cancer Brain Metastases.

The management of breast cancer brain metastases (BCBM) has historically involved local therapies. However, as novel systemic treatments have become more effective in controlling visceral disease, BCBM have also been better controlled. Immune checkpoint inhibitors (ICIs) have demonstrated efficacy in brain metastases in patients with lung cancer and melanoma and represent a promising option for patients with triple-negative BCBM, a group with limited systemic therapy options. In this review we summarize current data about the role of ICIs in the treatment BCBM. We identified 15 clinical trials that evaluated ICIs ± chemotherapy in patients with breast cancer. The studies were mostly focused on triple-negative breast cancer (TNBC). Of these trials, 4 excluded patients with BCBM, while 11 allowed patients with stable, treated or asymptomatic BCBM. In total, 2692 patients were enrolled in the identified clinical trials, but only 91 trial patients (3.3%) had BCBM. Furthermore, only 2 of these clinical trials reported BCBM-specific outcomes and none of the clinical trials reported BCBM-specific adverse events. Up to 45% of patients with TNBC will develop BCBM; however, only 3.3% of the patients included in the clinical trials that led to the U.S. Food and Drug Administration approvals for ICIs in advanced breast cancer had brain metastases. This review reinforces that efficacy data are greatly needed for patients with BCBM—this is an area of unmet need in oncology. More inclusive clinical trials and real-world data that evaluate the safety and efficacy of ICIs in patients with BCBM are greatly needed.

Cancers bronchiques non à petites cellules (CNPC) résécables et immunothérapie : état des lieux et perspectives: Resectable non-small cell lung cancers (CNPC) and immunotherapy: status and outlook

Surgery is the standard of care for stage I, II, and IIIA NSCLC. Adjuvant platinum-based chemotherapy (or neoadjuvant) provides an estimated 5% overall survival benefitat 5 years in stages II and IIIA and is recommended. Adjuvant radiotherapy is not recommended for N2 tumors. The impact of peri-operative targeted therapies in patients with molecular alterations is currently suggested by the ADAURA study in EGFR mutated patients showing a benefit in terms of recurrence-free survival. The role of immune checkpoint inhibitors is currently being studied in neoadjuvant and adjuvant trials and the first results are very encouraging. Initial results from the phase 3 CM-816 trial, testing the combination of nivolumab and chemotherapy versus chemotherapy, showed superiority of the combination in terms of complete pathological response and event-free survival. The phase 3 trial comparing atezolizumab versus control in the adjuvant setting was positive in terms of relapse-free survival, but only for PD-L1 positive stage II and III. In this review, we will discuss the results of immune checkpoint inhibitor (ICI) trials with or without chemotherapy only.© 2022 SPLF. Published by Elsevier Masson SAS. All rights reserved.

Extra-Nodal Follicular Dendritic Cell Sarcoma with Unusual Morphological Features and PDL1 Expression

AbstractFollicular dendritic cell (FDC) sarcoma, a rare tumor of FDCs, poses a diagnostic challenge due to its myriad morphologic and architectural patterns. We present a unique case of extra-nodal FDC sarcoma occurring in a 28-year-old gentleman who presented with multiple pelvic, peritoneal and retroperitoneal soft tissue, and axial skeletal lesions. The tumor was composed of islands and trabeculae of epithelioid cells with interspersed lymphocytes against a background of abundant myxoid matrix. On immunohistochemistry, in addition to the CD21, the tumor was positive for GATA3, inhibin, and programmed death-ligand 1 (PDL1), which have been rarely reported previously in FDC sarcoma. The patient underwent surgical excision of the tumor and was later offered immunotherapy. He has been disease-free for 2 years following immunotherapy. Our case highlights the potential role of immune checkpoint inhibitors in treating FDC sarcoma, which show immuno-expression of PDL1.

Intra-Tumoral CD8+ T-Cell Infiltration and PD-L1 Positivity in Homologous Recombination Deficient Pancreatic Ductal Adenocarcinoma.

The immune contexture of pancreatic ductal adenocarcinoma (PDAC) is generally immunosuppressive. A role for immune checkpoint inhibitors (ICIs) in PDAC has only been demonstrated for the rare and hypermutated mismatch repair (MMR) deficient (MMR-d) subtype. Homologous recombination repair (HR) deficient (HR-d) PDAC is more prevalent and may encompass up to 20% of PDAC. Its genomic instability may promote a T-cell mediated anti-tumor response with therapeutic sensitivity to ICIs. To investigate the immunogenicity of HR-d PDAC, we used multiplex immunohistochemistry (IHC) to compare the density and spatial distribution of CD8+ cytotoxic T-cells, FOXP3+ regulatory T-cells (Tregs), and CD68+ tumor-associated macrophages (TAMs) in HR-d versus HR/MMR-intact PDAC. We also evaluated the IHC positivity of programmed death-ligand 1 (PD-L1) across the subgroups. 192 tumors were evaluated and classified as HR/MMR-intact (n=166), HR-d (n=25) or MMR-d (n=1) based on germline testing and tumor molecular hallmarks. Intra-tumoral CD8+ T-cell infiltration was higher in HR-d versus HR/MMR-intact PDAC (p<0.0001), while CD8+ T-cell densities in the peri-tumoral and stromal regions were similar in both groups. HR-d PDAC also displayed increased intra-tumoral FOXP3+ Tregs (p=0.049) and had a higher CD8+:FOXP3+ ratio (p=0.023). CD68+ TAM expression was similar in HR-d and HR/MMR-intact PDAC. Finally, 6 of the 25 HR-d cases showed a PD-L1 Combined Positive Score of >=1, whereas none of the HR/MMR-intact cases met this threshold (p<0.00001). These results provide immunohistochemical evidence for intra-tumoral CD8+ T-cell enrichment and PD-L1 positivity in HR-d PDAC, suggesting that HR-d PDAC may be amenable to ICI treatment strategies.

Efficacy of Immune Checkpoint Inhibitors in Patients With EGFR Mutated NSCLC and Potential Risk Factors Associated With Prognosis: A Single Institution Experience.

BackgroundThe role of immune checkpoint inhibitors (ICIs) in NSCLC patients with EGFR mutations are controversial. In this study, we aim to investigate the therapeutic efficacy of ICIs alone or in combination in patients with EGFR mutated NSCLC in late-line settings, and explore the factors that may predict the efficacy of ICIs.Patients and MethodsWe retrospectively collected the clinical and pathological information of 75 patients with confirmed EGFR mutations. All patients have developed acquired resistance to EGFR-TKIs, and were treated with ICIs in late line settings from January 2019 to January 2021, at Shandong Caner Hospital and Institute. Therapeutic efficacy was evaluated by tumor response and survival.ResultsThe median follow-up period was 7.3months (range 1.8-31.8 months). The overall response rate (ORR) was 8.0%, and the disease control rate (DCR) was 78.7%. The median PFS for all patients was 3.9 months (95% CI, 2.7-5.0), while the median OS was 9.9 months (95% CI, 5.3-14.6). We found that patients with longer response duration to EGFR-TKIs (≥10 months) showed a longer PFS when treated with immunotherapy compared with patients with shorter PFS-TKI (<10 months), the median PFS in two groups were 5.2 months [95%CI 4.2-6.2] and 2.8 months [2.0-3.6]) respectively (HR, 0.53, 95%CI, 0.31-0.91, P=0.005). In exploratory analysis, we found that concurrent extracranial radiotherapy and higher body mass index (BMI) are associated with longer PFS (P values are 0.006 and 0.021 respectively).ConclusionsWe found that combination regimen of immunotherapy plus chemotherapy plus antiangiogenetic agents may yield longer survival in patients with EGFR mutated NSCLC. We also found that patients with longer PFS-TKI, concurrent extracranial radiotherapy and higher BMI may benefit more from immunotherapy.

PD-L1 as a Potential Therapeutic Target to Immune Checkpoint Blockade in Cervical Cancer: A Review of the Literature

Cervical cancer (CC) is still one of the most common malignant tumors in women worldwide. Malignant tumors are known for evading immune surveillance. In cervical lesions, the mechanism has received less attention. Evasion of immune surveillance through a variety of mechanisms; one of which is the immune checkpoint pathway has attracted interest because it can be therapeutically targeted, the programmed cell death 1 (PD-1) pathway that tumor cells use to block antitumoral immune responses. Increasing the prevalence of PD-L1 expression in up to 80% of cervical malignancies, there is a significant indication using immunotherapy to maintain the immune response against malignancies. The purpose of this literature review is to examine the potential role of immune checkpoint inhibitors in the treatment of cervical neoplastic lesions, by reviewing articles on cervical intraepithelial neoplasia (CIN) and cervical cancer that carried out histopathological and immunohistochemical examination PD-L1 as well as immunotherapy treatment with anti-PD-L1. There were 10 articles were found to be associated with anti-PD-1/PD-L1 immunotherapy. In conclusion, PD-L1 is a potential therapeutic target in cervical cancer

Phase I/II trial of pembrolizumab and AR signaling inhibitor +/- 225Ac-J591 for chemo-naive metastatic castration-resistant prostate cancer (mCRPC).

TPS216 Background: The role of immune checkpoint inhibition (ICI) in prostate cancer remains undefined outside of the subset with mismatch repair. Several studies have suggested that ICI combined with androgen receptor signaling inhibitors (ARSI) or kinase inhibitors may result in improved and/or more durable response in a proportion of men with mCRPC. While not yet proven, addition of external beam radiation to ICI may improve outcomes (for instance Kwon et al Lancet Oncol 2014, Fizazi K et al, Eur Urol 2020). PSMA targeted therapy with 177Lu-PSMA-617 improves survival in men with CRPC, has been combined with ICI in early phase studies, and we have previously demonstrated the benefit of PSMA targeted therapy using radiolabeled mAb J591. PSMA-targeted alpha-emitters have a very high potency and the potential to generate immune response. Based upon i) ARSI may increase PSMA expression, ii) ARSI may radiosensitize tumors, iii) ARSI resistance may lead to increased PD-L1 expression, and iv) alpha emitters may generate an immune response, we hypothesize that the addition of an alpha-emitting radionuclide (225Ac) targeting prostate cancer (i.e PSMA+ tumors targeted with J591) will lead to double-stranded DNA breaks, cell death, and subsequent release of neoantigens, and thus will increase the response proportion to pembrolizumab plus ARSI resulting in more durable response. Methods: Key eligibility criteria include progressive mCRPC by PCWG3 on at least 1 prior AR pathway inhibitor and no prior chemotherapy for mCRPC. A phase I dose-finding study will first test safety of the triplet combination of pembrolizumab, an ARSI of physician choice, and 2 different doses of 225Ac-J591 (one with minimal and one with moderate single-agent toxicity). Following determination of the optimal dose, a randomized phase II trial will treat subjects with a fixed dose of pembrolizumab 400 mg every 6 weeks (for up to 2 years) plus a standard ARSI (until progression or intolerance) with or without 225Ac-J591. The primary endpoint of the study will test the hypothesis that the addition of a PSMA-targeted alpha emitter increases the composite of RECIST measurable disease, PSA, and CTC count response to immuno-hormonal therapy with 90% power. Key secondary clinical endpoints include 1-year progression-free survival, duration of response, and overall survival. Exploratory objectives include assessment of immunogenic cell death, immune serologic and host microbiome changes, plasma ctDNA, serial PSMA PET, and patient reported outcomes (FACT-P, BPI, EQ-5D-5L). The phase I portion of this DOD-funded study was activated in summer 2021 with the randomized phase II portion expected to open at PCCTC sites in 2022. Clinical trial information: NCT04946370.

Abstract ES10-3: IO beyond TNBC

Abstract Hormone receptor-positive breast cancer is not considered an immunogenic tumor, since characterized by lower level of programmed death-ligand 1 (PD-L1) expression and tumor infiltrating lymphocytes. Despite being a cold tumor some studies are addressing the question on potential role of immune-checkpoint inhibitors in the adjuvant or metastatic setting. The phase II Checkmate7A8 trial (NCT04075604) is investigating the combination of nivolumab, anastrozole, and palbociclib versus anastrozole with palbociclib as neoadjuvant therapy for postmenopausal women with luminal BC. The phase II ImmunoADAPT trial (NCT03573648) is studying the combination of tamoxifen, palbociclib, and avelumab versus tamoxifen with avelumab for patients with early-stage luminal BC, expecting to show an improvement in the radiological complete response rates assessed after four cycles of treatment. A phase I safety study is also investigating the combination of durvalumab, abemaciclib, and anastrozole in a similar population (NCT04088032). The Phase 3 CA209-7FL trial is a randomized, multicenter, placebo-controlled phase 3 study of nivolumab versus placebo in combination with neoadjuvant chemotherapy and adjuvant endocrine therapy in patients with high-risk, estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) primary breast cancer. In the HER2 positive metastatic breast cancer the combination of pembrolizumab and trastuzumab administered upon progression on a trastuzumab-based regimen was investigated in the PANACEA study, which reported a response rate of 15%, restricted to PD-L1 positive tumors with a PFS benefit in the PD-L1 population. In the KATE2 trial, the addition of atezolizumab to trastuzumab emtansine in patients previously treated with trastuzumab demonstrated no significant benefit in PFS, although numerically higher PFS and response rates were observed in the PD-L1-positive population. A subsequent underpowered analysis (due to the small number of events) of the same trial suggested a possible OS benefit for patients with PD-L1-positive tumors. The combination of trastuzumab, pertuzumab, taxane, and atezolizumab is under investigation in the first-line setting (NCT03199885). The phase III IMpassion050 (NCT03726879) trial compares atezolizumab or placebo combined with neoadjuvant chemotherapy and dual anti-HER2 blockade for early-stage HER2-positive BC. This trial includes patients with PD-L1-positive and PD-L1-negative tumors and is considering pCR rates in the PD-L1-positive and ITT population as primary endpoints. In patients who do not achieve a pCR, TDM-1 is added in the adjuvant phase. The addition of atezolizumab to an anthracycline-free regimen of neoadjuvant chemotherapy and dual anti-HER2 blockade is the objective of the phase III APTneo trial (NCT035955592). In my presentation I will cover biological rational for IO studies beyond triple negative breast cancer in the attempt to provide an ideal immunogram for this population of patients. Citation Format: G Curigliano. IO beyond TNBC [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr ES10-3.