Approval Of Immune Checkpoint Inhibitors Research Articles

Defining clinically useful biomarkers of immune checkpoint inhibitors in solid tumours.

Although more than a decade has passed since the approval of immune checkpoint inhibitors (ICIs) for the treatment of melanoma and non-small-cell lung, breast and gastrointestinal cancers, many patients still show limited response. US Food and Drug Administration (FDA)-approved biomarkers include programmed cell death 1 ligand 1 (PDL1) expression, microsatellite status (that is, microsatellite instability-high (MSI-H)) and tumour mutational burden (TMB), but these have limited utility and/or lack standardized testing approaches for pan-cancer applications. Tissue-based analytes (such as tumour gene signatures, tumour antigen presentation or tumour microenvironment profiles) show a correlation with immune response, but equally, these demonstrate limited efficacy, as they represent a single time point and a single spatial assessment. Patient heterogeneity as well as inter- and intra-tumoural differences across different tissue sites and time points represent substantial challenges for static biomarkers. However, dynamic biomarkers such as longitudinal biopsies or novel, less-invasive markers such as blood-based biomarkers, radiomics and the gut microbiome show increasing potential for the dynamic identification of ICI response, and patient-tailored predictors identified through neoadjuvant trials or novel ex vivo tumour models can help to personalize treatment. In this Perspective, we critically assess the multiple new static, dynamic and patient-specific biomarkers, highlight the newest consortia and trial efforts, and provide recommendations for future clinical trials to make meaningful steps forwards in the field.

Reporting of immune-related adverse events (irAEs) in US Food and Drug Administration (FDA) approvals of immune checkpoint inhibitors.

e14693 Background: Evaluating immune checkpoint inhibitor (ICI) toxicity is complex given the interplay between the host immune system and tumor microenvironment leading to unpredictable timing and severity of irAEs. Monitoring of irAEs is critical as they can cause significant impact on morbidity and quality of life. Thus, we evaluated the consistency and pattern of reporting of irAEs in trials leading to FDA drug approvals. Methods: Using the FDA website, we identified 73 primary articles for ICI FDA approvals over a 10-year period (2011-2021). Data were collected independently by all authors as categorical variables for reporting of any grade and grade 3 or higher toxicity in the trial arm that led to FDA approval for 29 irAEs classified by the National Comprehensive Cancer Network Version 1.2024 guidelines. Our analyses were based on a binary classification of reported versus not reported, including the manuscript text, tables, and supplement, and reporting trends were analyzed based on the study year, phase, primary tumor, and monotherapy versus combination ICI therapy. Results: The majority of approvals were associated with Phase II (N=22) or Phase III (N=39) studies. Approvals included 14 primary tumors and 2 tumor agnostic approvals with the most common tumors including lung (N=22) and skin (N=14). irAE reporting ranged between 0% and 100% with a mean of 40% and a standard deviation of 35. Across the 29 irAEs, 45% were categorized as severely underreported with less than 25% reporting in trials, 17% were classified as underreported in 26-50% of trials, 17% were moderately reported in 51-75% of trials, and 21% were well reported in at least 75% of trials. For example, fatigue, diarrhea, and hypothyroidism were well reported at 100%, 99%, and 93%, respectively, while myocarditis, aseptic meningitis, and giant cell arteritis were severely underreported at 18%, 4%, and 1%, respectively. Additionally, certain systems were more reported than others, including gastrointestinal (100%) and endocrine (97%), while other systems were inconsistently reported such as cardiology (15%) and neurology (48%) (see Table). Conclusions: Our study identified significant inconsistencies in irAE reporting in clinical trials that led to ICI FDA approvals. In particular, rarer irAEs were reported infrequently while more common irAEs were well reported. Unified efforts are needed to standardize the irAE reporting in the primary literature to ensure reliable dissemination of information for timely recognition and treatment in clinical practice. [Table: see text]

QUIC: Phase 2 study of gemcitabine, cisplatin, quemliclustat (AB680), and zimberelimab (AB122) during first-line treatment of advanced biliary tract cancers (BTC)—Big Ten Cancer Research Consortium study BTCRC-GI22-564.

TPS4195 Background: Despite recent approvals of immune checkpoint inhibitors with chemotherapy in the first-line setting, the median overall survival (mOS) for patients with advanced biliary tract cancer (BTC) remains less than 15 months. CD73 is a key enzyme responsible for the conversion of extracellular adenosine 5’-monophosphate into adenosine and may play an important role in creating an immunosuppressed tumor microenvironment. High expression of CD73 in BTC is associated with decreased OS. Quemliclustat (Q) is a potent, selective, reversible inhibitor of CD73. Q in combination with chemotherapy has demonstrated promising activity in patients with advanced pancreatic cancer without significant increase in adverse events. The BTCRC-GI22-564 study evaluates safety and preliminary efficacy of Q in combination with zimberelimab (Z), a monoclonal antibody targeting human PD-1, with gemcitabine and cisplatin (GC) as first-line therapy for patients with advanced BTC, QUIC (Q and Immunotherapy in Cholangiocarcinoma). Methods: This is an open label, single arm, phase II multi-site trial, evaluating Q and Z in combination with GC in patients with advanced BTC who have not received systemic treatment for advanced disease or who completed adjuvant therapy > 6 months prior to development of recurrent disease. Chemotherapy is given on days 1, 8, 22 and 29 of each 42-day cycle as per local standards. Z is administered at a fixed dose of 360 mg via IV infusion every 3 weeks. Q is administered via IV infusion on days 1, 15, and 29. A safety run-in portion built into the study is planned to enroll 6 subjects to ensure there are no dose limiting toxicities (DLT). If a study defined DLT is observed, Q, gemcitabine and cisplatin will be reduced by 1 dose level, and an additional 6 subjects will be enrolled in the safety run-in portion. The primary efficacy endpoint is median progression free survival (mPFS) with null and alternative survival of 6.0 and 10.0 months, respectively. Based on an accrual rate of 3 patients per month, we expect to accrue 33-39 patients which will provide at least 83% power with a one-sided alpha of 0.1. Secondary endpoints include mOS, disease control rate, overall response rate, and duration of response. Correlative endpoints will assess clinical outcomes with immune infiltration within tumor microenvironment, CD73 and PD-L1 expression. The QUIC study is currently open to enrollment through BTCRC. Clinical trial information: NCT06048133 .

Renal Cell Carcinoma of Variant Histology: New Biologic Understanding Leads to Therapeutic Advances.

Renal cell carcinoma (RCC) is one of the 10 most commonly diagnosed solid tumors. Most RCCs are histologically defined as clear cell, comprising approximately 75% of diagnoses. However, the remaining RCC cases are composed of a heterogeneous combination of diverse histopathologic subtypes, each with unique pathogeneses and clinical features. Although the therapeutic approach to both localized and metastatic RCCs has dramatically changed, first with the advent of antiangiogenic targeted therapies and more recently with the approval of immune checkpoint inhibitor (ICI)-based combinations, these advances have primarily benefited the clear cell RCC patient population. As such, there remains critical gaps in the optimization of treatment regimens for patients with non-clear cell, or variant, RCC histologies. Herein, we detail recent advances in understanding the biology of RCC with variant histology and how such findings have guided novel clinical studies investigating precision oncology approaches for these rare subtypes. Among the most common variant histology RCCs are papillary RCC, comprising approximately 15%-20% of all diagnoses. Although a histopathologically diverse subset of tumors, papillary RCC is canonically associated with amplification of the MET protooncogene; recently completed and ongoing trials have investigated MET-directed therapies for this patient population. Finally, we discuss the unique biology of RCC with sarcomatoid dedifferentiation and the recent clinical findings detailing its paradoxical sensitivity to ICIs.

Current Progress in Vaccines against Merkel Cell Carcinoma: A Narrative Review and Update.

Merkel cell carcinoma is a rare, aggressive skin cancer that mainly occurs in elderly and immunocompromised patients. Due to the success of immune checkpoint inhibition in MCC, the importance of immunotherapy and vaccines in MCC has increased in recent years. In this article, we aim to present the current progress and perspectives in the development of vaccines for this disease. Here, we summarize and discuss the current literature and ongoing clinical trials investigating vaccines against MCC. We identified 10 articles through a PubMed search investigating a vaccine against MCC. From the international clinical trial database Clinical.Trials.gov, we identified nine studies on vaccines for the management of MCC, of which seven are actively recruiting. Most of the identified studies investigating a vaccine against MCC are preclinical or phase 1/2 trials. The vaccine principles mainly included DNA- and (synthetic) peptide-based vaccines, but RNA-based vaccines, oncolytic viruses, and the combination of vaccines and immunotherapy are also under investigation for the treatment of MCC. Although the management of MCC is changing, when compared to times before the approval of immune checkpoint inhibitors, it will still take some time before the first MCC vaccine is ready for approval.

Abstract PO1-19-07: A Phase I Study Accessing Immunotherapy Combination of Balstilimab and Ivermectin in Patients with Metastatic Triple Negative Breast Cancer

Abstract Background: Despite recent FDA approval of immune checkpoint inhibitor (ICI) and antibody-drug conjugates (ADCs), therapeutic options for metastatic triple negative breast cancer (mTNBC) remain limited. There is an unmet need to identify novel ICI combinations for improved efficacy. We recently demonstrated that ivermectin induces robust T cell infiltration into breast tumors and turning “cold” tumors “hot” in mouse model of TNBC. Balstilimab is a fully humanized IgG4 anti-PD-1 agent with proven safety and efficacy in metastatic cervical cancer. The current phase I/II trial is designed to test the safety and efficacy of the combination of ivermectin and balstilimab in patients with mTNBC. Methods: Key eligibility criteria include patients with unresectable or metastatic TNBC; progressed on 1-2 prior chemotherapies including an immune checkpoint inhibitor-containing regimen; ECOG 0-1; RECIST 1.1 measurable disease. Eligible patients receive balstilimab 450 mg, IV, on Day 1 and ivermectin (30, 45 or 60 mg po daily), PO, Days 1-3, 8-10, 15-17 of each 21 days cycle till disease progression or intolerance. The primary objection of the phase 1 portion of the study is t determine the recommended phase 2 dose of ivermectin in combination with balstilimab using NCI-CTCAE v5.0. The primary objective of the phase II portion of the study is to determine the efficacy of the combination in mTNBC who are PD-L1 negative using the objective response rate (ORR). Secondary objectives are progression free survival (PFS), overall survival (OS), duration of response (DOR), clinical benefit rate (CBR), and patients’ quality of life (QOL) by EORTC QLQ-C30. Peripheral blood, tumor tissue and gut microbiome will be collected for correlative aims include pharmacokinetics, tumor microenvironment ICDs and gut microbiota in association with response to therapy. In the Phase 1 portion, eligible patients will be enrolled to one of three doses using the IQ 3+3 design. In the Phase 2 portion, patients will continue to be accrued to the RP2D (either the MTD or a lower dose depending on clinical judgement considering all the clinical and correlative data available). The Phase 2 portion will be conducted in two stages. In stage 1, a total of 13 PDL1-negative TNBC breast cancer patients will be treated at the RP2D. If there are no responders, the Phase 2 portion will close. With at least one responder, accrual may continue until 25 patients are accrued to the Phase 2 portion. If at least 3 responders are noted in 25 patients, this will be sufficient to consider the combination promising. This rule provides a type I error of 12% for a true response rate of 5%, and a power of 88% for true response rate of 20%. The estimated targeted accrual is 34-41 (Phase 1: 14-16; Phase 2: 20-25). Clinical trial information: NCT05318469 Citation Format: Yuan Yuan, Stephen Shiao, Mourad Tighiouart, Monica Mita, Jin-Sun Bitar, Philomena McAndrew, Park Dorothy, Maryliza El-Masry, Paul Frankel, Peter Lee. A Phase I Study Accessing Immunotherapy Combination of Balstilimab and Ivermectin in Patients with Metastatic Triple Negative Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-19-07.

Longitudinal analysis of PD-L1 expression in patients with relapsed NSCLC

BackgroundThe use and approval of immune checkpoint inhibitors for the treatment of non-small cell lung cancer (NSCLC) depends on PD-L1 expression in the tumor tissue. Nevertheless, PD-L1 often fails to...

Abstract 2731: CCR5-001, a novel drug Fc-conjugate (DFC) targeting CCR5, demonstrates potent efficacy in a colorectal cancer mouse model

Abstract Background The approval of immune checkpoint inhibitors (ICI) such as PD-(L)1 inhibitors has revolutionized cancer therapy and established a role for immune effector cells, most notably CD8+ T cells, in tumor control and destruction. While anti-PD-(L)1 therapy has demonstrated durable responses, only a small subset of patients benefit and respond to therapy. CCR5 is expressed on multiple immune cells (e.g. myeloid-derived suppressor cells) and CCR5-dependent migration of these cells contribute to an immune-suppressive tumor microenvironment (TME) thereby limiting response to ICI therapy. In addition, expression of CCR5 on cancer cells has been linked to increased metastasis and resistance to ICI therapy. Upregulation of CCL5/CCR5 has been associated with poor outcomes in multiple solid tumor indications, including colorectal cancer (CRC). Therefore, targeting CCR5 has the potential to increase response rates to ICI therapy and improve outcomes. Herein, we describe a first-in-class CCR5 targeting DFC, CCR5-001, a multivalent conjugate of a potent, small molecule CCR5 antagonist conjugated to an immune-silent proprietary human IgG1 Fc. This CCR5 targeting DFC has the potential to improve responses to ICI therapy by preventing pro-tumorigenic reprogramming of the TME induced by CCL5/CCR5 expressing tumor and myeloid cells. Methods Binding of CCR5-001 to hCCR5 was measured by surface plasmon resonance (SPR) and to CCR5+ PathHunter cells (DiscoverX) by flow cytometry. Functional activity was determined in CCR5+ PathHunter β-arrestin assay with CCL3 to induce CCR5 signaling according to manufacturer’s instructions. Efficacy was determined in an immune-competent syngeneic mouse model using the CRC cell line, MC38. CCR5-001 was dosed at 20 mg/kg twice per week for two weeks. Tumor volumes were recorded and statistical analysis was conducted by t-test (Mann-Whitney) or two-way ANOVA in Prism. Results CCR5-001 displayed a KD of 4.2 nM to immobilized hCCR5 by SPR and IC50 of 0.63-0.98 nM for binding to engineered CCR5+ PathHunter cells. This high affinity binding translated to potent functional inhibition of CCL3-induced CCR5 signaling with an IC50 of 12.7 nM in CCR5+ cell-based assay. CCR5-001 demonstrated potent, statistically significant (p = 0.0052) tumor growth inhibition of 76% by day 13 in a syngeneic mouse model. Conclusions CCR5-001 demonstrated potent CCR5 binding and functional inhibition of CCR5 signaling in cell-based assays. The in vitro activity translated to robust efficacy as a monotherapy in a syngeneic mouse model. Based on these results and other emerging data, CCR5-001 represents an exciting new avenue for targeting CCR5 with DFCs in solid cancers where the pathology is driven by the CCR5/CCL5 axis. Citation Format: Simon Döhrmann, James Levin, Nicholas Dedeic, Amanda Almaguer, Doug Zuill, Elizabeth Abelovski, Jeffrey B. Locke, Joanne Fortier, Maria Hernandez, Qiping Zhao, Karin Amundson, Madison Moniz, Hongyuan Chen, Dhanya Panickar, Thanh Lam, Grayson Hough, Thomas P. Brady, Allen Borchardt, Jason N. Cole, Leslie W. Tari. CCR5-001, a novel drug Fc-conjugate (DFC) targeting CCR5, demonstrates potent efficacy in a colorectal cancer mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2731.

Abstract 7539: First-in-class anti-PVR mAb NTX1088 advancing through Phase I: Safe and potent in restoring DNAM1 expression to enhance antitumor immunity

Abstract NTX1088, a first-in-class anti-PVR (CD155) mAb, is currently evaluated in a Phase 1, open-label, multi-center study (NCT05378425). The trial initiated at MD Anderson Cancer Center, and was expanded into additional sites, including City of Hope, Ochsner Health, Sheba Medical Center and Hadassah Medical Center. Study objectives are safety, dose-finding, and efficacy with focus on pharmacokinetics, pharmacodynamics, and biomarker discovery. NTX1088 is investigated as a single agent and in combination with the anti-PD1 mAb, pembrolizumab (Keytruda) in patients with advanced solid malignancies. Ongoing dose escalation demonstrates a safe profile across ascending dose levels. NTX1088 is a high affinity humanized IgG4-S228P mAb that binds PVR and blocks all known interacting receptors at a single nM EC50. PVR, is a highly upregulated membrane protein on numerous tumor cells. PVR expression has been associated with worse patient outcome, due to its central role in immune suppression. PVR’s impact is mediated through interaction with the key stimulatory receptor, DNAM1 (CD226), on T and NK cells, leading to internalization and degradation of DNAM1. PVR also interacts with the inhibitory immune checkpoint receptors, TIGIT, CD96 and KIR2DL5A. Blocking PVR by NTX1088 has multiple immune-stimulating roles, through restoration of DNAM1 immune activation function, while simultaneously neutralizing TIGIT, CD96 and KIR2DL5A inhibitory signals in immune cells. Importantly, DNAM1 downmodulation was recently identified as a key resistance mechanism to approved immune checkpoint inhibitors, and its restoration by NTX1088 is a novel MoA, not demonstrated previously by other therapies.In vitro, as a monotherapy, NTX1088 significantly increased immune cell activation, superior to TIGIT, CD112R, and PD1 antibody blockade, leading to a greater immune-mediated tumor cell killing, IFNγ secretion, and CD137 induction. Importantly, only NTX1088 was able to restore DNAM1 to the surface of immune cells. Synergy was obtained when NTX1088 was combined with PD1 blockers, or with the anti-CD112R mAb, NTX2R13.Syngeneic models of PVRK.O, demonstrated a complete immune-mediated tumor regression. Numerous humanized murine xenograft models were investigated whereby NTX1088 exhibited robust tumor growth inhibition as a standalone and in combination with PD1 blockade.In conclusion, PVR blockade by NTX1088 has a remarkable pre-clinical efficacy, suggesting a potential clinical breakthrough, based on its ability to simultaneously overcome multiple tumor escape mechanisms. First-in-human (FIH) trial is currently ongoing and biomarker analysis is showing initial mechanistic proof of concept for NTX1088 mode of action, including the restoration of DNAM1 surface expression on patients’ immune cells. This is the first case of surface DNAM1 elevation in clinical settings. Citation Format: Anas Atieh, Akram Obeidat, Alon Vitenshtein, Guy Cinamon, Keren Paz, Tihana Roviš, Paola Brilc, Ofer Mandelboim, Stipan Jonjic, Pini Tsukerman. First-in-class anti-PVR mAb NTX1088 advancing through Phase I: Safe and potent in restoring DNAM1 expression to enhance antitumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7539.

Tumor-Infiltrating Lymphocyte and Other Cell Therapies for Metastatic Melanoma.

Major progress in prolonging survival of patients with advanced melanoma has been made in the past decade because of the development and approval of immune checkpoint inhibitor and targeted therapies. However, for nonresponding or relapsing patients, their prognosis is still dismal. Based on clinical trial data, treatment with adoptive cell therapies holds great promise. In patients with metastatic melanoma progressing on or nonresponsive to single-agent anti-programmed cell death 1, infusion of tumor-infiltrating lymphocytes can produce responses in up to half of patients, with durable complete responses in up to 20%. Genetic modification of peripheral blood T cells with T-cell receptors derived from tumor-specific T cells, or with chimeric antigen receptors, has the potential to further improve treatment outcomes in this refractory population. In this review, we will discuss the historical development, current status, and future perspectives of adoptive T-cell therapies in melanoma.

Approved immune checkpoint inhibitors in hepatocellular carcinoma: a large-scale meta-analysis and systematic review

A meta-analysis was performed to assess the benefits and safety profile of approved immune checkpoint inhibitors in hepatocellular carcinoma patients. Eligible studies were searched from Cochrane, Embase, and PubMed databases based on a well-established strategy. Following the exclusion of ineligible studies, 12 studies were included in this meta-analysis. Compared with control group, immune checkpoint inhibitors were associated with improved ORR (OR 3.03, 95% CI 2.26–4.05, P < 0.00001), SD (OR 0.77, 95% CI 0.62–0.95, P = 0.02), OS (HR 0.75, 95% CI 0.68–0.83, P < 0.00001), and PFS (HR 0.74, 95% CI 0.63–0.87, P < 0.0003). However, no significant differences were observed in DCR (OR 1.33, 95% CI 0.97–1.81, P = 0.07), PD (OR 0.90, 95% CI 0.67–1.21, P = 0.48), and all caused any-grade adverse events (OR 1.22, 95% CI 0.62–2.39, P = 0. 57), all caused ≥ grade 3 adverse events (OR 1.10, 95% CI 0.97–1.25, P = 0.14), treatment-related any-grade adverse events (OR 1.13, 95% CI 0.55–2.32, P = 0.73), and treatment-related ≥ grade 3 events (OR 0.82, 95% CI 0.34–1.97, P = 0.65) between the two groups. After subgroup analysis conducted, patients in the immune checkpoint inhibitor group compared with targeted drug group showed significant improvements in OS (HR 0.74, 95% CI 0.66–0.84, P < 0.00001) and PFS (HR 0.75, 95% CI 0.61–0.91, P = 0.004). Immune checkpoint inhibitors have demonstrated peculiar benefits in the treatment of HCC with an acceptable safety profile. Compared to targeted drugs, immune checkpoint inhibitors still offer advantages in the treatment of hepatocellular carcinoma. However, there is still considerable room for further improvement.

Immunotherapy Initiation at the End of Life in Patients With Metastatic Cancer in the US

While immunotherapy is being used in an expanding range of clinical scenarios, the incidence of immunotherapy initiation at the end of life (EOL) is unknown. To describe patient characteristics, practice patterns, and risk factors concerning EOL-initiated (EOL-I) immunotherapy over time. Retrospective cohort study using a US national clinical database of patients with metastatic melanoma, non-small cell lung cancer (NSCLC), or kidney cell carcinoma (KCC) diagnosed after US Food and Drug Administration approval of immune checkpoint inhibitors for the treatment of each disease through December 2019. Mean follow-up was 13.7 months. Data analysis was performed from December 2022 to May 2023. Age, sex, race and ethnicity, insurance, location, facility type, hospital volume, Charlson-Deyo Comorbidity Index, and location of metastases. Main outcomes were EOL-I immunotherapy, defined as immunotherapy initiated within 1 month of death, and characteristics of the cohort receiving EOL-I immunotherapy and factors associated with its use. Overall, data for 242 371 patients were analyzed. The study included 20 415 patients with stage IV melanoma, 197 331 patients with stage IV NSCLC, and 24 625 patients with stage IV KCC. Mean (SD) age was 67.9 (11.4) years, 42.5% were older than 70 years, 56.0% were male, and 29.3% received immunotherapy. The percentage of patients who received EOL-I immunotherapy increased over time for all cancers. More than 1 in 14 immunotherapy treatments in 2019 were initiated within 1 month of death. Risk-adjusted patients with 3 or more organs involved in metastatic disease were 3.8-fold more likely (95% CI, 3.1-4.7; P < .001) to die within 1 month of immunotherapy initiation than those with lymph node involvement only. Treatment at an academic or high-volume center rather than a nonacademic or very low-volume center was associated with a 31% (odds ratio, 0.69; 95% CI, 0.65-0.74; P < .001) and 30% (odds ratio, 0.70; 95% CI, 0.65-0.76; P < .001) decrease in odds of death within a month of initiating immunotherapy, respectively. Findings of this cohort study show that the initiation of immunotherapy at the EOL is increasing over time. Patients with higher metastatic burden and who were treated at nonacademic or low-volume facilities had higher odds of receiving EOL-I immunotherapy. Tracking EOL-I immunotherapy can offer insights into national prescribing patterns and serve as a harbinger for shifts in the clinical approach to patients with advanced cancer.

The Financial Burden of Guideline-recommended Cancer Medications for Metastatic Urothelial Carcinoma

Bladder cancer is a significant global health concern owing to its prevalence, negative impact on quality of life, and high treatment costs. Treatment for metastatic urothelial carcinoma (mUC) traditionally relies on platinum-based chemotherapy regimens. However, clinical trial results have led to the approval of immune checkpoint inhibitors (ICIs) as viable treatment options. We assessed the escalating costs and economic viability of mUC treatment guidelines in Europe. We used a pragmatic approach that involved: (1) collection of the costs of the recommended medications in the five most populous European countries; (2) conversion of the costs into international dollars to account for differences in purchasing power parity among countries; (3) evaluation of the cost trends over time; and (4) comparison of the medication costs to World Health Organization thresholds. Introduction of ICIs in European guidelines substantially increased the cost of medications for mUC. Intriguingly, important differences across European countries emerged: the annual cost of medications was twofold higher in Italy than in France and the UK. Despite limitations, our study sheds light on the escalating costs and economic challenges of mUC treatment, and highlights the need for assessments of sustainable and cost-effective management approaches. Patient summaryWe looked at the costs of treatments for metastatic bladder cancer and found that costs have been rising over time, especially with the introduction of new immune therapies, with notable differences among European countries. While these new treatments improve patient outcomes, they also come with a high price tag, which could strain health care budgets. Our results suggest that cost-effectiveness studies will be essential in determining the best and most sustainable treatment strategies in the future.

Abstract A050: Enhancing immune checkpoint inhibitor efficacy by targeting neurotrophic receptor tyrosine kinase 1 signaling in immune resistant non-small cell lung cancer patients

Abstract Introduction: The FDA’s approval of immune checkpoint inhibitors (ICI) in 2015 drastically changed the survival of late-stage non-small cell lung cancer (NSCLC) patients. However, only about 30% of NSCLC patients respond to treatment, while the other 70% are immune resistant. Through an analysis of 424 NSCLC patients at Atrium Wake Forest, we have identified a loss-of-function mutation in Neurotrophic Receptor Tyrosine Kinase 1 (NTRK1) as a biomarker for response to ICI. We hypothesize that by treating wild-type immune-resistant tumors with Entrectinib, we can mimic the effect of the mutation in NTRK1 and induce immune responses. Methods: To identify biomarkers, we collected genomic sequencing data and comprehensive clinical characteristics on 424 NSCLC patients who received ICI or chemo-ICI treatment at Atrium Health Wake Forest Baptist. To determine the role of NTRK1 in vivo, we implanted LL/2-scramble (wild-type NTRK1) or LL/2-shNTRK1, which diminished NTRK1, into C57/B6 mice. The animals were injected with either IgG or Anti-PD1. To determine if we could mimic the effect of a mutation in NTRK1, C57/B6 mice were inoculated with LL2-wildtype NTRK1 and treated with either a) IgG, b) Entrectinib, c) Anti-PD-1, or d) Anti-PD-1 + Entrectinib. All in vivo experiments had tumor growth monitored, and a flow cytometry panel was performed at the endpoint to understand the immune responses. Bulk RNA-Sequencing was performed on cell cultures and tumors. Results: Mice given the LL/2-shNTRK1 responded to Anti-PD-1 treatment and had a significant increase in CD4+ stem-like effector T cells in the spleen and tumor-draining lymph nodes. Animals that were inoculated with the LL/2 cell lines and treated with Anti-PD-1 + Entrectinib also responded. Mice treated with Anti-PD-1 + Entrectinib were found to have a significant increase in CD4+ stem-like effector T cells as well. RNA-Sequencing revealed that in the mutant cell line LL/2-shNTRK1 and LL/2 tumors treated with Anti-PD-1 + Entrectinib, there was a significant upregulation of C3 production. Conclusion: Our studies demonstrate that the loss of NTRK1 function, through either genetic ablation or enzymatic inhibition combined with Anti-PD-1, provides a potent treatment for immune-resistant NSCLC tumors. Citation Format: Margaret R Smith, Yuezhu Wang, Caroline B. Dixon, Ralph D'Agostino, Yin Liu, George C. Oliver, Lance D Miller, Umit Topaloglu, Michael D Chan, Micahel Farris, Jing Su, Kathryn F Mileham, Wencheng Li, Jason M. Grayson, Thomas Lycan, Fei Xing. Enhancing immune checkpoint inhibitor efficacy by targeting neurotrophic receptor tyrosine kinase 1 signaling in immune resistant non-small cell lung cancer patients [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2023 Oct 1-4; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Immunol Res 2023;11(12 Suppl):Abstract nr A050.

Abstract A022: CDK2 inhibition demonstrates synthetic lethality in SCLC through apoptotic induction

Abstract Small cell lung cancer (SCLC), a malignant thoracic neoplasm genetically defined by dysregulation of the Retinoblastoma (RB1) gene and tumor suppressor protein 53 (TP53), remains one of the world’s deadliest tumors with a 5-year overall survival rate ranging from 5% to 10%. Despite numerous clinical trials and recent FDA approval of immune checkpoint inhibitors, the prognosis for SCLC has not significantly improved in decades. There remains a strong need for new therapeutic approaches. In this study, we found that the combined effect of dysregulation or deletion of RB1 and TP53, as is found in the majority of SCLC, results in sensitivity to CDK2 inhibition or ablation. This relationship is reflected in the DepMap database, with cell lines harboring deleterious mutations in RB1 demonstrating markedly higher susceptibility to CDK2 inhibition. This relationship is surprising given CDK2’s established role in suppressing the growth inhibition activity of RB and CDK2’s ability to thus facilitate G1/S transition. To validate this discovery, we evaluated the effects of CDK2 inhibition on a panel of SCLC cell lines. ARTS-021 is a potent and highly selective orally administered inhibitor of CDK2 currently in clinical development. In contrast to CCNE1 amplified cells, which undergo G1 arrest upon ARTS-021 treatment, SCLC cells treated with ARTS-021 exhibited minimal G1 accumulation. Instead, ARTS-021 treatment induced apoptosis in SCLC cell lines with loss of functional RB1 and TP53, as demonstrated by a dose-dependent increase in Caspase 3/7 activity and the accumulation of cleaved PARP. This phenotype was further demonstrated to be CDK2 dependent though generation of stable cell lines expressing a dox-inducible shRNA targeting CDK2. Combination studies further demonstrated that this apoptotic phenotype can be enhanced synergistically through inhibition of the anti-apoptotic proteins BCL-2 and BCL-xL with clinical stage inhibitor Navitoclax. In addition, combinations with currently approved standard of care chemotherapies were tested both in vitro and in vivo, and demonstrated potent combinatorial activity. These findings suggest that the clinical development of CDK2 inhibitors for SCLC may represent a novel therapeutic option for this difficult to treat malignancy. Citation Format: Nathan Schomer, Jinhong Chen, Wei Pang, Tingru Zhou, Xipan Liu, Wenhen Liang, Yali Guo, Dai Cheng, Fang Li, Jiaqi Liang, Yaoyu Chen, Qing Sheng. CDK2 inhibition demonstrates synthetic lethality in SCLC through apoptotic induction [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A022.

Radiation and Immune Checkpoint Inhibitors: Combination Therapy for Treatment of Hepatocellular Carcinoma.

The liver tumor immune microenvironment has been thought to possess a critical role in the development and progression of hepatocellular carcinoma (HCC). Despite the approval of immune checkpoint inhibitors (ICIs), such as programmed cell death receptor 1 (PD-1)/programmed cell death ligand 1 (PD-L1) and cytotoxic T lymphocyte associated protein 4 (CTLA-4) inhibitors, for several types of cancers, including HCC, liver metastases have shown evidence of resistance or poor response to immunotherapies. Radiation therapy (RT) has displayed evidence of immunosuppressive effects through the upregulation of immune checkpoint molecules post-treatment. However, it was revealed that the limitations of ICIs can be overcome through the use of RT, as it can reshape the liver immune microenvironment. Moreover, ICIs are able to overcome the RT-induced inhibitory signals, effectively restoring anti-tumor activity. Owing to the synergetic effect believed to arise from the combination of ICIs with RT, several clinical trials are currently ongoing to assess the efficacy and safety of this treatment for patients with HCC.

CD47: The Next Frontier in Immune Checkpoint Blockade for Non-Small Cell Lung Cancer.

The success of PD-1/PD-L1-targeted therapy in lung cancer has resulted in great enthusiasm for additional immunotherapies in development to elicit similar survival benefits, particularly in patients who do not respond to or are ineligible for PD-1 blockade. CD47 is an immunosuppressive molecule that binds SIRPα on antigen-presenting cells to regulate an innate immune checkpoint that blocks phagocytosis and subsequent activation of adaptive tumor immunity. In lung cancer, CD47 expression is associated with poor survival and tumors with EGFR mutations, which do not typically respond to PD-1 blockade. Given its prognostic relevance, its role in facilitating immune escape, and the number of agents currently in clinical development, CD47 blockade represents a promising next-generation immunotherapy for lung cancer. In this review, we briefly summarize how tumors disrupt the cancer immunity cycle to facilitate immune evasion and their exploitation of immune checkpoints like the CD47-SIRPα axis. We also discuss approved immune checkpoint inhibitors and strategies for targeting CD47 that are currently being investigated. Finally, we review the literature supporting CD47 as a promising immunotherapeutic target in lung cancer and offer our perspective on key obstacles that must be overcome to establish CD47 blockade as the next standard of care for lung cancer therapy.

Bilobar Radioembolization Carries the Risk of Radioembolization-Induced Liver Disease in the Treatment of Advanced Hepatocellular Carcinoma: Safety and Efficacy Comparison to Systemic Therapy with Atezolizumab/Bevacizumab.

Recommended treatment options for advanced-stage hepatocellular carcinoma (HCC) include systemic therapy (ST) and trans-arterial radioembolization (TARE) with Yttrium-90 (Y90). Before the approval of immune-checkpoint inhibitors, a similar safety profile was reported for TARE and ST with tyrosine kinase inhibitors (TKI). However, whole-liver treatment and underlying cirrhosis were identified as risk factors for potentially lethal radioembolization-induced liver disease (REILD). Therefore, the safety and efficacy of TARE and ST with atezolizumab/bevacizumab were compared in patients with advanced HCC involving at least both liver lobes in a retrospective real-world cohort. In total, 74 patients with new or recurrent advanced-stage HCC (BCLC stage B/C) were included if treated with either bilobar TARE (n = 33) or systemic combination therapy with atezolizumab plus bevacizumab (n = 41). Most patients had compensated liver function (90.5% were classified as Child-Pugh Score A, 73% as ALBI Grade 1) at baseline. Although not significant, patients treated with ST showed a more prolonged overall survival than those treated with Y90 TARE (7.1 months vs. 13.0 months, p = 0.07). While a similar disease control rate could be achieved with bilobar TARE and atezolizumab/bevacizumab, in the TARE group, overall survival was curtailed by the occurrence of REILD. In patients with underlying liver cirrhosis, the liver function at baseline was a predictor for REILD.

Role of immunotherapy in stage IV non-small cell lung cancer with liver metastasis: A NCDB analysis.

9046 Background: Despite approvals of immune checkpoint inhibitors in stage IV non-small cell lung cancer (NSCLC), survival benefit of immunotherapy (IO) in those with liver metastasis is controversial. Randomized controlled trials demonstrated conflicting results. Methods: Using National Cancer Database (NCDB), Stage IV NSCLC cases diagnosed in 2016-2017 with at least 30-day follow up were analyzed. Clinical demographics included age (20-69 vs. 70+), sex (male vs. female), race (whites vs. others), institution (academic vs. others), Charlson-Deyo score (0-1 vs. 2-3), year of diagnosis (2016 vs. 2017), Histology (adenocarcinoma NOS vs. other), brain metastasis (Yes vs. No), bone metastasis (Yes vs. No), liver metastasis (Yes vs. No). They were divided into liver-metastasis positive (LM+) vs. negative (LM-). Information regarding cancer treatment was limited to the first course of therapy, including surgery for primary lesion (Yes vs. No), radiation (Yes vs. No), multi-agent chemotherapy (Yes vs. No), and IO (Yes vs. No). Overall Survival (OS) analysis was performed using Kaplan-Meier curves and Log-rank tests. Cox proportional hazard model was used for multivariate analyses. A two-sided p-value &lt; 0.05 was considered as significant. Results: A total of 13,594 LM+ and 69,885 LM- cases met eligibility and further analyzed. 2,944 and 15,553 patients were treated with IO, respectively. No significant association between use of IO and status of liver metastasis was observed (p = 0.124). The median OS in LM+ cases was significantly shorter than that in LM- cases (5.0 vs 8.8 months, respectively, p &lt; 0.0001). Use of IO was associated with improved OS in both LM+ and LM- cohorts with similar HRs/p-values (0.62/ &lt; 0.0001 and 0.64/ &lt; 0.0001, respectively). Multivariate analysis demonstrated that use of IO had a significantly improved OS in both LM+ (HR = 0.69, p &lt; 0.0001) and LM- (HR = 0.64, p &lt; 0.0001) cohorts. The OS benefit of IO in LM+ cohort remained with propensity score matching analysis (mOS 9.0 vs. 4.4 months, HR = 0.62, p &lt; 0.0001). Further exploratory analysis focusing on those treated with multiagent chemotherapy showed that the addition of IO improved OS in both LM+ (HR = 0.77, p &lt; 0.0001) and LM- (HR = 0.79, p &lt; 0.0001) cohorts. Conclusions: This retrospective study using one of the largest cancer databases suggests that use of IO improves OS of NSCLC patients with LM regardless of chemotherapy status, and its magnitude of OS benefit is similar to that in LM- patients. [Table: see text]

Guidance on Therapeutic Strategies for Metastatic Urothelial Cancer

Guidance on Therapeutic Strategies for Metastatic Urothelial Cancer