Immune Response Evaluation Criteria Research Articles

Abstract CT192: A first-in-human phase 1 study of TQB2916, a novel CD40 agonist antibody for advanced malignancies

Abstract Background: CD40 receptor is a member of the tumor necrosis factor receptor family that plays a prominent role in immune responses. TQB2916, a humanized IgG2 CD40 monoclonal antibody, has demonstrated CD40 agonistic activity and promising anti-tumor activity in preclinical studies. A first-in-human study of TQB2916 single agent in advanced solid tumors and lymphomas is ongoing (NCT05213767). Methods: Patients with an ECOG performance status of 0 or 1, adequate hematologic and organ function and refractory to standard therapies met inclusion criteria. TQB2916 was given intravenously every 3 weeks until progression or unacceptable toxicity. Bayesian optimal interval (BOIN) design was used to determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D). The objective is to assess the safety, tolerability, pharmacokinetics, and preliminary anti-tumor activity of TQB2916. Results: From April 2022 to November 2023, 18 patients with solid tumors and 2 with lymphoma have been treated with TQB2916 monotherapy, and were assigned to 7 cohorts (0.5 mg n=1, 2.5 mg n=1, 12.5 mg n=3, 60 mg n=3, 200 mg n=7, 300 mg n=2, and 400 mg n=3). Three dose limiting toxicities (DLTs) were observed: one with grade 3 pneumonia and one with grade 4 lipase/amylase increase in the 400 mg cohort; one with grade 3 pancreatitis in the 300 mg cohort. All patients experienced at least one treatment-related adverse event (TRAE). The most common TRAEs were lipase increase (n=15, 75%), amylase increase (n=14, 70%), lymphocyte count decrease (n=13, 65%), alanine aminotransferase (ALT) increase (n=12, 60%), alkaline phosphatase (ALP) increase (n=12, 60%), aspartate aminotransferase (AST) increase (n=11, 55%), hypoalbuminemia (n=11, 55%), and anorexia (n=11, 55%). Serious TRAEs occurred in 5 (25%) patients. Most of TRAEs were of grade 1 or grade 2 and manageable. Sixteen patients were evaluated for efficacy, and 3 of them achieved stable disease as per immune response evaluation criteria in solid tumors (iRECIST) and lymphoma response to immunomodulatory therapy criteria (LYRIC). The pharmacokinetics were well-behaved with increasing exposure dose-proportionally and no accumulation occurred after repeated dosing. The Cmax, AUC(0-t) and T1/2 of 400 mg single dosing were 109±21.8 μg/ml, 611±228 d*µg/mL and 5.54±3.37 d. Dose-dependent occupancy of CD40 was detected of 0.5 mg and above doses. Reduction in peripheral B cells and increasing in cytokines secretion were also observed. Conclusions: Pharmacodynamics analysis suggested that TQB2916 treatment achieved CD40 occupancy and immune activation with the changes in cytokines. Considering the safety profile and efficacy, 200 mg was determined as the preliminary expansion dose as it was well tolerated. Studies of TQB2916 in combination with immune checkpoint inhibitors and/or other anti-cancer therapies are ongoing. Citation Format: Yi Ba, Huilai Zhang, Ting Deng, Tao Ning, Qian Fan. A first-in-human phase 1 study of TQB2916, a novel CD40 agonist antibody for advanced malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT192.

Radioembolization plus Immune Checkpoint Inhibitor Therapy Compared with Radioembolization plus Tyrosine Kinase Inhibitor Therapy for the Treatment of Hepatocellular Carcinoma

PurposeTo investigate if combination therapy with immune checkpoint inhibitor (ICI) and yttrium-90 (90Y) radioembolization results in superior outcomes than those yielded by tyrosine kinase inhibitor (TKI) therapy and 90Y for the treatment of intermediate- to advanced-stage hepatocellular carcinoma (HCC). MethodsA retrospective review of patients presented at an institutional multidisciplinary liver tumor board between January 1, 2012 and August 1, 2023 was conducted. In total, 44 patients with HCC who underwent 90Y 4 weeks within initiation of ICI or TKI therapy were included. Propensity score matching was conducted to account for baseline demographic differences. Kaplan–Meier analysis was used to compare median progression-free survival (PFS) and overall survival (OS), and univariate statistics identified disease response and control rate differences. Duration of imaging response was defined as number of months between the first scan after therapy and the first scan showing progression as defined by modified Response Evaluation Criteria in Solid Tumors (mRECIST) or immune Response Evaluation Criteria in Solid Tumors (iRECIST). Adverse events were analyzed per Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. ResultsPatients in the 90Y+ICI therapy group had better objective response rates (ORRs) (89.5% vs 36.8%; P < .001) and disease control rates (DCRs) (94.7% vs 63.2%; P < .001) by mRECIST and iRECIST (ORR: 78.9% vs 36.8%; P < .001; DCR: 94.7% vs 63.2%; P < .001). Median PFS (8.3 vs 4.1 months; P = .37) and OS (15.8 vs 14.3 months; P = .52) were not statistically different. Twelve patients (63.1%) in the 90Y+TKI group did not complete systemic therapy owing to adverse effects compared with 1 patient (5.3%) in the 90Y+ICI group (P < .001). Grade 3/4 adverse events were not statistically different (90Y+TKI: 21.1%; 90Y+ICI: 5.3%; P = .150). ConclusionsPatients with HCC who received 90Y+ICI had better imaging response and fewer regimen-altering adverse events than those who received 90Y+TKI. No significant combination therapy adverse events were attributable to radioembolization.

Abstract C092: T cell responses and clinical outcomes in pancreatic and colorectal cancer patients with minimal residual disease in AMPLIFY-201, a phase 1 trial of a first-in-class amphiphile lymph node targeted mutant KRAS vaccine

Abstract Background: Mutations in RAS occur in &amp;gt; 25% of solid tumors and &amp;gt; 90% of patients (pts) with PDAC and &amp;gt; 40% of pts with CRC. ELI-002 2P is a vaccine comprised of lymph-node targeted Amphiphile (Amph)-modified G12D and G12R mutant KRAS peptides together with an Amph-modified CpG oligonucleotide adjuvant designed to expand polyfunctional mutant KRAS-specific T cells. Interim phase 1 AMPLIFY-201 data (O’Reilly et al; ASCO, 2023, #2528) showed that adjuvant administration of ELI-002 was well-tolerated, with T cell responses in 87%, and tumor biomarker responses in 77% (a subset of 32% had ctDNA clearance). Here we report relapse free survival data and correlations between ELI-002 2P- induced T cell levels and outcomes in pts with PDAC and colorectal cancer (CRC) at high risk for relapse following locoregional treatment. Methods: Resected PDAC (n=20) and CRC (n=5) pts with tumors harboring KRAS G12D or G12R who had minimal residual disease positivity (MRD+) defined as elevated circulating tumor DNA (ctDNA) and/or serum tumor biomarker (CA19-9/CEA), received up to 6 priming doses and 4 booster doses separated by a 3-month rest period of subcutaneous ELI-002 2P vaccine monotherapy comprised of Amph-peptides (700 mcg each G12D/G12R), admixed with Amph-CpG-7909 at 0.1, 0.5, 2.5, 5.0 and 10.0 mg per cohort dose level. Primary endpoints included safety and recommended phase 2 dose (RP2D) of Amph-CPG-7909; secondary endpoints: biomarker reduction/clearance; exploratory endpoints: included relapse free survival (RFS) using immune Response Evaluation Criteria in Solid Tumors (iRECIST) and immunogenicity assessed by direct ex vivo Fluorospot and intracellular cytokine staining of peripheral blood mononuclear cells. Results: Direct ex vivo polyfunctional mKRAS-specific T cell responses to ELI-002 2P were observed in 20/23 (87%; 50% induced both CD4+ and CD8+ T cells, median 13-fold and mean 56-fold increase from baseline), with response in 9/9 (100%) pts treated at highest two dose levels including the 10 mg RP2D. Clinical efficacy correlated with T cell response in evaluable pts (n=22): median tumor biomarker reduction/clearance was -86.9% vs -4.5% in above vs below median T cell responders, respectively (p &amp;lt; 0.0124). At 25 weeks median follow-up, the median RFS was not reached compared to 17.1 weeks in above versus below median T cell responders (HR 0.11; 95% CI 0.027-0.446; p = 0.0108). The association of RFS with T cell response was not confounded by other baseline prognostic variables (including tumor stage, recovery from prior cytotoxic therapy as assessed by absolute neutrophil count, or immune system subsets such as %CD4+ or %CD8+of CD3+ lymphocytes). Conclusions: The association of ELI-002 2P vaccine T cell responses with clinical outcomes in a novel MRD+ trial design underscores the potential to reduce recurrence in the setting of microsatellite stable PDAC and CRC. A new phase 1/2 trial, AMPLIFY-7P (NCT05726864), is evaluating a new seven peptide (G12D, G12R, G12V, G12C, G12A, G12S, G13D) ELI-002 7P formulation. Citation Format: Zev A. Wainberg, Shubham Pant, Colin D. Weekes, Muhammad Furqan, Pashtoon M. Kasi, Craig E. Devoe, Alexis D. Leal, Vincent Chung, James R. Perry, Lochana Seenappa, Lisa K. McNeil, Esther Welkowsky, Peter C. DeMuth, Christopher M. Haqq, Eileen M. O'Reilly. T cell responses and clinical outcomes in pancreatic and colorectal cancer patients with minimal residual disease in AMPLIFY-201, a phase 1 trial of a first-in-class amphiphile lymph node targeted mutant KRAS vaccine [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C092.

A Phase 2 Trial of Talazoparib and Avelumab in Genomically Defined Metastatic Kidney Cancer

BackgroundAlthough different kidney cancers represent a heterogeneous group of malignancies, multiple subtypes including Von Hippel-Lindau (VHL)-altered clear cell renal cell carcinoma (ccRCC), fumarate hydratase (FH)- and succinate dehydrogenase (SDH)-deficient renal cell carcinoma (RCC), and renal medullary carcinoma (RMC) are affected by genomic instability. Synthetic lethality with poly ADP-ribose polymerase inhibitors (PARPis) has been suggested in preclinical models of these subtypes, and paired PARPis with immune checkpoint blockade (ICB) may achieve additive and/or synergistic effects in patients with previously treated advanced kidney cancers. ObjectiveTo evaluate combined PARPi + ICB in treatment-refractory metastatic kidney cancer. Design, setting, and participantsWe conducted a single-center, investigator-initiated phase 2 trial in two genomically selected advanced kidney cancer cohorts: (1) VHL-altered RCC with at least one prior ICB agent and one vascular endothelial growth factor (VEGF) inhibitor, and (2) FH- or SDH-deficient RCC with at least one prior ICB agent or VEGF inhibitor and RMC with at least one prior line of chemotherapy. InterventionPatients received talazoparib 1 mg daily plus avelumab 800 mg intravenously every 14 d in 28-d cycles. Outcome measurements and statistical analysisThe primary endpoint was objective response rate (ORR) by Immune Response Evaluation Criteria in Solid Tumors at 4 mo, and the secondary endpoints included progression-free survival (PFS), overall survival, and safety. Results and limitationsCohort 1 consisted of ten patients with VHL-altered ccRCC. All patients had previously received ICB. The ORR was 0/9 patients; one patient was not evaluable due to missed doses. In this cohort, seven patients achieved stable disease (SD) as the best response. The median PFS was 3.5 mo (95% confidence interval [CI] 1.0, 3.9 mo). Cohort 2 consisted of eight patients; four had FH-deficient RCC, one had SDH-deficient RCC, and three had RMC. In this cohort, six patients had previously received ICB. The ORR was 0/8 patients; two patients achieved SD as the best response and the median PFS was 1.2 mo (95% CI 0.4, 2.9 mo). The most common treatment-related adverse events of all grades were fatigue (61%), anemia (28%), nausea (22%), and headache (22%). There were seven grade 3–4 and no grade 5 events. ConclusionsThe first clinical study of combination PARPi and ICB therapy in advanced kidney cancer did not show clinical benefit in multiple genomically defined metastatic RCC cohorts or RMC. Patient summaryWe conducted a study to look at the effect of two medications, talazoparib and avelumab, in patients with metastatic kidney cancer who had disease progression on standard treatment. Talazoparib blocks the normal activity of molecules called poly ADP-ribose polymerase, which then prevents tumor cells from repairing themselves and growing, while avelumab helps the immune system recognize and kill cancer cells. We found that the combination of these agents was safe but not effective in specific types of kidney cancer.

Efficacy evaluation of neoadjuvant immunotherapy plus chemotherapy for non-small-cell lung cancer: comparison of PET/CT with postoperative pathology.

To assess the value of positron emission tomography/computed tomography (PET/CT) in the efficacy evaluation of patients undergoing neoadjuvant immunotherapy plus chemotherapy, and to analyze its correlation with postoperative pathology. The PET/CT metabolic parameters and CT size were retrospectively analyzed before and after neoadjuvant immunotherapy plus chemotherapy in 67 patients with resectable stage II/IIIA non-small-cell lung cancer (NSCLC). CT assessment based on immune response evaluation criteria in solid tumor criteria ((i)RECIST) was compared with PET/CT assessment based on the response criteria in solid tumors (PERCIST). The correlations between PET/CT metabolic parameters and postoperative pathology were analyzed. The value of PET/CT in the efficacy evaluation was assessed. The PET/CT assessment showed high consistency with postoperative pathological evaluation, yet the CT assessment showed low consistency with postoperative pathological evaluation. The (i)RECIST and PERCIST criteria showed statistically significant differences (p < 0.001). The postoperative pathological response was negatively associated with ΔSUVmax (%) (r = - 0.812, p < 0.001), ΔSUVmean (%) (r = - 0.805, p < 0.001), and ΔSUVpeak (%) (r = - 0.800, p < 0.001). The cut-off values of 75.8 for ΔSUVmax (%), 67.8 for ΔSUVmean (%), and 74.6 for ΔSUVpeak (%) had the highest sensitivity and specificity. The PERCIST criteria are more sensitive and accurate than (i)RECIST criteria to identify more responders when evaluating the response of neoadjuvant immunotherapy plus chemotherapy for NSCLC. PET/CT shows high accuracy in predicting postoperative pathological response. Our study shows the important role PET/CT plays in the efficacy evaluation of NSCLC patients undergoing neoadjuvant immunotherapy plus chemotherapy, as well as in predicting the prognosis and guiding postoperative treatment. Neoadjuvant immunotherapy plus chemotherapy is highly effective in the treatment of non-small-cell lung cancer. And PET/CT played an important role in the efficacy evaluation following neoadjuvant immunotherapy plus chemotherapy for non-small-cell lung cancer. • Neoadjuvant immunotherapy plus chemotherapy is highly effective in the treatment of NSCLC. • The PERCIST criteria are more sensitive and accurate than (i)RECIST criteria to identify more responders when evaluating the response of neoadjuvant immunotherapy plus chemotherapy for NSCLC. • PET/CT played an important role in the efficacy evaluation; ΔSUVmax (%), ΔSUVmean (%), and ΔSUVpeak (%) following neoadjuvant immunotherapy plus chemotherapy for NSCLC had high consistency and strong correlations with postoperative pathology.

Checkpoint Inhibitors in Combination With Stereotactic Body Radiotherapy in Patients With Advanced Solid Tumors

Although immune checkpoint inhibitors (ICIs) targeting programmed cell death 1 (PD-1) and PD-1 ligand 1 have improved the outcome for many cancer types, the majority of patients fails to respond to ICI monotherapy. Hypofractionated radiotherapy has the potential to improve the therapeutic ratio of ICIs. To assess the addition of radiotherapy to ICIs compared with ICI monotherapy in patients with advanced solid tumors. This open-label, multicenter, randomized phase 2 trial was conducted in 5 Belgian hospitals and enrolled participants between March 2018 and October 2020. Patients 18 years or older with locally advanced or metastatic melanoma, renal cell carcinoma, urothelial carcinoma, head and neck squamous cell carcinoma, or non-small cell lung carcinoma were eligible. A total of 99 patients were randomly assigned to either the control arm (n = 52) or the experimental arm (n = 47). Of those, 3 patients (1 in the control arm vs 2 in the experimental arm) withdrew consent and thus were not included in the analysis. Data analyses were performed between April 2022 and March 2023. Patients were randomized (1:1) to receive anti-PD-1/PD-1 ligand 1 ICIs alone as per standard of care (control arm) or combined with stereotactic body radiotherapy 3 × 8 gray to a maximum of 3 lesions prior to the second or third ICI cycle, depending on the frequency of administration (experimental arm). Randomization was stratified according to tumor histologic findings and disease burden (3 and fewer or more than 3 cancer lesions). The primary end point was progression-free survival (PFS) as per immune Response Evaluation Criteria in Solid Tumors. Key secondary end points included overall survival (OS), objective response rate, local control rate, and toxic effects. Efficacy was assessed in the intention-to-treat population, while safety was evaluated in the as-treated population. Among 96 patients included in the analysis (mean age, 66 years; 76 [79%] female), 72 (75%) had more than 3 tumor lesions and 65 (68%) had received at least 1 previous line of systemic treatment at time of inclusion. Seven patients allocated to the experimental arm did not complete the study-prescribed radiotherapy course due to early disease progression (n = 5) or intercurrent illness (n = 2). With a median (range) follow-up of 12.5 (0.7-46.2) months, median PFS was 2.8 months in the control arm compared with 4.4 months in the experimental arm (hazard ratio, 0.95; 95% CI, 0.58-1.53; P = .82). Between the control and experimental arms, no improvement in median OS was observed (11.0 vs 14.3 months; hazard ratio, 0.82; 95% CI, 0.48-1.41; P = .47), and objective response rate was not statistically significantly different (22% vs 27%; P = .56), despite a local control rate of 75% in irradiated patients. Acute treatment-related toxic effects of any grade and grade 3 or higher occurred in 79% and 18% of patients in the control arm vs 78% and 18% in the experimental arm, respectively. No grade 5 adverse events occurred. This phase 2 randomized clinical trial demonstrated that while safe, adding subablative stereotactic radiotherapy of a limited number of metastatic lesions to ICI monotherapy failed to show improvement in PFS or OS. ClinicalTrials.gov Identifier: NCT03511391.

Patterns of pseudoprogression across different cancer entities treated with immune checkpoint inhibitors

BackgroundPseudoprogression (PsPD) is a rare response pattern to immune checkpoint inhibitor (ICI) therapy in oncology. This study aims to reveal imaging features of PsPD, and their association to other relevant findings.MethodsPatients with PsPD who had at least three consecutive cross-sectional imaging studies at our comprehensive cancer center were retrospectively analyzed. Treatment response was assessed according to immune Response Evaluation Criteria in Solid Tumors (iRECIST). PsPD was defined as the occurrence of immune unconfirmed progressive disease (iUPD) without follow-up confirmation. Target lesions (TL), non-target lesions (NTL), new lesions (NL) were analyzed over time. Tumor markers and immune-related adverse events (irAE) were correlated.ResultsThirty-two patients were included (mean age: 66.7 ± 13.6 years, 21.9% female) with mean baseline STL of 69.7 mm ± 55.6 mm. PsPD was observed in twenty-six patients (81.3%) at FU1, and no cases occurred after FU4. Patients with iUPD exhibited the following: TL increase in twelve patients, (37.5%), NTL increase in seven patients (21.9%), NL appearance in six patients (18.8%), and combinations thereof in four patients (12.5%). The mean and maximum increase for first iUPD in sum of TL was 19.8 and 96.8 mm (+ 700.8%). The mean and maximum decrease in sum of TL between iUPD and consecutive follow-up was − 19.1 mm and − 114.8 mm (-60.9%) respectively. The mean and maximum sum of new TL at first iUPD timepoint were 7.6 and 82.0 mm respectively. In two patients (10.5%), tumor-specific serologic markers were elevated at first iUPD, while the rest were stable or decreased among the other PsPD cases (89.5%). In fourteen patients (43.8%), irAE were observed.ConclusionsPsPD occurred most frequently at FU1 after initiation of ICI treatment. The two most prevalent reasons for PsPD were TL und NTL progression, with an increase in TL diameter commonly below + 100%. In few cases, PsPD was observed even if tumor markers were rising compared to baseline. Our findings also suggest a correlation between PsPD and irAE. These findings may guide decision-making of ICI continuation in suspected PsPD.

AMPLIFY-201, a first-in-human safety and efficacy trial of adjuvant ELI-002 2P immunotherapy for patients with high-relapse risk with KRAS G12D- or G12R-mutated pancreatic and colorectal cancer.

2528 Background: RAS mutations occur in 25% of solid tumors with G12D being the most frequent variant. ELI-002 2P is a vaccine comprised of lymph-node targeted Amphiphile (Amph)-modified G12D and G12R mutant KRAS peptides with an Amph-modified CpG oligonucleotide adjuvant designed to expand polyfunctional mutant KRAS-specific T cells. Preclinical amphiphile data (relative to non-amphiphile controls) showed increased immunogenicity, tumor clearance and survival in mouse models. Methods: This first-in-human multicenter phase I trial assessed safety, immunogenicity and antitumor activity using a novel adjuvant trial design in patients (pts) with minimal residual disease (MRD) following standard locoregional treatment. Eligibility: elevated circulating tumor DNA (ctDNA) and/or serum tumor biomarker elevation (CA19-9/CEA), and KRAS/NRAS mutation. In a 3+3 dose escalation, n=22 received a subcutaneous course of 6 prime and 4 booster injections of fixed dose Amph-peptides (1.4 mg), admixed with escalating Amph-CpG-7909 (Table). Dose escalation based on observed safety in first 28 days. Safety, antitumor activity including biomarker reduction/clearance and relapse free survival using immune Response Evaluation Criteria in Solid Tumors (iRECIST) were assessed. Immunogenicity assessed by direct ex vivo Fluorospot and intracellular cytokine staining of peripheral blood mononuclear cells (T-cell responders = ≥ 2-fold increase over baseline) and by tumor CD3 immunohistochemistry in subset who underwent a biopsy. Results: No dose-limiting toxicities, treatment related SAEs or cytokine release syndrome were observed, and no maximum tolerated dose was identified. Safety: all grade 1, fatigue (19%), headache (19%), and injection site reaction (9.5%). Biomarker reduction was observed in 15/19 (79%) and in 5/5 at highest doses; clearance of MRD was observed in 4/19 (21% - n=2 pancreas, n=2 colorectal). Polyfunctional mKRAS-specific T cell responses observed in 80% of pts (n=12/15), with both CD8+ and CD4+ T cell responses for most, and CD3+ T cells observed on biopsies. The recommended phase 2 dose (RP2D) is 10.0 mg Amph-CpG-7909. Conclusions: ELI-002 2P, evaluated in a novel MRD+ trial, was safe with ctDNA and serum tumor biomarker reduction and clearance and notable immune responses. The RP2D is the start dose for a phase 1/randomized phase 2 study evaluating a new seven peptide formulation for G12 D, R, V, S, A, C, and G13D mutated solid tumors (NCT05726864). Clinical trial information: NCT04853017 . [Table: see text]

Transarterial Chemoembolization for Refractory Hepatocellular Carcinoma Following Anti-angiogenic Therapy Combined with Immune Checkpoint Inhibitors: A Retrospective Single-center Analysis

Background: Hepatocellular carcinoma (HCC) is characterized by high morbidity and mortality rates around the world, ranking the sixth most common malignant tumor and the second cause of cancer-related mortality. Most patients are diagnosed in the advanced stage, and therefore, there are limited therapeutic options. Transarterial chemoembolization (TACE), anti-angiogenic therapy, and immune checkpoint inhibitors (ICIs) are the research hotspots in HCC treatment. Objectives: This study aimed to explore the treatment efficacy and safety of TACE for refractory HCC patients after anti-angiogenic therapy combined with ICIs. Patients and Methods: In this study, patients with HCC, who progressed after anti-angiogenic therapy combined with ICIs, were included from July 2019 to October 2022. The progression-free survival (PFS) was evaluated by the Kaplan-Meier method, and the tumor response was determined based on the modified immune response evaluation criteria in solid tumors (iRECIST). The Common Terminology Criteria for Adverse Events version 5.0 were also used to assess the adverse events. Results: A total of 34 patients were evaluated in this study, with a median PFS of five months (95% CI: 3.7 months, 6.3 months). The univariate analysis suggested that the level of aspartate aminotransferase was significantly associated with PFS (P &lt; 0.05). The objective response rates within three and six months were 26.4% and 14.6%, and the disease control rates were 58.8% and 55.9%, respectively. During the follow-up, one or more types of adverse events were reported in 10 (58.8%) patients after treatment with atezolizumab and bevacizumab, while severe adverse events beyond grade III did not occur in any of the patients. Conclusion: The TACE may improve the survival of HCC patients, whose disease progresses after anti-angiogenic therapy combined with ICIs. However, the lack of a control group is one of the limitations of this study.

Immune-related adverse events are associated with therapeutic efficacy of immunotherapy in patients with melanoma brain metastases.

Immunotherapy with T-cell checkpoint inhibitors have changed the treatment landscape for patients with melanoma brain metastases (MBMs), offering increased survival compared with historical outcomes. We sought to identify clinical features associated with intracranial tumour responses or progression-free survival (PFS) in patients with MBMs treated with immunotherapy. Patients with MBMs treated with immunotherapy from August 2013 to March 2020 were identified through local databases. Melanoma disease burdens and immune-related adverse events (irAEs) were assessed retrospectively by review of patient medical records. Efficacy was evaluated by determining objective response rates (ORRs) in brain metastases using immune-Response Evaluation Criteria in Solid Tumours criteria, MBM-specific survival and overall PFS. Twenty-six patients were identified as eligible for this study. The presence and volume of extracranial metastases (ECM) were associated with a non-significant trend of reduced intracranial ORRs and PFS. Patients with irAEs, on the other hand, had significantly increased intracranial ORRs and PFS compared to those without irAEs. Severe, grade ≥3 irAEs and co-occurrence of ≥2 irAEs were also significantly associated with longer PFS. The presence and volume of ECM correlated inversely with development and severity of irAEs. We report a strong association between the development of irAEs and favourable melanoma-specific outcomes in patients with MBMs receiving immunotherapy. Contrary to previous studies, we found that co-occurrence of ECM in these patients was associated with fewer irAEs and reduced treatment efficacy.

Effectiveness of pembrolizumab in patients with urothelial carcinoma receiving proton pump inhibitors

The association of concurrent proton pump inhibitor (PPI) use with treatment outcome of metastatic urothelial carcinoma (UC) remains controversial.We retrospectively analyzed the records of 227 patients with platinum-treated metastatic UC treated with pembrolizumab. The primary outcome was overall survival (OS). Immune progression-free survival (iPFS) and objective response per immune response evaluation criteria in solid tumors were also compared. Inverse probability of treatment weighting (IPTW)-adjusted multivariable Cox regression models and an IPTW-adjusted multivariable logistic regression model were used to evaluate the oncological outcomes. Furthermore, the heterogeneity of the treatment effect on OS was examined using interaction terms within the IPTW-adjusted univariate Cox regression models.Overall, 86 patients (37.9%) used PPIs. After weighting, no significant differences in patient characteristics were observed between PPI users and non-users. PPI use was significantly associated with a shorter OS (hazard ratio [HR]: 2.02, 95% confidence interval [CI]: 1.28-3.18, P = 0.003) and iPFS (HR: 1.70, 95% CI: 1.23-2.35, P = 0.001). Although not statistically significant, PPI use was associated with objective response as well (OR: 0.61, 95% CI: 0.36-1.02, P = 0.06). The interaction analyses showed that the effect of PPI significantly decreased with age (HR: 0.97, 95% CI: 0.93-1.00, P[interaction] = 0.048) and was increased in males (HR: 2.97, 95% CI: 1.10-8.05, P[interaction] = 0.032).PPI use was significantly associated with worse survival of patients with metastatic UC treated with pembrolizumab. Furthermore, the results suggested that its effects decreased with age and was increased in males.

Initial findings from a first-in-human, multicenter, open-label study of ATOR-1017, a 4-1BB antibody, in patients with advanced solid malignancies.

2529 Background: ATOR-1017 is a human agonist Fcγ-receptor cross-linking dependent IgG4 antibody targeting the co-stimulatory receptor 4-1BB (CD137). ATOR-1017 activates T cells and natural killer cells in the tumor environment, leading to immune-mediated tumor cell killing. Methods: In this first-in-human, dose escalation, multicenter, phase 1 study (NCT04144842), adult patients with solid tumors refractory to standard therapy were enrolled in single patient cohorts for doses up to 40 mg, and thereafter in cohorts of 3-6 patients, to receive ATOR-1017 in a 21-day cycle. Intra-patient dose escalation of ATOR-1017 is allowed depending on the occurrence of Dose-Limiting Toxicities (DLTs) during cycle 1. ATOR-1017 is administered intravenously as monotherapy every three weeks until unacceptable toxicity, progressive disease, or withdrawal of consent. The primary objectives of the study are to determine the maximum tolerated dose, assess adverse events (AEs), evaluate DLTs, and to determine the recommended phase 2 dose. Secondary objectives include pharmacokinetics (PK), immunogenicity, and clinical efficacy, assessed with CT scans using Immune Response Evaluation Criteria in Solid Tumors (iRECIST). Exploratory objectives include assessment of pharmacodynamic (PD) biomarkers. Results: 22 patients (18 females), median age 55 years (34-76) with solid tumors, previously treated with median of 4 (0-6) lines of chemotherapy and/or 2 (0-3) lines of immunotherapy, were included and received at least one cycle ATOR-1017. Nine dose levels have been evaluated; 0.38 mg, 1.5 mg, 5 mg, 15 mg; 40 mg, 100 mg, 200 mg, 360 mg, and 600 mg and dose escalation is ongoing. Treatment-related (TRAEs) were reported in 12 out of 22 patients (54.5%); most common (≥10%) were fatigue (13.6%) and neutropenia (13.6%). Five patients experienced a grade 3-4 TRAE; neutropenia (n = 2), febrile neutropenia (n = 1), chest pain (n = 1), increased liver enzymes (n = 1) and leukopenia/thrombocytopenia (n = 1). No patients discontinued due to TRAEs, no DLTs were observed, and the maximum tolerated dose has not been reached. The median time for patients in the study was 12 weeks (range 4-67). As per data cut-off, January 18, 2022, four patients remained on treatment and 18 patients had discontinued treatment. The reasons for discontinuation include confirmed disease progression (n = 10), clinical deterioration (n = 4), withdrawal of consent (n = 1), death due to disease progression (n = 3). Preliminary PK data showed dose-proportional kinetics. Dose-dependent increase in PD biomarkers demonstrated target-mediated biological activity and proof-of-mechanism. The best response was stable disease observed in a total of 10 patients (45%). Conclusions: ATOR-1017 is safe and well-tolerated at doses up to 600 mg and has shown biologic activity. No DLTs have been reported so far and dose escalation continues. Clinical trial information: NCT04144842.

MP03-12 ASSOCIATION OF USE OF POTASSIUM COMPETITIVE ACID BLOCKERS AND EFFECTIVENESS OF PEMBROLIZUMAB IN PATIENTS WITH METASTATIC UROTHELIAL CARCINOMA

You have accessJournal of UrologyCME1 May 2022MP03-12 ASSOCIATION OF USE OF POTASSIUM COMPETITIVE ACID BLOCKERS AND EFFECTIVENESS OF PEMBROLIZUMAB IN PATIENTS WITH METASTATIC UROTHELIAL CARCINOMA Wataru Fukuokaya, Takahiro Kimura, Kazumasa Komura, Taizo Uchimoto, Kazuki Nishimura, Yu Oyama, Hirokazu Abe, Haruhito Azuma, Jun Miki, and Shin Egawa Wataru FukuokayaWataru Fukuokaya More articles by this author , Takahiro KimuraTakahiro Kimura More articles by this author , Kazumasa KomuraKazumasa Komura More articles by this author , Taizo UchimotoTaizo Uchimoto More articles by this author , Kazuki NishimuraKazuki Nishimura More articles by this author , Yu OyamaYu Oyama More articles by this author , Hirokazu AbeHirokazu Abe More articles by this author , Haruhito AzumaHaruhito Azuma More articles by this author , Jun MikiJun Miki More articles by this author , and Shin EgawaShin Egawa More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002515.12AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Evidence showed that proton pump inhibitor use was associated with worse survival of patients with metastatic urothelial carcinoma (UC) treated with pembrolizumab. Potassium competitive acid blocker (P-CAB) is a new class of acid blockers which has distinct advantages compared to other conventional proton pump inhibitors (PPI) in terms of the effectiveness for acid suppression. However, the impact of its use on the effectiveness of pembrolizumab in these patients is still unclear. We investigated the impact of P-CAB use on the effectiveness of pembrolizumab in patients with metastatic UC. METHODS: We retrospectively analyzed the records of 227 patients with metastatic UC treated with pembrolizumab. The primary outcome was overall survival (OS). Immune progression-free survival (iPFS) per immune response evaluation criteria in solid tumors were also compared. Multivariable Cox regression models were performed to evaluate the association between P-CAB use and these outcomes. RESULTS: Overall, 30 (13.2%) and 56 (24.7%) patients used P-CABs and PPIs, respectively. Median follow-up period of was 12.8 months (95% CI: 10.6 to 19.3). There were significant differences in baseline platelet count (median; P-CAB users vs. PPI users vs. non-users: 292.5 vs. 271 vs. 249 *1000/uL; P=0.047) and the use of concomitant analgesics (P-CAB users vs. PPI users vs. non-users: 22 [73.3%] vs. 28 [50.0%] vs. 38 [27.0%]; P <0.001). Multivariable Cox regression models showed that both P-CAB and PPI use were associated with worse OS (P-CAB, hazard ratio [HR]: 2.51, 95% confidence interval [CI]: 1.44 to 4.38, P=0.001; PPI, HR: 1.58, 95% CI: 0.96 to 2.61, P=0.072) and iPFS (P-CAB, HR: 1.79, 95% CI: 1.12 to 2.86, P=0.015; PPI, HR: 1.56, 95% CI: 1.07 to 2.28, P=0.021). CONCLUSIONS: Similar to PPI, P-CAB use was significantly associated with worse survival of patients with metastatic UC treated with pembrolizumab. Source of Funding: None © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e24 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Wataru Fukuokaya More articles by this author Takahiro Kimura More articles by this author Kazumasa Komura More articles by this author Taizo Uchimoto More articles by this author Kazuki Nishimura More articles by this author Yu Oyama More articles by this author Hirokazu Abe More articles by this author Haruhito Azuma More articles by this author Jun Miki More articles by this author Shin Egawa More articles by this author Expand All Advertisement PDF DownloadLoading ...

Molecular Response Assessment with Immune Adaptive PERCIST in Lung Cancer Patients Treated with Nivolumab: Is It Better Than iRECIST?

Aims We compared the immune response evaluation criteria in solid tumors (iRECIST) with immune adaptive positron emission tomography response criteria in solid tumors (imPERCIST) in lung cancer patients treated with nivolumab. Materials and Methods Twenty lung cancer patients underwent fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) scan at baseline (PET-0), after four cycles (PET-1) and six to eight cycles (PET-2) of nivolumab were included. Kappa coefficient ( k ) was derived to see the level of agreement in two response criteria. Progression-free survival (PFS) curves were computed by the Kaplan–Meier method and compared with the Log Rank test. Univariate and multivariate regression for the percentage change in the sum of diameters (SoD), standard uptake value maximum (SUVmax), sum of metabolic tumor volume (SoMTV), and sum of total lesion glycolysis (SoTLG) was computed. A p -value less than 0.05 was considered significant. Results Kappa coefficient showed a substantial level of agreement (k 0.769) in two response criteria. Mean PFS in partial response, stable disease, and progressive disease (PD) patients in iRECIST and imPERCIST was 27.3, 17.7, 4.2, and 23.3, 18.8, 3.8 months, respectively. The Kaplan–Meier method with the log rank test showed a significant difference in PFS on intracomparison within both criteria; however, it was not significant on intercomparison. On univariate analysis, the percentage change in SoD, SoMTV, SoTLG was significant. However, on multivariate analysis, only percentage change in SoD was a significant predictor. Conclusions We concluded that imPERCIST was equally effective as currently recommended criteria iRECIST for response evaluation of nivolumab in lung cancer patients.

Molecular response assessment with immune adaptive positron emission tomography response criteria in solid tumors in lung cancer patients treated with nivolumab: Is it better than immune response evaluation criteria in solid tumors?

We compared the immune response evaluation criteria in solid tumors (iRECIST) to immune adaptive positron emission tomography response criteria in solid tumors (imPERCIST) in lung cancer patients treated with nivolumab. Twenty lung cancer patients underwent fluorodeoxyglucose positron emission tomography/computed tomography scan at baseline (PET-0) and after 4 cycles (PET-1) and 6–8 cycles (PET-2) of nivolumab were included. Kappa coefficient (κ) was derived to see the level of agreement in two response criteria. Progression-free survival (PFS) curves were computed by the Kaplan–Meier method and compared with the log-rank test. Univariate and multivariate regression for the percentage change in the sum of diameters (SoD), standard uptake value maximum, sum of metabolic tumor volume (SoMTV), and sum of total lesion glycolysis (SoTLG) was computed. P < 0.05 was considered statistically significant. Kappa coefficient showed a substantial level of agreement (κ = 0.769) in two response criteria. The mean PFS in partial response, stable disease, and progressive disease patients in iRECIST and imPERCIST was 27.3, 17.7, 4.2 and 23.3, 18.8, 3.8 months, respectively. The Kaplan–Meier method with the log-rank test showed a significant difference in PFS on intracomparison within both criteria, however, it was not significant on intercomparison. On univariate analysis, the percentage change in SoD, SoMTV, and SoTLG was significant, however, on multivariate analysis, only percentage change in SoD was a significant predictor. We concluded that imPERCIST was equally effective as currently recommended criteria iRECIST for response evaluation of nivolumab in lung cancer patients.

Outcome of Initial Progression During Nivolumab Treatment for Hepatocellular Carcinoma: Should We Use iRECIST?

Immune response evaluation criteria in solid tumors (iRECIST) is recommended during immune checkpoint inhibitors (ICIs) treatment, due to the possibility of pseudoprogression. We evaluated the frequency of pseudoprogression in hepatocellular carcinoma (HCC) patients. This retrospective multicenter study involved 158 consecutive patients who underwent nivolumab treatment for HCC in Korea. At the initial evaluation, 94 patients presented with immune unconfirmed progressive disease, and 22 continued nivolumab. At the second evaluation, 21 of the 22 patients (95.5%) had confirmed progression and no pseudoprogression was observed. Considering low possibility of pseudoprogression, iRECIST may not be required for HCC.

P42.04 Prognosis Factors in Advanced Lung Cancer Patients Treated With Checkpoint Inhibitor-Based Immunotherapy

This study aims to analyze the efficacy of checkpoint inhibitor-based immunotherapy in advanced lung cancer patients, and explore the prognosis factors. Lung cancer patients treated with checkpoint inhibitor-based immunotherapy at a single institution from May 2017 to May 2020 were reviewed retrospectively. Tumor response was assessed according to immune response evaluation criteria in solid tumors (iRECIST). Survival estimates were evaluated as overall survival (OS) and progression free survival (PFS) by Kaplan-Meier survival curves. Prognosis factors were assessed by univariate and multivariate Cox-regression analyses. Checkpoint inhibitor-based immunotherapy was administered in 84 lung cancer patients. Among these patients, only one was complete response, 25 were partial response, 34 were stable diseases and 24 were progressive disease. The median OS and median PFS were 25.93months and 6.90months, respectively. Cox multivariate analysis showed that, application of large dose corticosteroids (HR = 2.518，P = 0.004), late-line treatment（HR = 2.394，P = 0.003）and higher neutrophil to lymphocyte ratio (NLR) (HR = 2.682，P = 0.001) were related with poorer PFS. Application of large dose corticosteroids (HR = 3.216，P = 0.002) and higher NLR (HR = 4.125，P < 0.001) were associated with poorer OS. Checkpoint inhibitor-based immunotherapy is an effective strategy for advanced lung cancer patients. Patients who get first line immunotherapy may get more survival benefits, NLR level at the first best response might be a prognosis factor, and application of high dose corticosteroids was associated with poor prognosis.

Intra- and inter-reader agreement of iRECIST and RECIST 1.1 criteria for the assessment of tumor response in patients receiving checkpoint inhibitor immunotherapy for lung cancer

ObjectivesTo investigate the inter- and intra-reader agreement of immune Response Evaluation Criteria in Solid Tumors (iRECIST) and Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) in patients with lung cancer treated with immunotherapy. Materials and MethodsThis retrospective study included 85 patients with lung cancer treated with PD-1 blockade. Four radiologists evaluated computed topography (CT) scans before and after initiation of immunotherapy using iRECIST and RECIST 1.1. Weighted kappa (k) with equal weights was used to assess the intra-reader agreement between 2 repeated reads on overall response at all time points, best overall response, and the response at the time point of progression, as well as the intra-reader agreement between iRECIST and RECIST. The inter-reader agreement was calculated using Light’s kappa. ResultsIntra-reader agreement for overall response at all time points, best overall response, and time point of progression was substantial to almost perfect for both iRECIST and RECIST 1.1 (k = 0.651–0.983). Inter-reader agreement was substantial for iRECIST (κ = 0.657–0.742) while RECIST 1.1 was moderate to substantial (κ = 0.587–0.686). The level of inter-reader agreement was not higher on repeat read for iRECIST (κ = 0.677–0.709 and κ = 0.657–0.742 for first and second read, respectively) as well as for RECIST 1.1 (κ = 0.587–0.659 and κ = 0.633–0.686 for first and second read, respectively). Almost perfect agreement was observed between RECIST 1.1 and iRECIST at first (κ = 0.813–0.923) and second read (κ = 0.841–0.912). ConclusionThe inter- and intra-reader agreement of iRECIST is high and similar to RECIST 1.1 in patients with lung cancer treated with immunotherapy.

18F-FDG PET/CT in Relapsed Endometrial Cancer Treated with Preoperative PD-1 Inhibitor Dostarlimab.

Dostarlimab is an immune checkpoint inhibitor (ICI) targeting the Programmed-Death-1 (PD-1) co-receptor, recently approved by the European Medicines Agency (EMA) and the Food and Drug Administration (FDA) as a novel therapy for recurrent or advanced endometrial cancer. We report the case of a 64-year-old woman, experiencing vaginal recurrence with microsatellite instability high/hypermutated of a FIGO stage IA grade 2 endometrial endometrioid adenocarcinoma. She received preoperative chemotherapy with four cycles of carboplatin plus paclitaxel, with stable disease on pelvic magnetic resonance imaging (MRI) and fluorine-18 fluorodeoxyglucose positron emission tomography (18F-FDG PET/CT). Dostarlimab (500 mg intravenously every 3 weeks) was then introduced. The subsequent evaluation after three perfusions demonstrated a complete metabolic response on 18F-FDG PET/CT according to immunotherapy-modified PET response criteria in solid tumors (imPERCIST) criteria, then confirmed by MRI according to immune response evaluation criteria in solid tumors (iRECIST). This clinical description suggests that 18F-FDG PET/CT might take place among available tools for guiding the preoperative management for recurrent endometrial cancer patients receiving dostarlimab immunotherapy that should be further explored through clinical trials.

Immune response evaluation criteria in solid tumors for assessment of atypical responses after immunotherapy.

In 2017, immune response evaluation criteria in solid tumors (iRECIST) were introduced to validate radiologic and clinical interpretations and to better analyze tumor’s response to immunotherapy, considering the different time of following and response, between this new therapy compared to the standard one. However, even if the iRECIST are worldwide accepted, to date, different aspects should be better underlined and well reported, especially in clinical practice. Clinical experience has demonstrated that in a non-negligible percentage of patients, it is challenging to determine the correct category of response (stable disease, progression disease, partial or complete response), and consequently, to define which is the best management for those patients. Approaching radiological response in patients who underwent immunotherapy, a new uncommon kind of target lesions behavior was found. This phenomenon is mainly due to the different mechanisms of action of immunotherapeutic drug. Therefore, new groups of response have been described in clinical practice, defined as “atypical responses,” and categorized into three new groups: pseudoprogression, hyperprogression, and dissociated response. This review summarizes and reports these patterns, helping clinicians and radiologists get used to atypical responses, in order to identify patients that respond best to treatment.