Treatment Of Progressive Disease Research Articles

Radotinib Decreases Prion Propagation and Prolongs Survival Times in Models of Prion Disease.

The conversion of cellular prion protein (PrPC) into pathogenic prion isoforms (PrPSc) and the mutation of PRNP are definite causes of prion diseases. Unfortunately, without exception, prion diseases are untreatable and fatal neurodegenerative disorders; therefore, one area of research focuses on identifying medicines that can delay the progression of these diseases. According to the concept of drug repositioning, we investigated the efficacy of the c-Abl tyrosine kinase inhibitor radotinib, which is a drug that is approved for the treatment of chronic myeloid leukemia, in the treatment of disease progression in prion models, including prion-infected cell models, Tga20 and hamster cerebellar slice culture models, and 263K scrapie-infected hamster models. Radotinib inhibited PrPSc deposition in neuronal ZW13-2 cells that were infected with the 22L or 139A scrapie strains and in cerebellar slice cultures that were infected with the 22L or 263K scrapie strains. Interestingly, hamsters that were intraperitoneally injected with the 263K scrapie strain and intragastrically treated with radotinib (100 mg/kg) exhibited prolonged survival times (159 ± 28.6 days) compared to nontreated hamsters (135 ± 9.9 days) as well as reduced PrPSc deposition and ameliorated pathology. However, intraperitoneal injection of radotinib exerted a smaller effect on the survival rate of the hamsters. Additionally, we found that different concentrations of radotinib (60, 100, and 200 mg/kg) had similar effects on survival time, but this effect was not observed after treatment with a low dose (30 mg/kg) of radotinib. Interestingly, when radotinib was administered 4 or 8 weeks after prion inoculation, the treated hamsters survived longer than the vehicle-treated hamsters. Additionally, a pharmacokinetic assay revealed that radotinib effectively crossed the blood-brain barrier. Based on our findings, we suggest that radotinib is a new candidate anti-prion drug that could possibly be used to treat prion diseases and promote the remission of symptoms.

Abstract CT262: Durable responses following anti-TIGIT (BMS-986207) and anti-LAG3 (BMS-980616) in combination with pomalidomide in relapsed myeloma: MMRF MyCheckpoint trial

Abstract Background: T cell redirection with agents such as Chimeric Antigen Receptor T cells or bispecific T cell engagers is remarkably effective in relapsed multiple myeloma (MM), however, they are not curative. Translational studies suggest that T cell exhaustion, characterized by upregulation of immune checkpoints LAG-3 and TIGIT, is a potential resistance mechanism to T cell redirection. These findings support the hypothesis that checkpoint inhibition with anti-LAG-3 or anti-TIGIT mAbs may restore anti-myeloma T cell activity. There is an unmet need to assess the feasibility and safety of checkpoint blockade in this malignancy. Patients and Methods: MyCheckpoint (NCT04150965) is a phase 1/2 platform trial for relapsed MM patients who have received ≥3 lines of therapy, including a proteasome inhibitor, immunomodulatory drug, and anti-CD38 mAb. Primary objectives were safety and tolerability of the investigational agents alone and in combination with pomalidomide (Pom) and dexamethasone (Dex) and overall response rates in each arm. In the phase 1 portion subjects were randomized to Arm B (anti-LAG-3) or Arm C (anti-TIGIT mAb). Subjects received one cycle (C1) of mAb therapy alone, with the addition of Pom and Dex starting with cycle 2 (C2) onward. Bone marrow aspirates and peripheral blood were obtained at screening, C2D1, C3D1, and end of study for correlative analysis. Results: Fourteen (14) eligible subjects were enrolled (seven subjects in Arm B dose level (DL) 1, one not evaluable; six subjects in Arm C DL1, and 1 subject Arm C DL2 not evaluable). The most common adverse events (AE) were anemia and dyspnea. Grade 3-4 AEs related to therapy in the anti-LAG-3 arm were dyspnea and neutropenia; those in anti-TIGIT arm were neutropenia, thrombocytopenia, and anemia. There was 1 death due to progression of disease unrelated to the study treatment. There was 1 death due to a serious adverse event of pneumonia (unrelated). There was one adverse event of special interest in Arm B DL1 (grade 1 AST elevation). No autoimmune AEs were reported. Best overall responses for Arm B DL1 were 1 very good partial response (VGPR), 1 partial response (PR), 4 stable disease (SD); for Arm C DL1, 1 VGPR, 2 PR, and 3 SD. Eight subjects withdrew from treatment for disease progression, 2 for AE, and 2 for patient decision. Two subjects continue in Arm C DL1 as of December 2022, 1 PR as of C16D1 and 1 VGPR (C23D1). Conclusion: Anti-LAG-3 and anti-TIGIT mAb alone and in combination with Pom are safe, feasible and clinically active in relapsed MM after Pom and anti-CD38 mAb. These data provide the first evidence of clinical activity of TIGIT and LAG-3 blockade in MM. Translational results utilizing serial analyses with mass cytometry suggest evidence of immune activation following combination therapy. Citation Format: Hearn J. Cho, Shambavi Richard, Alex Lesokhin, Noa Biran, Barry Paul, Ravi Vij, Matthew Pianko, Deon Doxie, Mercedes Martillo, Katie Wozniak, Kavita Dhodapkar, Madhav Dhodapkar. Durable responses following anti-TIGIT (BMS-986207) and anti-LAG3 (BMS-980616) in combination with pomalidomide in relapsed myeloma: MMRF MyCheckpoint trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT262.

Mechanotransduction in the pathogenesis of non-alcoholic fatty liver disease.

Mechanobiology is a domain of interdisciplinary research that aims to explore the impact of physical force, applied externally or internally, on cell and tissue function, including development, growth, and differentiation. Mechanotransduction is a term that describes how cells sense physical forces (such as compression, stretch, and shear stress), convert them into biochemical signals, and mount adaptive responses integrated by the nucleus. There is accumulating evidence that mechanical forces extensively inform the biological behaviour of liver cells in health and disease. Recent research has elucidated many cellular and molecular mechanisms involved in this process including the pleiotropic control and diverse effects of the paralogous transcription co-activators YAP/TAZ, which play a prominent role in mechanotransduction. The liver sinusoids represent a unique microenvironment in which cells are exposed to mechanical cues originating in the cytoskeleton and at interfaces with adjacent cells, the extracellular matrix, and vascular or interstitial fluids. In non-alcoholic fatty liver disease (NAFLD), hepatocellular lipid accumulation and ballooning, activation of inflammatory responses, dysfunction of liver sinusoidal endothelial cells, and transdifferentiation of hepatic stellate cells into a pro-contractile and pro-fibrotic phenotype have been associated with aberrant cycles of mechanosensing and mechanoresponses. The downstream consequences of disrupted mechanical homeostasis likely contribute to the progression of NAFLD and promote the development of portal hypertension, cirrhosis, and hepatocellular carcinoma. Identification of molecular targets involved in pathogenic mechanotransduction will allow for the development of novel strategies to prevent the progression of liver disease in NAFLD.

Longitudinal nonlinear mixed effects modeling of EGFR mutations in ctDNA as predictor of disease progression in treatment of EGFR‐mutant non‐small cell lung cancer

Correlations between increasing concentrations of circulating tumor DNA (ctDNA) in plasma and disease progression have been shown. A nonlinear mixed effects model to describe the dynamics of epidermal growth factor receptor (EGFR) ctDNA data from patients with non‐small cell lung cancer (NSCLC) combined with a parametric survival model were developed to evaluate the ability of these modeling techniques to describe ctDNA data. Repeated ctDNA measurements on L858R, exon19del, and T790M mutants were available from 54 patients with EGFR mutated NSCLC treated with erlotinib or gefitinib. Different dynamic models were tested to describe the longitudinal ctDNA concentrations of the driver and resistance mutations. Subsequently, a parametric time‐to‐event model for progression‐free survival (PFS) was developed. Predicted L858R, exon19del, and T790M concentrations were used to evaluate their value as predictor for disease progression. The ctDNA dynamics were best described by a model consisting of a zero‐order increase and first‐order elimination (19.7/day, 95% confidence interval [CI] 14.9–23.6/day) of ctDNA concentrations. In addition, time‐dependent development of resistance (5.0 × 10−4, 95% CI 2.0 × 10−4–7.0 × 10−4/day) was included in the final model. Relative change in L858R and exon19del concentrations from baseline was identified as most significant predictor of disease progression (p = 0.001). The dynamic model for L858R, exon19del, and T790M concentrations in ctDNA and time‐to‐event model adequately described the observed concentrations and PFS data in our clinical cohort. In addition, it was shown that nonlinear mixed effects modeling is a valuable method for the analysis of longitudinal and heterogeneous biomarker datasets obtained from clinical practice.

Abstract P5-16-15: Post-progression therapy outcomes in patients (pts) from the phase 3 ASCENT study of sacituzumab govitecan (SG) in metastatic triple-negative breast cancer (mTNBC)

Abstract Background: SG is an antibody-drug conjugate composed of an anti-Trop-2 antibody coupled to the cytotoxic SN-38 payload via a proprietary, hydrolyzable linker. SG is FDA approved for pts with mTNBC who received ≥2 prior chemotherapies (≥1 in the metastatic setting). The confirmatory phase 3 ASCENT study (NCT02574455) in pts treated in second line or greater (2L+) mTNBC demonstrated significant progression-free survival (PFS) and overall survival (OS) benefit of SG over single-agent chemotherapy treatment of physician’s choice (median PFS: 4.8 vs 1.7 months, HR 0.43, P<0.001; median OS: 11.8 vs 6.9 months, HR 0.51) in the full trial population, with a manageable safety profile. However, outcomes and patterns of subsequent therapy for pts who discontinue SG following progressive disease (PD) are not well characterized. This post hoc subgroup analysis investigates post-progression treatment and OS of pts who discontinued SG due to PD during the ASCENT trial. Methods: In ASCENT, pts with mTNBC refractory/relapsing after ≥2 prior chemotherapies (≥1 in the metastatic setting) were randomized 1:1 to receive SG (10 mg/kg IV on d 1 and 8, every 21 d) or TPC (capecitabine, eribulin, vinorelbine, or gemcitabine) until unacceptable toxicity or progression. Post-progression outcomes were assessed in pts who discontinued SG due to progressive disease (PD). Pts were followed every 4 weeks for OS, including documentation of further therapy for breast cancer. Time to post-progression therapy was defined as the number of months from time of randomization until the initiation of subsequent anticancer therapy. OS was analyzed in pts who received post-progression therapy vs those who did not and defined as the number of months from randomization or from end of SG treatment, using Kaplan Meier estimates and Cox regression. Results: 222/267 (83%) pts who were randomized to receive SG discontinued SG due to PD. In these patients median age was 53 years (range, 27-82), median number of prior anticancer regimens was 4, and 7% had known germline BRCA1/2 mutations. Pts received SG for a median duration of 4.2 months (range, 0.0-18.7). Following SG discontinuation, post-progression therapy was received by 73% (n=163) of pts; common post-SG therapies included eribulin (n=70; 32%), carboplatin (n=34; 15%), capecitabine (n=34; 15%), and atezolizumab, (n=15; 7%). The median time to receipt of post-progression therapy was 5.4 months (range, 1.0-19.8). Median OS in pts who received any post PD treatment vs those who did not receive post PD treatment following SG was 13.4 vs 7.3 months (HR, 0.46; 95% CI, 0.32-0.67; P<0.0001) from time of randomization and 7.9 vs 2.0 months (HR, 0.14; 95% CI, 0.09-0.22; P<0.0001) from end of SG treatment, respectively. In pts who received eribulin, carboplatin, atezolizumab, or capecitabine, median OS was 14.1 (95% CI, 10.9-14.9), 13.6 (95% CI, 10.6-15.9), 16.5 (95% CI, 8.7 to not evaluable), and 14.9 (95% CI, 10.9-16.8) months from time of randomization and 8.4 (95% CI, 6.8-9.2), 8.9 (95% CI, 6.7-10.8), 8.6 (95% CI, 4.3 to not evaluable), and 8.9 (95% CI, 6.6-10.3) months from end of SG treatment, respectively. Conclusions: In ASCENT, the majority of pts who discontinued SG due to PD were able to receive subsequent therapy post-progression. Pts who received post PD therapy following SG had significantly improved median OS over those who did not receive further therapy. Pts who received eribulin, carboplatin, atezolizumab, or capecitabine, as post PD therapy had similar median OS. These results indicate that treatment with SG does not prevent receipt of further systemic therapy. Citation Format: Javier Cortés, Aditya Bardia, Delphine Loirat, Sara M. Tolaney, Kevin Punie, Mafalda Oliveira, Sara A. Hurvitz, Adam Brufsky, Sagar Sardesai, Kevin M Kalinsky, Tiffany Traina, Erika Hamilton, Joyce O’Shaughnessy, Véronique Diéras, Lisa A. Carey, Martine Piccart, Sibylle Loibl, Hope S. Rugo, Yanni Zhu, See Phan, Luca Gianni. Post-progression therapy outcomes in patients (pts) from the phase 3 ASCENT study of sacituzumab govitecan (SG) in metastatic triple-negative breast cancer (mTNBC) [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 P5-16-15.

Pembrolizumab Plus Vorinostat Induces Responses in Patients with Hodgkin Lymphoma Who Are Refractory to Prior PD-1 Blockade

Pembrolizumab Plus Vorinostat Induces Responses in Patients with Hodgkin Lymphoma Who Are Refractory to Prior PD-1 Blockade

Colonic Volvulus in Children: Surgical Management of a Challenging Condition.

Colonic volvulus (CV) is a rare but potentially life-threatening condition with unclear etiopathogenesis. To date, less than 80 pediatric cases have been described. Hirschsprung’s disease (HD) is associated with CV in 17% of cases, representing a significant risk factor. Non-HD CV is an even more complex entity. The aim of this study is to describe a series of patients with CV to accentuate some peculiar aspects of this disease. We performed a retrospective study (period: 2012–2021) collecting information of patients with CV. Data analyzed included: demographics, medical history, presenting symptoms and radiological and surgical details. Eleven patients (12.5 ± 2.8 years; 7F/4M) had CV (eight sigmoid, two transverse colon, one total colon). Five patients had associated anomalies and three had HD. A two-step approach with volvulus endoscopic/radiological detorsion followed by intestinal resection was attempted in eight cases (one endoscopic approach failed). Three patients required surgery at admission. At follow-up, two patients developed recurrent intestinal obstruction, one of whom also had anastomotic stenosis. Colonic volvulus is a challenging condition that requires prompt patient care. A missed diagnosis could lead to severe complications. The evaluation of the patient should include a careful histological examination (searching for HD and alpha-actin deficiency), immunologic and metabolic screening, neurological tests and detection of chronic intestinal pseudo-obstruction (CIPO). Lifelong follow-up is mandatory for the early recognition and treatment of progressive diseases involving the proximal gastrointestinal tract.

Enabling access to molecular monitoring for chronic myeloid leukemia patients is cost effective in China.

ObjectiveTo determine the cost effectiveness of molecular monitoring in patients with chronic myeloid leukemia in the chronic phase (CML-CP) compared to no molecular monitoring from a Chinese payer perspective.MethodsAnalyses were conducted using a semi-Markov model with a 50-year time horizon. Population data from multicenter registry-based studies of Chinese patients with CML-CP informed the model. Transition probabilities were based on time-to-event data from the literature. Utility values were obtained from published studies and were assumed to be the same for patients with and without molecular monitoring. Costs were based on values commonly used in the Chinese healthcare system, including drug acquisition, drug administration, follow-up, treatment for disease progression, molecular monitoring, and terminal care costs, and were in the local currency (2020 Chinese Yuan RMB [¥]). Outcomes were total life-years (LYs) and quality-adjusted life years (QALYs), lifetime costs, and incremental cost-effectiveness ratio.ResultsMolecular monitoring was dominant to no molecular monitoring, with increased LYs (1.52) and QALYs (1.90) and costs savings (¥93,840) over a lifetime compared to no monitoring in discounted analyses. The opportunity of patients that receive molecular monitoring to discontinue treatment during treatment-free remission, an opportunity not afforded to those without molecular monitoring, was the principle driver of this result. Results were similar across multiple clinical scenarios. Particularly, molecular monitoring remained dominant even if the proportion of patients achieving deep molecular response (DMR) was reduced by 10%-30%, or the proportion of patients maintaining DMR for 1 year was reduced by 10%-30% or increased by 10%. Cost savings in these scenarios ranged from ¥62,230 to ¥103,964.ConclusionsOverall, this analysis demonstrates that adherence to guideline recommendations of regular molecular monitoring of patients with CML-CP treated with TKIs provides significant clinical benefit that leads to substantial cost savings compared to no molecular monitoring from the perspective of a Chinese payer. In a time where healthcare systems have limited resources to allocate to optimal patient care, investment in molecular monitoring is an ideal choice for improving patient benefits at a reduced cost.

SKYSCRAPER-03: A Phase III, Open-Label, Randomized Study of Atezolizumab Plus Tiragolumab Compared With Durvalumab in Patients With Locally Advanced, Unresectable, Stage III NSCLC Who Have Not Progressed After Platinum-Based Concurrent Chemoradiation

<h3>Purpose/Objective(s)</h3> Until recently, the standard of care for patients (pts) with locally advanced, unresectable, stage III non-small cell lung cancer (NSCLC) has been platinum-based concurrent chemoradiation (cCRT); however, the 5-year OS rates are poor (13–36%; Goldstraw et al. J Thorac Oncol 2015). Durvalumab (anti-PD-L1) monotherapy was recently approved for pts without progressive disease (PD) after cCRT. However, long-term OS data are not yet available and further evaluation of novel cancer immunotherapy combinations should be explored. Targeted inhibition of a novel checkpoint TIGIT/PVR, by the anti-TIGIT antibody tiragolumab, may amplify the anti-cancer activity of anti-PD-L1/PD-1 antibodies. In the phase II CITYSCAPE study (NCT03563716), tiragolumab plus atezolizumab (anti-PD-L1) was well tolerated and improved ORR compared with atezolizumab alone (31.3 vs 16.2%) in 1L pts with PD-L1+ (TPS ≥1%) metastatic NSCLC; with greater benefit in the PD-L1-high (TPS ≥50%) subset. We hypothesize that tiragolumab plus atezolizumab may provide greater clinical benefit vs single-agent anti-PD-L1 as maintenance therapy in pts with unresectable, stage III NSCLC who have not progressed after platinum-based cCRT. SKYSCRAPER-03 (NCT04513925) will determine if tiragolumab plus atezolizumab provides superior clinical benefit to durvalumab in this setting. Current data suggests that cCRT upregulates PD-L1 expression, potentially enabling PD-L1 low or negative tumors to derive benefit, so outcomes will be evaluated in all-comer (ITT) and PD-L1+ sub-populations. <h3>Materials/Methods</h3> Eligible pts (≥18 years) must have unresectable, stage III NSCLC without PD after ≥2 cycles of platinum-based cCRT per NCCN/ESMO guidelines, and without an EGFR mutation or ALK rearrangement; known PD-L1 status; ECOG PS 0–1. Approximately 800 pts will be randomized 1:1 to receive tiragolumab 840mg IV plus atezolizumab 1680mg IV Q4W or durvalumab 10mg/kg IV Q2W / 1500mg IV Q4W. Treatment will continue for up to 13 cycles of 28 days, or until unacceptable toxicity or symptomatic deterioration due to PD; in pts with radiographic PD (per RECIST v1.1) treatment may continue if evidence of ongoing clinical benefit. Stratification factors include PD-L1 status, histology (squamous vs non-squamous), staging (IIIA vs IIIB or IIIC) and ECOG PS (0 vs 1). Primary endpoint is independent review facility-assessed PFS in the ITT and PD-L1+ (TC ≥1%) populations. Secondary endpoints include investigator-assessed PFS, OS, ORR and DoR. Safety and biomarker analyses will be performed. Recruitment is ongoing. <h3>Results</h3> forthcoming <h3>Conclusion</h3> forthcoming

An Explainable 3D Residual Self-Attention Deep Neural Network for Joint Atrophy Localization and Alzheimer's Disease Diagnosis Using Structural MRI.

Computer-aided early diagnosis of Alzheimer's disease (AD) and its prodromal form mild cognitive impairment (MCI) based on structure Magnetic Resonance Imaging (sMRI) has provided a cost-effective and objective way for early prevention and treatment of disease progression, leading to improved patient care. In this work, we have proposed a novel computer-aided approach for early diagnosis of AD by introducing an explainable 3D Residual Attention Deep Neural Network (3D ResAttNet) for end-to-end learning from sMRI scans. Different from the existing approaches, the novelty of our approach is three-fold: 1) A Residual Self-Attention Deep Neural Network has been proposed to capture local, global and spatial information of MR images to improve diagnostic performance; 2) An explainable method using Gradient-based Localization Class Activation mapping (Grad-CAM) has been introduced to improve the interpretability of the proposed method; 3) This work has provided a full end-to-end learning solution for automated disease diagnosis. Our proposed 3D ResAttNet method has been evaluated on a large cohort of subjects from real datasets for two changeling classification tasks (i.e. Alzheimer's disease (AD) vs. Normal cohort (NC) and progressive MCI (pMCI) vs. stable MCI (sMCI)). The experimental results show that the proposed approach has a competitive advantage over the state-of-the-art models in terms of accuracy performance and generalizability. The explainable mechanism in our approach is able to identify and highlight the contribution of the important brain parts (e.g., hippocampus, lateral ventricle and most parts of the cortex) for transparent decisions.

P36.05 Metastatic NSCLC Outcomes With Guideline-Recommended Treatment By KRAS Subtype

The impact of specific KRAS mutation on treatment outcomes remain unclear. We compared the association between systemic anti-cancer treatment (SACT) outcomes and specific KRAS mutations [G12C versus non-G12C mutants] in metastatic non-squamous NSCLC patients (mNSCLC). Patients’ data were retrieved from the institutional Glans-Look Lung Cancer Research database. mNSCLC (AJCC TNM 8th edition Stage IV) treated with guideline-recommended first-line SACT (1L) in Southern Alberta, Canada during 2018-2020 periods were included while excluding those with concurrent multiple malignancies. Outcomes including overall response rate (ORR, RECIST v1.1), adverse events (CTCAE criteria v5), progression-free and overall survival were compared using descriptive (Fisher’s Exact test), Kaplan-Meier survival (Log-Rank) and multivariate (Cox Proportional Hazard) statistics. A priori statistical significance was p < 0.05. Analyses were performed using SPSS statistical software (version 25). A total of 86 KRAS mutant mNSCLC were identified with a preponderance of G12C variant (45%) and women (63%). The non-G12C includes 36% G12V, 15% G12A, 13% G12D, 13% Q61H & 23% others. The median age was 67 years, ECOG performance of 0-1 in 52%, ≥2 in 28% and unknown in 20%. 95% were adenocarcinoma and 55% PD-L1 high (>50%). 1L were 51% pembrolizumab, 30% platinum-based chemotherapy and 17% pembrolizumab/chemotherapy. About 70% already discontinued 1L. 2L rate was 23%, immune therapy was the most common (55%). KRAS mutant G12C versus non-G12C differ by gender with more female only in G12C (p=0.02) and ECOG status at presentation with less ECOG 0-1 in G12C (p<0.01). Pembrolizumab was the commonest 1L regimen in both subtypes. Outcomes by SACT are summarized in Table 1. There were similar 1L treatment outcomes in G12C vs. non-G12C: ORR (21 vs. 30%, p=0.37), disease progression rate (67 vs 68%, p>0.05), grade ≥3 adverse event (8 vs. 9%, p=0.42) or immune-related events (18 vs 19%, p>0.05), median progression-free (5 vs. 6 months, p=0.9) and overall survival (15 months vs not yet reached, p=0.6). 31% of G12C received 2L versus 17% in non-G12C. Only pembrolizumab relative to chemotherapy receipt was significantly associated with better PFS [HR (chemotherapy)=2.34 (95 CI: 1.04-5.29)] and OS [HR (chemotherapy)=3.25 (1.17-9.0)] in multivariate analyses.Table 1Comparison of guideline-recommended treatment outcomes between G12C and non-G12C mutant KRAS metastatic non-squamous NSCLCG12C vs. non-G12C mutant KRAS NSCLCPembrolizumab (n= 44)Chemotherapy (n=26)Chemo/pembro (n=16)Uptake rate, %56 vs. 4728 vs. 3215 vs. 21DCR (PR & stable), %59 vs. 5555 vs. 5383 vs. 60PR-partial response, % (n)23 vs. 36 (5 vs 8)0 vs. 20 (0 vs 3)50 vs. 30 (3 vs. 3)Stable disease, % (n)36 vs 18 (8 vs 4)55 vs 33 (6 vs 5)33 vs 30 (2 vs 3)PFS, median, mo15 vs. 196 vs. 710 vs. 8PFS, HR for non-G12C (95% CI)0.97 (0.48-2.00)PFS, HR for Platin doublet (Pembro as reference)2.48 (1.10-5.60)**PFS, HR for Platin/pembro (Pembro as reference)1.52 (0.41-5.67)OS, median, mo18 vs. NR6 vs. 7Both= NROS, HR for non-G12C (95% CI)0.51 (0.22-1.17)OS, HR for Platin doublet (Pembro as reference)3.25 (1.17-9.0)**OS, HR for Platin/pembro (Pembro as reference)1.39 (0.31-6.33)** denotes statistical significance. CI= confidence interval, DCR= disease control rate, HR= hazard ratio, OS= overall survival, PFS= progression-free survival, mo. = month Open table in a new tab ** denotes statistical significance. CI= confidence interval, DCR= disease control rate, HR= hazard ratio, OS= overall survival, PFS= progression-free survival, mo. = month 67 There was no significant difference in response or survival outcomes with 1L in specific mutant KRAS variants (G12C versus non-G12C). 2L receipt in ∼1/3rd of G12C mutant patients suggest there may be greater appetite for further treatment of progressive disease should more tolerable treatment becomes available.

EFFICIENCY OF THE APPLE PROTECTION SYSTEM AGAINST PHILLOSTICTOSIS

There has been an increase in the harmfulness and the spread of various spots that affect the leaves and cause a significant deterioration of apple plants in the orchards of the Central Blackearth Region in recent years. It was determined during the mycological analysis of apple leaves that the pathogens are fungi Phyllosticta Pirina Sacc., Phyllosticta mali Pr.et Del. The permanent use of chemical protection products against diseases leads to the appearance of resistance and the violation of the ecological balance in the agrocenosis of the apple orchard. One of the promising methods to prevent the emergence of disease resistance to the products used is the alternation of preparations with a different mode of action. The use of highly resistant and immune to diseases varieties reduces the number of fungicide treatments in the protection system of apple orchards. The study was carried out to determine the effectiveness of the apple tree’s protection system against phyllosticta. The research was done in the experimental orchard of the I. V. Michurin Federal Scientific Center in 2018–2019. The objects of research were apple varieties immune to scab Akademik Kazakov, Vympel, Bylina, Rozhdestvenskoe, Fregat and scab resistant variety Kovalenkovskoye on grafted 54–118 rootstock. Our research studied the effectiveness of environmentally safe protection products with low consumption rates to reduce the harmfulness of phylostictosis on apple trees (Delan, 0,6 kg/ha; Zato 0,14 kg/ha; Medeya, 1,0 l/ha). The development of the disease in the сontrol option without any treatments varied from 0,5 % (‘Rozhdestvenskoye’ variety) to 3,3% (Vympel variety). In the experimental treatment the development of phylostictosis ranged from 0,05% (Rozhdestvenskoye variety) to 0,31% (Vympel variety). The biological effectiveness of the studied products in the researched varieties varied from 82,5 % (‘Kovalenkovskoye’ variety) to 88,4 % (‘Bylina’ variety). The high biological efficiency was observed in the ‘Rozhdestvenskoye’ variety (90,2 %) and in the ‘Vympel’ variety (90,6 %). The disease progression in treatment with the farm plant protection scheme was 1,3–2,5 times more than in the experimental option. The biological efficiency was lower on 7,9–17,2 %. The lowest yield was on ‘Kovalenkovskoye’ variety in the control option. The largest yield was in the experimental treatment and varied from 5 kg/tr. to 6,8 kg/tr. (2018) and from 6,8 kg/tr. to 9,0 kg/tr. (2019). The production of apple fruits using immune and resistant varieties and low-hazard products with low cost rates helps to reduce the fungicidal load and obtain high biological efficiency against diseases.

RARE-44. CLINICAL CHARACTERIZATION AND OUTCOME; OUR EXPERIENCE OF CHORDOMAS IN PEDIATRIC AND YOUNG ADULTS

Pediatric chordomas are exceedingly rare and there are limited data to guide treatment decisions. We report a retrospective analysis of 19 patients with chordomas who received treatment at our institution from 2001–2020. Of the 19 patients, 15 had clival (79%), 3 cervical and 1 sacral chordoma. There were 9 males (47%). Median age at diagnosis of 10.6 years. Eight patients had gross total (42%) and 11 (58%) had sub-total resection. As front line therapy 15 patients (79%) underwent surgery followed by radiation (1 photon and 14 proton), 3 patients (16%) received surgery and chemotherapy (anaplastic histology) and 1 patient received only surgery. For patients treated with radiation therapy the average prescribed dose was 70 Gy (range: 52–74). Post-surgery and radiation, 14 of 15 patients remained in remission. Five (26%) patients had progressive disease (PD) with median time to progression of 13 months of whom 3 died of disease at median of 18 months. Treatment of PD consisted of chemotherapy and radiation for 3, re-resection with radiation for 1 and chemotherapy alone for 1 patient. The patients with metastatic and anaplastic disease mean survival is 21 month versus 45 for the rest of the cohort. In summary, post-operative adjuvant radiation provided an overall good outcome in majority of patients. Patients with anaplastic pathology and metastasis at diagnosis had worse outcome. Those who relapsed, subsequent treatment was palliative at best with short survival. Molecular analysis is warranted in future for better disease stratification.

High Rates of Varicella Zoster Virus Antibody Seroconversion and Persistence after Administration of the Adjuvanted, Recombinant Varicella Zoster Vaccine in Multiple Myeloma Patients Undergoing Active Treatment

Multiple myeloma (MM) patients are predisposed to high rate of infectious complications, with viral infections and in particular varicella zoster virus infection having a more than 10-fold increased incidence compared to the general population. This risk increases with use of autologous stem cell transplant (ASCT), multiple lines of therapy for relapsed disease, and proteasome inhibitor (PI) or daratumumab treatment. An adjuvanted, recombinant vaccine, consisting of the varicella-zoster virus glycoprotein E antigen (Shingrix, GlaxoSmithKline; Triangle Park, NC) is now available but studies in MM patients have been limited to the post-ASCT setting. We aimed to analyze the initial seroconversion rates as well as persistence of seropositivity in our MM cohort undergoing active anti-myeloma treatment. We evaluated 85 MM patients undergoing active anti-myeloma treatment who were tested at baseline for VZV antibody (Ab) status. Nine (10.6%) patients were found to have high risk cytogenetics at diagnosis. The median number of prior lines of therapy was 1 (1-10), with 80 (94.1%) patients receiving a prior or current PI-based regimen, 66 (86.8%) receiving ASCT, and 15 (19.7%) receiving a prior or current daratumumab-based regimen. At the time of first vaccination, 35 (41.1%) patients were receiving post-ASCT immunomodulator (IMiD) maintenance. Seven (8.2%) patients had a prior history of VZV infection. 67 (78.8%) patients were actively receiving antiviral prophylaxis with either acyclovir or valacyclovir. To determine vaccine immunogenicity, we used an anti-VZV ELISA assay. Using this test, VZV Ab seropositivity was measured at baseline and after each of the 2 vaccinations. In the entire cohort, 41 (48.2%) patients were found to be VZV Ab negative at baseline. Multivariate modified Poisson regression models with adjustment for prognostic and clinical factors were used to estimate relative risk (RR) and 95% confidence intervals for baseline VZV Ab seropositive status. We identified ISS stage 2 (RR 0.31, 95% CI 0.21-0.61; p&amp;lt;0.001) or 3 (RR 0.52, 95% CI 0.32-0.86); p=0.010) disease and prior/ current daratumumab (RR 0.35, 95% CI 0.13-0.95; p=0.04) as strong predictors of baseline VZV seronegativity; IMiD maintenance (RR 2.15, 95% CI 1.00-4.65; p=0.05) and prior shingles (RR 2.61, 95% CI 1.24-5.51; p=0.011) were associated with VZV seropositivity. Sixty-two (72.9%) patients received one vaccine dose, 49 (57.6%) received 2 doses, and 3 (3.5%) refused the vaccine. The median time between both doses was 84 (53-189) days. Overall rates of seropositivity increased after 1 (87.9%; p=0.0002) and 2 (92.6%; p=0.0001) doses. Seroconversion from a baseline negative to positive test was observed in 16 (76.2%) and 23 (95.8%) patients after 1 and 2 doses, respectively. One patient who received prior cytotoxic chemotherapy failed to seroconvert after 2 doses, and 4 patients lost VZV seropositivity after a median of 348.5 days from the second vaccination dose. In a multivariate model, we observed that progressive disease and daratumumab treatment during time from vaccination to follow up VZV testing predicted for loss of VZV seropositivity. Of 42 patients on acyclovir after receiving both doses, 18 (42.9%) discontinued acyclovir with all patients but one remaining seropositive at most recent follow up. We report the first real world experience of the use of the adjuvanted, recombinant zoster vaccine in MM patients receiving active treatment. We show a high rate of initial VZV seronegativity and were able to show significant seroconversion after a single vaccine dose. In fact, despite studies showing benefit in patients receiving a total of 4 doses, we observed high seroconversion rates using 2 doses. Finally, we report for the first time strong predictors of baseline VZV seronegativity and maintenance of seropositivity in MM patients, in particular treatment with daratumumab. On the other hand, PI treatment was not associated with baseline seronegativity or loss of seropositivity. This data confirms that post-ASCT vaccination would be the optimal time to vaccinate patients, in particular when patients are immunocompetent while in remission on maintenance. The benefit of administering the vaccine in patients undergoing daratumumab or other treatment for progressive disease was not shown here and continued antiviral treatment rather than vaccination is likely to be the ideal prophylaxis strategy. Disclosures Calip: Flatiron Health: Current Employment. Patel:Amgen: Consultancy; Janssen: Consultancy; Celgene: Consultancy.

Final Results of a Phase II Study of Fc Engineered, CD19 Antibody Tafasitamab in Combination with Lenalidomide or Ibrutinib in Patients with Chronic Lymphocytic Leukemia (CLL)

Final Results of a Phase II Study of Fc Engineered, CD19 Antibody Tafasitamab in Combination with Lenalidomide or Ibrutinib in Patients with Chronic Lymphocytic Leukemia (CLL)

Analyzing Relative Flow Speeds in Diabetic Retinopathy Using Variable Interscan Time Analysis OCT Angiography

Further insight into the flow characteristics of the vascular features associated with diabetic retinopathy (DR) may improve assessment and treatment of disease progression. The variable interscan time analysis (VISTA) algorithm is an extension of OCT angiography (OCTA) that detects relative blood flow speeds, which then can be depicted on a color-coded map. This study used VISTA to analyze relative blood flow speeds in the microvascular changes associated with DR. Cross-sectional study. Thirteen patients with varying severities of DR treated at New England Eye Center, Boston, Massachusetts. OCT angiography images centered at the fovea were obtained on a prototype swept-source OCT device, and the VISTA algorithm was applied to visualize relative blood flow speeds. Descriptive flow analysis of the retinal vascular features of DR was conducted on the VISTA-generated images. Twenty-six eyes were included in this study. Of these, 3 eyes had mild nonproliferative DR (NPDR), 6eyes had moderate NPDR, 4 eyes had severe NPDR, 9 eyes had proliferative DR, and 4 eyes were normal controls. Microaneurysms, intraretinal microvascular abnormalities (IRMAs), and neovascularization appeared to originate from areas of relatively slow blood flow speeds. Microaneurysms showed relatively slower flow, IRMAs showed turbulent, intermediate to slow flow, and venous beading and looping presented with relatively high flow speeds that tapered progressively. Neovascularization of venous origin demonstrated slower flow speeds, whereas that of arterial origin showed relatively high flow speeds. Additionally, increased disease severity was associated with globally slower flow speeds, with particularly slower flow around the foveal avascular zone. The VISTA algorithm seems to be a useful extension of OCTA that overcomes some of the limitations of normal gray-scale OCTA. It seems to have some potential in providing relevant insight into the pathogenesis of the microvascular changes associated with DR. These findings may assist in improving our understanding of the pathogenic changes that take place in DR.

Osimertinib in patients with advanced/metastatic epidermal growth factor receptor T790M mutation-positive non-small cell lung cancer - the Belgian ASTRIS data

ABSTRACT Objectives: The aim of ASTRIS, a real-world study, was to assess the safety and efficacy of osimertinib in patients with locally advanced or metastatic (stage IIIB-IV) epidermal growth factor receptor (EGFR) T790M mutation-positive non-small cell lung cancer (NSCLC) who had received prior EGFR-tyrosine kinase inhibitor (TKI) therapy. Here, we describe the Belgian subset of the global ASTRIS study. Methods: Patients received osimertinib orally as one 80 mg tablet once daily until disease progression or unacceptable toxicity. Socio-demographic data, medical history, disease progression and survival status were collected and molecular testing for EGFR status was performed. Safety was also assessed. All collected data were summarized using descriptive statistics. Results: Of the 31 Belgian patients enrolled in the study, 9 (29.0%) discontinued treatment for disease progression and 5 (16.1%) due to other reasons. Among the 31 patients treated with osimertinib, 16 (51.6%, 95% CI 33.1–69.8) had a clinical response and 13 (41.9%) had stable disease as best response assessed by the investigator, with a disease control rate of 93.5%. The clinical response rate was 66.7% (6/9) in patients with brain/leptomeningeal metastases and 50.0% (4/8) in patients without brain/leptomeningeal metastases. About one third of the patients (11/31) reported at least one adverse event (AE) (35.5%) or serious AE (10/31; 32.3%) and 3/31 (9.7%) patients discontinued treatment due to AEs. Conclusion: We here demonstrate the effectiveness of osimertinib in a real-world setting in Belgian patients with locally advanced or metastatic T790M-positive NSCLC who had received previous EGFR-TKI treatment. No new safety signals were identified.

ATIM-49 (LTBK-01). AMG 596, A NOVEL ANTI-EGFRVIII BISPECIFIC T CELL ENGAGER (BITE®) MOLECULE FOR THE TREATMENT OF GLIOBLASTOMA (GBM): PLANNED INTERIM ANALYSIS IN RECURRENT GBM (RGBM)

Abstract OBJECTIVES The class III variant of the epidermal growth factor receptor (EGFRvIII) represents the most common EGFR mutation in GBM. AMG 596 is a bispecific T cell engager (BiTE®) molecule designed to engage a patient’s own CD3-positive T cells to EGFRvIII-positive tumor antigens. This is the first clinical data readout for AMG 596. METHODS This phase 1, first-in-human, open-label, sequential dose-escalation/expansion study evaluates continuous intravenous AMG 596 in patients with EGFRvIII-positive GBM or malignant glioma in recurrent (Group 1) or newly diagnosed in maintenance treatment (Group 2) settings. Eligible patients: adults with EGFRvIII-positive GBM or malignant glioma; ≤2 mg/day dexamethasone, ECOG performance status ≤1; life expectancy ≥3 months; and acceptable renal, hematological, and hepatic function. The primary objective evaluates safety and tolerability. Additional assessments include objective response rate per modified Response Assessment in Neuro-Oncology (RANO) Criteria. RESULTS As of June 2019, 15 rGBM patients (Group 1) were enrolled; 14 patients received ≥1 dose AMG 596. 14/15 (93.3%) patients were evaluable at time of analysis (safety analysis set). Median age was 54.5 years (range, 44–68); 50% were male. Seven patients discontinued for progressive disease (PD). AEs occurred in all patients and were serious in 7/14 (50%). None resulted in discontinuation; two (14.3%) fatal AEs were related to PD. Headache and depressed consciousness (both n=2, 14.3%) were the most common grade ≥3 treatment emergent AEs. In patients with sufficient follow-up to assess response (n=8), 1 (12.5%) achieved partial response, 2 (25%) had stable disease, 4 (50%) had PD at initial scan, and 1 (12.5%) discontinued treatment for PD. Semi-quantitative EGFRvIII expression analysis revealed a median H-score of 115 (range, 8–280). CONCLUSION This interim analysis suggests a first indication that AMG 596 may be well-tolerated and offer anti-tumor activity in patients with rGBM. Enrollment is ongoing and additional data will be presented. NCT03296696.

Circulating tumour cells and hypercoagulability: a lethal relationship in metastatic breast cancer

PurposeCirculating tumour cells (CTCs) are a marker of poor prognosis and are associated with increased risk of venous thromboembolism in metastatic breast cancer (MBC). We aimed to determine if the presence of CTCs and plasma markers of hypercoagulability [thrombin–antithrombin III (TAT), fibrinogen and d-dimer] are biomarkers of survival in MBC.Methods/patientsIn a prospective study of MBC patients, CTC (CellSearch®) enumeration and plasma TAT, fibrinogen and d-dimer measured prior to commencement of treatment for disease progression were correlated to overall survival.ResultsAt study completion, of 50 MBC patients recruited (median age 59 years, range 36–82), 40 patients had died (median survival 417 days, range 58–2141). CTCs (≥ 1/7.5 ml) were identified in 16 patients (median number of cells per 7.5 ml, 3 (range 1–31) and were associated with systemic hypercoagulability (medians TAT: 8.1 vs. 5.2 ng/ml, p = 0.03; fibrinogen: 4.3 vs. 3.1 g/l, p = 0.03; d-dimer: 1327 vs. 683 ng/ml, p = 0.0001). At 1 year, of 16 patients with ≥ 1 CTC, 7 had died (44%), compared to 5 of 26 (19%) patients in the no-CTC group. The presence of ≥ 1 CTC was associated with a trend for reduced overall survival (median 455 days vs. 614 days, p = 0.15). Plasma TAT inversely correlated with survival and was significantly higher in patients dying within 1 year (median 9.8 vs. 5.2 ng/ml, p = 0.004) whilst d-dimer showed a trend for reduced 1-year survival (median 1211 vs. 817 ng/ml, p = 0.06). MBC patients with combined high d-dimer (≥ 895 ng/ml) and CTC positivity (≥ 1/7.5 ml whole peripheral blood) had significantly reduced survival (p = 0.04).ConclusionsThe correlation between CTCs, hypercoagulability and reduced survival in MBC suggests the coagulation system supports tumour cell metastasis and is, therefore, a potential therapeutic target.

Outcomes of men with prostate cancer managed with active surveillance and tested with clinical cell-cycle risk score.

e16566 Background: The indolent nature of many prostate cancers (PC) makes some men eligible to undergo active surveillance (AS) rather than immediate definitive treatment. Accurate risk classification is critical for selection of appropriate candidates for AS. The clinical cell-cycle risk (CCR) score, a combined clinical and molecular score, provides improved prognostic information about tumor aggressiveness over clinical parameters alone. This study aimed to evaluate the clinical outcomes of men with low-risk PC by NCCN guidelines and CCR score who selected AS. Methods: This study retrospectively reviewed men with localized PC who received CCR testing (2013-2017) and had low-risk disease according to NCCN guidelines and CCR score (N = 664). Low-risk by CCR score was defined as having a risk of disease-specific mortality &lt; 3.2%. Men selected AS (no definitive treatment within 6 months of diagnosis) or underwent immediate definitive treatment. Durability of AS was evaluated beginning from diagnosis. Clinical outcomes were determined by reporting adverse events (biochemical recurrence (BCR), progression to metastasis as confirmed by radiographic imaging, prostate cancer specific mortality). Results: In this study, 547 men (82%) selected AS (median follow-up time 2.2 years [1.5, 3.1]). Of those managed by AS, two (0.4%) men experienced an adverse event. One man experienced BCR 3.7 years after diagnosis, and the other experienced metastasis 0.9 years after diagnosis. There were no reported cases of disease-specific mortality. The probability of remaining on AS for 3 years was 69.6%. Common reasons for exiting AS were patient choice (27.1%), increase in Gleason score (23.3%), and change in prostate specific antigen (PSA) (10.5%). Of those patients that left AS due to change in PSA (N = 14), only 4 exhibited a clinically significant increase in PSA ( &gt; 10 ng/mL). Conclusions: The majority of men with molecularly-confirmed (CCR), NCCN low-risk PC selected AS in both academic and community settings. The incidence of metastatic disease or BCR after definitive treatment for disease progression was rare. The majority of men who selected AS remained on AS for the duration of the study.