Subsequent Chemo Research Articles

Abstract B035: Nanoparticle delivery of innate immune agonists combines with senescence- inducing agents to mediate T cell control of pancreatic cancer

Abstract Pancreatic ductal adenocarcinoma has quickly risen to become the 3rd leading cause of cancer- related death. This is in part due to its fibrotic tumor microenvironment (TME) that contributes to poor vascularization and immune infiltration and subsequent chemo- and immunotherapy failure. Here we investigated an innovative immunotherapy approach combining delivery of STING and TLR4 innate immune agonists via lipid-based nanoparticles (NPs) co-encapsulation with senescence-inducing RAS-targeted therapies that can remodel the immune suppressive PDAC TME through the senescence-associated secretory phenotype. Treatment of transplanted and autochthonous PDAC mouse models with these regimens led to enhanced uptake of NPs by multiple cell types in the PDAC TME, induction of type I interferon and other pro-inflammatory signaling, increased antigen presentation by tumor cells and antigen presenting cells, and subsequent activation of both innate and adaptive immune responses. This two-pronged approach produced potent T cell-driven and Type I interferon-mediated tumor regressions and long-term survival in preclinical PDAC models dependent on both tumor and host STING activation. STING and TLR4-mediated Type I interferon signaling were also associated with enhanced NK and CD8+ T cell immunity in human PDAC. Thus, combining localized immune agonist delivery with systemic tumor-targeted therapy can synergize to orchestrate a coordinated Type I interferon-driven innate and adaptive immune assault to overcome immune suppression and activate durable anti-tumor T cell responses against PDAC. Citation Format: Kelly D DeMarco, Loretah Chibaya, Christina F Lusi, Griffin I Kane, Meghan L Brassil, Chaitanya N Parikh, Katherine C Murphy, Shreya R Chowdury, Junhui Li, Boyang Ma, Tiana E Taylor, Julia Cerrutti, Haruka Mori, Miranda Diaz-Infante, Jessica Peura, Jason R Pitarresi, Lihua Julie Zhu, Katherine A Fitzgerald, Prabhani U Atukorale, Marcus Ruscetti. Nanoparticle delivery of innate immune agonists combines with senescence- inducing agents to mediate T cell control of pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr B035.

Total Synthesis of the Phenylnaphthacenoid Type II Polyketide Antibiotic Formicamycin H via Regioselective Ruthenium-Catalyzed Hydrogen Auto-Transfer [4 + 2] Cycloaddition.

The first total synthesis of the pentacyclic phenylnaphthacenoid type II polyketide antibiotic formicamycin H is described. A key feature of the synthesis involves the convergent, regioselective assembly of the tetracyclic core via ruthenium-catalyzed α-ketol-benzocyclobutenone [4 + 2] cycloaddition. Double dehydration of the diol-containing cycloadduct provides an achiral enone, which upon asymmetric nucleophilic epoxidation and further manipulations delivers the penultimate tetracyclic trichloride in enantiomerically enriched form. Subsequent chemo- and atroposelective Suzuki cross-coupling of the tetracyclic trichloride introduces the E-ring to complete the total synthesis. Single-crystal X-ray diffraction analyses of two model compounds suggest that the initially assigned stereochemistry of the axially chiral C6-C7 linkage may require revision.

Nanoparticle delivery of innate immune agonists combined with senescence-inducing agents promotes T cell control of pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) has quickly risen to become the third leading cause of cancer-related death in the United States. This is in part because of its fibrotic tumor microenvironment (TME) that contributes to poor vascularization and immune infiltration and subsequent chemo- and immunotherapy failure. Here, we investigated an immunotherapy approach combining delivery of stimulator of interferon genes (STING) and Toll-like receptor 4 (TLR4) innate immune agonists by lipid-based nanoparticle (NP) coencapsulation with senescence-inducing RAS-targeted therapies, which can remodel the immune suppressive PDAC TME through the senescence-associated secretory phenotype. Treatment of transplanted and autochthonous PDAC mouse models with these regimens led to enhanced uptake of NPs by multiple cell types in the PDAC TME, induction of type I interferon and other proinflammatory signaling pathways, increased antigen presentation by tumor cells and antigen-presenting cells, and subsequent activation of both innate and adaptive immune responses. This two-pronged approach produced potent T cell-driven and type I interferon-mediated tumor regression and long-term survival in preclinical PDAC models dependent on both tumor and host STING activation. STING and TLR4-mediated type I interferon signaling was also associated with enhanced natural killer and CD8+ T cell immunity in human PDAC samples. Thus, combining localized immune agonist delivery with systemic tumor-targeted therapy can orchestrate a coordinated type I interferon-driven innate and adaptive immune response with durable antitumor efficacy against PDAC.

Rhodium(I)-Catalyzed Annulation of Bicyclo[1.1.0]butyl-Substituted Dihydroquinolines and Dihydropyridines.

Bicyclo[1.1.0]butane-containing compounds feature a unique chemical reactivity, trigger "strain-release" reaction cascades, and provide novel scaffolds with considerable utility in the drug discovery field. We report the synthesis of new bicyclo[1.1.0]butane-linked heterocycles by a nucleophilic addition of bicyclo[1.1.0]butyl anions to 8-isocyanatoquinoline, or, alternatively, iminium cations derived from quinolines and pyridines. The resulting bicyclo[1.1.0]butanes are converted with high regioselectivity to unprecedented bridged heterocycles in a rhodium(I)-catalyzed annulative rearrangement. The addition/rearrangement process tolerates a surprisingly large range of functional groups. Subsequent chemo- and stereoselective synthetic transformations of urea, alkene, cyclopropane, and aniline moieties of the 1-methylene-5-azacyclopropa[cd]indene scaffolds provide several additional new heterocyclic building blocks. X-ray structure-validated quantum mechanical DFT calculations of the reaction pathway indicate the intermediacy of rhodium carbenoid and metallocyclobutane species.

Phase II Study of Toripalimab in Combination with Induction Chemotherapy and Subsequent Chemo- Radiation in Patients with Advanced/Metastatic Esophageal Carcinoma (TR-EAT Trial)

<h3>Purpose/Objective(s)</h3> Immune checkpoint inhibitor therapy combined with chemotherapy is safe and effective in treating advanced esophageal carcinoma; however, some patients still experience tumor progression and/or metastasis. Whether the addition of radiotherapy to immunotherapy combined with chemotherapy improves the prognosis of patients with advanced/metastatic esophageal carcinoma needs to be investigated. <h3>Materials/Methods</h3> This is an open-label, single-arm, and single-center phase II trial. Patients with unresectable stage IV esophageal squamous cell carcinoma (ESCC) who had not received prior systemic therapy were enrolled. The patients were treated with two cycles of toripalimab (240 mg d1, Q3w) combined with induction chemotherapy (paclitaxel 135-175 mg/m2, d1+carboplatin AUC=4-6, d1, Q3W), sequentially combined with concurrent chemoradiotherapy (30-50 Gy in 15-25 fractions, paclitaxel 135-175 mg/m2, d1+carboplatin AUC=4-6 d1, Q3W), followed by maintenance treatment with toripalimab (240 mg d1, Q3W) for 1 year. The primary objective of this trial is to evaluate the progression-free survival (PFS) of this combination therapy; and the secondary objective is related to the assessment of objective response rate (ORR), the disease control rate (DCR), the duration of remission (DOR), the 1-and 2-year overall survival (OS) rates, the safety and tolerability of patients to treatment, and the identification of the changes in the health-related quality of life (HRQoL) of patients. <h3>Results</h3> Up to date, a total of 23 patients were screened, and 22 were enrolled. The median age of the patients was 58 years (range, 43-70 years), and 19 patients were males. Four patients completed two cycles of chemotherapy combined with immunotherapy, two patients were in the concurrent chemoradiotherapy phase, and 10 patients were in the immune maintenance phase. The median follow-up period was 4.3 months (1.3-8.2 months). After two cycles of chemotherapy combined with immunotherapy, treatment results of 18 patients were evaluated. The results showed complete response (CR) in 0 patients, partial response (PR) in 6, stable disease (SD) in 9 and progressive disease (PD) in 3. ORR was 33.3% and DCR was 83.3%. After concurrent chemoradiotherapy, the treatment results of 11 patients were evaluated. The results showed CR in 1 patient, PR in 8, SD in 2 and PD in 0. ORR was 81.8% and DCR was 100%. Most patients experienced only grade 1-2 adverse effects and laboratory abnormalities, and no grade 3 or worse adverse effects or laboratory abnormalities occurred. <h3>Conclusion</h3> The interim analysis showed that the sequential CRT therapy is proved to be effective in the initial treatment of advanced esophageal squamous cell carcinoma (ESCC) after the treatment with toripalimab combined with chemotherapy. The initial results are encouraging and the final results are to be expected.

Diagnostic workup following a multicancer early detection test with a cancer signal origin prediction.

e15037 Background: A blood-based multi-cancer early detection (MCED) test is available for use as a complement to single cancer screening modalities, though clinical experience is limited. PATHFINDER (NCT04241796; enrollment complete, n = 6662) is a prospective study in asymptomatic adults ≥50 y that returns MCED test results (‘signal not detected’ or ‘signal detected’) with ≥1 cancer signal origin (CSO) prediction to direct diagnostic workup. MCED testing is a novel approach to cancer screening, so clinical guidance on how to best utilize MCED test findings is critical. To review follow-up testing required to achieve a definitive diagnosis after a signal detected result and corresponding CSO prediction, the diagnostic workups of PATHFINDER trial participants are summarized. Methods: Participants from the interim PATHFINDER data set (data cutoff Mar-19-2021) with a confirmed new cancer identified by the MCED test and post-diagnosis clinical notes were included. Participants with a predicted or confirmed heme-related cancer were excluded as were those for whom a determinate CSO or staging information was unavailable. Key diagnostic steps from signal detected (Day 1) to resolution were summarized. A multidisciplinary review board guided initial diagnostic follow-up. Results: Five individuals met the eligibility criteria for consideration; three with gastrointestinal cancers have been described elsewhere and are therefore not summarized here. Of the remaining two participants identified, the first was a male smoker &gt; 60y (CSO prediction = Head and Neck). Based on the CSO, laryngoscopy and head and neck CT were performed. Laryngoscopy was negative, but CT revealed necrotic lymph nodes suggestive of metastases. A subsequent PET-CT found an incidental T1N0M0 stage I renal cell carcinoma and an FDG-avid base of tongue lesion, which was biopsied (moderately differentiated squamous cell carcinoma). A stage II (T2N2M0) head and neck cancer was diagnosed at Day 81. The patient underwent radiation therapy, chemotherapy, and nephrectomy and is alive with no evidence of cancer ≥502 days post-diagnosis. The second was a female smoker &gt; 60y (CSO prediction = Lung). Based on the CSO, she received a non-contrast chest CT, revealing a 2.1 cm spiculated mass highly suspicious for primary lung malignancy. PET-CT confirmed the mass was FDG-avid, and core biopsy revealed well to moderately differentiated adenocarcinoma. The participant was diagnosed with Stage IIIB (T1N3M0) lung cancer (Day 22). She underwent subsequent radiation, chemo, and immunotherapy. She is alive ≥683 days post-diagnosis, but metastatic disease has subsequently developed. Conclusions: The MCED test detected cancer signals and accurately predicted CSO for these participants, both of whom achieved diagnostic resolution &lt; 3 months. Clinical insight from the CSO prediction was used to direct the workup required to achieve a definitive diagnosis.

WJOG13219G: Triplet versus doublet in patients with previously untreated BRAFV600E-mutant metastatic colorectal cancer: A multi-institutional real-world data analysis (BRACELET study).

37 Background: The survival benefit of FOLFOXIRI plus bevacizumab (Triplet) over Doublet in patients (pts) with BRAFV600E-mutant metastatic colorectal cancer (mCRC) remains controversial. We compared Triplet therapy with Doublet and explored the pts subgroups that could benefit from intensive chemotherapy (chemo) using real-world data. Methods: WJOG13219G was a multicenter, retrospective registry-based study of pts with BRAFV600E-mutant mCRC who received first-line doublet or triplet chemo with/out molecular targeted agents in January 2014–December 2019. Primary analysis focused on pts who received VEGF inhibitor-containing chemo. To adjust pts background, the inverse probability of treatment weighting (IPTW) method based on propensity scores calculated by age, ECOG PS, and disease status (recurrent/metastatic) was used. Results: A total of 232 pts from 33 hospitals were registered. After excluding 18 pts treated with anti-EGFR antibody-containing regimen and 44 without any targeted agents, 79 pts with Triplet and 91 with Doublet were analyzed. Baseline pts disposition was as follows: median age, 61 y; male proportion, 51%; PS 0/1/≥2, 63%/32%/5%; recurrent/metastatic, 26%/74%; and right/left primary, 68%/32%. Significant differences were noted in age and PS between the two groups. At median follow-up of 24.0 months, no statistical difference was noted in progression-free survival (PFS) (median 9.7 months of Triplet vs. 7.8 months of Doublet, HR = 0.89, P = 0.49) and overall survival (OS) (median 18.7 vs. 18.3 months, HR = 0.87, P = 0.52). The objective response rate was 53% in the Triplet group and 41% in Doublet (P = 0.10). Curative surgery after chemo was more frequent in the Triplet group than in Doublet (13% vs. 3%, P = 0.02). Two pts (3%) in the Triplet group and 6 (7%) in Doublet received immunotherapy as subsequent chemo; 13 (16%) and 6 (7%) also received BRAF inhibitor-containing therapy. IPTW analysis showed no difference between the two groups in PFS (HR = 0.82, P = 0.07) and OS (HR = 0.92, P = 0.57). In the subgroup analysis, pts with right-sided primary tumor in the Triplet group showed favorable trends of PFS (HR, 0.87; 95% CI, 0.65–1.16) and OS (HR, 0.71; 95%CI, 0.50–1.01), whereas pts with left-sided tumor in the Triplet group showed the reverse trends of PFS (HR, 1.17; 95% CI, 0.77–1.78) and OS (HR, 1.68; 95% CI, 0.97–2.91). Conclusions: Some baseline characteristics were significantly different between real-world pts in the Triplet and Doublet groups. Although the Triplet group did not show any survival benefit compared with Doublet in the original and IPTW cohorts, pts with right-sided BRAFV600E-mutant mCRC could benefit from Triplet therapy.

Perilesional edema in brain metastases as predictive factor of response to systemic therapy in non-small cell lung cancer patients: a preliminary study.

BackgroundThe significance of upfront systemic therapies as an alternative to whole brain radiotherapy (WBRT) for multiple brain metastases (BM) is debatable. Our purpose is to investigate if peritumoral edema could predict the intracranial response to systemic chemotherapy (chemo) in patients with advanced non-squamous non-small cell lung cancer (non-SQ-NSCLC) and synchronous multiple BM.MethodsIn this observational cohort study, we evaluated the outcome of 28 patients with multiple BM (≥3) treated with chemo based on cisplatin/carboplatin plus pemetrexed (chemo, group A, n=17) or WBRT plus subsequent chemo (group B, n=11). The intracranial response, assessed by the response assessment neuro-oncology (RANO) BM criteria, was correlated with the degree of BM-associated edema estimated by the maximum diameter ratio among fluid attenuated inversion recovery (FLAIR) and gadolinium-enhanced T1WI (T1Gd) per each BM at the baseline brain magnetic resonance imaging (MRI).ResultsNo differences were observed in baseline characteristics between both groups, except for the number of patients under steroid treatment that was clearly superior in group B (P=0.007). Median OS was similar between groups. Regarding FLAIR/T1Gd ratio (F/Gd), patients treated with chemo alone exhibited significantly higher values (P=0.001) in those who developed intracranial progression disease (PD) (2.80±0.32 mm), compared with those who achieved partial response (PR) (1.30±0.11 mm) or stable disease (SD) (1.35±0.09 mm). In patients treated with WBRT, F/Gd ratio was not predictive of response.ConclusionsPeritumoral edema estimated by F/Gd ratio appears a promising predictive tool to identify oligosymptomatic patients with multiple BM in whom WBRT can be postponed.

TP53/p53-FBXO22-TFEB controls basal autophagy to govern hormesis

ABSTRACT Preconditioning with a mild stressor such as fasting is a promising way to reduce severe side effects from subsequent chemo- or radiotherapy. However, the underlying mechanisms have been largely unexplored. Here, we demonstrate that the TP53/p53-FBXO22-TFEB (transcription factor EB) axis plays an essential role in this process through upregulating basal macroautophagy/autophagy. Mild stress-activated TP53 transcriptionally induced FBXO22, which in turn ubiquitinated KDM4B (lysine-specific demethylase 4B) complexed with MYC-NCOR1 suppressors for degradation, leading to transcriptional induction of TFEB. Upregulation of autophagy-related genes by increased TFEB dramatically enhanced autophagic activity and cell survival upon following a severe stressor. Mitogen-induced AKT1 activation counteracted this process through the phosphorylation of KDM4B, which inhibited FBXO22-mediated ubiquitination. Additionally, fbxo22−/− mice died within 10 h of birth, and their mouse embryonic fibroblasts (MEFs) showed a lowered basal autophagy, whereas FBXO22-overexpressing mice were resistant to chemotherapy. Taken together, these results suggest that TP53 upregulates basal autophagy through the FBXO22-TFEB axis, which governs the hormetic effect in chemotherapy. Abbreviations: BBC3/PUMA: BCL2 binding component 3; CDKN1A/p21: cyclin dependent kinase inhibitor 1A; ChIP-seq: chromatin immunoprecipitation followed by sequencing; DDB2: damage specific DNA binding protein 2; DRAM: DNA damage regulated autophagy modulator; ESR/ER: estrogen receptor 1; FMD: fasting mimicking diet; HCQ: hydroxychloroquine; KDM4B: lysine-specific demethylase 4B; MAP1LC3/LC3: microtubule associated protein 1 light chain 3 alpha; MEFs: mouse embryonic fibroblasts; MTOR: mechanistic target of rapamycin kinase; NCOR1: nuclear receptor corepressor 1; SCF: SKP1-CUL-F-box protein; SQSTM1: sequestosome 1; TFEB: transcription factor EB

Integrated Discourse Therapy After Glioblastoma: A Case Report of Face-To-Face and Tele-NeuroRehabilitation Treatment Delivery

Background: Language and communication impairments are among the most frequently reported long-term behavioral consequences of brain tumor. Such deficits may persist long after a patient has been discharged from the hospital and can significantly impact return to work, resumption of prior social roles, and interpersonal relations, as well as full engagement in leisure activities. While considerable research has centered on identifying and describing communication impairments in brain tumor survivors, relatively little research has investigated language therapy for this population.Aims: This report (1) reviews the literature and describes the language and cognitive-communicative profile of a 35-year-old man 6 years post glioblastoma excision with subsequent chemo- and radiation therapies; (2) presents cognitive-communication outcome data for this individual following an integrated discourse therapy; and (3) assesses treatment feasibility in face-to-face (F2F) and tele-neurorehabilitation (TNR) contexts.Methods: A battery of tests and weekly conversation probes were administered to evaluate baseline performance and potential changes associated with F2F and TNR treatment delivery. Integrated Conversation Therapy (ICT) was administered across four alternating (F2F and TNR) treatment blocks over 2 months. ICT is a solution-focused discourse intervention that simultaneously targets word finding, sentence processing, and authentic patient-selected conversational interactions.Results: Although the participant presented with long term-language impairments that were clinically distinct from stroke-associated aphasia, statistically significant post-treatment gains (>2 SEM) were evident following F2F and TNR treatment delivery on standardized measures of apraxia, discourse production, verbal memory, and self-ratings of discourse production, communication, and living with aphasia. While objective measures of treatment effect size (probes of CIU discourse data) were consistent across F2F and TNR delivery models, results of a satisfaction survey indicated a slight but statistically significant participant preference for TNR treatment delivery.Conclusions: This study provides preliminary support for F2F and TNR delivery of ICT discourse intervention for glioblastoma survivors. It also highlights the need for more research specifically dedicated to language therapy for this population.

Improved Outcomes for Responders After Treatment with Induction Chemotherapy and Chemo(re)irradiation for Locally Recurrent Rectal Cancer.

Despite improvements in the multimodality treatment for patients with locally recurrent rectal cancer (LRRC), oncological outcomes remain poor. This study evaluated the effect of induction chemotherapy and subsequent chemo(re)irradiation on the pathologic response and the rate of resections with clear margins (R0 resection) in relation to long-term oncological outcomes. All consecutive patients with LRRC treated in the Catharina Hospital Eindhoven who underwent a resection after treatment with induction chemotherapy and subsequent chemo(re)irradiation between January 2010 and December 2018 were retrospectively reviewed. Induction chemotherapy consisted of CAPOX/FOLFOX. Endpoints were pathologic response, resection margin and overall survival (OS), diseasefree survival (DFS), local recurrencefree survival (LRFS), and metastasisfree survival (MFS). A pathologic complete response was observed in 22 patients (17%), a "good" response (Mandard 2-3) in 74 patients (56%), and a "poor" response (Mandard 4-5) in 36 patients (27%). An R0 resection was obtained in 83 patients (63%). The degree of pathologic response was linearly correlated with the R0 resection rate (p = 0.026). In patients without synchronous metastases, pathologic response was an independent predictor for LRFS, MFS, and DFS (p = 0.004, p = 0.003, and p = 0.024, respectively), whereas R0 resection was an independent predictor for LRFS and OS (p = 0.020 and p = 0.028, respectively). Induction chemotherapy in addition to neoadjuvant chemo(re)irradiation is a promising treatment strategy for patients with LRRC with high pathologic response rates that translate into improved oncological outcomes, especially when an R0 resection has been achieved.

Plasma circulating tumor DNA (ctDNA) based clinical outcomes in metastatic castration-resistant prostate cancer (mCRPC).

160 Background: mCRPC is a heterogeneous disease state with variable survival and molecular markers that define survival continue to be determined. We applied a 120 gene panel based targeted next-gen sequencing (NGS) approach to probe plasma ctDNA based outcomes for survival. Methods: mCRPC chemo-naive patients (pts) were enrolled in a prospective study and plasma cell free DNA (cfDNA) extracted. ctDNA fractions estimated based on somatic variants. NGS of plasma cfDNA was performed using HiSeq X Ten on a panel of 120 genes (PredicineLDT). Clinical and molecular prognostic factors were determined for overall survival (OS). Cox proportional hazard regression was used to estimate hazard ratios (HR) at the univariate level and only significant associations included in multivariate analysis (significance at P&lt;0.05). Results: 96 mCRPC pts were enrolled. 17/96 pts failed NGS QC. Median cfDNA, ctDNA yields for 79/96 pts are provided in Table. Median follow up for study cohort was 92.5 months (mon) (Range:62.3-109.6); median survival time was 25.9 mon (95% CI:19.9, 31.4) and 72/79 pts had died. TMPRSS2-ERG fusion was detected in 18/79 pts. Significant alterations associated with OS are listed in Table. 49/59 pts underwent subsequent docetaxel chemo. In chemo treated pts significant copy number alterations predictive of survival included AR amplification (p=0.01, HR=2.0, 95% CI[1.2, 3.5], RB1 loss (p=3.20E-06, HR=5.0, 95% CI[2.4, 10.6], PTEN(p=0.009, HR=2.6, 95% CI[1.2, 5.4]), CDH1(p=0.001, HR=4.3, 95% CI[1.6, 11.4]). Conclusions: ctDNA yield in mCRPC state was the most significant prognostic factor for survival, Several specific plasma genomic perturbations were observed topredict docetaxel efficacy and need further evaluation.[Table: see text]

Real-world utilization of radium-223 (Ra-223) for the treatment of metastatic castration-resistant prostate cancer (mCRPC): A U.S. tertiary oncology center analysis.

223 Background: Guidelines for optimal sequencing of approved mCRPC therapies do not exist. This study evaluated treatment patterns and overall survival (OS) among patients (pts) with mCRPC treated with Ra-223 in an academic clinical setting. Methods: A retrospective chart review study was conducted at Dana-Farber Cancer Institute of bone metastases-predominant mCRPC pts treated with Ra-223. Treatment patterns from 2013-2018 were evaluated including Ra-223 initiation pre- vs. post-chemotherapy (chemo). OS was examined using Kaplan-Meier medians and 95% confidence intervals (CIs). Results: 220 pts were treated with Ra-223 (64 pre-chemo, 83 post-chemo, 73 no chemo). Median Ra-223 injections per pt was 6.0 and 5.0 in the pre- vs. post-chemo cohorts, respectively (p&lt;0.001). Mean chemo cycles received was 9.0 (pre-chemo) and 9.2 (post-chemo); on average, Ra-223 was given in the 3rd and 5th mCRPC line of therapy (pre- and post-chemo, p&lt;0.001). 41.8% of pts were treated with Ra-223 in combination (combo) with another mCRPC therapy, commonly abiraterone acetate (37.0%) or enzalutamide (44.4%). The majority received combo therapy for the duration of Ra-223 treatment. 17.6% started another agent after Ra-223 initiation; 17.6% initiated Ra-223 while on an established therapy. Median OS from Ra-223 initiation was 12.4 months (95% CI 10.2, 13.9). Median OS from first mCRPC treatment was slightly longer for pts with Ra-223 pre- vs. post-chemo (by 2 months) and for pts with Ra-223 combo vs. monotherapy (by 3 months). Conclusions: Ra-223 improves OS in mCRPC, and longest OS was seen in those with Ra-223 pre-chemo. Retrospective analysis of 5 years of Ra-223 treatment data from an academic center demonstrates that pts treated pre-chemo on average obtained 1 additional cycle of Ra-223, subsequent chemo administration was not limited and OS measured from first mCRPC therapy was not significantly different.[Table: see text]

P1.14-18 ALK Inhibitor Sequencing and Outcomes Among ALK-Positive (ALK+) NSCLC Patients in the US Community Oncology Setting

Several ALK inhibitors, including 2nd and 3rd generation agents are available for patients with ALK+ NSCLC. Treatment patterns and outcomes with use of multiple sequential ALK inhibitors is limited. A retrospective observational cohort study of patients with ALK+ NSCLC treated with 1st generation (crizotinib) and 2nd generation (alectinib, brigatinib, ceritinib) ALK inhibitors from 1 September 2011 to 31 December 2017. Structured data were obtained via programmatic extraction from the iKnowMed EHR database of the US Oncology Network. Patient demographics and treatment sequences were characterized. Index was the start date of the first ALK. Duration of therapy (DOT) from index to end of the last ALK, and overall survival (OS) were assessed using the Kaplan-Meier method. A total of 410 ALK+ NSCLC patients were included. Median age at index was 62 years, 54% were female, 78% Caucasian, 87% adenocarcinoma histology, and 54% never smokers. 233 (57%), 144 (35%), and 33 (8%) patients received 1, 2, or 3-4 different ALK inhibitors, respectively. Crizotinib monotherapy (50%) was most common. Among patients that received 2 or more ALK inhibitors (n=177), most were crizotinib-led sequences. In 59% of patients, chemotherapy was given prior to the first ALK (median time from start of chemo to index 6.64 mo), and 53% of patients ended their ALK sequence and received subsequent chemo. Median cumulative ALK DOT in the full study population, regardless of line of therapy or sequence was 16 mo (95% CI 6-19). Median OS from index for the full study population was 28 mo (95% CI 24, 36). Median OS among patients who received 1, 2, or 3-4 ALK inhibitors was 15 mo (95% CI 10, 22), 42 mo (95% CI 38, 60) and 56 mo (95% CI 31, 72). Patients received a range of 1 to 4 ALK inhibitors. Crizotinib-led sequences were most common, likely reflecting the approval history of ALK inhibitors during the study period. Longer DOT and OS were observed in patients receiving multiple ALK inhibitors. This study provides an initial view of treatment patterns following the emergence of new ALK inhibitors and suggests feasibility of sequential ALK therapies. Follow-up studies will help improve understanding of outcomes of patients treated with 2nd generation-led sequences.

Outcome of germinal center B-cell type compared to non-germinal center/activated B-cell type diffuse large b-cell lymphoma as determined by immunohistochemistry using the Hans algorithm.

e20076 Background: Classification of diffuse large B cell lymphoma (DLBCL) takes into consideration - cell of origin, germinal center B-cell (GCB) vs non germinal center/activated B-cell type (non-GCB/ABC), since its determination by gene expression profiling predicts prognosis when treated with standard therapy. In this report we evaluated impact of choice of therapy and stem cell transplant (SCT) on the outcome of GBC and ABC subtype determined by immunohistochemistry (IHC) using Hans algorithm. Methods: We reviewed pathology reports DLBCL patients diagnosed from 2009 - 2016. For GCB and non-GCB/ABC patients data was collected including demographics, stage, initial and subsequent chemo, response and SCT. Results: Out of total 267 patients with DLBCL Per Hans algorithm, 117 (43.8%) were GCB, 94 (35.2%) ABC. GCB group - Median age at diagnosis was 65 years. 65% were older than 60 years. 27% Double expressors (DE). Frontline therapy was R-CHOP in 67.5% patients. 38% received other chemo - BR, hyperCVAD, RICE, RCVP. 26% patients had multiple lines of treatment. Average duration of first remission was 2.6 years. Complete response (CR) was achieved in 53% patients. Partial response (PR) in 27%. Median survival was 84.8 months. 12% underwent SCT. After SCT - 8 achieved CR, 3 PR, and 1 in PD. ABC group - Median age at diagnosis was 67 years. 67% were older than 60 years. DE were 19%. Frontline therapy was R-CHOP in 78% patients. 20% received other chemo. 21% needed multiple lines of treatment. CR was achieved in 76%. Median survival was 59.2 month. Median duration of remission for patients who received R-CHOP was 2 years and 1.25 years for other chemo. 7.4% had SCT - 5 auto and 2 allo. Conclusions: GCB and non-GCB/ABC DLBCL identified by IHC who received R-CHOP as induction had better outcome than who received other chemo. GCB had better overall survival compared to non-GCB/ABC. Median duration of first remission was 2 to 2.6 years and 30% patients received multiple lines of therapy. Only 15% patients underwent SCT – 66% achieved CR in GCB and 85% in ABC. Clinical trials adding newer agents and better stratifying patients who benefit from SCT are warranted. [Table: see text]

Clinical and immune responses using anti-CD3 x anti-EGFR bispecific antibody armed T cells (BATs) for locally advanced or metastatic pancreatic cancer.

4135 Background: Conventional chemotherapy (chemo) for locally advanced pancreatic cancer (LAPC) and metastatic pancreatic cancer (MPC) has dismal responses and poor survival rates. Arming activated T cells (ATC) with anti-CD3 x anti-EGFR bispecific antibody (BATs) makes every ATC into an EGFR-specific cytotoxic T cell that secretes cytokines, proliferates, and kills tumor. Methods: We report on 5 phase I (P1) and 15 phase II (P2) patients. In our phase I study, BATs were used to treat LAPC or MPC patients at Karmanos Cancer Institute (NCT0140874) in a dose escalation involving 3 weekly infusions of 1, 2, and 4 x 1010 BATs/infusion, followed by a booster infusion at 3 months (mos) for a total of up to 8 x 1010 BATs. No dose limiting toxicities were observed in the outpatient infusions. Fifteen patients treated on a phase II (NCT02620865) at KCI and (NCT03269526) at University of Virginia received biweekly infusions of 1010 BATs/infusion over 4 weeks for a total of 8 x 1010 EGFR BATs. Results: Four patients had stable disease (SD) for 6.1, 6.5, 5.3, and 36 mos. Two patients had complete responses (CR) when chemo was restarted after BATs. The median overall survival (OS) for 17 evaluable patients (3 of 4 infusions in the P1 and all 8 infusions in the P2) was 31 mos, and the median OS for all 20 patients (3 in the P2 who did not complete 8 infusions) is 14.5 mos (95% CI, 7.5-45.2 mos). Patient IT20104 had an apparent “pseudoprogression” after 3 BATs infusions, but achieved a CR after restarting capcitabine and is alive off therapy at 54 mos (24 mos after stopping capecitabine). Immune evaluations on the P1 patients show specific cytotoxicity to MiaPaCa-2 by peripheral blood mononuclear cells (PBMC) increased from 21% to 31% 2 weeks after the 3rd infusion, and IFN-γ EliSpots increased from &lt; 20 to 1000 IFN-γ EliSpots/106 PBMC (p &lt; 0.03). Patient IT 20121 (SD for 36 mos) increased IFN-γ EliSpots from 250 to 3200/106 PBMC after 8 infusions. Innate cytotoxicity responses in the P1 patients increased significantly after infusions (p &lt; 0.04). Levels of IP-10 increased significantly (p &lt; 0.04), and levels of IL-8 decreased but not significantly (p &lt; 0.07). Conclusions: Infusions of BATs are safe and induce endogenous adaptive anti-tumor responses. Targeting PC with BATs may stabilize disease, leading to improved OS, as well as evidence that BATs infusions can induce anti-tumor activity and immunosensitize tumors to subsequent chemo. Clinical trial information: NCT014084,NCT03269526,NCT02620865.

Breaking immune tolerance for the treatment of pancreatic cancer: Phase I/II clinical experience.

54 Background: Escalating Intratumoral heterogeneity resulting in xenogenization which is countered by overexpression of TGF-β. Here we report on the use of OT-101/Chemo to break immune tolerance to cure pancreatic cancer (PC). OT-101 is an antisense against TGF-β2. Methods: Total of 37 pts 2nd line and beyond received OT-101 with option to go on subsequent Chemo (OT-101/Chemo) or Best Supportive Care (BSC) (OT-101/BSC). Stratification by treatment line, schedule, metastasis location, disease control (DC), and baseline CA19-9, was performed. Plasma levels of 31 cyto-/chemokine were measured in a subset of 12 pts. Results: mOS of the 18 pts receiving OT-101/Chemo was 9.4 mos vs. OT-101/BSC (2.8 mos, p=0.0004). No significance was observed on stratification. However, pts with only liver metastasis had a mOS of 9.5 mos while those with liver metastasis and others only had a mOS of 4.7 mos (p=0.0077). Among the former, 1006 has Complete Response beyond 77.3 mos and 1022 had Stable Disease with OS of 40.3 mos; and OS was higher with OT-101/Chemo – 12.4 mos versus 1.9 mos, p=0.0006. There were 16 of 37 pts with DC, with mOS of 9.7 mos vs. 3.0 mos (p&lt;0.0001); and OS was higher with OT-101/Chemo – 11.8 mos vs. 5.0 mos, p=0.0021. Pts exhibited spike in IL-8 level which returned to basal level at treatment stop. R squares relating the IL-8 spike and OS were 0.8522 and 0.9895 and p values were 0.0011 and 0.0053 for OT-101/Chemo and OT-101/BSC, respectively. Preclinically, OT-101 enhanced PBMC activity in cell kill assay and in vivo xenograft. Conclusions: The MOA for OT-101/Chemotherapy is consistent with the reactivation of immunity during TGF-β suppression and subsequent boosting/expansion of immunity during Chemo. Contrary to traditional tumor vaccine- this is universally applicable to all patients.

PCN78 - EVALUATING THE ECONOMIC CONSEQUENCES OF NOVEL AGENTS FOR TREATING HODGKIN LYMPHOMA IN GREECE

The objective of this study was to map the current treatment algorithm in order to estimate Hodgkin’s Lymphoma (HL) disease management cost and calculate the economic burden for SSF from the introduction of novel agents in clinical practice. An expert panel consisting of seven special hematologists from public hospitals and academia was asked to document patient distribution within the different treatment lines, various therapeutic options (regiments: ABVD; BEACOPP; ChlVPP; GND; GN; GDP; IGEV; ESHAP; C-MOPP; DICE; Mini –BEAM, brentuximab vedotin; nivolumab, radiotherapy, auto and allo SCT) and resource use. Cost analysis was carried out from the social security perspective based on national reimbursed prices and DRGs tariffs (2018). Approximately, 45% of those submitted to anti-HL treatment related to first line, while the rest were almost equally classified to second (29%) and third line (25%). Amongst HL patients, 39% resides in a different prefecture than the one being treated. Between those prior submitted to auto- SCT, 43% received an antibody-drug conjugate as consolidation after the transplantation (mean 15 cycles). Economic burden was estimated at ∼€48,200/patient (on average for all treatment lines), almost threefold country’s per capita GDP. More than 81% of total cost was related to drugs, followed by drugs’ administration & prophylaxis / optimum supportive care (6.4%), and cost of diagnostic and follow up laboratory exams (5.2%). Third line (relapsed stages) was estimated to be the most costly due to increased and long term use of expensive novel treatments. Although novel treatments increased cost, emphasis needs to be placed on estimating the value of care, taking into consideration improved outcomes (in terms of overall survival and avoidable exposure to subsequent chemo toxicities) correlated to novel regimens.

IL-8 as PD biomarker for TGF-b antisense (OT-101) therapy: Results of a phase II trial.

e15742 Background: Trabedersen (OT-101) is a phosphorothioate antisense specific for human TGF-β2 mRNA. In a Phase I/II study of OT-101 in patients with advanced pancreatic cancer (PAC) treated second line and beyond, improved Overall Survival (OS) was observed when OT-101 was followed with chemotherapy. Here, we examined the association between plasma levels of cyto-/chemokines and OS outcomes and identified IL-8 as a biomarker for improved OS. Methods: 37 patients with PAC were treated with OT-101 by IV infusion in escalating doses of 2 treatment schedules (7-days on, 7-days off and 4-days on, 10-days off). Plasma levels of 31 cyto-/chemokine were measured over 8 time points during 3 cycles of OT-101 therapy (140 mg/m2/day on a 4-days on, 10-days off cycle). IL-8 levels were measured in 12 patients before and during 3 cycles of treatment on Days 2 and 5. Maximum levels of IL-8 on Day 2 were subtracted from levels on Day 5 and these standardized scores were correlated with log10 transformed OS values. Feedback interactions with PK parameters were also investigated utilizing an ANCOVA model. Results: We observed OS of 14.5 months and 2.6 months for those treated with and without subsequent chemotherapies, respectively (p = 0.0009). Peak IL-8 levels were apparent after 2 days of OT-101 treatment. A significant regression and 95% CI was evident, whereby increasing difference of IL-8 following Day 2 vs Day 5 was positively correlated with OS (R2 = 0.58, F1,9 = 12.32, P = 0.0066). R- squared increased from 0.4955, p &lt; 0.0001, for all patients to 0.8524, p &lt; 0.0001, for patients without subsequent chemo and 0.9744, p &lt; 0.0001, for patients with subsequent chemo. The ANCOVA model for two PK parameters exhibited significant model fits (F3,7 = 7.89, P = 0.012 for Simulated Vz Mean; F3,7 = 8.18, P = 0.011 for Simulated Cl Mean) and the interaction effects resulted in lower p-values for the correlation of OS vs IL-8 levels. Conclusions: Peak of IL-8 response on Day 2 of OT-101 treatment was correlated with OS in PAC patients. The correlation existed between OS whether patients received subsequent chemo or not suggesting that the IL-8 spike is a PD biomarker for OT-101. Clinical trial information: NCT00844064.

Abstract P2-15-04: A phase 1/2 study of Ad.p53 DC vaccine with indoximod immunotherapy in metastatic breast cancer

Abstract Background: Indoleamine 2,3 dioxygenase (IDO) is a tryptophan-catabolizing enzyme that causes immunosuppression in the tumor microenvironment. Indoximod is an IDO pathway inhibitor. Preclinical data suggests indoximod enhancs the activity of dendritic cell (DC) vaccines. Ad.p53 is an adenovirus used to generate autologous dendritic cell (DC) vaccines against p53 epitopes. We initiated a phase 1/2a trial of indoximod + Ad.p53DC to explore the safety and efficacy of the combination along with response to subsequent chemo. The phase 1 safety data were previously presented and the treatment was well tolerated with no DLTs. (Soliman, ASCO 2013) This abstract includes new phase 2a safety/efficacy data and updated outcomes on all phase 1/2 metastatic breast cancer patients who received Adp53DC+indoximod and any subsequent response to salvage chemo. Methods: The phase 2a study combined indoximod 1600mg PO BID with up to 6 Ad.p53 DC vaccinations q2wks. The trial used a single arm, Simon two stage design (n=12 in 1st stage, 25 in 2nd stage) with objective response as the primary endpoint. One response out of 12 was required for progression into second stage. The study had 90% power to detect 20% response rate with a p=.09. Patients with measurable, metastatic breast cancer, &amp;lt;3 lines of chemo in metastatic setting, p53 IHC &amp;gt;5%, ECOG 0-2, no autoimmune disease were eligible. Study treatment continued until disease progression or unacceptably toxicity. Results: Twelve phase 2 patients were accrued, 9 (7 TNBC, 2 ER+/HER2-) received ≥ 1 dose of Ad.p53DC+indoximod (3 did not due to rapid disease progression during vaccine preparation). Six patients had ≥ 1 prior line of chemo. Seven (58%) subjects experienced any grade AE, there were no treatment related AEs ≥G3. All treatment attributable AEs were G1-2, &amp;lt;10% frequency, and included anemia, nausea, lymphopenia, photophobia, and headache. All discontinuations were due to disease progression. Best response to immunotherapy in phase 2=1 SD, 8 PD. Phase 2 median TTP = 6.85 wks (3.8-18.1), OS = 18.1 wks (3.8-52) with 3 patients alive as of June 2014. Five patients who received ≥ 2 cycles of chemotherapy after immunotherapy demonstrated 1 PR, 3 PD, 1 pending scan. For the entire phase 1/2 breast cohort (21 in phase 1, 9 in phase 2) the median TTP = 9.85 weeks (3.8-22.1), OS=38.7 (3.8-122.1) weeks, with 1 patient from the phase 1 cohort alive as of June 2014. Ten out of 21 evaluable patients (1 CR, 7 PR, 2 SD, 11 PD) had clinical benefit from chemotherapy after immunotherapy (9 patients had rapid decline and did not get one full cycle of therapy). All but one of the responders had seen prior chemotherapy in the metastatic setting (including a CR after 4 prior lines of chemo). Median OS in the chemo responders was 69.4 wks (30.1-122.1). Conclusions: Indoximod+Ad.p53DC was well tolerated. Across phase 1/2 the best response to immunotherapy alone was SD in 4 pts while 10 of 21 (47%) (including 1 CR) responded to subsequent chemotherapy in this largely pretreated cohort. There may be a chemosensitization effect of indoximod+Ad.p53DC. Future trials should combine this treatment with chemotherapy in appropriately selected patients. Citation Format: Hatem H Soliman, Susan E Minton, Roohi Ismail-Khan, Hyo S Han, Nicholas N Vahanian, Charles J Link, Gene Kennedy, Howard Streicher, Daniel Sullivan, Scott J Antonia. A phase 1/2 study of Ad.p53 DC vaccine with indoximod immunotherapy in metastatic breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P2-15-04.