Publications

Searchable abstracts of presentations at key conferences in oncology ISSN 2631-4657 (online)

9537 Background: Avelumab is a human anti–PD-L1 IgG1 antibody that showed a favorable efficacy and toxicity profile in pts with mMCC and progressive disease (PD) on or after chemotherapy (CT) in the phase 2 JAVELIN Merkel 200 trial (JM 200; NCT02155647), leading to accelerated approval in the US and Europe. We describe real-world experience with avelumab in a global EAP for pts with mMCC. Methods: Pts participating in the EAP (NCT03089658) had stage IV mMCC and PD on or after CT or were ineligible for CT. In contrast to JM 200, pts in the EAP could have ECOG performance status of 2, treated brain metastases, or immunosuppressive conditions with sponsor medical approval. Pts received avelumab 10 mg/kg IV Q2W until PD or unacceptable toxicity. A 3-mo supply of avelumab for approved pts was provided to treating physicians; additional re-supply was allowed for pts who had complete response (CR), partial response (PR), stable disease (SD), or clinical benefit per treating physician assessment. No central imaging was obtained. Results: Between Jan 2016 and Jan 2018, 460 requests for avelumab were received from 37 countries: 395 were approved, 45 were medically rejected for various reasons (eg, incorrect diagnosis, lack of appropriate prior therapy, incomplete information), and 37 were withdrawn. Most requests were from France (n = 97), Italy (n = 69), and Australia (n = 46). Median age was 74 y (range, 28-95), and 65.7% of pts were male. Among 131 response-evaluable pts, the objective response rate was 51.1%, including CR in 22.1% (n = 29) and PR in 29.0% (n = 38; including 1 pt with HIV); 19.1% (n = 25) had SD and 29.8% (n = 39) had PD. Durable responses were observed in immune-competent and immunosuppressed pts. Updated data will be presented. The safety profile was similar to that of JM 200. The EAP is ongoing but will close in 2018 (US closed in April 2017) with regulatory approval in multiple countries. Conclusions: The avelumab EAP rapidly enrolled many pts with mMCC and answered an unmet, urgent medical need for pts ineligible for clinical trials or for whom no approved alternative treatments were available. In a real-world setting, avelumab demonstrated safety and efficacy consistent with JM 200. Clinical trial information: NCT03089658.

One innovative and effective technique to enhance the compression response of concrete-filled steel tube (CFST) columns is the compression of the fresh concrete, which actively confines the concrete core by prestressed steel tubes. To utilize active confinement in structural design, the behavior of prestressed CFST columns under different conditions should be investigated. In this research, the compression response of steel fiber-reinforced concrete-filled steel tube (SFRCFST) stub columns prestressed by the fresh concrete compression (FCC) technique was assessed before and after experiencing heat. Toward this goal, 60 cylindrical SFRCFST specimens were fabricated, with key variables of the prestressing ratio, volume percentage of steel fibers, applied temperature, external diameter-to-wall thickness ratio (D/t) of steel tube, and water/cement ratio. Post-heating axial compression tests examined the loading capacity, ductility, peak strain, toughness, and load-strain response. It was revealed that due to prestressing and the temperature rise to 600 °C, the heat-induced reduction in load capacity was negligible, while this drop was notable in the specimens without prestressing. At a temperature of 600°C, the load-bearing capacity of the specimens with a prestressing ratio of 0.5 f y increased by 40 % compared to the non-confined specimens, while the axial and lateral strain capacities decreased by 40 and 49 %, respectively. With an increase in the prestressing ratio to 0.7 f y , the load-bearing capacity increased by 50 %, and the axial and lateral strain capacities decreased by 26 and 25 %, respectively. In prestressed and non-prestressed SFRCFST columns, with or without thermal exposure, a steel fiber content of up to 1.5 % improved toughness and increased peak strain and ductility in most specimens. Finally, the nonlinear regression analysis was employed to present a proper prediction model for the loading capacity of SFRCFST columns. • Active confinement by the FCC technique improves SFRCFST axial performance. • Prestressing mitigates heat-induced load capacity reduction up to 600 °C. • Prestressing and steel fiber inclusion enhance SFRCFST thermal behavior. • Steel fiber addition up to 1.5 % increases strength, toughness, and strain capacity. • Validated nonlinear model accurately predicts SFRCFST stub column load capacity.

340 Background: Prostate cancer is frequently cured with high-dose rate brachytherapy as a front-line treatment. However, a significant number unfortunately develop intrinsic resistance. Although considered to be an immune-excluded tissue, immune responses are implicated in driving tumour-eradication in prostate cancer. This has not been proven, and yet is used as the rationale for numerous clinical trials combining radiation and immunotherapies. We hypothesise that there is a predictable but differential relationship between radiation and the immune responses in prostate cancer that could be used to fulfil a clinical need - identifying patients that would benefit from immune intervention in conjunction with radiation. Methods: We present here the results of comprehensive immunological profiling of a cohort of world-unique pre- and post-radiation tissues from 24 patients (RadBank cohort). These were assessed using pathological classification, tissue segmentation (cancer/surrounding stroma), multiplex IHC, gene expression profiling, T-cell receptor sequencing, and spatial computational analysis. Results: Our data resolved three classes of prostate cancer tissue based on immune infiltrate level, immune-activation and -checkpoint gene signatures, spatial clustering and T cell clone sequencing: We have begun to resolve clear patient and clinical classifiers based on immune responses to radiation, and identified patients groups likely to benefit from immune therapy alongside radiation. Conclusions: Importantly, these classifications are associated with baseline gene expression profiles that may be used for pre-clinical stratification and more sophisticated treatment paradigms.

3006 Background: The mTOR pathway regulates cell growth, proliferation and survival; and is a clinically validated target for cancer therapy. Current rapamycin analogs preferentially target TORC1, with therapeutic efficacy limited by compensatory feedback loops resulting in AKT and ERK activation. OSI-027 is an oral inhibitor of TORC1 and TORC2 kinase activity and may have additional clinical activity over TORC1 selective inhibitors. Methods: Patients (pts) with advanced solid tumors or lymphoma received escalating doses of OSI-027 in 3 schedules (S1: days (d) 1-3 q7d, S2: once weekly, and S3: continuous once daily) to determine safety, maximum tolerated dose, pharmacokinetics (PK) and preliminary antitumor activity. Pharmacodynamic (PD) effects on phosphorylation of 4E-BP1 at threonine 37/46, a rapamycin insensitive, mTOR-dependent phosphorylation site, were examined. Results: To date, 34 pts have been enrolled (13M/21F, median age 59 yrs) and 31 treated (S1 11 pts, S2 12 pts, S3 8 pts). S1 and S2 pts were dosed at 10, 15 and 20 mg, S3 pts at 5, 10 and 20 mg. Median number of weeks on study was 6 (range <1-34). Three DLTs have been reported: grade (G) 2 decreased LVEF (10mg S1), and 2 pts with G3 fatigue (15 mg S2 and 20 mg S3). Other drug-related toxicities included G3 nausea and vomiting (1), G3 pneumonia (1); G1/2 fatigue (4), nausea (2), diarrhea (1), anorexia (1), elevated creatinine (1), and reversible increase in QTc (1). Preliminary PK indicate exposure (AUC, Cmax) of OSI-027 increased with dose. The median Tmax and terminal T3/4 were 2-6 hrs and 6-17 hrs, respectively. Preliminary PD data indicate that substantial decreases in 4E-BP1 (T37/46) phosphorylation were observed in PBMCs from 13 of 23 pts following OSI-027 treatment. Eight pts have had SD lasting ≥ 12 wks (26% of pts treated, range 12-33 wks); tumor types were colorectal (3 pts), melanoma, neuroendocrine, endometrial, renal, and cervical cancer (1 pt each). Conclusions: OSI-027 is a potent TORC1/2 kinase inhibitor. Preliminary evidence of pharmacological activity has been observed. It is well tolerated at the doses and schedules tested to date. MTD has not been reached and dose escalation is ongoing. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration OSI OSI

<h3>Background</h3> Prostate cancer is frequently cured with high dose-rate brachytherapy (HDRBT) radiation as a front-line treatment. Although considered to be an immune-excluded tissue, immune responses to radiation are implicated in driving tumour-eradication in prostate cancer.¹ This has not been proven, and yet is used as the rationale for clinical trials combining radiation and immunotherapies.² We hypothesise that there is a predictable relationship between radiation and the immune responses in prostate cancer that could be used to provide sound rationale for specific immune interventions in solid tumours that are made possible by radiation therapy. <h3>Methods</h3> We present here new results stemming from our recently published immunoprofiling study of world-unique pre- and post-radiation tissues from 24 prostate cancer patients (figure 1A), RadBank cohort).³ These samples were assessed using immune cell multiplex IHC, gene expression profiling, digital spatial profiling (DSP) and computational analysis of cell distribution. <h3>Results</h3> This study unequivocally revealed that high dose-rate radiation converts predominately 'cold' prostate tumour tissue to a more activated 'hot' state comprised of two sub-types (high and a less activated intermediate state). These changes were evident in increased tumour inflammation gene signatures and immune checkpoint expression, immune cell composition changes, and alterations in spatial interactions. However, as 20% of the patients did not respond, we also explored pre-treatment gene signatures of patient responses to radiation – identifying potential mechanisms that prime tissues to respond more favourably. Most recently, we have explored three other important facets of the immune response to HDRBT: (i) putative differential drivers of high and intermediate responses (figure 1B), (ii) TCR clonality changes (figure 1C), and (iii) the influence of clinical features (e.g. Gleason grade) and treatment (e.g. androgen deprivation) (figure 1D). Differential expression analysis has identified key molecules (e.g. CD40LG and Lck expression) which are associated with higher activation responses. TCR sequencing of pre- and post-HDRBT tissue and peripheral circulating cells is also suggestive of engagement of the adaptive immune system and the emergence of tumor-specific T cells. Finally, multivariate analysis has also revealed that higher grade tumours exhibit higher basal levels of activation and IC expression – making them less sensitive to immune activation by HDRBT. <h3>Conclusions</h3> We have begun to resolve clear patient and clinical classifiers based on immune responses to radiation, and identified patient groups likely to benefit from immune therapy alongside radiation. Importantly, these classifications are associated with baseline gene expression profiles that may be used for pre-clinical stratification and more sophisticated treatment paradigms. <h3>Ethics Approval</h3> All participants provided consent covering tissue research as part of a prospective tissue collection study for prostate radiobiology research, approved by the Human Research Ethics Committee at the Peter MacCallum Cancer Centre (PMCC; HREC approvals 10/68, 13/167, 18/204). <h3>Consent</h3> Written informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal. <h3>References</h3> Dudzinski SO, et al., Combination immunotherapy and radiotherapy causes an abscopal treatment response in a mouse model of castration resistant prostate cancer. <i>J Immunother Cancer</i> 2019. 7(1): p. 218. Kwon E.D., et al., Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicentre, randomised, double-blind, phase 3 trial. <i>Lancet Oncol</i> 2014;15(7): p. 700–12. Keam SP, et al., High dose-rate brachytherapy of localized prostate cancer converts tumors from cold to hot. <i>J Immunother Cancer</i> 2020;8(1).

Purpose To determine the usefulness of whole-body diffusion-weighted imaging (DWI) to assess the response of bone metastases to treatment in patients with metastatic castration-resistant prostate cancer (mCRPC). Materials and Methods A phase II prospective clinical trial of the poly-(adenosine diphosphate–ribose) polymerase inhibitor olaparib in mCRPC included a prospective magnetic resonance (MR) imaging substudy; the study was approved by the institutional research board, and written informed consent was obtained. Whole-body DWI was performed at baseline and after 12 weeks of olaparib administration by using 1.5-T MR imaging. Areas of abnormal signal intensity on DWI images in keeping with bone metastases were delineated to derive total diffusion volume (tDV); five target lesions were also evaluated. Associations of changes in volume of bone metastases and median apparent diffusion coefficient (ADC) with response to treatment were assessed by using the Mann-Whitney test and logistic regression; correlation with prostate-specific antigen level and circulating tumor cell count were assessed by using Spearman correlation (r). Results Twenty-one patients were included. All six responders to olaparib showed a decrease in tDV, while no decrease was observed in all nonresponders; this difference between responders and nonresponders was significant (P = .001). Increases in median ADC were associated with increased odds of response (odds ratio, 1.08; 95% confidence interval [CI]: 1.00, 1.15; P = .04). A positive association was detected between changes in tDV and best percentage change in prostate-specific antigen level and circulating tumor cell count (r = 0.63 [95% CI: 0.27, 0.83] and r = 0.77 [95% CI: 0.51, 0.90], respectively). When assessing five target lesions, decreases in volume were associated with response (odds ratio for volume increase, 0.89; 95% CI: 0.80, 0.99; P = .037). Conclusion This pilot study showed that decreases in volume and increases in median ADC of bone metastases assessed with whole-body DWI can potentially be used as indicators of response to olaparib in mCRPC. Online supplemental material is available for this article.

IrAEs typically occur within 4 months of starting anti-PD1-based therapy (anti-PD1 +/- anti-CTLA4), but there are isolated reports of delayed irAEs (onset >12 months after commencement). This study describes the incidence, nature and management of delayed irAE in melanoma patients (pts). Pts from 20 centres with delayed irAEs were studied. The incidence of delayed irAEs was estimated as a proportion of melanoma pts treated with anti-PD1-based therapy and surviving >1yr. irAE onset, clinical features, management and outcomes were examined. 122 pts developed a total of 144 delayed irAEs (23 after initial combination anti-PD-1 with anti-CTLA-4); with an estimated incidence of 5.7% (95% CI 4.3-7.3, 57/999 pts at sites with complete data). The median duration of therapy was 17.7 months (range 0.7-56.0), and median onset of delayed irAE was 16.3 months (range 12.0-53.2). 74% (90 pts) were on anti-PD1 at irAE onset, 12% (15 pts) were <3 months from last dose, 14% (17 pts) were >3 months from last dose of anti-PD1. The most common delayed irAEs were colitis, rash and pneumonitis (Table); 16% (19 pts) had multiple delayed irAEs, 39% (56 irAEs) were ≥G3. Steroids were required in 66% (81 pts), as well as an additional immunosuppressive agent in 23% (28 pts). There were 2 irAE-related deaths; encephalitis with onset during anti-PD1 and a multiple organ-irAE (colon, liver, kidney, lung and haem irAE) with onset 11.4 months after ceasing anti-PD1. Early irAEs (<12 months) had also occurred in 60% (73 pts), affecting a different organ to delayed irAEs in 86% (63 pts).Table: 1138PDelayed irAETotal patientsG1/G2G3/G4G5N (%) requiring systemic corticosteroidsN (%) requiring additional immunosuppressionTOTAL no pts with 144 irAE1227446281 (66%)28 (23%)Colitis31 (22%)1318029 (94%)13 (42%)Rash26 (18%)22407 (27%)1 (4%)Pneumonitis18 (13%)162017 (94%)0 (0%)Rheumatological14 (10%)11309 (64%)7 (50%)Hepatitis12 (8%)210010 (83%)2 (17%)Neurological10 (7%)3618 (80%)3 (30%)Hypophysitis7 (5%)5200 (0%)0 (0%)Renal7 (5%)1607 (100%)3 (43%)Other19 (13%)15405 (26%)1 (5%) Open table in a new tab Delayed irAEs occur in a small but relevant subset of pts, are often different to previous irAE, high grade, difficult to manage and can lead to death. Delayed irAEs mostly occur in pts still receiving anti-PD1, such that the risks of irAE need to be weighed against the benefits of continuing treatment in responding pts beyond 1 year, however pts who stopped treatment remained at risk for developing delayed irAE.

Abstract Purpose: In this article, we describe a combination chimeric antigen receptor (CAR) T-cell therapy that eradicated the majority of tumors in two immunocompetent murine pancreatic cancer models and a human pancreatic cancer xenograft model. Experimental Design: We used a dual-specific murine CAR T cell that expresses a CAR against the Her2 tumor antigen, and a T-cell receptor (TCR) specific for gp100. As gp100 is also known as pMEL, the dual-specific CAR T cells are thus denoted as CARaMEL cells. A vaccine containing live vaccinia virus coding a gp100 minigene (VV-gp100) was administered to the recipient mice to stimulate CARaMEL cells. The treatment also included the histone deacetylase inhibitor panobinostat (Pano). Results: The combination treatment enabled significant suppression of Her2+ pancreatic cancers leading to the eradication of the majority of the tumors. Besides inducing cancer cell apoptosis, Pano enhanced CAR T-cell gene accessibility and promoted CAR T-cell differentiation into central memory cells. To test the translational potential of this approach, we established a method to transduce human T cells with an anti-Her2 CAR and a gp100-TCR. The exposure of the human T cells to Pano promoted a T-cell central memory phenotype and the combination treatment of human CARaMEL cells and Pano eradicated human pancreatic cancer xenografts in mice. Conclusions: We propose that patients with pancreatic cancer could be treated using a scheme that contains dual-specific CAR T cells, a vaccine that activates the dual-specific CAR T cells through their TCR, and the administration of Pano.