In-field Response Research Articles

Factors associated with response to talimogene laherparepvec in the treatment of advanced melanoma

Talimogene laherparepvec (T-VEC) is currently the only United States Food and Drug Administration-approved intralesional therapy for advanced melanoma. Recent studies have assessed the integration of T-VEC with systemic immunotherapy, though the response remains variable. Therefore, we sought to identify factors associated with the response to T-VEC by conducting a retrospective, single-center analysis involving melanoma patients treated with T-VEC. In the present study, we recorded demographic and clinicopathological data, details of T-VEC treatments, prior and concurrent treatments, and clinical outcomes. The primary endpoint was the in-field overall response rate (ORR: complete + partial). Secondary endpoints included complete in-field response, defined as complete resolution of disease or a negative biopsy; disease failure-free survival (DFFS), defined from the initiation of treatment as the time to progression in patients who did not experience a disease-free interval and time to recurrence in those who did; and overall survival (OS). We used two-sample t-tests for continuous variables and Fisher’s exact test for categorical variables. DFFS and OS were further analyzed using the Kaplan–Meier method and log-rank tests for selected variables. Among the 18 patients who met the inclusion criteria, an in-field response was observed in 14 (78%) patients. Low disease burden (<5 lesions or a total diameter <5 cm) was associated with a higher in-field ORR compared to high-burden disease (100% vs. 43%, P = 0.01). There was a trend toward decreased in-field ORR for patients with >2 prior lines of systemic therapy (P = 0.18). With a median follow-up of 386 days, DFFS was associated with BRAF wild-type melanoma (P = 0.04), an in-field ORR (P = 0.007), and a measurable bystander response (P = 0.01). Two or more prior lines of immunotherapy were associated with poorer survival (P = 0.006) and worse DFFS (P = 0.02). In conclusion, despite a low sample size, we identified covariates associated with in-field ORR, DFFS, and OS, warranting further study.

Five-Fraction High-Conformal Ultrahypofractionated Radiotherapy for Primary Tumors in Metastatic Breast Cancer.

To report on the local control and toxicity of 5-fraction, high-conformal ultrafractionated radiation therapy (RT) for primary tumors in patients with metastatic breast cancer (MBC) who did not undergo planned surgical intervention. We retrospectively reviewed 27 patients with MBC who underwent 5-fraction high-dose ultrafractionated intensity-modulated RT for their primary tumors between 2017 and 2022 at our institution. A median dose of 66.8 Gy (range, 51.8-83.6 Gy) was prescribed to the gross tumor, calculated in 2-Gy equivalents using an α/β ratio of 3.5, along with a simultaneous integrated boost of 81.5%. The primary endpoint of this study was local control. The median tumor size and volume were 5.1 cm and 112.4 cm3, respectively. Treatment was generally well tolerated, with only 15% of the patients experiencing mild acute skin toxicity, which resolved spontaneously. The best infield response rate was 82%, with the objective response observed at a median time of 10.8 months post-RT (range, 1.4-29.2), until local progression or the last follow-up. At a median follow-up of 18.3 months, the 2-year local control rate was 77%. A higher number of prior lines of systemic therapy was significantly associated with poorer 2-year local control (one-two lines, 94% vs three or more lines, 34%; p = 0.004). Post-RT, 67% of the patients transitioned to the next line of systemic therapy, and the median duration of maintaining the same systemic therapy post-RT was 16.3 months (range, 1.9-40.3). In our small dataset, 5-fraction, high-conformal ultrahypofractionated breast RT offered promising 2-year local control with minimal toxicity. Further studies are warranted to investigate the optimal dose and role in this setting.

Outcomes of Bridging and Salvage Radiotherapy in Relapsed or Refractory Mantle Cell Lymphoma Patients Undergoing CD19-Targeted CAR T-Cell Therapy.

We sought to describe our early experience of using bridging and salvage radiation therapy (RT) in patients with relapsed/refractory mantle cell lymphoma (MCL) undergoing CD19-targeted chimeric antigen receptor (CAR) T-cell therapy. A retrospective study was conducted for consecutive MCL patients who were treated with commercially available CD19-targeted CAR T-cell therapy between 2020 and 2022 at a single institution. Patients who received RT pre-and post-CAR T-cell therapy were identified and analyzed using descriptive and statistical analysis. Overall survival (OS) from the date of CAR T infusion was estimated with the Kaplan-Meier method. The duration of local control (LC) was defined as the time between the start date of RT and the date of in-field progression/relapse. Response to RT was analyzed based on the total number of irradiated sites. A total of 21 patients with MCL who received CD19-targeted CAR T-cell therapy were identified (17 brexu cel, 3 tisa-cel, and 1 liso-cel) with a median follow-up of 15.3 months (24 days-36.2 months). The median age was 65 years at time of apheresis (43-83 years). The median OS for the entire cohort following CAR T-cell therapy was 17 months (95% CI: 14.2 months-not reached). Of the 21 patients, 1 patient received bridging RT prior to CAR T infusion, 1 patient received RT pre-and post-CAR T, and 5 patients received salvage RT post-CAR T with a total of 23 irradiated sites. Sites of RT include: extremities (10), central nervous system (3), pelvis/groin (3), head and neck (3), chest (2), abdomen (1), and multiple sites (1). The median dose/fractionation were 16.5 Gy (range, 3.6-45 Gy) and 5.5 fractions (range, 2-16 fractions)- radiation data was incomplete only for 1 patient who received RT at an outside institution. The in-field responses of the 21 evaluable sites were as follows: complete response (CR) (n = 18, 86%) and partial response (PR) (n = 3, 14%), translating into an LC rate of 100%; the remaining 2 sites were not evaluable since the patient died shortly after receiving RT due to progressive lymphoma. Notably, there was no correlation between RT dose and LC; 9 sites received low-dose RT (3.6-6 Gy) with responses as follows: CR (n = 6, 67%) and PR (n = 3, 33%). Only 1 patient experienced grade 3-4 RT-related toxicities. At the time of the last follow-up, 4 patients remained alive, and 3 patients succumbed to progressive lymphoma. As no studies exclusively focusing on CAR T-cell therapy and bridging or salvage RT have been published among relapsed/refractory MCL patients, our early experience underlines that using RT as a bridging and salvage approach is associated with excellent in-field control and limited toxicity in the peri-CAR T setting. Low-dose RT for MCL appears to be very effective in this highly refractory population and warrants further investigation.

RADIOTHERAPY BRIDGING IN LARGE B‐CELL LYMPHOMA PATIENTS RECEIVING CD19 CAR‐T – THE UK EXPERIENCE

Background: Radiotherapy (RT) has potential synergistic effects with CAR T but is not widely used as bridging therapy for lymphoma patients due to logistical challenges, uncertainty about patient selection and lack of standardised protocols. Published data on RT bridging are so far restricted to single-centre analyses. Methods: We analysed RT bridging in a large multi-centre national cohort of large B-cell lymphoma (LBCL) patients approved for 3rd line axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel) between December 2018 and October 2022 across 12 UK centres. Results: Of 763 approved patients, 722 (95%) were leukapheresed, 717 had data available on bridging therapy. 170/717 (24%) received RT bridging, 129 as single modality and 41 as combined modality treatment (CMT). Use of RT bridging varied between centres from 11% to 32%, and increased from 19% (2018–19) to 26% (2021–22; p = 0.034). Median age of RT bridged patients was 60 y. 69% had de novo LBCL, 8% PMBL, 35% tFL and 6% transformed from other low-grade lymphoma. Disease characteristics for RT bridged patients with available data were as follows: 66% advanced stage, 41% bulk, 87% elevated LDH, 42% IPI ≥ 3, 17% double/triple hit. Patients given single modality RT were less likely to have advanced stage or ≥2 extranodal sites versus those receiving systemic therapy/CMT (61% vs. 85/83% and 18% vs. 30/39%, respectively; p < 0.05). Median time from approval to infusion was 56 days with no difference between bridging modalities. Infusion rates were 88% for RT bridging (vs. 84%, 85%, 85% for no bridging, steroids, or systemic therapy, respectively (p = 0.41)). Data on bridging (in-field) response was available for 46 RT patients: 10% CR, 65% PR, 6% SD, 10% PD. Details on RT techniques, anatomical locations and toxicities were available for 68 patients and will be provided at the meeting. Doses of 2–39 Gy were used, including combination of multiple doses; 40 patients received IMRT. Only one patient experienced G3–4 toxicity from RT. The overall incidence of G ≥ 3 CRS was 5.2% and G ≥ 3 ICANS 16.3%, with no significant difference according to bridging approaches. Median follow-up was 16 months. RT bridged patients had favourable outcomes with 1-y PFS of 56% for single modality and 47% for CMT, and 1-y OS of 65% and 56%, respectively (Figure 1). RT bridging was associated with favourable outcomes both in limited and advanced stage (1-y PFS 59% (43—72) and 50% (39–61), respectively. Keywords: aggressive B-cell non-Hodgkin lymphoma, cellular therapies, radiation therapy Conflicts of interests pertinent to the abstract A. Kuhnl Consultant or advisory role: Kite/Gilead, Novartis, BMS Honoraria: Kite/Gilead, Novartis A. Kirkwood Honoraria: Kite/Gilead A. Gibb Consultant or advisory role: Kite/Gilead A. Latif Honoraria: Kite/Gilead, Novartis

A phase II study of nivolumab and ipilimumab with radiation therapy in patients with metastatic, microsatellite stable pancreatic adenocarcinoma.

4143 Background: Metastatic pancreatic ductal adenocarcinoma (PDAC) is incurable for most patients. While immune checkpoint inhibitors (ICIs) have limited efficacy in microsatellite stable (MSS) tumors, radiation therapy (RT) may promote responsiveness to ICIs. In our phase 2 trial (NCT03104439), 25 patients with metastatic MSS PDAC were enrolled to receive ipilimumab and nivolumab with RT (24 Gy/3 fractions) starting on C2D1. The disease control rate (DCR) was 20% (5/25) and overall response rate (ORR) was 12% (3/25). In 17 patients who received RT (32% dropout rate), DCR was 29% (5/17) and ORR was 18% (3/17). To confirm this signal and address dropout prior to RT, we conducted a phase 2 study of nivolumab and ipilimumab with RT moved to C1D1. Methods: In this open-label, single-arm, phase 2 study (NCT04361162), eligible patients had histologically confirmed metastatic MSS PDAC, ECOG PS 0-2, and progressed on at least one line of chemotherapy. Treatment consisted of ipilimumab 1 mg/kg q6weeks for the first 4 cycles, nivolumab 240 mg q2weeks on a 6-week cycle, and RT (24 Gy/3 fractions) to a single site starting on C1D1. Treatment continued until disease progression, discontinuation, or withdrawal. The primary endpoint was RECIST 1.1 ORR by centrally reviewed imaging q3months. Secondary endpoints included DCR, PFS, OS, and safety. 30 patients were enrolled in a single-stage design for intention-to-treat (ITT) analysis of patients receiving at least one dose of study treatment. The per protocol analysis included patients who completed C1D1. The treatment regimen was considered to have promising activity if at least 3 of 30 patients had an objective response, providing 85% power to reject 5% ORR in favor of 15% ORR at a significance level of 20%. Results: We enrolled 30 patients (median age 68 years [range 52-80], 60% male, 90% white, 97% ECOG PS 0-1, median 3 [range 2-6] prior lines of chemotherapy) from 05/2020 to 11/2021. ITT ORR was 3% (1/30; 95% CI, 0-17%), DCR was 10% (3/30; 95% CI, 2-27%), median PFS was 2.2 months (95% CI, 1.5-2.6), and median OS was 2.8 months (95% CI, 2.1-5.2). In the per protocol analysis, ORR was 4% (1/28; 95% CI, 0-18%), DCR was 11% (3/28; 95% CI, 2-28%), PFS was 2.3 months (range, 1.6-2.7), and OS was 2.9 months (range, 2.2-5.5). One patient enrolled in hospice after 1 month, had a complete response at 13 months, and is alive at 21 months. 7 patients had grade 3-4 treatment-related serious adverse events, including lymphopenia (grade 4 in 1 patient), neutropenia, fatigue, muscle weakness, ALT/AST increase, hepatobiliary dysfunction, acute kidney injury, hyperglycemia, and hypokalemia. Conclusions: The treatment regimen of ipilimumab and nivolumab with RT did not meet the pre-specified criteria for promising activity in metastatic MSS PDAC. Further correlative analyses of the patient with a complete response and evaluation of in-field responses are ongoing. Clinical trial information: NCT04361162 .

Salvage radiotherapy for relapsed/refractory non‐Hodgkin lymphoma following CD19 chimeric antigen receptor T-cell (CART) therapy

CD19-targeting chimeric antigen receptor T-cell (CART) therapy is a promising treatment for relapsed/refractory non-Hodgkin lymphoma, but most patients experience post-CART progression. We describe our institutional experience of salvage radiotherapy (SRT) in this setting. Of 94 patients who received CART therapy from 2018 to 2020, 21 received SRT for post-CART progression. Patients were divided into two groups: locoregional disease (n=9 [43%], all disease encompassable within an RT field) and advanced disease (n=12 [57%]). Patterns of failure, progression-free survival (PFS), overall survival (OS), and toxicity were assessed. Median time from CART infusion to SRT was 4.0months (range, 0.6-11.5months). In the locoregional disease group, 8/9 patients (89%) were treated with comprehensive SRT to a median dose of 37.5Gy in a median of 15 fractions. In the advanced disease group, all patients (n=12) were treated with focal SRT to a median dose of 20.8Gy in a median of 5 fractions. Median follow-up post-SRT was 15.2months. In-field response was observed in 8/9 (89%) in the locoregional disease and 8/9 (89%) evaluable patients in the advanced disease groups. 17/18 evaluable patients (94%) patients experienced post-SRT progression, all with a distant component. Median OS was 7.4months; 21months for locoregional disease versus 2.4months for advanced disease (p=0.0002). Median PFS was 1.1month, and similarly poor regardless of group. No grade≥3 toxicities occurred. SRT post-CART therapy appears safe with encouraging in-field response but high rates of out-of-field progression, even for those presenting with locoregional disease, highlighting the need for integration of novel systemic agents.

Greco-2: A randomized, phase 2 study of stereotactic body radiation therapy (SBRT) in combination with rucosopasem (GC4711) in the treatment of locally advanced or borderline resectable nonmetastatic pancreatic cancer.

TPS766 Background: While treatment of pancreatic cancer has advanced, survival rates remain low. Stereotactic body radiotherapy (SBRT; high dose per fraction radiation) may exhibit improved clinical outcomes in locally advanced pancreatic cancer but carries potential gastrointestinal toxicity risks. Rucosopasem (GC4711) is one of a class of investigational selective dismutase mimetics that rapidly and specifically converts superoxide to hydrogen peroxide. Studies have shown that normal cells tolerate hydrogen peroxide fluxes better than cancer cells. As radiation response modifiers, dismutase mimetics have the potential to increase tumor control of SBRT without compromising radiation safety. In a pilot phase 1/2 trial in patients with pancreatic cancer, avasopasem, a dismutase mimetic related to rucosopasem, nearly doubled median overall survival in patients receiving SBRT vs placebo plus SBRT. Improvements versus placebo were also observed in local tumor control, time to metastases, and progression-free survival. Altogether, these data support the hypothesis that rucosopasem may improve survival and the benefit-risk ratio of SBRT by improving efficacy without increasing gastrointestinal toxicity. Methods: GRECO-2 is a phase 2, multicenter, randomized, double-blind, placebo-controlled study (NCT04698915) to determine the effect of adding rucosopasem to SBRT on overall survival in patients with borderline resectable or locally advanced, unresectable nonmetastatic pancreatic cancer following initial chemotherapy with a FOLFIRINOX-based regimen or a gemcitabine doublet. Approximately 160 patients will be randomized (approximately 35 sites) to receive rucosopasem 100 mg or placebo via IV infusion over 15 minutes, prior to each SBRT fraction (5 x 10 Gy). Patients judged to be resectable will undergo surgical exploration within 8 weeks after SBRT. The primary endpoint is overall survival. Secondary endpoints include progression-free survival, locoregional control, time to metastasis, surgical resection rate, RO resection rate, best overall response, in-field local response, and safety (acute and late toxicities). Exploratory endpoints include PRO-CTCAE and CA19-9 normalization. This trial (NCT04698915) is now enrolling. Clinical trial information: NCT04698915 .

Dose Response of Bulky Tumors in Relapsed/Refractory Diffuse Large B-Cell Lymphoma

<h3>Purpose/Objective(s)</h3> This study sought to assess whether there is a radiotherapy (RT) dose response for bulky tumors in relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL). <h3>Materials/Methods</h3> Patients with r/r DLBCL (age ≥18 years) treated with salvage- or palliative-intent RT (2008-2020) at a single institution were included. Course-level data were examined to assess in-field responses of index lesions. Courses used for either post-therapy consolidation, CNS or skin disease, and TBI conditioning were excluded. Index lesion size ≥7.5 cm was considered bulky. EQD2s (α/β = 10) were calculated to accurately compare biologic effective doses between conventional and hypofractionated (≥2.5 Gy/fraction) schemes. Post-treatment responses of index lesions were classified using Lugano Criteria. Objective response rates (ORR), defined as achieving either CR or PR, were compared between non-bulky and bulky tumors using Fisher's exact test. Freedom from local progression (FFLP) and overall survival (OS, patient-level data) from RT start date were recorded. Bulky disease impacts on FFLP and OS were assessed using Kaplan-Meier and multivariable-adjusted Cox proportional hazard regression analyzes. <h3>Results</h3> 151 r/r DLBCL patients underwent 183 RT courses (median follow-up time: 6 months, IQR: 2-17 months). Median age at RT was 67 years (IQR: 56-72 years) with a male/female ratio of 55%/45%. Non-bulky and bulky tumors were treated in 109 (60%) and 74 (40%) cases, respectively. Intent was classified as salvage or palliative in 68 (37%) and 115 (63%) cases, respectively. Median EQD2 was 33 Gy (IQR: 23-39 Gy) with hypofractionation used in 84 (46%) cases. Of those with post-RT imaging (n = 146, 80%), there was a trend towards lower ORR for bulky vs. non-bulky tumors (50% vs. 65%, p = 0.087; CR: 21% vs. 42%, PR: 29% vs. 23%, SD: 28% vs. 14%, PD: 22% vs. 22%). For bulky tumors, RT regimens with EQD2s >30 Gy were associated with better ORR (≤30 Gy vs. >30 Gy: 27% vs. 64%, p = 0.014), whereas a lower EQD2 cut-off was sufficient for non-bulky tumors (<20 Gy vs. ≥20 Gy: 38% vs. 73%, p = 0.0076). In all courses, bulky tumors were significantly associated with shorter FFLP (median: 5.6 months vs. not reached, HR = 2.30, 95% CI: 1.24-4.26, p = 0.0079) and OS (median: 3.7 vs. 10.1 months, HR = 1.66, 95% CI: 1.06-2.58, p = 0.025). Amongst bulky tumors, there was a trend towards improved FFLP with RT regimens with higher EQD2s (20-30 Gy vs. <20 Gy - median: 4.2 vs. 2.3 months, HR = 0.38, 95% CI: 0.09-1.62, p = 0.19; >30 Gy vs. <20 Gy - median: not reached vs. 2.3 months, HR = 0.34, 95% CI: 0.11-1.01, p = 0.053). <h3>Conclusion</h3> In this study, bulky r/r DLBCL tumors were associated with less favorable outcomes in salvage and palliative settings. If durable local control of bulky tumors is needed, RT regimens using higher EQD2s (>30 Gy) should be considered, including cases where shortened, hypofractionated courses are opted for such as during the SARS-CoV-2 pandemic, bridging to CAR-T cell infusion, or prior to allogeneic stem cell transplantation.

Radiotherapy as a Bridging Approach in High-Grade B-Cell Lymphomas before CD19-Targeted CAR T-Cell Therapy

<h3>Purpose/Objective(s)</h3> To evaluate the safety and efficacy of bridging radiation therapy (RT) in patients with relapsed/refractory high-grade B cell lymphomas (HGBCL) undergoing CD19-targeted chimeric antigen receptor (CAR) T-cell therapy. <h3>Materials/Methods</h3> A multi-institutional retrospective study was performed for 352 patients with HGBCL treated with CAR T-cell therapy. 140 of 352 patients (40%) received bridging therapy prior to CAR T infusion: systemic therapy alone in 98 patients, and RT +/- systemic therapy in 42 patients. This report focuses on the outcome of the 42 patients who received bridging RT. Overall survival (OS) from the date of CAR T infusion was estimated with the Kaplan-Meier method. The time to in-field progression was defined as the time from the start date of bridging RT until the time of in-field progression. <h3>Results</h3> The median follow-up from the date of CAR T infusion was 5.2 months (range, 9 days-33.6 months). Thirty-four patients (81%) received RT within 30 days of CAR T infusion, while 8 patients (19%) received RT at least 30 days before infusion. The most common indication for bridging RT was symptomatic local progression, with 16 patients starting RT prior to apheresis due to clinical urgency. Sites of RT include: head and neck (12), central nervous system (8), chest (5), pelvis (5), abdomen (4), extremities (2), paraspinal area (3), and multiple sites (3). The median dose/fractionation were 24 Gy (range, 8-37.5 Gy) and 8 fractions (range, 2-15 fractions). Three patients (7%) had in-field progression at a median time of 3.2 months (range, 1.2-4.6 months), all of whom had bulky disease (≥5 cm) at the time of apheresis. Superior median OS was observed among the 38 patients (90%) who achieved objective in-field responses after bridging-RT (25.6 months vs. 2.1 months; p=<0.001). Only 2 patients experienced grade 3-4 RT-related toxicities. <h3>Conclusion</h3> Our data supports that RT is an effective bridging approach for patients with locally progressive HGBCL prior to CAR T-cell therapy. It is associated with limited toxicity, and offers excellent in-field control in the immediate post-CAR T timeframe. Patients with in-field response to bridging RT have significantly better survival outcome.

GRECO-1: Phase 1/2 Study of Stereotactic Body Radiation Therapy (SBRT) with or without Rucosopasem (GC4711) for Early Stage, Peripheral or Centrally Located Non-Small Cell Lung Cancer (NSCLC)

<h3>Purpose/Objective(s)</h3> The number of patients diagnosed with early-stage non-small cell lung cancer (NSCLC) has been increasing with screening programs and more frequent thoracic imaging. SBRT is an alternative for patients who are not candidates for surgery. SBRT for larger and/or centrally located tumors may have reduced efficacy and lead to higher-grade toxicity (Timmerman 2006; Dunlap 2010). Rucosopasem (GC4711) is one of a class of investigational selective dismutase mimetics that rapidly and specifically produces hydrogen peroxide from superoxide (Riley 2006). In preclinical models including NSCLC, the addition of a dismutase mimetic to SBRT regimens demonstrated mechanism-related anticancer synergy with SBRT while protecting normal tissues from radiation damage (Sishc 2021). The purpose of this trial is to test the hypothesis that rucosopasem may improve tumor control without increasing pulmonary toxicity after SBRT. <h3>Materials/Methods</h3> This phase 1/2 trial is designed to test the safety of rucosopasem and its potential to improve tumor control and reduce lung injury due to SBRT for cT1c-3N0M0 peripheral or centrally located (within 2 cm of the proximal bronchial tree) NSCLC. An open-label, phase 1 run-in cohort of 5 patients received rucosopasem 100 mg as a 15-minute IV infusion within a 180-minute window prior to each of 5 SBRT fractions of 10–12 Gy delivered on sequential weekdays. A placebo-controlled phase 2 cohort of approximately 66 patients randomized to either rucosopasem or placebo concurrent with SBRT follows and is ongoing. The primary endpoint for phase 1 is dose-limiting toxicities during treatment or within 30 days post-SBRT, and for phase 2, in-field tumor response. Reduction from baseline in diffusion capacity of lung for carbon monoxide (DLCO) at 6 months (Stone 2015) is a secondary endpoint for phase 2. Progression-free and overall survival, locoregional control, and distant metastasis rate will be followed over 24 months. Additional secondary endpoints include clinical (CTCAE 5.0) and radiological pneumonitis, measured at the same timepoints as quarterly lung function tests, and other adverse events. Trial-in-progress NCT04476797 is currently enrolling. This study is funded by Galera Therapeutics, Inc. <h3>Results</h3> TBD <h3>Conclusion</h3> TBD

In-field dynamic response of instrumented wine tanks subjected to aftershock earthquakes

An experimental investigation of the dynamic behaviour of anchored flat-based wine storage tanks in a winery located in Marlborough, New Zealand is presented herein. Six wine storage tanks with different dimensions, capacities, and anchorage systems were instrumented with accelerometers for approximately six weeks following the 2016 Kaikōura earthquake, providing an opportunity to conduct a parametric study of their dynamic response when subjected to 37 aftershock earthquakes. The largest accelerations measured in the horizontal (X and Y) and vertical (Z) axes directions at the top of the six tanks occurred in conjunction with a Mw5.48 aftershock earthquake, with analysis indicating that the peak acceleration at the tank top occurred along the horizontal (Y) axis with a value of 0.545 g.Analysis of accelerations recorded at the top of the six tanks revealed that for low-intensity earthquake shaking the largest accelerations were measured at the top of the 40kL tank. A comparison of the tank instrumentation data indicated that the 175kL tank with a shear bolt anchorage system performed better than the nominally identical 175kL tank with a necked tension anchorage system, with the maximum lateral accelerations attained in the horizontal X and Y axes directions for the tank with the necked tension anchorage system being on average 1.59 times and 1.39 times the acceleration attained for the tank with the shear bolt anchorage system. Analysis of the results for the highest intensity earthquake shaking (Mw5.48) also indicated that the two tanks with installed energy dissipation systems sustained less acceleration when compared to tanks with a traditional anchorage system. Also, good agreement was observed between the values of the impulsive period attained from the analysis of the tank instrumentation data and from finite element (FE) modal analysis.

GRECO-2: A randomized, phase 2 study of stereotactic body radiation therapy (SBRT) in combination with rucosopasem (GC4711) in the treatment of locally advanced or borderline resectable nonmetastatic pancreatic cancer.

TPS4184 Background: While treatment of pancreatic cancer has advanced, survival rates remain low. Stereotactic body radiotherapy (SBRT; high dose per fraction radiation) may exhibit improved clinical outcomes in locally advanced pancreatic cancer but carries potential gastrointestinal toxicity risks (Zhong 2017). Rucosopasem (GC4711) is one of a class of investigational selective dismutase mimetics that rapidly and specifically converts superoxide to hydrogen peroxide (Riley 2006). Studies have shown that normal cells tolerate hydrogen peroxide fluxes better than cancer cells (Doskey 2016). As radiation response modifiers, dismutase mimetics have the potential to increase tumor control of SBRT without compromising radiation safety (El-Mahdy 2020, Sishc 2021). In a pilot phase 1/2 trial in patients with pancreatic cancer, avasopasem, a dismutase mimetic related to rucosopasem, nearly doubled median overall survival in patients receiving SBRT vs placebo plus SBRT. Improvements versus placebo were also observed in local tumor control, time to metastases, and progression-free survival. Altogether, these data support the hypothesis that rucosopasem may improve survival and the benefit-risk ratio of SBRT by improving efficacy without increasing gastrointestinal toxicity. Materials/Methods: GRECO-2 is a phase 2, multicenter, randomized, double-blind, placebo-controlled study (NCT04698915) to determine the effect of adding rucosopasem to SBRT on overall survival in patients with borderline resectable or locally advanced, unresectable nonmetastatic pancreatic cancer following initial chemotherapy with a FOLFIRINOX-based regimen or a gemcitabine doublet. Approximately 160 patients will be randomized (approximately 35 sites) to receive rucosopasem 100 mg or placebo via IV infusion over 15 minutes, prior to each SBRT fraction (5 x 10 Gy). Patients judged to be resectable will undergo surgical exploration within 8 weeks after SBRT. The primary endpoint is overall survival. Secondary endpoints include progression-free survival, locoregional control, time to metastasis, surgical resection rate, RO resection rate, best overall response, in-field local response, and safety (acute and late toxicities). Exploratory endpoints include PRO-CTCAE and CA19-9 normalization. This trial is now enrolling. Clinical trial information: NCT04698915.

A phase II study of niraparib and dostarlimab with radiation in patients with metastatic pancreatic cancer.

564 Background: PARP inhibitors have activity as monotherapy in BRCA1/2 mutated metastatic pancreatic cancer; however, several other genes and associated proteins exist in the homologous recombination repair (HRR) pathway promoting resistance to chemotherapy and radiation-induced damage. Tumors with HRR deficiency have an impaired ability to repair themselves and are susceptible to PARP inhibition, but ionizing radiation can also induce DNA breaks. Ongoing research suggests that PARP inhibitors may cause radio-sensitization and may also enhance sensitivity to immunotherapy. We conducted a phase 2 study of niraparib and dostarlimab with radiation in a biomarker unselected PDAC population given PARP inhibitors' immunomodulatory and radiosensitizing effects. Methods: In this open-label, single-arm, phase-2 study, eligible patients had histologically confirmed MSS PDAC, ECOG PS 0-1, and progressed on at least one line of jm. Treatment consisted of niraparib 200 mg daily on a 21-day cycle, dostarlimab 500 mg every 3 weeks every 4 weeks for the first four doses, then 1000 mg every 6 weeks, and 3 fractions of 8 Gy at Cycle 2. Treatment continued until progressive disease, discontinuation, or withdrawal. The primary endpoint was DCR by RECIST 1.1 with radiological evaluations every 3 months. Secondary endpoints included DCR by irRECIST, PFS, OS, and safety. Responses were defined as disease control outside the radiation field. We obtained serial tumor biopsies, including pre-treatment. A two-stage design was used, requiring disease control in at least one of the first 15 patients before proceeding to the full accrual of 25 patients. Intention to treat analysis included all patients receiving at least one dose of any study agent. Results: We enrolled and treated 15 pts (median age 60 years [range 37-77], 53% male) from 08/2020 to 05/2021. Overall, DCR was 0/15 (95% CI: 0-22%), median PFS was 1.6 months (95% CI: 1.1-2.7), and median OS 3.1 months (95% CI: 1.5-7.7). Among 27 treatment-related serious adverse events, 15 (56%) were grade 3, including decreased CD4 lymphocytes, thrombocytopenia, anemia, and fatigue being the most common. Conclusions: The combination of niraparib and dostarlimab with radiation did not meet the pre-specified criteria for expansion to full accrual. Further analyses of dose intensity in this heavily pretreated and evaluation of in-field responses are underway. Further investigation of the combination with biomarker selection is warranted. Clinical trial information: NCT04409002.

Radiotherapy Is an Excellent Bridging Strategy in Large B-Cell Lymphoma Patients Selected for CAR T-Cell Therapy

Purpose/ObjectiveAnti-CD19 chimeric antigen receptor (CAR) T-cell therapy has emerged as a potential curative treatment regime in patients with Large B-cell Lymphoma (LBCL) who have refractory or relapsed disease after two lines of systemic therapy. CAR T-cells are generated from autologous T-cells in specialized laboratories and the planning of the apheresis and manufacturing slot to the final infusion of the CAR T-cells into the patient may take up to 8 weeks for European centers, as the CAR T-cells are manufactured in the US. This logistic and time-consuming process might well be detrimental for patients with symptomatic and progressive disease.In these cases, bridging therapy may be indicated, referring to therapy administered after apheresis until CAR T-cell infusion. Early reports on radiotherapy (RT) as a bridging strategy have shown feasibility, safety, and effectivity, but patient numbers were limited.Here we present our experience with bridging therapy in patients selected for CAR T-cell therapy in a relatively large cohort. The current analysis focuses on the evaluation of safety and response rates.Material and MethodsAll patients treated with anti-CD19 CAR T-cell therapy are included in a prospective data registration program including data on patient and tumor characteristics, treatment, toxicity, and outcomes. All patients were treated with an anti-CD19 CAR containing a CD28 costimulatory molecule (Axi cel). For this analysis, patients with LBCL who underwent apheresis for CAR T-cell therapy were included. Bridging therapy consisted of steroids, chemotherapy, immunotherapy (systemic therapy; ST), RT, or a combination of these. Responses to bridging therapy were based on 18F-Fluordeoxyglucose PET (FDG-PET) before CAR T-cell infusion and Progression Free Survival (PFS), defined as time to clinical or FDG-PET based progression of disease, and Overall Survival (OS) are reported.ResultsIn total, 49 patients underwent an apheresis procedure. Median follow-up after apheresis was 72 months. Sixteen of these patients (32.7%) did not receive bridging treatment, 19 (38.7%) underwent RT alone, 6 (12.2%) received ST alone and 8 (16.3%) received ST and RT. RT was given on bulky tumor or burdensome lesions, in most patients to a total dose of 20 Gy in 5 fractions (See figure). 81.5 percent of patients had an infield response to RT. 16 of 17 (94.1%) patients with multiple lesions, who received RT alone had out of field progression, compared to 75.0% in patients who received RT and ST and 60.0% after ST alone. No CTCAE v5.0 grade 2 or higher radiotherapy related toxicity was observedFinally, 45 patients (91.8%) received CAR T-cells, while 3 patients did not because of rapid progression and 1 patient due to no residual disease. On day 28, two patients had died due to progression. Of the remaining 43 patients, FDG-PET evaluation showed progressive disease in 7 (16.3%) patients, stable disease in one patient (2.3%), partial response in 12 (27.9%) , and complete response in 23 (53.5%). The 2-year PFS of patients who did not receive bridging treatment was 47%, compared to 49% in patients bridged with RT alone and 31% in patients treated with ST or combined treatment. The 2-year OS was 63% versus 46%, and 34%, respectively.ConclusionBridging the time between apheresis and CAR T-cell infusion is a critical phase in CAR T-cell therapy. Selection of bridging treatment type is based on prior treatment, tumor load and symptoms. RT is an excellent bridging option with a high local control rate and favorable toxicity profile and should be considered in this heavily pre-treated patient population. [Display omitted] DisclosuresVan Meerten: Kite, a Gilead Company: Honoraria; Janssen: Consultancy.

Radiotherapy Bridging in Patients With R/R High-Grade Lymphoma Receiving CD19 CAR-T in the UK

Radiotherapy Bridging in Patients With R/R High-Grade Lymphoma Receiving CD19 CAR-T in the UK

Salvage Radiotherapy for Relapsed/Refractory Non‐Hodgkin Lymphomas Following CD19 Chimeric Antigen Receptor T-Cell (CART) Therapy

<h3>Purpose/Objective(s)</h3> CD19-directed CART therapy has emerged as a promising treatment for relapsed/refractory non-Hodgkin lymphoma. However, sustained efficacy is limited with durable complete response rates of 40% (Schuster & Locke, 2019). Salvage radiotherapy (SRT) is potentially an important strategy post‐CART, but current data is limited to one series of 14 patients. <h3>Materials/Methods</h3> We retrospectively analyzed 21 patients who received SRT after commercial CART therapy between 8/2018 and 6/2020. Patients who relapsed after CART were divided into two groups: locoregional disease (LD, all relapsed disease encompassable within an RT field) and advanced disease (AD). SRT was defined as comprehensive (treated all sites of active disease) or focal. Post-SRT in-field objective response rates (ORR) were recorded according to Deauville or RECIST criteria with a response characterized as a complete response or partial response. Progression-free survival (PFS) and overall survival (OS) were estimated by the Kaplan-Meier method. Acute RT toxicity was graded by CTCAEv5. <h3>Results</h3> Median time from CART infusion to SRT was 4.0 months (m) (range, 0.6-11.6m). Within the LD group, 8/9 patients were treated with comprehensive SRT (median SRT dose 37.5 Gy, range 8-45 Gy, and number fractions 15, range 2-25 fractions). The in-field ORR was 8/9 (89%). For the AD group, 12/12 patients were treated with focal SRT (median SRT dose 20.8 Gy, range 8-30 Gy, and number fractions 5, range 1-12 fractions). 11/12 AD patients were treated with hypofractionated SRT (≥2.5Gy fractions). Three patients died prior to subsequent imaging with an ORR of 8/9 (89%) for the remaining evaluable patients. Distant progression occurred in 17/18 patients post-SRT (Table). Three-month PFS was 24% for the entire cohort, and 33% and 17% for the LD and AD groups, respectively (<i>P</i> = 0.258). Median OS was 7.4m for the entire cohort, and 21.1m and 2.4m for the LD and AD groups, respectively (<i>P</i> < 0.001). Grade 1 (G1) and G2 acute SRT toxicities occurred in 10 and 4 patients, respectively. No G3 or higher toxicities occurred. <h3>Conclusion</h3> SRT post-CART therapy appears safe (no ≥G3 RT toxicities) in our series. SRT led to an ORR of 89% with only 1 observed local relapse. Patients with LD relapse post-CART had significantly improved survival compared with AD relapse. Unfortunately, prognosis remains poor as 17/18 patients with evaluable imaging progressed outside of the RT field. Thus, prolonged RT courses may not be warranted given the practical inevitability of out of field disease progression. Multi-institutional review of SRT following CART is warranted to further elucidate the impact of RT dose and fractionation on disease outcomes.

Post-Stereotactic Body Radiotherapy Circulating Immune Cells and Local Tumor Control for Patients With Recurrent Hepatocellular Carcinoma

Host immune status plays an important role in treatment outcome prediction and prognosis in patients with various cancers. However, the relationship between circulating immune cell and tumor control has not been well studied in hepatocellular carcinoma (HCC) after stereotactic body radiation therapy (SBRT).Patients with recurrent HCC received liver SBRT were eligible. Patients must be deemed surgically unresectable, and had Trans Arterial Chemotherapy Embolization (TACE). The local tumor control was defined as no disease progression by treatment response assessment CT or MRI around 3 months, largely according to mRECIST. Complete metabolic responses were defined either with no enhancement on MRI or no FDG activity. The risk factors of our interest included demographics factors, liver disease history, Child Pugh score, pathology stage, and prior treatments. The counts of whole leukocytes, lymphocyte and neutrophil pre- and post-SBRT were recorded from clinical laboratory. Leukopenia was graded according to CTCAE v 5.0. The associations of variables with in-field treatment response were analyzed using Chi-square test and one-way ANOVA.A total of 22 patients enrolled between August 2015 and September 2020. All patients had disease progression after TACE treatment and received 5 fractions of SBRT. Twenty patients received a definitive dose of 40-50 Gy. The local tumor was controlled in 86.4% (19/22), and increased to 90% (18/20) after excluding 2 patients receiving lower doses of palliative SBRT. There were 2 (10%), 5 (25%) and 13 (65%) defined as progressive disease, stable disease, partial response, and complete metabolic response, respectively. Large tumor/multiple tumor (P = 0.003), vascular invasion (P = 0.042), surgery history (P = 0.023), and BCLC stage (P = 0.040) were significantly associated with the tumor control, while age, gender, family history, heavy drinking, smoking history, BMI, ECOG, hepatitis, cirrhosis, Child Pugh score, portal vein tumor emboli, TNM, tumor size, and radiation dose were not. In 20 patients with complete blood testing peri-SBRT and uninterrupted radiation treatment, 17 (85%), 18 (90%), 13 (65%) and 9 (45%) patients had reduction in leukocyte, lymphocyte, neutrophil and monocyte after SBRT, respectively. Post-SBRT leukocyte counts (P = 0.036), pre-monocyte (P = 0.029), pre-lymphocyte (P = 0.073) and post- lymphocyte (P = 0.092) were associated with tumor control. The pre-RT leukocyte, neutrophil, post-RT neutrophil and monocyte were not.This limited study suggests that SBRT may provide excellent local tumor control for patients with recurrent HCC after surgical resection and TACE with no local treatment options. The significance in post-SBRT circulating immune cell suggest a role of immune function on radiation tumor control and a potential value of improving SBRT technique to decrease damage of immune cells. Further validation study with large sample size and longer follow-up is needed.

Talimogene Laherparepvec (T-VEC) for the Treatment of Advanced Locoregional Melanoma After Failure of Immunotherapy: An International Multi-Institutional Experience.

Talimogene laherparepvec (T-VEC) is an oncolytic virus approved for the treatment of unresectable, recurrent melanoma. The role of T-VEC after progression on systemic immunotherapy (IO) remains undefined. The goal of this study was to characterize the efficacy of T-VEC after failure of IO in patients with unresectable metastatic melanoma. An international, multi-institutional review of AJCC version 8 stage IIIB-IV melanoma patients treated with T-VEC after failure of IO was performed at six centers from October 2015-December 2020. Primary outcome was in-field response; secondary outcomes included analyses of in-field and overall progression-free survival (PFS) and in-field and overall disease-free survival (DFS) after a complete response. Subset analysis of T-VEC initiation sequentially after or concurrently with IO was performed. Of 112 patients, median age at T-VEC initiation was 69 years (range 21-93); 65 (58%) were male. Before T-VEC, 57% patients received one IO regimen, 42% received two or more, with most patients (n = 74, 66%) receiving T-VEC sequential to IO. Most were stage 3C (n = 51, 46%) at T-VEC initiation, 29 (26%) received injections to nodal disease. Over median follow-up of 14 months, in-field response at final T-VEC injection was 37% complete (CR), 14% partial (PR). T-VEC initiation sequentially or concurrently did not significantly affect in-field response (p = 0.26). Median in-field PFS was 15 months (95% confidence interval 4.6-NE). Median overall DFS after CR was 32 months (95% confidence interval 17-NE). T-VEC after failure of IO is effective in unresectable, metastatic stage IIIB-IV melanoma. T-VEC initiation sequentially or concurrently did not significantly affect in-field response.

A narrative review of combining radiation and immunotherapy in gastroesophageal cancers.

Despite advances in chemotherapy, radiation, and surgery, prognosis in gastroesophageal cancers (GEC) remains poor. Recent studies have demonstrated that immune checkpoint inhibitors specific to the PD-1/PD-L1 axis can improve survival with dramatic durability for a subset of patients with GEC. Radiation therapy (RT) has been shown to enhance priming and anti-tumor immunogenicity. The combination of these two treatments has shown promising results acting synergistically in pre-clinical and clinical models. Much of this synergy appears linked to in-field radiation responses, but also the abscopal response where out-of-field tumors demonstrate regression. In this review, we summarize the current role of immunotherapy and radiation in GEC. We also highlight progress from preclinical studies and translational biomarker analyses that provide rationale for ongoing efforts combining immune checkpoint inhibition and radiotherapy specifically in GECs. Questions that remain unanswered in the clinic are the optimal radiation dosing, timing, and fractionation strategies to augment abscopal immune responses. Increasing recognition of the heterogeneity of immunosuppressive mechanisms that can arise in response to radiation indicates the need for novel immune checkpoint inhibitors that target beyond the PD-1/PD-L1 axis. Smartly designed prospective trials incorporating these two approaches with ongoing translational analyses will be critical in increasing the success of combinatorial radiation and immunotherapy strategies in this disease.

Radiotherapy and Immunotherapy for Head and Neck Cancer: Current Evidence and Challenges.

Immune checkpoint inhibitors (ICI) have revolutionized cancer treatment over the past decade. However, although the immune landscape suggests a strong rationale for the use of these agents in patients with head and neck squamous cell carcinoma, the available clinical evidence indicates that most patients currently do not respond to ICI monotherapy. Radiotherapy is a primary treatment modality for many patients with locally advanced head and neck cancer. While ionizing radiation traditionally has been thought to act in a purely cytotoxic fashion, a growing body of preclinical studies have demonstrated additional profound immunomodulatory effects. Consequently, there has been a surge of interest in the potential synergy between radiotherapy and immunotherapy, both the potential for radiotherapy to augment the systemic anti-tumor immune response and the potential for immunotherapy to improve in-field tumor response to radiation. In this review, we summarize the current preclinical and clinical evidence for radioimmunotherapy, with a particular focus on studies directly relevant to head and neck squamous cell carcinoma, as well as existing challenges and future directions for this emerging field.