Dose Of Durvalumab Research Articles

A Pilot Trial of Proton-Based Cardiac Sparing Accelerated Fractionated Radiation Therapy in Unresectable Non-small Cell Lung Cancer With Extended Durvalumab Therapy (PARTICLE-D)

Purpose: Concurrent chemoradiotherapy is the current non-surgical standard of care for locally advanced non-small cell lung cancer (NSCLC). However, this is a difficult regimen to tolerate especially for those who are elderly, have multiple comorbidities or poor performance status. Alternative treatment regimens are needed for this vulnerable population. We report initial results of concurrent durvalumab, an immune checkpoint inhibitor, and hypofractionated, dose-escalating, proton external beam radiotherapy (EBRT).Patients and Methods: This phase I, pilot dose-escalation trial enrolled seven patients with newly diagnosed stage IIIA-IIIC NSCLC who were unable or unwilling to undergo concurrent chemoradiotherapy. Patients previously treated with immunotherapy were excluded. Five patients in the initial phase of this 3+3 study design received a fixed dose of durvalumab each 28-day cycle plus hypofractionated proton EBRT 60 Gy in 20 fractions while two patients received the escalation dose of 69 Gy in 23 fractions. The primary objective assessed safety while secondary objectives assessed feasibility and adverse events.Results: All patients experienced treatment-related adverse events, primarily grades 1-2. Pneumonitis and anemia were the most common. Only one dose limiting toxicity occurred, in arm one, which was a grade 3 pneumonitis leading to grade 5 pneumonia. Additionally, two delayed-onset grade 5 tracheal necrosis events occurred > 13 months after treatment initiation.Conclusions: Concurrent durvalumab plus hypofractionated proton EBRT was well tolerated in the short term. However, three treatment-related deaths, including two delayed-onset grade 5 tracheal necroses negatively impacted overall safety. A dose de-escalation protocol of proton-based radiotherapy plus durvalumab is warranted.

Abstract CT052: A phase IB study of mRNA-based active cancer vaccine, BI1361849, combined with durvalumab and tremelimumab immunotherapy in patients with non-small cell lung cancer (NSCLC)

Abstract Introduction. BI1361849 is an RNA-based cancer vaccine, encoding for 6 tumor-associated antigens, including MUC1, survivin, NY-ESO-1, 5T4, MAGE-C2 and MAGE-C1, to balance systemic antigen-specific immune response. This open-label multicenter 2-arm Phase IB study evaluated the safety and preliminary efficacy of the addition of BI1361849 to durvalumab with or without tremelimumab for NSCLC. Methods. Patients with metastatic NSCLC were enrolled in one of the two arms, Arm A: BI1361849 + durvalumab and Arm B: BI1361849 + durvalumab+ tremelimumab, to determine Recommended Combination Dose (RCD) for durvalumab according to a standard 3 + 3 design with a starting dose of 1500 mg and possible de-escalation to 750 mg, and a fixed total dose of BI1361849 at 960 μg and tremelimumab at 75 mg. Primary endpoints were safety and tolerability. Secondary endpoints were progression free survival (PFS), objective response rate (ORR), disease control rate (DCR), duration of response (DOR), and overall survival (OS), based on irRECIST and RECIST. Statistical analysis included descriptive statistics, Fisher exact test, and Kaplan-Meier method. Results. A total of 57 patients were treated with 23 patients in Arm A and 34 patients in Arm B for safety analysis. Among them, 36 patients received at least 75% of the scheduled doses of durvalumab and tremelimumab and at least 4 vaccine doses in the first 2 cycles to meet efficacy analysis requirement with 17 patients in Arm A and 19 patients in Arm B. The RCD was durvalumab at 1500 mg, BI 1361849 at 960 μg, and tremelimumab at 75 mg. Both arms had comparable treatment related adverse events (56-57%) with generally low grade and manageable within current guidelines. Both arms had a comparable rate of treatment discontinuation (22-24%). For efficacy analysis, patients in Arm A had 29% ORR and 71% DCR, median months of 10, 7.3 5.7, and not reached for DOR, irPFS, PFS, and OS, respectively. In contrast, Arm B yielded 11% ORR and 53% DCR, median months of 6, 2.5, 2.5 and 10 for DOR, irPFS, PFS, and OS, respectively. Conclusions. Overall, the doublet and triplet regimens were well tolerated. In comparison to recent published studies treated with durvalumab and/or tremelimumab, incorporation of BI1361849 to durvalumab yielded comparable or better treatment response, PFS, and OS than durvalumab alone or with chemotherapy. However, tremelimumab did not add clinical benefit. Citation Format: Dung-Tsa Chen, Joshua Sabari, Jonathan Thompson, Jiaxin Niu, Hirva Mamdani, Ram Thapa, Zachary Thompson, Thanmai Posina, Aileen Ryan, Ralph Venhaus, Toni Ricciardi, Kristen Ramirez, Tawee Tanvetyanon, Jhanelle Gray. A phase IB study of mRNA-based active cancer vaccine, BI1361849, combined with durvalumab and tremelimumab immunotherapy in patients with non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT052.

Glutamine antagonist DRP-104 in combination with durvalumab in patients with advanced fibrolamellar carcinoma (FLC) following progression on prior anti-PD(L)1 therapy.

TPS573 Background: Fibrolamellar carcinoma (FLC) is a rare, aggressive form of primary liver cancer predominantly affecting children and young adults under the age of 30. There is no established standard therapy and most patients with advanced disease succumb to their illness with a median prognosis of only 12 months. A chimeric transcript between DNAJB1 and PRKACA, which encodes the catalytic subunit of protein kinase A (PKA), was identified as a signature genomic event in FLC. However, pharmacological inhibition of PKAc for FLC with traditional small molecule inhibitors has been infeasible due to unacceptable on-target toxicity. Preclinical work from our laboratory and others has revealed that the DNAJB1- PRKACA fusion results in a metabolic rewiring of the tumor characterized by glutamine dependence. This glutamine dependence also creates a nutrient-depleted tumor immune microenvironment (TiME) enriched in immunosuppressive metabolites (e.g., ammonia, acidosis) that prohibits an effective antitumor immune response. Through this trial, we will test the hypothesis that glutamine antagonism in FLC reverses resistance to immune checkpoint inhibitor (ICI) therapy through modulating the TiME. Methods: We are conducting a single-arm phase 1b/2 clinical trial of glutamine antagonist DRP-104 in combination with durvalumab in children (age ≥ 12) and adults with advanced FLC who have progressed on prior anti-PD(L)1 therapy. Patients will receive DRP-104 (145 mg s.c. twice weekly) in combination with a fixed dose of durvalumab (1500 mg i.v. every 28 days). The primary clinical endpoints are safety and objective response rate (ORR), defined as the percentage of patients achieving a complete response (CR) or partial response (PR) based on the Response Evaluation Criteria in Solid Tumors (RECIST 1.1). Secondary objectives include progression free survival (PFS), overall survival (OS), and immunological correlates. Key eligibility criteria include histologically confirmed FLC that is metastatic or unresectable; demonstrated radiographic progression on at least one line of prior anti-PD(L)1 therapy; Age ≥ 12 years; ECOG performance status of ≤2; measurable disease according to RECIST 1.1; and adequate end organ function. Patients will undergo fresh core tumor biopsy pre-treatment and at approximately week 4. Biopsies will be used to prepare paraffin embedded and flash-frozen samples. Research bloodwork will be collected prior to dosing at baseline, prior to dosing on cycles 2-5, and every 3 months thereafter to be processed for PBMC isolation. This study has been registered under NCT06027086 and is expected to begin enrollment in December 2023. Clinical trial information: NCT06027086 .

Prospective Phase II Trial of Primary Lung Tumor Stereotactic Body Radiation Therapy (SBRT) Followed By Concurrent Mediastinal Chemoradiation and Adjuvant Immunotherapy for Locally-Advanced Non-Small Cell Lung Cancer (LA NSCLC)

To report the efficacy and toxicity outcomes of a prospective phase II trial of primary tumor SBRT followed by conventional chemoradiation to the lymph nodes and adjuvant immunotherapy in patients (pts) with unresectable LA NSCLC. Eligible pts included stage II-III LA NSCLC with peripheral primary tumors ≤ 7cm or centrally based tumors that had at least 2 cm separation from involved nodal disease. Pts received SBRT to the primary tumor (50-54 Gy in 3-5 fractions) followed by standard radiation to 60 Gy in 30 fractions to the involved lymph nodes with concurrent platinum doublet chemotherapy. The trial was amended to allow pts without disease progression after chemoradiation to receive adjuvant durvalumab per the PACIFIC trial. The primary endpoint was 1 year progression free survival (PFS), evaluated as a binary variable. Frequencies and proportions were used for reporting this primary endpoint, in addition to adverse events and patterns of failure. Median PFS and OS were estimated using Kaplan Meier methods. Safety and efficacy is reported on the first 50 pts enrolled in the trial with a median follow-up of 24 months (mos) (range, 1-54 mos). Pts were primarily stage IIIA (60%) or stage IIIB (34%), with 6% of pts stage IIB. Overall grade 3 or higher toxicity related to SBRT and/or mediastinal radiation was 8% with two pts (4%) developing grade 3 pneumonitis and one pt having a grade 5 lung infection possibly related to radiation. Overall grade 2 pneumonitis related to SBRT or mediastinal radiation was 20%. Only one pt (2%) developed grade 3 esophagitis. No late cardiac events have been observed. The one-year PFS for all pts was 62% with a median PFS of 26.3 mos and median overall survival of 40.8 mos. Of the 50 pts enrolled, 37 received at least one dose of adjuvant durvalumab. The one-year PFS for pts who received at least one dose of durvalumab was 70.3% with a median PFS not yet reached in this group (median follow-up 24 mos). Patterns of failure were mostly distant with 26% of pts experiencing distant failure, 6% regional, and 2% distant and regional. There was only one local failure (2%) after SBRT in all 50 pts. SBRT to the primary tumor followed by conventional chemoradiation to the involved lymph nodes and adjuvant immunotherapy was well tolerated and showed improved 1-year PFS compared to prior conventional chemoradiation trials for locally advanced NSCLC. The results of this trial will be further evaluated in a randomized phase III study, NRG LU-008. Pts will receive either conventional chemoradiation vs. SBRT to the primary tumor followed by chemoradiation to the involved lymph nodes followed by consolidative immunotherapy to evaluate the possibility of utilization of SBRT as a new standard of care for LA NSCLC.

Durvalumab Treatment Patterns for Patients with Unresectable Stage III Non-Small Cell Lung Cancer in the Veterans Health Administration (VHA): A Nationwide, Real-World Study.

Durvalumab is approved for the treatment of adults with unresectable stage III non-small cell lung cancer (NSCLC) post-chemoradiotherapy (CRT). This real-world study describes patient characteristics and durvalumab treatment patterns (number of doses and therapy duration; treatment initiation delays, interruptions, discontinuations, and associated reasons) among VHA-treated patients. This was a retrospective cohort study of adults with unresectable stage III NSCLC receiving durvalumab at the VHA between 1 January 2017 and 30 June 2020. Patient characteristics and treatment patterns were presented descriptively. A total of 935 patients were included (median age: 69 years; 95% males; 21% Blacks; 46% current smokers; 16% ECOG performance scores ≥ 2; 50% squamous histology). Durvalumab initiation was delayed in 39% of patients (n = 367). Among the 200 patients with recorded reasons, delays were mainly due to physician preference (20%) and CRT toxicity (11%). Overall, patients received a median (interquartile range) of 16 (7-24) doses of durvalumab over 9.0 (2.9-11.8) months. Treatment interruptions were experienced by 19% of patients (n = 180), with toxicity (7.8%) and social reasons (2.6%) being the most cited reasons. Early discontinuation occurred in 59% of patients (n = 551), largely due to disease progression (24.2%) and toxicity (18.2%). These real-world analyses corroborate PACIFIC study results in terms of the main reasons for treatment discontinuation in a VHA population with worse prognostic factors, including older age, predominantly male sex, and poorer performance score. One of the main reasons for durvalumab initiation delays, treatment interruptions, or discontinuations was due to toxicities. Patients could benefit from improved strategies to prevent, identify, and manage CRT and durvalumab toxicities timely and effectively.

Plain language summary of the HIMALAYA study: tremelimumab and durvalumab for unresectable hepatocellular carcinoma (liver cancer).

This is a summary of results from a phase 3 clinical study called HIMALAYA. HIMALAYA looked at treatment with one dose of a medication called tremelimumab combined with multiple doses of a medication called durvalumab (the STRIDE regimen) or multiple doses of durvalumab alone. These treatments were compared with a medication called sorafenib in participants with unresectable hepatocellular carcinoma (HCC). HCC is a type of liver cancer that is difficult to treat because it is often diagnosed when it is unresectable, meaning it can no longer be removed with surgery. Sorafenib has been the main treatment for unresectable HCC since 2007. However, people who take sorafenib may experience side effects that can reduce their quality of life, so alternative medicines are being trialed. Tremelimumab and durvalumab are types of drugs called immunotherapies, and they both work in different ways to help the body's immune system fight cancer. Participants who took STRIDE lived longer than participants who took sorafenib, whilst participants who took durvalumab alone lived a similar length of time as participants who took sorafenib. Participants who took STRIDE or durvalumab had a lower relative risk of experiencing worsening in their quality of life than participants who took sorafenib. The side effects that participants who received STRIDE or durvalumab experienced were expected for these types of treatments and could mostly be managed. Overall, STRIDE is more effective than sorafenib for people with unresectable HCC. Clinical Trial Registration: NCT03298451 (HIMALAYA) (ClinicalTrials.gov).

A phase 1/2a trial of yttrium-90 radioembolization in combination with durvalumab for locally advanced unresectable hepatocellular carcinoma.

Synergistic effect of radiotherapy and immunotherapy for the treatment of hepatocellular carcinoma (HCC) has been reported. This phase 1/2a pilot trial evaluated preliminary efficacy and safety of combination of radioembolization with yttrium-90 microspheres (Y90-radioembolization) and durvalumab in patients with locally advanced unresectable HCC. Patients with Child-Pugh score ≤7 and locally advanced HCC, defined as Barcelona Clinic Liver Cancer (BCLC) stage B HCC or BCLC-C disease without extrahepatic metastases, received Y90-radioembolization followed by intravenous durvalumab 1500 mg 7-14 days after Y90-radioembolization and every 4 weeks thereafter. Primary endpoint was time to progression (TTP) assessed by modified RECIST (mRECIST). Secondary endpoints included overall survival (OS), progression-free survival (PFS), objective response rate (ORR) determined by mRECIST, and safety. All 24 patients enrolled received Y90-radioembolization and 23 received at least one dose of durvalumab. Median follow-up duration was 19.0 months (range, 2.2-24.2). Median TTP was 15.2 months (95% confidence interval [CI], 6.1-not estimated). Median OS was not reached and 18-month OS rate was 58.3% (95% CI, 36.4-75.0). Median PFS was 6.9 months (95% CI, 5.4-15.2). Seven (29.2%) patients had a complete response and 13 (54.2%) had a partial response; ORR was 83.3% (95% CI, 62.6-95.3). Eleven (47.8%) patients experienced any-grade treatment-related adverse events. Two (8.7%) patients had grade 3 treatment-related adverse events (neutropenia and fever). None experienced any treatment-related serious adverse events. In patients with locally advanced unresectable HCC, the combination of Y90-radioembolization and durvalumab demonstrated promising efficacy and safety, warranting further evaluation in large-scale controlled trials.

Health Equity in Patients Receiving Durvalumab for Unresectable Stage III Non-Small Cell Lung Cancer in the US Veterans Health Administration.

Real-world evidence is limited regarding the relationship between race and use of durvalumab, an immunotherapy approved for use in adults with unresectable stage III non-small cell lung cancer (NSCLC) post-chemoradiotherapy (CRT). This study aimed to evaluate if durvalumab treatment patterns differed by race in patients with unresectable stage III NSCLC in a Veterans Health Administration (VHA) population. This was a retrospective analysis of White and Black adults with unresectable stage III NSCLC treated with durvalumab presenting to any VHA facility in the US from January 1, 2017, to June 30, 2020. Data captured included baseline characteristics and durvalumab treatment patterns, including treatment initiation delay (TID), interruption (TI), and discontinuation (TD); defined as CRT completion to durvalumab initiation greater than 42 days, greater than 28 days between durvalumab infusions, and more than 28 days from the last durvalumab dose with no new durvalumab restarts, respectively. The number of doses, duration of therapy, and adverse events were also collected. A total of 924 patients were included in this study (White = 726; Black = 198). Race was not a significant factor in a multivariate logistic regression model for TID (OR, 1.39; 95% CI, 0.81-2.37), TI (OR, 1.58; 95% CI, 0.90-2.76), or TD (OR, 0.84; 95% CI, 0.50-1.38). There were also no significant differences in median (interquartile range [IQR]) number of doses (White: 15 [7-24], Black: 18 [7-25]; P = .25) or median (IQR) duration of therapy (White: 8.7 months [2.9-11.8], Black: 9.8 months [3.6-12.0]; P = .08), although Black patients were less likely to experience an immune-related adverse event (28% vs. 36%, P = .03) and less likely to experience pneumonitis (7% vs. 14%, P < .01). Race was not found to be linked with TID, TI, or TD in this real-world study of patients with unresectable stage III NSCLC treated with durvalumab at the VHA.

Tebentafusp in combination with durvalumab and/or tremelimumab in patients with metastatic cutaneous melanoma: a phase 1 study

BackgroundImmune checkpoint inhibitors have significantly improved outcomes in first line cutaneous melanoma. However, there is a high unmet need for patients who progress on these therapies and combination therapies are...

Durvalumab and tremelimumab for hepatocellular carcinoma in patients listed for a liver transplant.

TPS4188 Background: Hepatocellular carcinoma (HCC) is an aggressive malignancy, developing most often in the setting of liver cirrhosis (Sohal et al Current Oncol Rep 2011; Gordan et al JCO 2020). For advanced disease, immunotherapy has now become standard of care – a combination of atezolizumab and bevacizumab has shown the best overall survival outcome so far (Finn et al NEJM 2020). For earlier stage disease, however, there is no systemic therapy standard. The best treatment for HCC in the setting of cirrhosis is a liver transplant allowing potential cure for both the cancer and cirrhosis. Nonetheless, 25-35% of patients fail to reach liver transplant because of disease progression while waiting for a transplant (Sinha et al, Hepatology 2019) and approximately 15% experience HCC recurrence after transplant (Mehta et al, Transplantation 2020). Taken together, this constitutes a large subset of this patient population who cannot achieve a cure. Given the success of immunotherapy in the advanced setting, it is imperative to study this in the pre-transplant setting, to improve the outcomes cited above. However, there is a theoretical risk of graft rejection with immunostimulatory treatment. Methods: This is a single-arm, open-label, Phase II, multicenter study designed to evaluate the safety and efficacy of durvalumab and tremelimumab for the treatment of HCC patients who have cirrhosis or portal hypertension and are eligible for listing for a liver transplant. Eligibility requirements include adult patients with HCC within UCSF criteria, a Child-Pugh score of up to 7, and ECOG PS of 0 or 1. Treatment includes an immunotherapy combination of 1 dose of tremelimumab and 5 doses of durvalumab for up to 4 months. After a minimum 28-day gap following the final durvalumab dose, patients undergo locoregional therapy per institutional standards. After a minimum 72-day gap from the end of immunotherapy, patients undergo liver transplant. Primary outcome is a binary endpoint, and it will be assessed in patients undergoing liver transplant. Historically, 10-20% of patients are expected to experience acute cellular rejection within 30 days of transplant. We propose that an observed proportion of 20% treatment failure will be a clear indicator of safety in this pilot study, whereas an observed proportion of 50% failure will be a clear indicator of failure. Using these guardrails, with at least 20 patients going to transplant, we will have 80.6% power to demonstrate a failure proportion of 20% (4 patients experiencing failure) versus a null of 50% (10 patients experiencing failure), with a one-sided alpha of 0.05. With 25 patients going to transplant, the power will increase to 86% (other parameters being the same). Clinical trial information: NCT05027425 .

Hypofractionated Stereotactic Re-irradiation and Anti-PDL1 Durvalumab Combination in Recurrent Glioblastoma: STERIMGLI Phase I Results.

Hypofractionated stereotactic radiotherapy (hFSRT) is a salvage option for recurrent glioblastoma (GB) which may synergize anti-PDL1 treatment. This phase I study evaluated the safety and the recommended phase II dose of anti-PDL1 durvalumab combined with hFSRT in patients with recurrent GB. Patients were treated with 24 Gy, 8 Gy per fraction on days 1, 3, and 5 combined with the first 1500 mg Durvalumab dose on day 5, followed by infusions q4weeks until progression or for a maximum of 12 months. A standard 3 + 3 Durvalumab dose de-escalation design was used. Longitudinal lymphocytes count, cytokines analyses on plasma samples, and magnetic resonance imaging (MRI) were collected. Six patients were included. One dose limiting toxicity, an immune-related grade 3 vestibular neuritis related to Durvalumab, was reported. Median progression-free interval (PFI) and overall survival (OS) were 2.3 and 16.7 months, respectively. Multi-modal deep learning-based analysis including MRI, cytokines, and lymphocytes/neutrophil ratio isolated the patients presenting pseudoprogression, the longest PFI and those with the longest OS, but statistical significance cannot be established considering phase I data only. Combination of hFSRT and Durvalumab in recurrent GB was well tolerated in this phase I study. These encouraging results led to an ongoing randomized phase II. (ClinicalTrials.gov Identifier: NCT02866747).

Abstract PD4-02: PD4-02 Spatial and temporal heterogeneity of predictive and prognostic signatures in triple-negative breast cancer treated with neoadjuvant combination immune-chemotherapy

Abstract Background: It is well known that immunological pathways are relevant for response to classical neoadjuvant chemotherapy as well as combined chemo-immunotherapy. In addition, it has been shown that combined chemo-immunotherapy significantly improves survival, even in the context of only moderate effects on pCR. Due to the window therapy with durvalumab-alone and the option to analyze multiple consecutive biopsies, the GeparNuevo trial offers the opportunity to 1) determine gene expression patterns for pCR and DDFS endpoints 2) identify pathways most relevant for pCR and DDFS 3) identify genes specifically regulated by immunotherapy (comparison of samples pre-and post-window) 4) identify genes specifically regulated by chemotherapy (comparison of samples pre-Tx and after 4 cycles of chemotherapy 5) identify longitudinal patterns of gene expression by comparison of up to four time points and 6) identify changes in the tumor microenvironment by spatial sequencing of tumor cell and stroma areas. Methods: 292 tumor samples were evaluated by gene expression analysis: 162 pretherapeutic core biopsies, 79 post-window biopsies, 32 biopsies during chemotherapy and 19 biopsies of the residual tumor after therapy. These samples were analyzed by HTG OBP panel targeting 2549 genes which are assigned to 25 different biological mechanisms or cellular pathways. In addition, spatial profiling was compared in a subset of pre-and post-window samples using Nanostring GeoMx spatial profiling system. Endpoints were pCR and DDFS. Results: A total of more than 600 genes were significantly associated with either the pCR or the DDFS endpoint in either the complete GeparNuevo cohort or one of the two therapy arms. Interestingly, there was a large number of predictive or prognostic genes (n=247 for pCR and n=179 for DDFS) in the durvalumab arm, while the number of genes in the placebo arm was considerably lower (n=113 for pCR and n=61 for DDFS). We used existing pathway information for HTG OBP panel to analyze the contribution of different cellular processes to pCR and DDFS signatures in different therapy arms. Immune pathways were particularly relevant for durvalumab signatures (pCR and DDFS), while cell cycle related gene expression patterns were particularly involved in signatures predictive of pCR in both therapy arms. To further assign genes to the cellular response to durvalumab-alone or chemotherapy-alone, we compared gene expression patterns in durvalumab arm before and after the window phase (gene expression patterns induced by one dose of durvalumab) with gene expression patterns in placebo arm before and after 4 cycles of chemotherapy. Further longitudinal alterations were analyzed by comparison of longitudinal samples for 4 different time-points (a: before NACT, n=162; b: after window phase, n=79; c: after 4 cycles, n=31 and d: at surgery, n=19). Using the Nanostring GeoMx spatial RNA profiling system guided by cytokeratine immunofluorescence, we compared areas with high tumor cell content with stromal areas with or without TILs. In combination with the HTG gene expression data, we were able allocate the changes induced by durvalumab vs chemotherapy to the stromal cell and tumor cell compartment, indicating a re-organization of the tumor-microenvironment. Conclusions: In our analysis, we show that immune gene signatures are particularly relevant for neoadjuvant response to durvalumab as well as prognosis after durvalumab treatment, while proliferation signatures are involved in pCR-signatures after durvalumab as well as chemotherapy. The spatial analysis showed that relevant changes occur in the stromal compartment, indicating a re-organization of the tumor microenvironment. The parallel targeting of immune- and proliferation pathways might explain why a combined immunotherapy-chemotherapy approach is more successful than each single therapy strategy alone. Citation Format: Carsten Denkert, Andreas Schneeweiss, Julia Rey, Akira Hattesohl, Thomas Karn, Michael Braun, Paul Jank, Jens Huober, Hans-Peter Sinn, Dirk-Michael Zahm, Claus Hanusch, Frederik Marmé, Jenny Furlanetto, Jörg Thomalla, Jens-Uwe Blohmer, Marion van Mackelenbergh, Thorsten Stiewe, Peter Staib, Christian Jackisch, Julia Teply-Szymanski, Peter A. Fasching, Bruno V. Sinn, Michael Untch, Karsten Weber, Sibylle Loibl. PD4-02 Spatial and temporal heterogeneity of predictive and prognostic signatures in triple-negative breast cancer treated with neoadjuvant combination immune-chemotherapy [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD4-02.

Abstract P4-07-16: B-IMMUNE final analysis: a phase Ib/II study of durvalumab combined with dose-dense EC in a neoadjuvant setting for patients with locally advanced luminal B HER2(-) or triple negative breast cancers

Abstract Background: Neoadjuvant association of immune checkpoints inhibitors (ICI) and dose dense chemotherapy is promising for triple negative breast cancers (TNBC). However, response rates vary from one study to another. Timing, best chemotherapy partner and efficacy in less immunogenic breast cancer (BC), like luminal B tumors, should be further investigated. This study evaluates for TNBC and luminal B HER2(-) BC the neoadjuvant treatment with paclitaxel followed by a short combination of an anti-PD-L1 antibody with anthracyclines. Method B-IMMUNE (NCT03356860), a multicentric phase Ib/II prospective trial, included patients with stage I to III luminal B HER2(-) or TNBC treated with paclitaxel 80mg/m2 weekly from week 1 to 12 followed by 4 cycles of epirubicine 90mg/m2 and cyclophosphamide 600 mg/m2 (EC) Q2W in a neoadjuvant setting. Phase Ib evaluated a single infusion of durvalumab (anti-PD-L1) combined with the 3rd cycle of EC. Phase II evaluated infusions of durvalumab with the 1st and 3rd EC cycles. Surgery was planned 3 weeks after the last EC cycle. Primary objectives were safety and pathological complete response (pCR) rate compared to a historical control. Secondary endpoint was the overall response rate (ORR) based on breast MRI. Eleven patients were enrolled in a control arm without durvalumab, exclusively for translational research purposes. Based on a 2-stage Simon design with an α = 0.1 and β = 0.1, 22 TNBC patients were needed in the phase II to test a null hypothesis of 30% pCR rate against a one-side alternative of 60%, and 24 luminal B BC patients to test a null hypothesis of 15% pCR rate against a one-side alternative of 40% (including an additional accrual margin of 10% for eventual dropouts). At least 9 pCRs had to be observed among the first 20 evaluable TNBC patients and 6 among the first 22 evaluable luminal B patients to rule out the null hypothesis. Results This analysis concerns the 50 patients treated with the experimental treatment, 3 from the phase Ib and 47 from the phase II part. Median age was 51 y-old (31 to 72y), tumor subtypes were 24 TNBC, 25 Luminal B and one sarcoma excluded from the efficacy analysis. Seven (14%) patients had a stage I tumor, 17 (34%) a stage IIA, 13 (26%) a stage IIB, 8 (16%) a stage IIIA, 4 (8%) a stage IIIB and 1 (2%) a stage IIIC. Concerning safety, 232 AEs were reported on 39/50 patients and 34 (14,6%) were graded ≥ 3. The 5 most frequent all-grade AEs were fatigue (8,2%), diarrhea (5,6%), neutropenia (5,2%), anemia and nausea (4,3%). Most frequent grade 3 AEs were anemia and neutropenia (14,7%). Among 4 immune-related adverse events, all were thyroid disorders. One patient died 10 months after the end of treatment due to progressive disease in the liver. Forty-six of the 47 phase II patients were evaluable for efficacy. pCR was reported in 12/22 TNBC patients (55%) and 8/24 luminal B HER2(-) patients (33%). Subgroup analyses based on PD-L1 expression and TILs score are planned. Conclusions The B-IMMUNE study met its primary objective showing a significant improvement in pCR versus the historical control in both TNBC and in Luminal B HER2(-) BC cohorts with the addition of only 2 doses of durvalumab to the anthracyclines. The safety profile is comparable to those previously described with reported immune related adverse events limited to thyroid endocrine disorders. Citation Format: Alix Devaux, Gabriela Beniuga, Claire Quaghebeur, Stéphanie Henry, Mieke Van Bockstal, Christine Galant, Paul Delrée, Jean-Luc Canon, Brigitte Honhon, Dominique Korman, Vincent Verschaeve, Christophe Lonchay, Sarah Lefevre, Lionel D’Hondt, Martine Berlière, Sophie Delmarcelle, Jean-Michel Mine, Timour Willems, Gebhard Müller, Nathalie Myant, Isabelle Bar, Sandy Haussy, Pierre G. Coulie, François P. Duhoux, Javier Carrasco. B-IMMUNE final analysis: a phase Ib/II study of durvalumab combined with dose-dense EC in a neoadjuvant setting for patients with locally advanced luminal B HER2(-) or triple negative breast cancers. [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-07-16.

Durvalumab and tremelimumab for hepatocellular carcinoma in patients listed for a liver transplant.

TPS638 Background: Hepatocellular carcinoma (HCC) is an aggressive malignancy, developing most often in the setting of liver cirrhosis (Sohal et al Current Oncol Rep 2011; Gordan et al JCO 2020). For advanced disease, immunotherapy has now become standard of care – a combination of atezolizumab and bevacizumab has shown the best overall survival outcome so far (Finn et al NEJM 2020). For earlier stage disease, however, there is no systemic therapy standard. The best treatment for HCC in the setting of cirrhosis is a liver transplant allowing potential cure for both the cancer and cirrhosis. Nonetheless, 25-35% of patients fail to reach liver transplant because of disease progression while waiting for a transplant (Sinha et al, Hepatology 2019) and approximately 15% experience HCC recurrence after transplant (Mehta et al, Transplantation 2020). Taken together, this constitutes a large subset of this patient population who cannot achieve a cure. Given the success of immunotherapy in the advanced setting, it is imperative to study this in the pre-transplant setting, to improve the outcomes cited above. However, there is a theoretical risk of graft rejection with immunostimulatory treatment. Methods: This is a single-arm, open-label, Phase II, multicenter study designed to evaluate the safety and efficacy of durvalumab and tremelimumab for the treatment of HCC patients who have cirrhosis or portal hypertension and are eligible for listing for a liver transplant. Eligibility requirements include adult patients with HCC within UCSF criteria, a Child-Pugh score of up to 7, and ECOG PS of 0 or 1. Treatment includes an immunotherapy combination of 1 dose of tremelimumab and 5 doses of durvalumab for up to 4 months. After a minimum 28-day gap following the final durvalumab dose, patients undergo locoregional therapy per institutional standards. After a minimum 72-day gap from the end of immunotherapy, patients undergo liver transplant. Primary outcome is a binary endpoint, and it will be assessed in patients undergoing liver transplant. Historically, 10-20% of patients are expected to experience acute cellular rejection within 30 days of transplant. We propose that an observed proportion of 20% treatment failure will be a clear indicator of safety in this pilot study, whereas an observed proportion of 50% failure will be a clear indicator of failure. Using these guardrails, with at least 20 patients going to transplant, we will have 80.6% power to demonstrate a failure proportion of 20% (4 patients experiencing failure) versus a null of 50% (10 patients experiencing failure), with a one-sided alpha of 0.05. With 25 patients going to transplant, the power will increase to 86% (other parameters being the same). Correlative studies include tumor molecular profiling, peripheral blood immunophenotyping, and circulating tumor DNA for early recurrence detection. Clinical trial information: NCT05027425 .

The ROWAN study: Safety and efficacy of transarterial radioembolization with Y-90 glass microspheres and the STRIDE regimen in hepatocellular carcinoma.

TPS622 Background: In patients with early and intermediate hepatocellular carcinoma (HCC) who are ineligible for resection, thermal ablation, or liver transplant, transarterial radioembolization (TARE) with yttrium-90 glass microspheres has shown superior efficacy compared to transarterial chemoembolization; a subset of patients progress despite effective local therapy. Immunotherapy using the single tremelimumab regular interval durvalumab (STRIDE) regimen has demonstrated superior overall survival to sorafenib in advanced HCC. Recent work showed that TARE upregulates both the innate and adaptive immune systems. The possibility for TARE and STRIDE to have additive or synergistic effects when combined is of current scientific and clinical interest. The primary objective of the Phase II ROWAN Study is to assess the objective response rate and durability of local tumor control with TARE followed by STRIDE vs. TARE alone. Methods: ROWAN is a global, open-label, prospective, multicenter randomized controlled trial comparing treatment with TARE using glass microspheres followed by the STRIDE regimen (a single dose of 300 mg tremelimumab combined with 1500 mg monthly dose of durvalumab for 18 months) to TARE alone in HCC. ROWAN will include 150 patients across approximately 20 study sites in North America and Europe. Key inclusion criteria: HCC, diagnosed by radiographic imaging or histology; ineligible for or declined liver resection, thermal ablation, or transplantation; Child-Pugh A; ECOG 0; life expectancy ≥6 months; treatment naïve; unilobar tumor; measurable by mRECIST; tumor volume ≤25% of whole liver volume; and untreated future liver remnant volume ≥30% of whole liver volume. Key exclusion criteria: extrahepatic metastases; shunt fraction with a lung dose of &gt;30 Gy; macrovascular invasion; infiltrative disease not evaluable by mRECIST; history of any organ allograph; autoimmune or inflammatory disorder; current use of immunosuppressive medication; history of malignancy other than HCC within past 3 years; and active infection. Patients will be randomized in a 1:1 ratio to two study arms (TARE followed by STRIDE or TARE alone) using two stratification factors (TARE treatment goal [ablative vs. non-ablative] and alpha fetoprotein level [&gt;400 vs. ≤400 ng/mL]). Tumor and blood samples will be collected for correlative studies. Co-primary efficacy endpoints are objective response rate and duration of response (localized mRECIST). The primary safety endpoint is the number of adverse events (AEs) and serious AEs. Interim statistical analyses will be conducted after 25 patients have been randomized to each arm and completed the second imaging assessment 6 months post-randomization; final analysis will be after the last evaluable patient has completed the 18 months follow-up visit post-randomization or discontinued treatment. Clinical trial information: 05063565 .

Timing of PD-L1 Blockade with Durvalumab May Affect Outcomes of CD19 CAR-T Cell Therapy for Relapsed/Refractory Large B-Cell Lymphoma

Introduction CD19-targeted chimeric antigen receptor T (CAR-T) cell therapy has shown high overall response rates (ORRs) in patients (pts) with relapsed/refractory (R/R) large B-cell lymphoma (LBCL); however, CD19 CAR-T cells fail to elicit a complete response (CR) in a considerable proportion of pts. PD-L1 expression in the tumor microenvironment could impair the efficacy of CAR-T cell therapy. PD-1/PD-L1 pathway blockade may enhance the function and antitumor activity of CAR-T cells. Here, we report the analysis of a phase I dose-finding study (NCT02706405) of combination therapy with CD19-targeted 4-1BB-costimulated CAR-T cells (JCAR014) and escalating doses of durvalumab (durva), an anti-PD-L1 monoclonal antibody, in adults with R/R LBCL. Methods Pts were treated in 1 of 2 groups. All pts received lymphodepletion (LD) with cyclophosphamide (Cy) and fludarabine (Flu) followed by JCAR014 infusion. Pts in group 1 (Grp 1) received the first dose of durva (225 mg or 750 mg) after JCAR014 infusion. Pts in group 2 (Grp 2) received the first dose of durva (7.5 mg, 22.5 mg, 75 mg, 225 mg, or 750 mg) 1 day prior to JCAR014 infusion. Up to 10 doses of durva were administered at 4-week intervals after JCAR014 at the highest identified safe dose until toxicity or disease progression. Adverse events (AEs) were graded by CTCAE 4.03, except for cytokine release syndrome (CRS), which was graded according to Lee 2014 consensus criteria. Response was reported according to PET/CT 2014 Lugano criteria. Results Between 01/23/2017 and 07/02/2020, 34 pts were screened, 32 underwent leukapheresis, and 29 were enrolled and received LD and JCAR014. Eleven pts were treated in Grp 1 and 18 in Grp 2 (Table 1). All pts received 2 x 106 JCAR014 cells/kg, except for the first 2 pts treated on the study who received 7 x 105 cells/kg. The most common AEs of any grade related to LD and JCAR014 with or without durva were CRS (41%), neutropenia (21%), neurotoxicity (17%), and hypogammaglobulinemia (17%). The incidences of any grade and grade ≥ 3 CRS and neurotoxicity were similar between Grp 1 and Grp 2 (Table 2A). Patients in Grp 2 had later onset of CRS after JCAR014 infusion compared with Grp 1 (median of 6 vs. 4 days, P = .05) and shorter duration of CRS (median of 3 vs. 8 days, P = .08). Among the 27 pts evaluable for dose-limiting toxicity (DLT), 2 (7%) had DLT: 1 pt with grade 4 CRS in Grp 2 (durva 225 mg) and 1 pt with prolonged grade 3 neurotoxicity in Grp 2 (durva 750 mg). No maximum-tolerated dose of durva was identified. In pts evaluable for response (n = 26), the ORR and the CR rate at 3 months were 35% (95% CI, 17-56) and 27% (95% CI, 14-46). We retrospectively compared the response rates of LBCL pts treated with JCAR014 in combination with durva (NCT02706405) with LBCL pts who received the same Cy/Flu lymphodepletion regimen and JCAR014 dose (2 x 106 cells/kg) without durva (JCAR014 alone cohort) on our previous phase I/II clinical trial (NCT01865617). There was a trend towards lower ORR (P = .08) and CR rate (P = .09) in pts treated with JCAR014 in combination with durva compared with those treated in the JCAR014 alone cohort (Table 2B). There were no significant differences in ORR and CR rate between patients in Grp 1 and those who received JCAR014 alone. However, despite a trend towards lower tumor burden, pts in Grp 2 (first durva before JCAR014) had lower ORR (P = .07) and CR rate (P = .03) compared with those treated in the JCAR014 alone cohort, and a trend towards lower CR rate compared with those treated in Grp 1 (first durva after JCAR014; P = .16). Patients treated with JCAR014 alone had significantly shorter time to CAR-T cell peak counts in blood compared with patients treated with JCAR014 in combination with durva (median of 8 vs. 14 days, P = .01). We did not observe significant differences in peak CAR-T cell expansion, area under the curve (AUC) from day 0 to 28 after JCAR014 infusion, and day 28 CAR-T cell counts by qPCR between the cohorts. Conclusion The combination of JCAR014 with durva for the treatment of adult pts with LBCL was safe. Our findings suggest that the timing of initiation of durva therapy is a key variable that may affect outcomes. To our knowledge, this is the first report suggesting that PD-L1 blockade may impact toxicity and antitumor response in pts with LBCL undergoing CD19 CAR-T cell therapy. Additional studies will be required to determine the optimal approach for combining CD19 CAR-T cell therapy with PD-1/PD-L1 pathway blockade in LBCL. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Neoadjuvant durvalumab for resectable non-small-cell lung cancer (NSCLC): results from a multicenter study (IFCT-1601 IONESCO)

BackgroundThe IONESCO (IFCT-1601) trial assessed the feasibility of neoadjuvant durvalumab, for early-stage resectable non-small-cell lung cancer (NSCLC).MethodsIn a multicenter, single-arm, phase II trial, patients with IB (≥4 cm)-IIIA, non-N2, resectable...

Safety results of NRG-LU004: Phase I trial of accelerated or conventionally fractionated radiotherapy combined with durvalumab in PD-L1–high locally advanced non-small cell lung cancer.

8513 Background: In advanced non-small cell lung cancer (NSCLC), high Programmed-Death-1 Ligand (PD-L1) (&gt;50%) expression demonstrate superior response and survival with immune checkpoint inhibitors compared to chemotherapy. We hypothesize that it is safe and feasible to substitute durvalumab instead of chemotherapy concurrently with radiotherapy (RT) in patients with Locally Advanced-NSCLC (LA-NSCLC) and high PD-L1. Methods: NRG-LU004 (NCT03801902) is a Phase I study for patients with stage II-III unresectable or inoperable, LA-NSCLC with PD-L1&gt; 50% (Dako 22C3 or Ventana SP263) expression. There were safety and expansion phases with a primary endpoint of safety. Patients started with 1500 mg durvalumab Q4 weeks and thoracic RT within 2 weeks from 1st infusion. Durvalumab continued once a month up to 1 year. In the safety cohort, 6 patients in cohort 1 were treated with accelerated fractionated RT (ACRT) to 60 Gy in 15 fractions, followed by a required safety hold for 90 days. During cohort 1 safety hold, cohort 2 patients were treated with conventional RT 60 Gy in 30 fractions (CONV) followed by a 60-day safety hold. A cohort advanced to the expansion phase to enroll 6 more patients if safety criteria (0-1 patients with a dose limiting toxicity [DLT]) were met. If both cohorts were deemed safe, patients would be randomized 1:1 to ACRT or CONV with safety defined as &lt; 4 of 12 evaluable patients per arm experiencing a DLT. Feasibility was defined as at least 80% of patients in each arm receiving at least 80% of the planned dose of durvalumab during the first 8 weeks. Results: 24 evaluable patients enrolled between January 2019 and June 2021. No DLTs were reported in cohort 1, and 1 (unrelated bronchopulmonary hemorrhage leading to discontinuation of durvalumab) in cohort 2. Both safety cohorts advanced to the expansion phase. All but one patient (CONV) received RT per protocol/with an acceptable variation. At the time of analysis, 24% had received all 13 cycles of durvalumab. For the ACRT cohort, there were 4 grade 3, 1 grade 4 (lymphopenia), and 1 grade 5 AE (lung infection, assessed as unrelated to therapy). For CONV, there were 8 grade 3, 0 grade 4, and 1 grade 5 AE (respiratory failure, unrelated to therapy). For feasibility, 10 of 12 (85%) patients in the ACRT cohort received the second dose of durvalumab (2 not received due to shingles and unrelated death), while 9 of 12 (75%) of the CONV cohort received the second dose (reasons for not receiving: viral hepatitis, bronchopulmonary hemorrhage, and respiratory failure, all assessed as unrelated to therapy). Conclusions: Chemotherapy-free thoracic RT approaches (ACRT or CONV RT) are safe, when given with concurrent durvalumab in patients with PD-L1 high LA-NSCLC. A trial to compare immunoradiotherapy and consolidation durvalumab to standard chemoradiation and consolidation durvalumab is planned. Clinical trial information: NCT03801902.

Inflammatory signals hidden in the CBC are detectable prior to durvalumab-induced pneumonitis.

e21116 Background: For patients with unresectable stage III non-small cell lung cancer (NSCLC), chemoradiation followed by 1 year of durvalumab is standard of care. Treatment-induced pneumonitis can be life-threatening. Neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and systemic immune inflammation index (SII, defined as platelet x neutrophil / lymphocyte counts) are calculated from the CBC and have been studied as inflammatory biomarkers in a variety of settings. This study assessed trends in these indices among patients treated for stage III NSCLC. Methods: We reviewed medical records of adults with stage III NSCLC who completed chemoradiation and durvalumab from 1/2017 to 9/2021 as part of routine care. Patients who developed non-pneumonitis immune toxicity were excluded. NLR, PLR and SII were calculated at dates of first and last radiation dose and first durvalumab dose. For patients who developed pneumonitis, indices were also calculated at each of 8 weeks leading up to pneumonitis onset, defined as the first diagnostic CT scan and graded as 1-5 based on CTCAE criteria. Indices were compared between the pneumonitis and no pneumonitis group using rank-sum test. P values &lt; 0.05 were considered statistically significant without adjustment for multiple testing. The slope of linear trend for each index was examined via log-gamma generalized linear regression model using a random intercept for each patient and robust standard error. Results: Of 65 patients who received chemoradiation followed by durvalumab, 2 were excluded because they were on clinical trial and 28 were excluded for non-pneumonitis immune toxicity. Among the 35 patients eligible for analysis, median age was 67 years; 20 (57%) were female; 6 (17%) were current smokers; 15 (43%) had COPD; and 17 (49%) developed pneumonitis (2 G1; 11 G2; 3 G3; 0 G4; 1 G5). In the pneumonitis group, NLR (p = 0.022), PLR (p = 0.007) and SII (p = 0.001) showed a statistically significant linear increase in the 5 weeks preceding pneumonitis onset. There were no differences in clinical characteristics, SII, NLR or PLR between the pneumonitis and no pneumonitis groups at the 3 time points examined. Conclusions: In this exploratory analysis, patients who developed pneumonitis showed a linear increase in inflammatory indices for 5 weeks before pneumonitis onset, suggesting information hidden in routine blood tests can anticipate development of a life-threatening complication. Our hypothesis-generating study will need validation in a larger prospective analysis with a control group. Future directions may also include examination of selected acute phase reactants or cytokines.

Phase 1 clinical trial of durvalumab in children with solid and central nervous system tumors.

10029 Background: Immune checkpoint inhibitors targeting PDL-1 have shown clinical benefit in adults with cancer. We conducted a first in pediatrics, phase 1 clinical trial to assess safety, pharmacokinetics (PK), and pharmacodynamics of durvalumab in children with solid and central nervous system malignancies. Methods: This single center investigator-initiated trial enrolled eligible patients considered incurable with measurable/evaluable disease (exception: osteosarcoma in 3rd remission), no prior exposure to checkpoint inhibitors and adequate organ function on 2 dose levels: 10 mg/kg (DL1) and 15 mg/kg (DL2), utilizing a standard 3+3 design. The primary objectives were to assess safety and PK of durvalumab. Durvalumab was administered intravenously (IV) Q2 weeks for a maximum of 24 doses (12 cycles) on study or until disease progression/unacceptable toxicity. Patients were assessed for dose-limiting toxicity (DLT) in the first 28 days. The tolerable dose level was expanded to obtain PK on at most 6 patients age ≥12 years (yrs) and 6 patients &lt; 12 yrs weighing &lt; 35 kg). Soluble PDL-1 (sPDL1) and anti-drug antibody (ADA) levels were also assessed. Results: Fifteen patients (8M/7F) were enrolled (3 DL1, 12 DL2) with median age of 12.7 (2.9-16.6) yrs. Diagnoses included 5 osteosarcoma, 4 ependymoma and 1 each of glioblastoma, astrocytoma, rhabdomyosarcoma, synovial sarcoma, hepatoblastoma and adrenocortical carcinoma. Of the 14 patients evaluable for DLT, 3 were on DL1 and 11 on DL2. Only 1 DLT was observed, Grade (Gr) 3 intracranial hemorrhage (ICH). Median number of cycles administered was 3 (1-12). There were no treatment related deaths. There were 72 treatment-related adverse events (TRAEs) observed in 11 patients in a total of 73 cycles administered on the trial. The most common TRAE was AST elevation (7 instances in 4 patients). All TRAEs were &lt; Gr 3 except for 1 instance each of Gr 3 AST elevation, anemia, and ICH. All 15 patients had PK, sPDL1 and ADA samples analyzed. PK for DL2 in patients ≥35 Kg and &lt; 35 Kg were comparable to PK in adults dosed with durvalumab 10 mg/kg IV Q2W. Mean (SD) DL2 Cmax 292 (102) mg/mL, Ctrough 85.1 (27.7) mg/mL, AUC 2220 (986) day*mg/mL in pts ≥35 Kg and Cmax 442 (338), Ctrough 120 (123), AUC 2470 (1870) in pts &lt; 12 yrs weighing &lt; 35 kg. sPDL1 was completely suppressed in all patients 2 weeks after a single dose of durvalumab. No ADA were detected in any patients. Five patients (2 osteosarcoma, 3 ependymoma) completed &gt; 6 cycles and 3 (1 osteosarcoma, 2 ependymoma) completed all 12 cycles of treatment. One objective response (PR) was seen in a patient with anaplastic ependymoma by RECIST1.1. Four patients were alive at the time of data cut-off with a median follow up of 30.5 (8.8-58.1) months. Conclusions: Durvalumab at 15 mg/kg IV Q2W was well tolerated in children with drug exposures comparable to adults receiving10 mg/kg IV Q2W. A signal for activity was noted in ependymoma where 3 of 5 children benefitted clinically. Clinical trial information: NCT02793466.