Durvalumab In Patients Research Articles

Phase I study of a recombinant attenuated oncolytic virus, MEDI5395 (NDV–GM-CSF), administered systemically in combination with durvalumab in patients with advanced solid tumors

BackgroundMEDI5395 is a recombinant attenuated Newcastle disease virus engineered to express a human granulocyte-macrophage colony-stimulating factor transgene. Preclinically, MEDI5395 demonstrated broad oncolytic activity, augmented by concomitant programmed cell death-1/programmed cell death ligand-1 (PD-L1) axis blockade. Durvalumab is an anti-PD-L1 immune checkpoint inhibitor approved for the treatment of various solid tumors. We describe the results of the first-in-human study combining intravenous MEDI5395 with durvalumab in patients with advanced solid tumors.MethodsThis phase I, open-label, multicenter, dose-escalation, dose-expansion study recruited adult patients with advanced solid tumors, who had relapsed or were refractory or intolerant to ≥1 prior line of standard treatment. MEDI5395 was administered intravenously as six doses over 15–18 days. The dose-escalation phase assessed four-dose levels (108, 109, 1010, 1011focus forming units (FFU)) of MEDI5395, with sequential or delayed durvalumab. Durvalumab 1500 mg was administered intravenously every 4 weeks up to 2 years. The dose-expansion phase was not initiated. The primary objectives were to evaluate safety and tolerability, dose-limiting toxicities (DLTs) and the dose and schedule of MEDI5395 plus durvalumab administration. Secondary objectives included the assessment of the efficacy, pharmacokinetics, pharmacodynamics, and immunogenicity of MEDI5395.Results39 patients were treated with MEDI5395; 36 patients also received durvalumab. All 39 patients experienced ≥1 treatment-emergent adverse event (TEAE), most commonly fatigue (61.5%), nausea (53.8%) and chills (51.3%). Grade 3–4 TEAEs occurred in 27 (69.2%) patients; these were deemed MEDI5395-related in 12 (30.8%) patients. Two patients experienced a DLT, and the maximum tolerated dose of MEDI5395 with sequential and delayed durvalumab at study termination was 1011and 1010FFU, respectively. Four patients (10.3%) achieved a partial response (PR). Patients with PR or stable disease tended to have higher baseline PD-L1 and CD8+ levels in their tumor tissue. A tendency to dose-dependent pharmacokinetics of the viral genome was observed in whole blood and a tendency to dose-dependent viral shedding was observed in saliva and urine. Neutralizing antibodies were observed in all patients but did not appear to impact efficacy negatively.ConclusionThis study demonstrates the feasibility, safety and preliminary efficacy of MEDI5395 with durvalumab in patients with advanced solid tumors.Trial registration numberNCT03889275

WNT/β-catenin Signaling and CD8+ Tumor-infiltrating Lymphocytes in Tremelimumab Plus Durvalumab for Advanced Hepatocellular Carcinoma.

Tremelimumab plus durvalumab is an approved first-line therapy for advanced hepatocellular carcinoma (HCC). Previous studies identified WNT/β-catenin mutations or CD8+ tumor-infiltrating lymphocytes (TILs) as biomarkers that can predict responsiveness to immune checkpoint inhibitor therapy in HCC. However, biomarkers for effectiveness of tremelimumab plus durvalumab in HCC have not been reported. This study investigated whether evaluation of WNT/β-catenin signaling and CD8+ TILs by immunohistochemical staining of tumor biopsy tissues can predict the response to tremelimumab plus durvalumab in patients with HCC. Fifteen HCC patients who underwent tumor biopsies were classified into three groups based on WNT/β-catenin signal activation and CD8+ TIL infiltration. The clinical responses to treatment in the groups were evaluated. Four patients had HCC with WNT/β-catenin signal inactivation and high-level CD8+ TIL infiltration, four patients had HCC with WNT/β-catenin signal activation and low-level CD8+ TIL infiltration, and seven patients had WNT/β-catenin signal activation and high-level CD8+ TIL infiltration or WNT/β-catenin signal inactivation and low-level CD8+ TIL infiltration. A better response rate was observed in the WNT/β-catenin signal inactivation and high-level CD8+ TIL infiltration group, and a worse response rate was observed in the WNT/β-catenin signal activation and low-level CD8+ TIL infiltration group. Although the present study involved a small number of patients, the findings suggest that the efficacy of tremelimumab plus durvalumab may be affected by WNT/β-catenin signaling and CD8+ TIL infiltration.

PD-L1 as a Biomarker for the Efficacy of Durvalumab in Stage III EGFR Mutant NSCLC.

Durvalumab consolidation is less effective in patients with epidermal growth factor receptor mutant (EGFR M+) NSCLC. Studies of durvalumab on EGFR M+ NSCLC as an expression of programmed death-ligand 1 (PD-L1) expression are limited. The purpose of this study was to determine the effect of durvalumab on PD-L1 expression in EGFR M+ patients. This study included 249 unresectable stage III NSCLC patients treated with durvalumab. The primary outcome was progression-free survival (PFS). Cox multivariate analysis was performed based on EGFR and PD-L1 statuses: EGFR M-, PD-L1 ≥50% (cohort A); EGFR M-, PD-L1 <50% (cohort B); EGFR M+, PD-L1 ≥50% (cohort C); and EGFR M+, PD-L1 <50% (cohort D). Overall, 31 of 249 (12.4%) and 218 of the 249 (87.6%) patients had EGFR M+ and EGFR M- NSCLC, respectively. Median PFSs and OSs did not differ (PFS: 16.6 vs. 18.7 months, p=0.591; OS: 37.4 vs. 35.7 months, p=0.271). Median PFS of cohort A did not significantly differ from the median PFSs of cohorts B and C, but it was significantly longer than the median PFS of cohort D (23.7 vs. 15.2 months, p=0.045). Cox multivariate analysis revealed that cohort D exhibited a worse PFS (adjusted hazard ratio=2.27, 95% confidence interval=1.11-4.66, p=0.025) compared with cohort A. Median OSs were not different between the four cohorts. Durvalumab consolidation provided similar benefit in EGFR M+ patients with PD-L1 ≥50% compared with EGFR M- patients. A therapeutic role of durvalumab in patients with EGFR M+, high PD-L1 unresectable stage III NSCLC should be considered.

Efficacy, safety and differential outcomes of immune‐chemotherapy with gemcitabine, cisplatin and durvalumab in patients with biliary tract cancers: A multicenter real world cohort

Efficacy, safety and differential outcomes of immune‐chemotherapy with gemcitabine, cisplatin and durvalumab in patients with biliary tract cancers: A multicenter real world cohort

Consolidation ALK Tyrosine Kinase Inhibitors Versus Durvalumab or Observation After Chemoradiation in Unresectable Stage III ALK-Positive NSCLC

IntroductionPatients with advanced ALK-positive NSCLC typically have poor response to immunotherapy; the benefit of consolidation durvalumab in patients with unresectable stage III ALK-positive NSCLC remains unclear. Herein, we compare the efficacy and safety of consolidation ALK tyrosine kinase inhibitor (TKI) versus durvalumab or observation after concurrent chemoradiation. MethodsWe conducted a retrospective study using a multicenter study of 17 institutions globally. Patients with unresectable stage III ALK-positive NSCLC treated between 2015 and 2022 were included. Patients received ALK TKI, durvalumab, or observation after concurrent chemoradiation. Real-world progression-free survival (rwPFS) and overall survival (OS) were estimated using Kaplan-Meier method. Treatment-related adverse events (trAEs) were classified by Common Terminology Criteria for Adverse Events version 5.0. Outcomes were assessed by multivariable Cox regression analysis. ResultsA total of 67 patients were included, of whom 39 (58%) were female. Median age was 57 (interquartile range: 49–67) years. Furthermore, 15 received consolidation ALK TKI, 30 received durvalumab, and 22 underwent observation. Baseline characteristics were similar across the three groups other than differences in race. After adjusting for stage, age, and nodal status, median rwPFS was significantly longer for ALK TKI (rwPFS not reached, 95% confidence interval [CI]: 22.7– not reached) versus durvalumab (11.3 mo, 95% CI: 8.9–18.5, hazard ratio [HR] = 0.12, 95% CI: 0.026–0.5, p-adjusted [p-adj] = 0.006) or observation (7.2 mo, 95% CI: 3.4–10.6, HR = 0.04, 95% CI: 0.009–0.2, p-adj < 0.0001). Durvalumab significantly improved median rwPFS compared with observation (HR = 0.37, 95% CI: 0.19–0.71, p-adj = 0.002). Median OS in the ALK TKI and durvalumab cohorts was significantly improved compared with patients on observation (ALK TKI-observation: p = 0.04; durvalumab-observation: p = 0.03). TrAE of any grade occurred in eight (53%) and 11 (37%) patients treated with ALK TKI and durvalumab, respectively. Grade greater than or equal to three trAEs occurred in 27% (n = 4) of patients treated with ALK TKI and 6.7% of patients treated with durvalumab. ConclusionsPatients with ALK-positive NSCLC experience significantly improved rwPFS when treated with consolidation ALK TKI therapy, surpassing outcomes found with either durvalumab or observation. Although both ALK TKI therapy and durvalumab offer an extension in OS compared with observation alone, it seems that ALK TKI therapy is the superior choice, underscoring its pivotal role in enhancing patient survival.

1981P Cabozantinib plus durvalumab in patients with advanced and chemotherapy-treated urothelial carcinoma (UC) and variant histology (VH): An open-label, phase II, single-arm proof-of-concept trial: ARCADIA study. Subgroup analysis for bone metastasis

1981P Cabozantinib plus durvalumab in patients with advanced and chemotherapy-treated urothelial carcinoma (UC) and variant histology (VH): An open-label, phase II, single-arm proof-of-concept trial: ARCADIA study. Subgroup analysis for bone metastasis

NSGO-OV-UMB1/ENGOT-OV30: A phase II study of durvalumab in combination with the anti-CD73 monoclonal antibody Oleclumab in patients with relapsed ovarian cancer

ObjectivesIn patients with epithelial ovarian cancer (EOC), the clinical efficacy of monotherapy with immune checkpoint inhibitors (ICIs) against PD-1/PD-L1 is modest. To enhance response rates to these immunotherapeutic agents and broaden the indications for their use, new approaches involving combinational therapy are needed. The immune regulator CD73 is a potential target, as it promotes tumor escape by producing immunosuppressive extracellular adenosine in the tumor microenvironment. Here, we present the results from the NSGO-OV-UMB1/ENGOT-OV-30 trial evaluating the activity of combining the anti-CD73 antibody oleclumab with the anti-PD-L1 checkpoint inhibitor durvalumab in patients with recurrent EOC. MethodsIn this phase II open-label non-randomized study, patients with CD73-positive relapsed EOC were intravenously administered oleclumab (3000 mg, Q2W) and durvalumab (1500 mg, Q4W). The primary endpoint was disease control rate (DCR) at 16 weeks. The expression of PD-L1 and CD8 was assessed by immunohistochemistry of archival tumors. ResultsThis trial included 25 patients with a median age of 66 years (47–77 years). Twenty-two patients were evaluable for treatment activity analysis. The DCR was 27%, the median progression-free survival was 2.7 months (95% CI: 2.2–4.2) and the median overall survival was 8.4 months (95% CI: 5.0–13.4). Infiltration of CD8+ cells and PD-L1 expression on tumor cells were observed in partially overlapping sets of 74% of the tumor samples. Neither CD8- nor PD-L1-positivity were significantly associated with better DCR. ConclusionsCombined treatment with oleclumab and durvalumab was safe and demonstrated limited anti-tumor activity in patients with recurrent EOC.

A phase II trial of olaparib and durvalumab in patients with recurrent IDH-mutated gliomas.

2013 Background: Isocitrate dehydrogenase mutations (IDHmt) define astrocytomas and oligodendrogliomas. IDHmt results in accumulation of R-2-hydroxyglutarate (2HG), leading to epigenetic dysregulation and defective homologous recombination repair, providing a rationale for poly (adenosine 5’-diphophate-ribose) polymerase (PARP) inhibitors. PARP inhibition upregulates PD-L1 so the combination with immune checkpoint inhibition is potentially synergistic. Methods: Patients (pts) with recurrent high-grade IDHmt gliomas were enrolled in this phase II open-label study (NCT03991832). Eligibility included progressive disease with up to 2 prior lines of systemic therapies and ECOG 0–1. Pts received olaparib 300 mg twice daily continuously and durvalumab 1500 mg IV every 4 weeks. Simon’s optimal two-stage design was used. The primary objective was overall response rate (ORR) and disease control rate (DCR) by RANO criteria. Secondary objectives included overall survival (OS), progression free survival (PFS) and safety.Exploratory biomarkers of response and resistance were assessed with serial blood samples using cell-free methylated DNA immunoprecipitation and high-throughput sequencing (cfMeDIP-seq) as well as multiplex-immunohistochemistry. Results: In the 29 pts enrolled between January 2020–February 2023, median age was 40.5 (range 23–66) and 41% were female. Initial tumor grade was 2 in 9, 3 in 8 and 4 in 12 pts, respectively. Median time to enrollment from tumour diagnosis was 5.9 years. All had prior resection and median number of prior systemic therapies was 2. One patient clinically deteriorated before starting treatment. ORR was 10%, 95% CI 2.2–27%, with responses in 3 pts. One pt with grade 4 astrocytoma had a complete response and remains on treatment after 33 months. The other 2 responders with grade 4 astrocytoma had response durations of 4.1 and 9.8 months. DCR was 28% (95% CI 12.7–47.2%) with 5 additional pts demonstrating stable disease. With a median follow-up of 33 months, mOS was 9.5 months (95% CI 4.3–19.3) and mPFS was 1.9 months (95% CI 1.8–3.0). There was no treatment-related grade 3–4 toxicities. Any grade toxicities included fatigue (48%), nausea (17%), diarrhea (10%), and cytopenias (3%). Using serial cfMeDIP-seq, cell free DNA methylomes comparing responders versus progressors using the top differentially methylated regions can predict treatment response with high accuracy (AUC 0.833). Post progression, differentially methylated genes converge on TGF-β and signal transduction pathways, suggesting possible mechanisms of resistance. Multi-modal analysis of long-term responders will additionally be presented. Conclusions: Combination treatment with olaparib and durvalumab for pts with IDHmt glioma is well tolerated but has limited efficacy in unselected pts. cfMeDIP-seq can reliably predict tumour progression providing a blood-based biomarker of treatment response. Clinical trial information: NCT03991832 .

Abstract PO2-19-11: NOBLE – Neoadjuvant Olaparib and Durvalumab for patients with BRCA-associated TripLE Negative Breast Cancer

Abstract Background The standard of care for patients with early triple-negative breast cancer (TNBC) is neoadjuvant chemotherapy followed by surgery. Recently, immune checkpoints inhibitors (ICI) added to neoadjuvant chemotherapy have shown efficacy. Among TNBC, BRCA mutations and other homologous recombination deficiency (HRD) signals are relatively frequent. As opposed to other types of breast cancer, TNBC show a high neoantigen load, a large number of tumour infiltrating lymphocytes (TILs), and a high PD-L1 expression. In BRCA/HRD breast cancer, PARP inhibitors (PARPi) exhibit a distinct anticancer activity. In addition, they show immunomodulatory effects by promoting PD-L1 expression and DNA damage, increasing neoantigen load. Chemotherapy-free regimens combining PARPi and ICI result in promising synergistic activity as shown in the metastatic setting, supporting investigation in the neoadjuvant setting. Trial design NOBLE is an EORTC phase 2, randomized, international, multicentre, open label, clinical trial. Eligible patients will undergo central screening for tumoral BRCA/HRD (Institute Curie, 455 patients), 152 patients will be randomized 1:1 between olaparib vs olaparib and durvalumab for 4 cycles (16 weeks) of neoadjuvant treatment. Thereafter, patients will undergo surgery. All patients will be followed-up to 2 years (y) after surgery. The trial will be conducted in 3 steps (screening/randomization): Step 1 – Feasibility (60/20): to assess the central testing failure rate, the turn-around time for central testing and the prevalence of tBRCA/HRD; Step 2 (193/64) – Futility; and Step 3 (202/152) – Expansion of recruitment. The primary endpoint is the rate of pathologic complete response (pCR) at the time of surgery, defined as ypT0/is ypN0. Secondary endpoints are response based on RECIST v1.1, surgery rate, 2-y event-free-survival, 2-y overall survival, safety, and quality of life. The study is expected to be activated in early autumn 2023 and the primary endpoint will be available approximately 5 years after the screening of the first patient. Main inclusion criteria Histologically confirmed primary TNBC, defined as: - ER and PgR ≤ 10% - HER2-negative per ASCO CAP guidelines Stage T1c-T2 N0-N1 M0 BRCA mutation and/or HRD based on methylation as determined by central testing ECOG status 0-1 Written informed consent Age ≥18 years No prior systemic therapy nor surgery for the current Main exclusion criteria Previous treatment with a PARPi or an immune-checkpoint inhibitor History of previous invasive breast cancer Bilateral and/or multifocal and/or multicentric BC Autoimmune or inflammatory disease Specific aims The aim of this study is to provide a safe and effective neoadjuvant treatment free of chemotherapy to a distinct subpopulation among patients with TNBC. We will evaluate the pCR after neoadjuvant treatment with olaparib alone and with olaparib in combination with durvalumab in patients with TNBC showing a BRCA1/2 mutation or HRD based on methylation. Statistical methods The sample size was calculated based on the minimax Simon two-stage design including an interim analysis for futility of the primary endpoint. Decision rules are pre-specified in the study protocol. Each treatment arm will be analyzed independently. There will be no formal comparison between the two experimental treatment arms. A minimization technique will be used for random treatment allocation stratifying for the type of HRD alteration, PD-L1 expression level and for TILs. Accrual We expect to start recruiting in September 2023. We aim to screen 455 patients to randomize 152 patients. Contact information for people with a specific interest in the trial Etienne Brain (study coordinator): etienne.brain@curie.fr Anne-Sophie Hamy-Petit (study co-coordinator): anne-sophie.hamy-petit@curie.fr Citation Format: Emanuel Buhrer, Eleni Xenophontos, Anne-Sophie Hamy-Petit, Jose Casas-Martin, Céline Callens, Thomas Meyskens, Coralie Poncet, Anastasia Lanzi, Etienne Brain. NOBLE – Neoadjuvant Olaparib and Durvalumab for patients with BRCA-associated TripLE Negative Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-19-11.

Phase 1b study of batiraxcept in combination with durvalumab in patients with platinum-resistant ovarian cancer

Combining an immune checkpoint inhibitor with batiraxcept (AVB-S6-500), an AXL inhibitor that acts via selective binding to growth arrest-specific protein 6 (GAS6), may improve anti-tumor immunity in platinum-resistant ovarian cancer (PROC). This phase 1b trial of durvalumab in combination with escalating doses of batiraxcept enrolled patients with recurrent PROC (NCT04019288). The primary objective was to determine the toxicity profile of the combination. Eleven patients were enrolled on the trial. No dose-limiting toxicities were observed, and no objective responses were noted. Median progression free survival (PFS) was 1.81months (95% confidence interval (CI) 1.71-2.40), and median overall survival (OS) was 4.53months (95% CI 2.10-24.74). Batiraxcept effectively reduced serum GAS6 levels at 1-h post-treatment, resulting in trough levels below the limit of detection in all cases but one. In conclusion, the combination of batiraxcept and durvalumab was safe and tolerable but did not demonstrate anti-tumor activity in a heterogenous population of patients with recurrent PROC.

Abstract CT203: Multi-omic analysis of serial biopsies to inform biomarkers of sensitivity to olaparib and durvalumab in patients with metastatic BRCA-wildtype triple negative breast cancer (mTNBC)

Abstract Background: The phase 2 Adaptive Multi-Drug Treatment of Evolving Cancers (AMTEC) trial (NCT03801369) evaluated the efficacy of the combination of the PARP inhibitor Olaparib (Ola) and the PD-L1 inhibitor Durvalumab (Durva) in participants with BRCA-wildtype mTNBC. The combination was found to be effective with a median progression free survival (mPFS) of 5.5 months (AACR 2022). Here we report on updated biomarker analyses from paired biopsies (Bx) pre- and on-Ola therapy from 14 AMTEC participants. Methods: AMTEC participants undergo a pre-Ola Bx (Bx1), then one (28-day) cycle of Ola monotherapy with a repeat on-Ola Bx (Bx2) before adding Durva to Ola. Multi-omic profiling of DNA, RNA, and protein signals in Bx1 and Bx2 using Deep candidate gene sequencing, RNAseq, Nanostring Digital Spatial Profiling (DSP), and multiplex immunohistochemistry (mIHC) was correlated with clinical outcomes to identify predictors of Ola + Durva sensitivity, and adaptive resistance to PARPi therapy. Results: We identified over 30 biomarkers, with the optimal predictive value arising from Bx2. Key potential biomarkers were confirmed in an independent test set. Markers of good prognosis: • Basal Immune Activated (BLIA)/Basal Immune Suppressed (BLIS subtype) - A BLIA subtype on Bx2 was associated with a mPFS of 7.36 months compared to 1.71 months for BLIS/Luminal androgen receptor subtypes (p=0.001) • Multi-omic immune composite - A positive immune consensus signature (RNA, DSP, mIHC) on Bx2 was associated with a mPFS of 7.36 months compared to 2.29 months (p=0.005) • B cell activation signature - We developed a novel B-cell RNA activation signature that was highly predictive of response in Bx2, with mPFS of 8.54 and 1.04 months in signature-positive and signature-negative tumors, respectively (p=0.0004) Markers of poor prognosis: • AKT/MAPK pathway - AKT pathway gene mutations in Bx2 with concomitant protein phosphorylation of pathway members correlated with a shorter mPFS of 2.4 months compared to 7.13 months for no pathway mutation/activation (p=0.03). MAPK pathway protein phosphorylation in Bx2 was a negative prognostic factor, with mPFS of 2.17 months (p=0.004) • Angiogenesis - An upregulated Hallmark of Cancer angiogenesis RNA signature on Bx2 was associated with a shorter mPFS of 1.94 months compared to 7.95 months with no angiogenesis upregulation (p=0.0009) The following markers did not show significant association with survival outcomes on AMTEC: • PD-L1 positivity by IHC (defined as &amp;gt;1% Tumor Proportion Score, 22C3 antibody) • Tumor mutational burden • HRD, as measured by Rad51 foci or by mutations in HR pathway members Conclusions: Findings highlight the value of paired Bxs to identify predictive biomarkers of PARPi + immune checkpoint inhibitor sensitivity. The striking predictive value of the BLIA/BLIS signature warrants evaluation in a larger trial. Emerging resistance mechanisms justify AMTEC trial expansion to include PARPi + MEKi or PARPi + AKTi in biomarker selected patients, which is now in progress. Citation Format: Zahi I. Mitri, Allison L. Creason, Jayne M. Stommel, Daniel Bottomly, Jeong Youn Lim, SMMART Clinical Trials Program, Christopher L. Corless, Shannon McWeeney, Gordon B. Mills. Multi-omic analysis of serial biopsies to inform biomarkers of sensitivity to olaparib and durvalumab in patients with metastatic BRCA-wildtype triple negative breast cancer (mTNBC) [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 CT203.

80 A single-centre experience of adjuvant Durvalumab in patients with Non-small cell lung cancer (NSCLC) treated with radical concurrent chemo-radiotherapy

80 A single-centre experience of adjuvant Durvalumab in patients with Non-small cell lung cancer (NSCLC) treated with radical concurrent chemo-radiotherapy

Bevacizumab, olaparib, and durvalumab in patients with relapsed ovarian cancer: a phase II clinical trial from the GINECO group

Most patients with advanced ovarian cancer (AOC) ultimately relapse after platinum-based chemotherapy. Combining bevacizumab, olaparib, and durvalumab likely drives synergistic activity. This open-label phase 2 study (NCT04015739) aimed to assess activity and safety of this triple combination in female patients with relapsed high-grade AOC following prior platinum-based therapy. Patients were treated with olaparib (300 mg orally, twice daily), the bevacizumab biosimilar FKB238 (15 mg/kg intravenously, once-every-3-weeks), and durvalumab (1.12 g intravenously, once-every-3-weeks) in nine French centers. The primary endpoint was the non-progression rate at 3 months for platinum-resistant relapse or 6 months for platinum-sensitive relapse per RECIST 1.1 and irRECIST. Secondary endpoints were CA-125 decline with CA-125 ELIMination rate constant K (KELIM-B) per CA-125 longitudinal kinetics over 100 days, progression free survival and overall survival, tumor response, and safety. Non-progression rates were 69.8% (90%CI 55.9%-80.0%) at 3 months for platinum-resistant relapse patients (N = 41), meeting the prespecified endpoint, and 43.8% (90%CI 29.0%-57.4%) at 6 months for platinum-sensitive relapse (N = 33), not meeting the prespecified endpoint. Median progression-free survival was 4.1 months (95%CI 3.5–5.9) and 4.9 months (95%CI 2.9–7.0) respectively. Favorable KELIM-B was associated with better survival. No toxic deaths or major safety signals were observed. Here we show that further investigation of this triple combination may be considered in AOC patients with platinum-resistant relapse.

Clinical and biomarker results from a phase II trial of combined cabozantinib and durvalumab in patients with chemotherapy-refractory colorectal cancer (CRC): CAMILLA CRC cohort

CAMILLA is a basket trial (NCT03539822) evaluating cabozantinib plus the ICI durvalumab in chemorefractory gastrointestinal cancer. Herein, are the phase II colorectal cohort results. 29 patients were evaluable. 100% had confirmed pMMR/MSS tumors. Primary endpoint was met with ORR of 27.6% (95% CI 12.7-47.2%). Secondary endpoints of 4-month PFS rate was 44.83% (95% CI 26.5-64.3%); and median OS was 9.1 months (95% CI 5.8-20.2). Grade≥3 TRAE occurred in 39%. In post-hoc analysis of patients with RAS wild type tumors, ORR was 50% and median PFS and OS were 6.3 and 21.5 months respectively. Exploratory spatial transcriptomic profiling of pretreatment tumors showed upregulation of VEGF and MET signaling, increased extracellular matrix activity and preexisting anti-tumor immune responses coexisting with immune suppressive features like T cell migration barriers in responders versus non-responders. Cabozantinib plus durvalumab demonstrated anti-tumor activity, manageable toxicity, and have led to the activation of the phase III STELLAR-303 trial.

First-line durvalumab in patients with PD-L1 positive, advanced non-small cell lung cancer (NSCLC) with a performance status of 2 (PS2). Primary analysis of the multicenter, single-arm phase II trial SAKK 19/17

IntroductionThe safety and efficacy of first-line durvalumab in PS2 patients with advanced NSCLC is unknown. Here, we present the primary analysis of first-line durvalumab in PS2 patients, unsuitable for combination chemotherapy. MethodsIn this single-arm, multicenter, phase II trial patients with PD-L1 positive (tumor proportional score ≥25%), advanced NSCLC with PS2, received four-weekly durvalumab 1500 mg. The primary endpoint was overall survival (OS) at 6 months. ResultsForty-eight patients were included. Median follow-up was 23.3 months (95% CI: 14.3–28.6). OS at 6 months was 60% (95% CI: 45–74%). Median OS was 8.5 months (95%CI: 4.4–16.7). Objective response rate and median progression free survival were 17% (95% CI: 8–30%) and 2.5 months (95% CI: 1.8–7.1), respectively. Thirty-three deaths were observed at the time point of the analysis. Seven early fatal events considered not treatment-related occurred during the first 5 weeks of treatment. Four out of the first 7 early fatal events (4/7; 57%) were respiratory failure in patients with advanced symptomatic primary lung tumors. Three more early fatal events occurred after exclusion of patients with grade ≥ 3 dyspnea. Treatment-related AEs ≥G3 were reported in 9 patients (19%) and included colonic perforation in one patient (grade 5), colitis in 4 patients (8%), increased lipase in 3 patients (6%), and hepatitis in 2 patients (4%). ConclusionsFirst-line durvalumab in PS2 patients with advanced PD-L1 positive NSCLC results in a high number of early fatal events. When patients with grade ≥ 3 dyspnea are excluded a promising 6-month OS with an acceptable toxicity profile can be observed. Durvalumab could be an option instead of single agent chemotherapy for PS2 patients who are not candidates for platinum doublet chemotherapy provided they are well selected.

Phase 1/2 study of monalizumab plus durvalumab in patients with advanced solid tumors

BackgroundThe combination of monalizumab (anti-NKG2A/CD94) and durvalumab (anti-programmed death ligand-1) may promote antitumor immunity by targeting innate and adaptive immunity. This phase 1/2 study of monalizumab and durvalumab evaluated safety,...

Phase I/II clinical trial of regorafenib plus durvalumab (MEDI4736) in patients with chemotherapy-refractory advanced biliary tract cancers.

TPS581 Background: Biliary tract cancers (BTC) are a heterogeneous group of cancers affecting the epithelial lining of the intra- and extrahepatic portions of the biliary tree, ranking as the second most prevalent primary liver cancer after hepatocellular carcinoma. A subgroup of BTC was found to have an abundant tumor specific neoantigen expression, enriched expression of immune related genes and genes regulating inhibitory immune checkpoint proteins. Recent advancements in BTC treatment include the TOPZ-1 trial, which established the survival advantage of adding durvalumab to the gemzar + cisplatin regimen with an estimated 24-month overall survival rate of 24.9% versus 10.4% for placebo. The hazard ratio for progression-free survival favored durvalumab at 0.75 (95% CI, 0.63 to 0.89; P=0.001). Objective response rates also showed improvement, with 26.7% for durvalumab and 18.7% for placebo. Furthermore, single agent regorafenib has exhibited efficacy in patients with refractory advanced metastatic cholangiocarcinoma, particularly in terms of progression-free survival, favoring regorafenib over placebo, the overall toxicity profile was as expected. Regorafenib targets multiple tyrosine kinases and has been reported to show immunomodulatory properties that may counteract tumor-induced immunosuppression, providing a rationale for combining it with checkpoint inhibitors. We believe that modulating the tumor microenvironment with small molecule inhibitors like regorafenib will have synergistic effect when combined with checkpoint-based immunotherapy like durvalumab in patients with chemo refractory BTC. Methods: This study comprises a single-arm, unblinded Phase I/II trial designed to assess the safety and efficacy of the combination therapy involving regorafenib and durvalumab in patients with chemo-refractory advanced BTC. The Phase I portion employed a 3 + 3 design with two dose levels of regorafenib (80 mg and 120 mg) administered in conjunction with 1500 mg IV durvalumab every 28 days. Phase I successfully completed, and the Data Monitoring Committee (DMC) endorsed the continuation of the trial as planned. Eligibility: Histologically confirmed unresectable or metastatic disease. Progressed on at least one line of therapy. May have received checkpoint inhibitor in the past. Inclusion criteria also include ECOG PS 0-1. Objectives:Primary Phase I: Safety of regorafenib in combination with durvalumab.Phase II: Progression-free survival (PFS).Secondary:Disease Control Rate (DCR), Overall response rate (ORR), Overall survival (OS). Statistical Plan: Interim futility testing after one year, halting if conditional power &lt; 20%. Final analysis: PFS and OS via Weibull Regression. Enrollment is currently ongoing with 8 out of 40 patients enrolled.

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 .

Contribution of Enhanced Locoregional Control to Improved Overall Survival with Consolidative Durvalumab after Concurrent Chemoradiotherapy in Locally Advanced Non-Small Cell Lung Cancer: Insights from Real-World Data.

This study aimed to assess the real-world clinical outcomes of consolidative durvalumab in patients with unresectable locally advanced non-small cell lung cancer (LA-NSCLC) and to explore the role of radiotherapy in the era of immunotherapy. This retrospective study assessed 171 patients with unresectable LA-NSCLC who underwent concurrent chemoradiotherapy (CCRT) with or without consolidative durvalumab at Asan Medical Center between May 2018 and May 2021. Primary outcomes included freedom from locoregional failure (FFLRF), distant metastasis-free survival (DMFS), progression-free survival (PFS), and overall survival (OS). Durvalumab following CCRT demonstrated a prolonged median PFS of 20.9 months (p=0.048) and a 3-year FFLRF rate of 57.3% (p=0.008), compared to 13.7 months and 38.8%, respectively, with CCRT alone. Furthermore, the incidence of in-field recurrence was significantly greater in the CCRT-alone group compared to the durvalumab group (26.8% vs. 12.4%, p=0.027). While median OS was not reached with durvalumab, it was 35.4 months in patients receiving CCRT alone (p=0.010). Patients positive for programmed cell death ligand 1 (PD-L1) expression showed notably better outcomes, including FFLRF, DMFS, PFS, and OS. Adherence to PACIFIC trial eligibility criteria identified 100 patients (58.5%) as ineligible. The use of durvalumab demonstrated better survival regardless of eligibility criteria. The use of durvalumab consolidation following CCRT significantly enhanced locoregional control and OS in patients with unresectable LA-NSCLC, especially in those with PD-L1-positive tumors, thereby validating the role of durvalumab in standard care.

A phase 1 study of the CD40 agonist MEDI5083 in combination with durvalumab in patients with advanced solid tumors.

Aim: This first-in-human study evaluated safety and efficacy of CD40 agonist MEDI5083 with durvalumab in patients with advanced solid tumors.Methods: Patients received MEDI5083 (3-7.5mg subcutaneously every 2 weeks×4doses) and durvalumab (1500mg every 4 weeks) either sequentially (N=29) or concurrently (N=9). Primary end point was safety; secondary end points included efficacy.Results: Thirty-eight patients received treatment. Most common adverse events (AEs) were injection-site reaction (ISR; sequential: 86%; concurrent: 100%), fatigue (41%; 33%), nausea (20.7%; 55.6%) and decreased appetite (24.1%; 33.3%). Nine patients had MEDI5083-related grade ≥3 AEs with ISR being the most common. Two patients experienced dose limiting toxicities (ISR). One death occurred due to aMEDI5083-related AE. MEDI5083 maximum tolerated dose was 5mg. Objective response rate was 2.8% (1 partial response and 11 stable disease).Conclusion: MEDI5083 toxicity profile limits its further development.