348P First findings from SYNERGY, a phase I/II trial testing the addition of the anti-CD73 oleclumab (O) to the anti-PD-L1 durvalumab (D) and chemotherapy (ChT) as first line therapy for patients (pts) with metastatic triple-negative breast cancer (mTNBC)

Eiger, Daniel; Maurer, Christian; Brandão, Mariana; Aftimos, Philippe; Punie, Kevin; Taylor, D. P.; Mooter, Tom Van den; Poncin, R.; Canon, J-L; Duhoux, FP; Casert, Vinciane; Clatot, Florian; Velghe, C.; Craciun, Ligia; Paesmans, Marianne; Azambuja, Evandro de; Ignatiadis, Michail; Larsimont, Denis; Piccart, M.; Buisseret, Laurence

doi:10.1016/j.annonc.2020.08.450

Cited by 9 publications

(4 citation statements)

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“…A previous phase I study showed that oleclumab monotherapy had a tolerable safety profile; no DLTs were observed, and the incidence of Grade 3–4 treatment-related AEs was 7.1% [ 13 ]. However, oleclumab in combination with durvalumab or osimertinib was shown to increase the incidence of AEs in previous studies: in a previous phase I study, no DLTs were reported when administered in combination with durvalumab, but the incidence of Grade 3–4 treatment-related AEs was 20.8% [ 13 ]; in another phase II study, the incidence of Grade ≥ 3 treatment-emergent AEs was 40.7% when administered in combination with durvalumab [ 15 ]; in a previous phase Ib/II study, the incidence of Grade 3–4 treatment-emergent AEs was 38.1% when administered in combination with osimertinib [ 16 ]; and in another phase I/II study, five out of six patients experienced Grade ≥ 3 neutropenia outside of the DLT period when administered in combination with durvalumab and chemotherapy [ 17 ]. In these studies, it was concluded that the combination treatment was tolerable [ 13 , 15 – 17 ].…”

Section: Discussionmentioning

confidence: 99%

“…In another phase II study of oleclumab administered in combination with durvalumab, ORR was 30.0% in patients with Stage III non-small-cell lung cancer after concurrent chemoradiation therapy [ 15 ]. In a previous phase Ib/II study of oleclumab administered in combination with osimertinib, ORR was 19% and median PFS was 11 months [ 16 ], and in another phase I/II study, four out of six patients with locally advanced unresectable or metastatic triple-negative breast cancer who were treated with oleclumab administered in combination with durvalumab and chemotherapy had a clinical benefit [ 17 ].…”

Section: Discussionmentioning

confidence: 99%

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Safety, tolerability, pharmacokinetics, and antitumour activity of oleclumab in Japanese patients with advanced solid malignancies: a phase I, open-label study

et al. 2022

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Background Cluster of differentiation (CD) 73-targeted immunotherapy and CD73 inhibition may reduce adenosine production, which can augment the host and/or immunotherapy response to tumours. We aimed to assess the safety and tolerability, pharmacokinetics, and antitumour activity of oleclumab, an anti-CD73 monoclonal antibody, in adult Japanese patients with advanced solid malignancies resistant to standard therapy. Methods In this phase I, single-centre, open-label study, patients received oleclumab 1500 mg (Cohort 1) or 3000 mg (Cohort 2) intravenously every 2 weeks. Results In total, six patients were enrolled in the study (three in each cohort), and all six patients received the study treatment. The median patient age was 56.0 years and 4/6 were males. All patients (100%) reported adverse events (AEs) during the study; five (83.3%) patients reported AEs related to the study treatment. One (16.7%) patient reported a Grade 3 AE (neutrophil count decreased) that was not related to the study treatment. No AEs with an outcome of death were reported, and no patients reported AEs or serious AEs leading to oleclumab discontinuation/dose interruption. No dose-limiting toxicities were reported, and no patient discontinued due to an AE related to the study treatment. Oleclumab exposure increased dose proportionally. No patient achieved disease control at 8 weeks, and all six patients developed progressive disease. Conclusions Oleclumab was well tolerated in adult Japanese patients with advanced solid malignancies and no unexpected safety concerns were raised; oleclumab exposure increased with dose. Future studies on combination therapy with other agents are warranted.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Safety, tolerability, pharmacokinetics, and antitumour activity of oleclumab in Japanese patients with advanced solid malignancies: a phase I, open-label study

et al. 2022

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“…Similar studies include NCT03616886 phase I/II trial testing anti-CD73, anti-PD-L1 and chemotherapy in subjects with advanced TNBC ( 87 ), NCT03611556 phase Ib/II trial testing anti-CD73 alone or combination with gemcitabine chemotherapy and anti-PD-L1 in 212 patients with metastatic PDAC, and NCT03334617 HUDSON Platform multi-arm phase II trial for NSCLC patients who previously failed anti-PD(L)1 immunotherapy. These trials have yet to report the results (NCT03611556), or else had limited patient numbers ( 87 ) (NCT03616886) or short treatment duration (NCT03334617) ( 88 ) insufficient to assess clinical benefits.…”

Section: Clinical Trials Targeting the Cd73-adenosinergic Pathwaymentioning

confidence: 99%

Inhibitors of the CD73-adenosinergic checkpoint as promising combinatory agents for conventional and advanced cancer immunotherapy

et al. 2023

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The cell surface enzyme CD73 is increasingly appreciated as a pivotal non-redundant immune checkpoint (IC) in addition to PD-1/PD-L1 and CTLA-4. CD73 produces extracellular adenosine (eADO), which not only inhibits antitumor T cell activity via the adenosine receptor (AR) A2AR, but also enhances the immune inhibitory function of cancer-associated fibroblasts and myeloid cells via A2BR. Preclinical studies show that inhibition of the CD73-adenosinergic pathway in experimental models of many solid tumors either as a monotherapy or, more effectively, in combination with PD-1/PD-L1 or CTLA-4 IC blockades, improves antitumor immunity and tumor control. Consequently, approximately 50 ongoing phase I/II clinical trials targeting the CD73-adenosinergic IC are currently listed on https://clinicaltrials.gov. Most of the listed trials employ CD73 inhibitors or anti-CD73 antibodies alone, in combination with A2AR antagonists, and/or with PD-1/PD-L1 blockade. Recent evidence suggests that the distribution of CD73, A2AR and A2BR in tumor microenvironments (TME) is heterogeneous, and this distribution affects CD73-adenosinergic IC function. The new insights have implications for the optimally effective, carefully tailored approaches to therapeutic targeting of this essential IC. In the mini-review, we briefly discuss the cellular and molecular mechanisms of CD73/eADO-mediated immunosuppression during tumor progression and therapy in the spatial context of the TME. We include preclinical data regarding therapeutic CD73-eADO blockade in tumor models as well as available clinical data from completed trials that targeted CD73-adenosinergic IC with or without PD-1/PD-L1 inhibitors and discuss factors that are potentially important for optimal therapeutic outcomes in cancer patients.

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“…Preliminary results were presented at ESMO in 2020: 0 of six patients experienced dose-limiting toxicity and four patients had a clinical benefit at week 24. 28 Results of the phase II study are forthcoming.…”

Section: Immunotherapymentioning

confidence: 99%

Emerging treatment strategies for metastatic triple-negative breast cancer

2022

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Triple-negative breast cancer (TNBC) is a heterogeneous subtype of breast cancer that is often associated with an aggressive phenotype and a poor prognosis. Cytotoxic chemotherapy remains the mainstay of treatment for most patients with metastatic TNBC (mTNBC), but duration of response is often short and median overall survival is only 12–18 months. Therefore, it is critical to identify novel treatment strategies to improve outcomes for these patients. In this review article, we discuss recent advances in treatment strategies for patients with mTNBC including the use of immune checkpoint inhibitors, targeted therapies, and antibody–drug conjugates. For each topic, we summarize important preclinical and clinical data, discuss implications for clinical practice, and highlight future research directions.

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348P First findings from SYNERGY, a phase I/II trial testing the addition of the anti-CD73 oleclumab (O) to the anti-PD-L1 durvalumab (D) and chemotherapy (ChT) as first line therapy for patients (pts) with metastatic triple-negative breast cancer (mTNBC)

Cited by 9 publications

References 0 publications

Safety, tolerability, pharmacokinetics, and antitumour activity of oleclumab in Japanese patients with advanced solid malignancies: a phase I, open-label study

Safety, tolerability, pharmacokinetics, and antitumour activity of oleclumab in Japanese patients with advanced solid malignancies: a phase I, open-label study

Inhibitors of the CD73-adenosinergic checkpoint as promising combinatory agents for conventional and advanced cancer immunotherapy

Emerging treatment strategies for metastatic triple-negative breast cancer

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