Publications by authors named "Edith Borcoman"

30 Publications

  • Page 1 of 1

A phase II study of monalizumab in patients with recurrent/metastatic squamous cell carcinoma of the head and neck: The I1 cohort of the EORTC-HNCG-1559 UPSTREAM trial.

Eur J Cancer 2021 Oct 9;158:17-26. Epub 2021 Oct 9.

Service d'Oncologie Médicale, Institut Roi Albert II, Cliniques Universitaires Saint-Luc and Institut de Recherche Clinique et Expérimentale, Université Catholique de Louvain (UCLouvain), Avenue Hippocrate 10, 1200 Brussels, Belgium. Electronic address:

Purpose: Monalizumab is a monoclonal antibody targeting the inhibitory natural killer group 2A (NKG2A) receptor localised on natural killer (NK) and T cells. Its ligand, the human leukocyte antigen E (HLA-E), is overexpressed in squamous cell carcinoma of the head and neck (SCCHN). By targeting the HLA-E-NKG2A pathway, monalizumab may enhance NK and T cell activity.

Experimental Design: The UPSTREAM trial is a biomarker-driven umbrella trial studying targeted therapies and immunotherapies in patients with recurrent/metastatic (R/M) SCCHN progressing after platinum therapy. The immunotherapy 1 (I1) cohort was a phase II, single-arm substudy evaluating monalizumab (10 mg/kg intravenously on day 1 of a 14-day cycle). The primary end-point was the objective response (OR) rate (Response Evaluation Criteria in Solid Tumours 1.1) over the first 16 weeks. A two-stage Simon design was used (H1 15%, H0 3%, α 8%, power 90%) with pre-planned interruption of accrual if no OR was observed after the first 25 patients.

Results: Twenty-six eligible patients were enrolled. Seventeen (65%) patients had received ≥2 previous lines of systemic treatment, and 15 (58%) patients were PD(-L)1 inhibitor pretreated. No OR was observed. Stable disease was observed in 6 patients (23%) with a median duration of 3.8 months (95% confidence interval [CI]: 2.7-NE). The median progression-free survival and overall survival were 1.7 months (95% CI: 1.5-1.8) and 6.7 months (95% CI: 3.0-9.6), respectively. The most frequent treatment-related adverse event was grade I/II fatigue (19%).

Conclusions: Monalizumab monotherapy has limited activity in R/M SCCHN. The I1 cohort did not meet its primary objective. Monalizumab combined with durvalumab is under investigation within UPSTREAM.
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http://dx.doi.org/10.1016/j.ejca.2021.09.003DOI Listing
October 2021

Dissociated Responses in Patients with Metastatic Solid Tumors Treated with Immunotherapy.

Drugs R D 2021 Sep 25. Epub 2021 Sep 25.

Department of Drug Development and Innovation (D3i), Institut Curie, Paris and Saint-Cloud, 26 rue d'Ulm, 75005, Paris, France.

Background: Immune checkpoint inhibitors have been demonstrated to improve overall survival. Atypical patterns of response have been reported, including dissociated response (DR). We evaluated the prevalence of DR.

Patients And Methods: Patients had to have a baseline computed tomography (CT) scan and at least one follow-up CT scan and two target lesions (TLs). Three types of DR were evaluated using RECIST1.1: DR1, defined as at least one progressive and one responding TL; DR2, defined as at least one progressive and one stable TL; and DR3, defined as at least one stable and one responding TL.

Results: A total of 1244 measurements of 272 TLs were performed in 100 patients. Forty-nine out of the 272 TLs (18%) had received old or recent radiotherapy, and 42 (15%) had been biopsied. An objective response was observed in 22 patients (22%) and on 52 TLs (19%). DR1 were observed in 8% of patients. At the tumor measurement level, the response rate was lower in the case of prior radiotherapy (29% vs 34%, p = 0.01) and higher in the case of prior biopsy (40% vs 32%, p = 0.02).

Conclusions: A DR was observed in 8% of patients. Response rate was lower in the case of prior radiotherapy and higher in the case of prior biopsy.
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http://dx.doi.org/10.1007/s40268-021-00362-3DOI Listing
September 2021

Efficacy and safety of immune checkpoint inhibitors in elderly patients (≥70 years) with squamous cell carcinoma of the head and neck.

Eur J Cancer 2021 Sep 15;157:190-197. Epub 2021 Sep 15.

Department of Head and Neck Oncology, Gustave Roussy Cancer Campus, Villejuif, France.

Background: Recent meta-analysis showed that immune checkpoint inhibitors (ICIs) have comparable activity between younger and older patients. However, little is known about efficacy and safety of ICI in elderly patients with relapsed/metastatic squamous cell carcinoma of the head and neck (R/M SCCHN). The aim of this study is to compare the efficacy of ICI for patients aged ≥70 y to that for younger patients, while taking into account potential confounding factors.

Methods: A retrospective study was conducted at four hospitals in France. Patients treated with ICI for R/M SCCHN between September 2014 and December 2018 were eligible. Patients' charts were reviewed for clinical and radiological data as well as oncologic outcomes.

Results: We included 226 patients, of whom 67 were aged ≥70 years. Objective response rate (ORR), median overall survival (OS) and median progression-free survival (PFS) were 23%, 9.7 months and 2.7 months, respectively, for elderly patients, compared to 13%, 8.7 months and 1.9 months for younger patients (respective p-values: 0.071, 0.87 and 0.21). After adjustment for performance status, site of progression, number of ICI drugs, time between initial diagnosis and ICI start and number of previous lines, age ≥70 years was significantly associated with a better PFS (hazard ratio [HR], 0.66; p = 0.021) but not OS (HR, 0.91; p = 0.59). Grade 3-5 adverse events (AEs) occurred in 15% of patients aged ≥70 years and in 8% of younger patients (p = 0.13).

Conclusion: Patients aged ≥70 years with R/M SCCHN may respond to ICI similarly as younger patients in terms of ORR, OS and PFS, while maintaining comparable rate of AEs.
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http://dx.doi.org/10.1016/j.ejca.2021.08.030DOI Listing
September 2021

Phase I trial of copanlisib, a selective PI3K inhibitor, in combination with cetuximab in patients with recurrent and/or metastatic head and neck squamous cell carcinoma.

Invest New Drugs 2021 Dec 28;39(6):1641-1648. Epub 2021 Jul 28.

Department of Drug Development and Innovation (D3i), Institut Curie, Paris & Saint-Cloud, France.

Background The phosphatidylinositol-3 kinase pathway is often altered in head and neck squamous cell carcinoma (HNSCC), and is involved in the resistance to EGFR inhibitors. Objective We investigated the dose-limiting toxicities (DLTs), maximum tolerated dose, pharmacokinetics, and preliminary efficacy of the combination of copanlisib, an intravenous, pan-class I PI3K inhibitor, with the anti-EGFR monoclonal antibody cetuximab in recurrent and/or metastatic HNSCC patients in a phase I dose-escalation trial. Patients and methods Copanlisib was given intravenously on days 1, 8, and 15 of 28-day cycles at the dose of 45 mg and 30 mg, in combination with standard doses of weekly cetuximab (400 mg/m loading dose followed by 250 mg/m on days 8, 15, and 22, and weekly thereafter). Results Three patients received copanlisib 45 mg, of whom two experienced grade 3 hyperglycemia during Cycle 1 that met the DLT criteria. Eight patients were then treated with copanlisib at the dose of 30 mg. Because of the occurrence of hyperglycemia, a premedication with metformine was introduced on the day of the injections. No DLTs were reported at this dose level. The trial was stopped early because of the unfavourable toxicity profile of the combination. Among eight evaluable patients for response, four patients (50%) had disease stabilization according to RECIST1.1 as best response. Conclusion Copanlisib combined with cetuximab demonstrated unfavorable toxicity and limited efficacy in heavily pretreated recurrent and/or metastatic HNSCC patients.Trial registration NCT02822482, Date of registration: June 2016.
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http://dx.doi.org/10.1007/s10637-021-01152-zDOI Listing
December 2021

["Immunotherapy in head and neck squamous cell carcinoma"].

Rev Prat 2021 Apr;71(4):396-399

"Department of Drug Development and Innovation (D3i), Institut Curie, Paris et Saint-Cloud, France" - "Inserm U900, Institut Curie, Mines Paris Tech, Saint-Cloud, France" - "Université Paris-Saclay, Paris, France".

"Immunotherapy in head and neck squamous cell carcinoma.Immune checkpoint inhibitors became recently the standard of care for recurrent and/or metastatic head and neck squamous cell carcinoma not amenable to surgery and/or radiotherapy. Nivolumab as single agent is approved regardless of PD-L1 expression for recurrent and/or metastatic patients following progression within 6 months of platinum therapy administered either in the first line recurrent setting, or concomitantly with radiotherapy. Pembrolizumab in combination with platinum and 5-FU and pembrolizumab a single agent are two approved regimens in the first line recurrent and/or metastatic setting, provided: PD-L1 expression on tumour cells and/or inflammatory cells, and lack of disease progression within 6 months of platinum therapy given concomitantly with radiotherapy."
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April 2021

Paradigm Change in First-Line Treatment of Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma.

Cancers (Basel) 2021 May 24;13(11). Epub 2021 May 24.

Department of Drug Development and Innovation (D3i), Institut Curie, 75005 Paris, France.

Cetuximab, a monoclonal antibody targeting the epidermal growth factor receptor (EGFR) in combination with platinum-based chemotherapy has been for the decade standard of care for the treatment of head and neck squamous cell carcinomas (HNSCC) patients in the first-line recurrent and/or metastatic setting. The KEYNOTE-048 trial published last year established a new paradigm in this setting with the demonstration that immunotherapy should be given either alone or in combination with chemotherapy. Indeed, pembrolizumab, an antiprogrammed cell death 1 (PD-1) immune checkpoint inhibitor, improved overall survival as compared to the EXTREME regimen in patients expressing PD-L1 in the tumor microenvironment, which represents a large majority of the patient population. In this review, we will decipher this important change of paradigm in the first-line treatment of recurrent and/or metastatic HNSCC, and discuss associated challenges.
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http://dx.doi.org/10.3390/cancers13112573DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8197177PMC
May 2021

Prognostic value of intratumoral Fusobacterium nucleatum and association with immune-related gene expression in oral squamous cell carcinoma patients.

Sci Rep 2021 04 12;11(1):7870. Epub 2021 Apr 12.

Department of Genetics, Institut Curie, PSL Research University, Paris, France.

Changes in the oral microbiome, particularly Fusobacterium nucleatum, are associated with oral squamous cell carcinoma (OSCC). F. nucleatum has been reported to modulate local immunity in cancers. We aimed to assess the association between intratumoral F. nucleatum and clinico-pathological features, relapse, and overall survival (OS) in two independent cohorts of patients with OSCC, and to explore the interplay with immune-related genes. We retrospectively analyzed tissue samples from a first cohort of 122 patients with head and neck squamous cell carcinoma, including 61 OSCC (cohort #1), and a second cohort of 90 additional OSCC (cohort #2). We then performed a sensitivity analysis on the merged cohort of OSCC patients (N = 151). F. nucleatum 16S rRNA gene sequences were quantified using real-time quantitative PCR. The presence of gram-negative bacteria and macrophages was confirmed by LPS and CD163 immunostainings, respectively. F. nucleatum positivity was associated with older age, less alcohol and combined alcohol plus tobacco consumption, and less frequent lymph node invasion. There was a trend for a lower recurrence rate in F. nucleatum-positive cases, with less metastatic relapses compared to F. nucleatum-negative tumors, and significantly longer OS, relapse-free and metastasis-free survival. F. nucleatum status was independently associated with OS in multivariate analysis. Immune-related gene and immunohistochemistry analyses showed that gram-negative bacteria load inversely correlated with M2 macrophages. F. nucleatum-associated OSCC has a specific immune microenvironment, is more frequent in older, non-drinking patients, and associated with a favorable prognosis.
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http://dx.doi.org/10.1038/s41598-021-86816-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8041800PMC
April 2021

Exploratory window-of-opportunity trial to investigate the tumor pharmacokinetcs/pharmacodynamics of the IAP antagonist Debio 1143 in patients with head and neck cancer.

Clin Transl Sci 2021 Mar 20. Epub 2021 Mar 20.

Debiopharm International S.A, Lausanne, Switzerland.

Inhibitor of apoptosis proteins (IAPs) regulate apoptosis and modulate NF-κB signalling thereby driving expression of genes involved in immune/inflammatory responses. The orally available IAP antagonist Debio 1143 has potential to enhance tumor response to chemoradiotherapy and/or immunotherapy. Patients with pre-operative squamous cell carcinomas of the head and neck (SCCHN) received: Debio 1143 monotherapy (200 mg/day D1-15 +/-2); Debio 1143 (200 mg/day D1-15 +/-2) plus cisplatin (40 mg/m D-1 and 8); cisplatin alone (40 mg/m D-1 and 8) (EudraCT: 2014-004655-31). Pharmacokinetic/pharmacodynamic effects were assessed in plasma and resected tumors. Primary endpoint; effect of Debio 1143 on cellular IAP-1 (cIAP-1). Levels of cIAP-1/-2, X-linked inhibitor of apoptosis protein (XIAP), tumor infiltrating lymphocytes (TILs) including CD8+ T cells, programmed cell death protein 1 (PD-1) and PD-ligand 1 (PD-L1) and gene expression were also analyzed. Twenty-three of 26 patients completed treatment. In the Debio 1143 monotherapy cohort (n=13), mean tumor concentrations of Debio 1143 were 18-fold (maximum 55.2-fold) greater than in plasma, exceeding the IC for cIAPs and XIAP by 100 to 1000-fold, with significant engagement/degradation of cIAP-1 (p <0.05). Overall, levels of CD8+ TILs, PD-1 and PD-L1 positive immune cells increased significantly (p <0.05) following Debio 1143 treatment. Changes were observed in the expression of genes related to NF-κB signalling. Treatments were well tolerated. Debio 1143 penetrated SCCHN tumors, engaged cIAP-1 and induced immune inflammatory changes in the tumor microenvironment. Based on the mode of action demonstrated here and in previous studies, these data support future combinations of Debio 1143 with immune-checkpoint agents.
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http://dx.doi.org/10.1111/cts.13002DOI Listing
March 2021

[Imaging strategy for breast cancer screening].

Rev Prat 2020 09;70(7):722-725

Département de médecine oncologique, institut Gustave- Roussy, Villejuif, France.

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September 2020

Phase I dose-escalation study of NBTXR3 activated by intensity-modulated radiation therapy in elderly patients with locally advanced squamous cell carcinoma of the oral cavity or oropharynx.

Eur J Cancer 2021 03 16;146:135-144. Epub 2021 Feb 16.

Department of Drug Development and Innovation (D3i), Institut Curie, Paris, France; INSERM U900 Research Unit, Saint-Cloud, France; Paris-Saclay University, Paris, France. Electronic address:

Purpose: This phase I study assessed the safety of first-in-class radioenhancer nanoparticles, NBTXR3, in elderly or frail patients with locally advanced head and neck squamous cell carcinoma (HNSCC), ineligible for chemoradiation.

Methods: Patients with stage III or IVA (American Joint Committee on Cancer (AJCC) guidelines, 7th edition, 2010) HNSCC of the oral cavity or oropharynx, aged ≥70 or ≥65 years and ineligible to receive cisplatin, amenable to radiotherapy (RT) with curative intent, received NBTXR3 as a single intratumoural (IT) injection followed by activation by intensity-modulated radiation therapy (IMRT; 70 Gy). The NBTXR3 dose corresponded to a percentage of the baseline tumour volume, measured by magnetic resonance imaging. The primary objectives were to determine the recommended phase II dose (RP2D), dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD). Safety and tolerability were assessed using National Cancer Institute CTCAE version 4.0. Antitumour activity was assessed by Response Evaluation Criteria in Solid Tumours 1.1.

Results: Nineteen patients were enrolled: 3 at the dose level of 5%, 3 at the dose level of 10%, 5 at the dose level of 15% and 8 at the dose level of 22% of the tumour volume. The MTD was not reached, and no DLTs or serious adverse event (SAEs) related to NBTXR3 were observed. Four adverse events related to NBTXR3 and/or the IT injection were reported (grade I-II). NBTXR3 remained in the injected tumour throughout RT, with no leakage in the surrounding healthy tissues. Specific RT-related toxicity was as expected with IMRT. The RP2D was determined as 22% baseline tumour volume. Preliminary signs of antitumour activity were observed.

Conclusion: Intratumoural injection of NBTXR3 followed by IMRT is feasible and demonstrated a good safety profile, supporting further evaluation at the RP2D in this patient population.

Trial Registration: ClinicalTrials.govNCT01946867.
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http://dx.doi.org/10.1016/j.ejca.2021.01.007DOI Listing
March 2021

Keynote-158 study, FDA granted accelerated approval of pembrolizumab for the treatment of patients with advanced PD-L1-positive cervical cancer.

Ann Transl Med 2020 Dec;8(23):1611

Department of Drug Development and Innovation (D3i), Institut Curie, Paris & Saint-Cloud, France.

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http://dx.doi.org/10.21037/atm-20-2656DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7791256PMC
December 2020

Phase I Trial of Debio 1143, an Antagonist of Inhibitor of Apoptosis Proteins, Combined with Cisplatin Chemoradiotherapy in Patients with Locally Advanced Squamous Cell Carcinoma of the Head and Neck.

Clin Cancer Res 2020 12 29;26(24):6429-6436. Epub 2020 Sep 29.

Department of Radio-Oncology, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland.

Purpose: Debio 1143 is an oral antagonist of inhibitor of apoptosis proteins, which enhances tumor response with concomitant chemoradiotherapy. Addition of Debio 1143 to cisplatin-based chemoradiotherapy in locally advanced squamous cell carcinomas of the head and neck (LA-SCCHN) was evaluated in a phase I/II study to determine the MTD and recommended phase II dose (RP2D). Here, phase I results are reported.

Patients And Methods: Treatment-naïve patients with LA-SCCHN (stages III/IVA/IVB) received Debio 1143 (100, 200, 300 mg/day), for 14 days every 3 weeks, with cisplatin (100 mg/m², every 3 weeks), for three cycles, and concomitant conventional fractionation radiotherapy (70 Gy/7 weeks). Dose-limiting toxicity (DLT) was evaluated over 9 weeks using continual reassessment.

Results: Fourteen patients were treated/evaluable for DLT. Median age was 64.5 years, and all patients were current/former smokers. Primary tumors were hypopharynx, oropharynx (all human papillomavirus/p16 negative), larynx, and oral cavity. Two of six patients at 200 mg/day had DLT (grade 3 tubular necrosis, grade 3 aspartate aminotransferase/alanine aminotransferase increase, grade 4 febrile neutropenia, and grade 3 lipase increase), which was considered the MTD and RP2D. Common grade 3-4 adverse events were dysphagia (36%) and mucositis (29%). Laboratory abnormalities were frequent and generally mild, including anemia, white blood cell decrease, and increased creatinine. Addition of Debio 1143 did not compromise chemotherapy administration. Overall locoregional control rate at 18 months was 85%. Overall response rate was 85%, including 69% complete responses. Progression-free survival rate at 24 months was 74%.

Conclusions: The RP2D of Debio 1143 is 200 mg/day for 14 days, every 3 weeks, when combined with concomitant high-dose cisplatin chemoradiotherapy in LA-SCCHN. Debio 1143 addition to chemoradiotherapy was safe and manageable. Preliminary efficacy is encouraging and supports further development.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-0425DOI Listing
December 2020

A Phase 1 dose-escalation study to evaluate safety, pharmacokinetics and pharmacodynamics of AsiDNA, a first-in-class DNA repair inhibitor, administered intravenously in patients with advanced solid tumours.

Br J Cancer 2020 11 25;123(10):1481-1489. Epub 2020 Aug 25.

Medical Oncology, Centre Léon Bérard, Lyon, France.

Background: AsiDNA, a first-in-class oligonucleotide-mimicking double-stranded DNA breaks, acts as a decoy agonist to DNA damage response in tumour cells. It also activates DNA-dependent protein kinase and poly (adenosine diphosphate [ADP]-ribose) polymerase enzymes that induce phosphorylation of H2AX and protein PARylation.

Methods: The aim of this Phase 1 study was to determine dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), safety and pharmacokinetics/pharmacodynamics of AsiDNA administered daily for 3 days in the first week then weekly thereafter. Twenty-two patients with advanced solid tumours were enrolled in 5 dose levels: 200, 400, 600, 900, and 1300 mg, using a 3 + 3 design.

Results: The MTD was not reached. IV AsiDNA was safe. Two DLTs (grade 4 and grade 3 hepatic enzymes increased at 900 and 1300 mg), and two related SAE at 900 mg (grade 3 hypotension and grade 4 hepatic enzymes increased) were reported. AsiDNA PK increased proportionally with dose. A robust activation of DNA-PK by a significant posttreatment increase of γH2AX was evidenced in tumour biopsies.

Conclusion: The dose of 600 mg was identified as the optimal dose for further clinical development.

Clinical Trial Registration: Clinical trial registration (NCT number): NCT03579628.
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http://dx.doi.org/10.1038/s41416-020-01028-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7653034PMC
November 2020

Fine-needle aspiration as an alternative to core needle biopsy for tumour molecular profiling in precision oncology: prospective comparative study of next-generation sequencing in cancer patients included in the SHIVA02 trial.

Mol Oncol 2021 01 15;15(1):104-115. Epub 2020 Sep 15.

Department of Radiology, Institut Curie, PSL Research University, Paris & Saint-Cloud, France.

High-throughput molecular profiling of solid tumours using core needle biopsies (CNB) allows the identification of actionable molecular alterations, with around 70% success rate. Although several studies have demonstrated the utility of small biopsy specimens for molecular testing, there remains debate as to the sensitivity of the less invasive fine-needle aspiration (FNA) compared to CNB to detect molecular alterations. We aimed to prospectively evaluate the potential of FNA to detect such alterations in various tumour types as compared to CNB in cancer patients included in the SHIVA02 trial. An in-house amplicon-based targeted sequencing panel (Illumina TSCA 99.3 kb panel covering 87 genes) was used to identify pathogenic variants and gene copy number variations (CNV) in concomitant CNB and FNA samples obtained from 61 patients enrolled in the SHIVA02 trial (NCT03084757). The main tumour types analysed were breast (38%), colon (15%), pancreas (11%), followed by cervix and stomach (7% each). We report 123 molecular alterations (85 variants, 23 amplifications and 15 homozygous deletions) among which 98 (80%) were concordant between CNB and FNA. The remaining discordances were mainly related to deletions status, yet undetected alterations were not exclusively specific to FNA. Comparative analysis of molecular alterations in CNB and FNA showed high concordance in terms of variants as well as CNVs identified. We conclude FNA could therefore be used in routine diagnostics workflow and clinical trials for tumour molecular profiling with the advantages of being minimally invasive and preserve tissue material needed for diagnostic, prognostic or theranostic purposes.
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http://dx.doi.org/10.1002/1878-0261.12776DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7782085PMC
January 2021

Pseudoprogression and Hyperprogression as New Forms of Response to Immunotherapy.

BioDrugs 2020 Aug;34(4):463-476

Department of Drug Development and Innovation (D3i), Institut Curie, Saint-Cloud, Paris, France.

Indications of immunotherapy in oncology are continuously expanding, and unconventional types of response have been observed with these new treatments. These include transient progressive disease followed by a partial response, described as pseudoprogression, that raises the question of treatment beyond progression; and rapid disease progression associated with clinical decline, reported as hyperprogression. However, there are currently no consensual definitions of these phenomena and their impact on daily practice remains unclear. We reviewed existing data on pseudoprogression and hyperprogression with a focus on the definitions, incidence, predictive factors, potential biological mechanisms, and methods published to help distinguish pseudoprogression from progression and hyperprogression. The incidence of pseudoprogression ranged from 0 to 15%, with some authors also including disease stabilization after a first progression. For hyperprogression, incidence ranged from 4 to 29% with various definitions, and several authors reported a correlation with worse survival. Both phenomena were observed in a large panel of cancer types. Several radiological and biological methods have been reported to help distinguish pseudoprogression from progression and hyperprogression, such as analysis of radiomics, and circulating-tumor DNA or cell-free DNA, but these need to be confirmed in larger prospective cohorts. In conclusion, pseudoprogression and hyperprogression are both frequent types of responses under immunotherapy, and there is a need to better characterize these to improve the management of cancer patients. Treatment beyond progression should always be considered with caution and necessitates close clinical monitoring. In case of suspected hyperprogression, immunotherapy should be stopped early.
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http://dx.doi.org/10.1007/s40259-020-00425-yDOI Listing
August 2020

Clinical Development of Molecular Targeted Therapy in Head and Neck Squamous Cell Carcinoma.

JNCI Cancer Spectr 2019 Dec 12;3(4):pkz055. Epub 2019 Nov 12.

Department of Drug Development and Innovation (D3i), Institut Curie, Paris & Saint-Cloud, France.

A better understanding of cancer biology has led to the development of molecular targeted therapy, which has dramatically improved the outcome of some cancer patients, especially when a biomarker of efficacy has been used for patients' selection. In head and neck oncology, cetuximab that targets epidermal growth factor receptor is the only targeted therapy that demonstrated a survival benefit, both in the recurrent and in the locally advanced settings, yet without prior patients' selection. We herein review the clinical development of targeted therapy in head and neck squamous cell carcinoma in light of the molecular landscape and give insights in on how innovative clinical trial designs may speed up biomarker discovery and deployment of new molecular targeted therapies. Given the recent approval of immune checkpoint inhibitors targeting programmed cell death-1 in head and neck squamous cell carcinoma, it remains to be determined how targeted therapy will be incorporated into a global drug development strategy that will inevitably incorporate immunotherapy.
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http://dx.doi.org/10.1093/jncics/pkz055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7049986PMC
December 2019

Sepsis and Septic Shock in Patients With Malignancies: A Groupe de Recherche Respiratoire en Réanimation Onco-Hématologique Study.

Crit Care Med 2020 06;48(6):822-829

Medical ICU, Saint-Louis Teaching Hospital, Paris, France.

Objectives: Cancer affects up to 20% of critically ill patients, and sepsis is one of the leading reasons for ICU admission in this setting. Early signals suggested that survival might be increasing in this population. However, confirmation studies have been lacking. The goal of this study was to assess trends in survival rates over time in cancer patients admitted to the ICU for sepsis or septic shock over the last 2 decades.

Data Source: Seven European ICUs.

Study Selection: A hierarchical model taking into account the year of admission and the source dataset as random variables was used to identify risk factors for day 30 mortality.

Data Extraction: Data from cancer patients admitted to ICUs for sepsis or septic shock were extracted from the Groupe de Recherche Respiratoire en Réanimation Onco-Hématologique database (1994-2015).

Data Synthesis: Overall, 2,062 patients (62% men, median [interquartile range] age 59 yr [48-67 yr]) were included in the study. Underlying malignancies were solid tumors (n = 362; 17.6%) or hematologic malignancies (n = 1,700; 82.4%), including acute leukemia (n = 591; 28.7%), non-Hodgkin lymphoma (n = 461; 22.3%), and myeloma (n = 244; 11.8%). Two-hundred fifty patients (12%) underwent allogeneic hematopoietic stem cell transplantation and 640 (31.0%) were neutropenic at ICU admission. Day 30 mortality was 39.9% (823 deaths). The year of ICU admission was associated with significant decrease in day 30 mortality over time (odds ratio, 0.96; 95% CI, 0.93-0.98; p = 0.001). Mechanical ventilation (odds ratio, 3.25; 95% CI, 2.52-4.19; p < 0.01) and vasopressors use (odds ratio, 1.42; 95% CI, 1.10-1.83; p < 0.01) were independently associated with day 30 mortality, whereas underlying malignancy, allogeneic hematopoietic stem cell transplantation, and neutropenia were not.

Conclusions: Survival in critically ill oncology and hematology patients with sepsis improved significantly over time. As outcomes improve, clinicians should consider updating admission policies and goals of care in this population.
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http://dx.doi.org/10.1097/CCM.0000000000004322DOI Listing
June 2020

One-year survival in patients with solid tumours discharged alive from the intensive care unit after unplanned admission: A retrospective study.

J Crit Care 2020 06 30;57:36-41. Epub 2020 Jan 30.

Medical ICU, APHP Hopital Saint Louis, 1 avenue Claude Vellefaux, 75010 Paris, France. Electronic address:

Purpose: Outcomes in cancer patients after unplanned ICU admission was reassessed.

Methods: retrospective cohort of patients with solid tumours admitted to ICU over a 10 years period.

Results: 622 patients (age 62 [53-70]) were analysed. The most common primary sites of cancer were lung (n = 133; 21.4%) and digestive tract (n = 126; 20.2%) The ICU mortality rate was 22.2% (n = 138). Among 470 ICU survivors, the 1-year mortality was 41.3% (95% CI, 36-45.9) (n = 167). Factors independently associated with 1-year mortality were ICU admission after 2010 (HR 0.53 (0.37-0.76), p < .001), disease status (respectively, HR = 1.88 (1.0.2-3.45), p = .002) for locally advanced cancer and HR = 2.23 (1.35-3.67), p = .003) for metastatic cancer), poor performance status (HR = 1.58 (1.08-2.31), p = .019), newly diagnosed cancer at ICU admission (HR = 2.02 (1.28-3.20), p = .003), inability to receive oncologic treatment after ICU discharge (HR = 5.34 (3.49-8.18), p < .001) and decision to withhold life-sustaining treatment during ICU stay (HR = 2.34 (1.50-3.65), p < .001).

Conclusions: Among the factors associated with one-year mortality after ICU discharge, the possibility of receiving oncologic treatment after ICU discharge seems crucial.
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http://dx.doi.org/10.1016/j.jcrc.2020.01.027DOI Listing
June 2020

Hyperprogressive Disease during Anti-PD-1 (PDCD1) / PD-L1 (CD274) Therapy: A Systematic Review and Meta-Analysis.

Cancers (Basel) 2019 Nov 1;11(11). Epub 2019 Nov 1.

Internal Medicine V, Department of Hematology & Oncology, Medical University Innsbruck, 6020 Innsbruck, Austria.

Hyperprogressive disease (HPD) is a recently acknowledged pattern of rapid tumor progression after the initiation of immune checkpoint inhibitors. HPD has been observed across various types of tumors and has been associated with poor survival. We performed a meta-analysis to identify baseline (i.e., prior to programmed cell death 1 [PD-1, PDCD1] / programmed cell death 1 ligand 1 [PD-L1, CD274] inhibitor therapy) patient factors associated with risks of developing HPD during PD-1/PD-L1 inhibitor therapy. We searched eight databases until 6 June 2019. We calculated the summary odds ratio (OR) and its 95% confidence interval (CI) using the random-effects model and explored between-study heterogeneity and small-study effects. A total of nine articles was eligible (217 HPD cases, 1519 cancer patients) for meta-analysis. There was no standard definition of HPD, and the incidence of HPD ranged from 1 to 30%. We identified twenty-three baseline patient factors, of which five factors were statistically significantly associated with HPD. These were serum lactate dehydrogenase (LDH) above the upper normal limit (OR = 1.89, 95% CI = 1.02-3.49, = 0.043), more than two metastatic sites (OR = 1.86, 1.34-2.57, < 0.001), liver metastases (OR = 3.33, 2.07-5.34, < 0.001), Royal Marsden Hospital prognostic score of 2 or above (OR = 3.33, 1.96-5.66, < 0.001), and positive PD-L1 expression status that was inversely correlated with HPD (OR = 0.60, 0.36-0.99, = 0.044). Between-study heterogeneity was low. Evidence of small-study effect was found in one association (PD-L1 expression). Subset analyses of patients with non-small cell lung cancer showed similar results. Future studies are warranted to identify underlying molecular mechanisms and to test their roles as predictive biomarkers of HPD.
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http://dx.doi.org/10.3390/cancers11111699DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6896059PMC
November 2019

Immune gene expression in head and neck squamous cell carcinoma patients.

Eur J Cancer 2019 11 5;121:210-223. Epub 2019 Oct 5.

Department of Drug Development and Innovation, Institut Curie, Paris & Saint-Cloud, France; INSERM U900 Research Unit, Institut Curie, Saint-Cloud, France; Versailles-Saint-Quentin-en-Yvelines University, Montigny-le-Bretonneux, France. Electronic address:

Background: Nivolumab and pembrolizumab targeting programmed cell death protein 1 (PD-1) have recently been approved among patients with recurrent and/or metastatic head and neck squamous cell carcinoma (HNSCC) who failed platinum therapy. We aimed to evaluate the prognostic value of selected immune gene expression in HNSCC.

Patients And Methods: We retrospectively assessed the expression of 46 immune-related genes and immune-cell subpopulation genes including immune checkpoints by real-time polymerase chain reaction among 96 patients with HNSCC who underwent primary surgery at Institut Curie between 1990 and 2006. Univariate and multivariate analyses were performed to assess the prognostic value of dysregulated genes.

Results: The Median age of the population was 56 years [range: 35-78]. Primary tumour location was oral cavity (45%), oropharynx (21%), larynx (18%) and hypopharynx (17%). Twelve patients (13%) had an oropharyngeal human papillomavirus-positive tumour. Most significantly overexpressed immune-related genes were TNFRSF9/4-1BB (77%), IDO1 (75%), TNFSF4/OX40L (74%) and TNFRSF18/GITR (74%), and immune-cell subpopulation gene was FOXP3 (62%). Eighty-five percent of tumours analysed overexpressed actionable immunity genes, including PD-1/PD-L1, TIGIT, OX40/OX40L and/or CTLA4. Among the immune-related genes, high OX40L mRNA level (p = 0.0009) and low PD-1 mRNA level (p = 0.004) were associated with the highest risk of recurrence. Among the immune-cell subpopulation genes, patients with high PDGFRB mRNA level (p < 0.0001) and low CD3E (p = 0.0009) or CD8A mRNA levels (p = 0.004) were also at the highest risk of recurrence.

Conclusions: OX40L and PDGFRB overexpression was associated with poor outcomes, whereas PD-1 overexpression was associated with good prognosis in patients with HNSCC treated with primary surgery, suggesting their relevance as potential prognostic biomarkers and major therapeutic targets.
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http://dx.doi.org/10.1016/j.ejca.2019.08.028DOI Listing
November 2019

Pembrolizumab for the treatment of cervical cancer.

Expert Opin Biol Ther 2019 09 23;19(9):871-877. Epub 2019 Jul 23.

b Department of Drug Development and Innovation (D3i), Institut Curie , Paris & Saint-Cloud , France.

: The prognosis of patients with recurrent and/or metastatic cervical cancer remains poor, with a 5-year survival rate of 17%. Most of cervical cancers are associated with the human papillomavirus (HPV) infection that leads to viral antigens production, supporting the development of immunotherapy in cervical cancer. : Here we report the pharmacologic properties, clinical efficacy, and safety profile of pembrolizumab, an IgG4-kappa humanized monoclonal antibody against the programmed cell death protein 1 (PD-1) receptor, for the treatment of cervical cancer. : Single agent pembrolizumab has limited efficacy in the recurrent and/or metastatic setting in an unselected patient population. However, durable responses in PD-L1-expressing cervical cancer patients led the U.S. Food and Drug Administration to grant accelerated approval of pembrolizumab in this patient population. Outside this patient population, further development involves combinations with other treatment options including chemotherapy, radiotherapy and other immunotherapeutic agents. The identification of biomarkers of efficacy beyond PD-L1 expression will be essential in order to identify patients who will most likely benefit from pembrolizumab.
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http://dx.doi.org/10.1080/14712598.2019.1646721DOI Listing
September 2019

Molecular screening programs in different countries: what we learned and perspectives.

Curr Opin Oncol 2019 09;31(5):445-453

Department of Drug Development and Innovation (D3i), Institut Curie.

Purpose Of Review: Precision medicine arised as a new paradigm in oncology in which molecular profiling aims at guiding therapy in oncology. The implementation of precision medicine necessitates setting up molecular tumor boards (MTBs) that coordinate the workflow of tumor samples to efficiently seek for actionable molecular alterations. We review here the main precision medicine initiatives that involve MTBs and decipher challenges that still need to be overcome along with future perspectives for a broader implementation of precision medicine in routine patient care.

Recent Findings: MTBs have been implemented in multiple countries. They identify actionable molecular alteration in up to 50% of patients. However, around 10-20% receive matched therapy and less than 6% of patients experience an objective response. The challenges that need to be overcome for a successful implementation of precision medicine include an earlier molecular profiling of patients during their disease course, the use of liquid biopsies that allow sequential analyses, along with more exhaustive gene panels and extended access to drugs.

Summary: Molecular screening programs allow to successfully guiding patients to individualized therapy in a minority of patients, and few patients actually benefit from these programs.
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http://dx.doi.org/10.1097/CCO.0000000000000561DOI Listing
September 2019

Hyperprogression under Immunotherapy.

Int J Mol Sci 2019 May 30;20(11). Epub 2019 May 30.

Department of Drug Development and Innovation (D3i), Institut Curie, Paris & Saint-Cloud, France.

Immunotherapy is now widely prescribed in oncology, leading to the observation of new types of responses, including rapid disease progression sometimes reported as hyperprogression. However, only a few studies have assessed the question of hyperprogression and there is no consensual definition of this phenomenon. We reviewed existing data on hyperprogression in published studies, focusing on reported definitions, predictive factors, and potential biological mechanisms. Seven studies retrospectively assessed hyperprogression incidence, using various definitions, some based on the tumoral burden variation across time with repeated computed-tomography (CT) scan, others based on an association of radiological and clinical criteria. Reported hyperprogression incidence varied between 4% and 29% of all responses, mostly in multi-tumor cohorts and with patients receiving immune checkpoint inhibitors. Hyperprogression correlated with worse chances of survival than standard progression in two studies. However, no strong predictive factors of hyperprogression were identified, and none were consistent across studies. In total, hyperprogression is a frequent pattern of response under immunotherapy, with a strong impact on patient outcome. There is a need for a consensual definition of hyperprogression. Immunotherapy should be stopped early in cases where there is suspicion of hyperprogression.
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http://dx.doi.org/10.3390/ijms20112674DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6600249PMC
May 2019

Inhibition of PI3K pathway increases immune infiltrate in muscle-invasive bladder cancer.

Oncoimmunology 2019;8(5):e1581556. Epub 2019 Mar 16.

Institut Curie, PSL Research University, INSERM U932, Paris, France.

Although immune checkpoint inhibitors have shown improvement in survival in comparison to chemotherapy in urothelial bladder cancer, many patients still fail to respond to these treatments and actual efforts are made to identify predictive factors of response to immunotherapy. Understanding the tumor-intrinsic molecular basis, like oncogenic pathways conditioning the presence or absence of tumor-infiltrating T cells (TILs), should provide a new rationale for improved anti-tumor immune therapies. In this study, we found that urothelial bladder cancer from human samples bearing gene mutations was significantly associated with lower expression of a defined immune gene signature, compared to unmutated ones. We identified a reduced 10-gene immune gene signature that discriminates muscle-invasive bladder cancer (MIBC) samples according to immune infiltration and mutation. Using a humanized mouse model, we observed that BKM120, a pan-PI3K inhibitor, significantly inhibited the growth of a human bladder cancer cell line bearing a mutation, associated to increased immune cell infiltration (hCD45+). Using qRT-PCR, we also found an increase in the expression of chemokines and immune genes in mutated tumors from mice treated with BKM120, reflecting an active immune infiltrate in comparison to untreated ones. Moreover, the addition of BKM120 rendered -mutated tumors sensitive to PD-1 blockade. Our results provide a relevant rationale for combination strategies of PI3K inhibitors with immune checkpoint inhibitors to overcome resistance to immune checkpoint inhibitors.
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http://dx.doi.org/10.1080/2162402X.2019.1581556DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6492984PMC
March 2019

Molecular profiling in precision medicine oncology.

Nat Med 2019 05;25(5):711-712

Department of Drug Development and Innovation (D3i), Institut Curie, Paris & Saint-Cloud, France.

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http://dx.doi.org/10.1038/s41591-019-0442-2DOI Listing
May 2019

[Hot topics about early clinical trials at ASCO congress 2018: News pathways, new targets, new associations].

Bull Cancer 2018 Nov 16;105(11):1084-1093. Epub 2018 Oct 16.

Institut Jean Godinot, département oncologie médicale, avenue du Général Koenig, 51100 Reims, France.

Looking at the results of the early trials presented at the 2018 American Society of Clinical Oncology (ASCO) conference can help identify the molecules and strategies that will potentially enter the practices of tomorrow. It is in this spirit that this subject has justified the attention of residents in oncology and the writing of this synthesis. Molecules that can represent breakthrough innovations are presented as well as new therapeutics under development acting on targets already validated in clinical practice and early data of checkpoint inhibitors in combination with different immunomodulators, as well as new strategies for immunotherapies (vaccines and cell therapy).
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http://dx.doi.org/10.1016/j.bulcan.2018.08.010DOI Listing
November 2018

Patterns of Response and Progression to Immunotherapy.

Am Soc Clin Oncol Educ Book 2018 May;38:169-178

From the Department of Drug Development and Innovation, Institut Curie, Paris and Saint-Cloud, France; Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY; Melanoma Institute Australia, North Sydney, NSW, Australia; INSERM U900 Research Unit, Saint-Cloud, France; Versailles Saint-Quentin-en-Yvelines University, Montigny-le-Bretonneux, France.

Patterns of response and progression to immunotherapy may differ from those observed with drugs such as chemotherapy and molecularly targeted agents. Specifically, some patients experience a response after progression that is retrospectively named pseudoprogression. This phenomenon of pseudoprogression, first reported in patients with melanoma who were treated with ipilimumab, has led to the development of immune-specific related response criteria, such as irRC (immune-related response criteria), irRECIST (immune-related RECIST), and iRECIST (immunotherapy RECIST) that allow continued treatment beyond progression. However, the rate of pseudoprogression has never exceeded 10% of patients across tumor types. Conversely, rapid progressions after immunotherapy, called hyperprogressions, were reported by three different teams in 9% to 29% of patients treated with immunotherapy. Because of the absence of control arms in these studies, it remains to be determined whether these rapid progressions reflect a detrimental effect of immunotherapy in these patients. Finally, preliminary data suggest that immunotherapy might also affect response to subsequent standard therapies. In total, given the rarity of pseudoprogressions across tumor types and the recent description of hyperprogressions, classic RECIST remains a reasonable and rational method to assess response to immunotherapy. Continuation of treatment beyond progression should be proposed only in carefully selected patients whose clinical conditions have improved and who have not experienced severe toxicities. Although there is an urgent need to identify predictive biomarkers of efficacy to immunotherapy, there is an equally urgent need to identify predictive factors of progression or possibly hyperprogression.
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http://dx.doi.org/10.1200/EDBK_200643DOI Listing
May 2018

Precision medicine strategies in oncology: mixed approaches to matched therapies.

Future Oncol 2018 01 11;14(2):105-109. Epub 2017 Dec 11.

Department of Medical Oncology, Institut Curie, Paris & Saint-Cloud, France.

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http://dx.doi.org/10.2217/fon-2017-0524DOI Listing
January 2018

Pembrolizumab in cervical cancer: latest evidence and clinical usefulness.

Ther Adv Med Oncol 2017 Jun 8;9(6):431-439. Epub 2017 May 8.

Department of Medical Oncology, Institut Curie, INSERM U900 Research unit, 35 rue Dailly, 92210 Saint-Cloud, France.

Cervical cancer is the fourth most common cause of cancer-related deaths in women worldwide. With the development of detection of precancerous lesions and preventive human papillomavirus (HPV) vaccination program, a survival improvement has been observed in these patients in developed countries, although disparities in accessibility to treatments exist across countries. While early-stage cervical cancer can be curable with surgery, prognosis of patients who recur remains poor, with limited treatment options. In this latter setting, recently, bevacizumab, an antiangiogenic monoclonal antibody targeting vascular endothelial growth factor (VEGF), has been shown to improve overall survival in combination with chemotherapy as compared with chemotherapy alone. No standard treatments exist beyond this treatment regimen. New effective treatments are therefore much needed in this setting. Immunotherapy has represented a breakthrough in recent years in oncology, with antitumor activity reported with immune-checkpoint inhibitors in a variety of tumor types. We discuss here the latest evidence and clinical usefulness of pembrolizumab, anti-PD-1 checkpoint inhibitor, in the treatment of advanced cervical cancer.
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http://dx.doi.org/10.1177/1758834017708742DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5455883PMC
June 2017

Antibody drug conjugates: the future of chemotherapy?

Curr Opin Oncol 2016 09;28(5):429-36

aDepartment of Medical Oncology, Institut Curie, Paris & Saint-Cloud bEA7285, Versailles-Saint-Quentin-en-Yvelines University, Versailles, France.

Purpose Of Review: The current review describes the rationale and current clinical development of antibody drug conjugates (ADCs), along with their perspectives for the future.

Recent Findings: Trastuzumab emtansine was the first ADC approved by the U.S. Food and Drug Administration for the treatment of human epidermal growth factor receptor 2 positive metastatic breast cancer in the second-line setting, with a high efficacy and a favorable safety profile. ADC represents an exciting new class of cancer therapeutics that combines a targeted approach for delivering cytotoxic agents. About 30 new ADCs are currently under investigation in oncology.

Summary: ADCs are empowered antibodies designed to exploit the targeting ability of monoclonal antibodies (mAbs) by linking them to cytotoxic agents, giving them higher tumor selectivity, and potentially an increased therapeutic window, as compared with cytotoxic agents alone. The key components of ADCs include a mAb, a stable linker and a cytotoxic agent. In linking mAbs with cytotoxic agents, the aim is to optimize the properties of both components, bringing their complementary features together. Trastuzumab emtansine has been the first ADC to be marketed in human epidermal growth factor receptor 2 positive metastatic breast cancer. Current clinical development of ADCs includes a variety of targets, as well as combinations with other therapeutic agents, such as chemotherapy, radiotherapy, targeted therapies, and immune checkpoint inhibitors.
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http://dx.doi.org/10.1097/CCO.0000000000000310DOI Listing
September 2016
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