Publications by authors named "Amaury Daste"

42 Publications

Avelumab for platinum-ineligible/refractory recurrent and/or metastatic squamous cell carcinoma of the head and neck: phase Ib results from the JAVELIN Solid Tumor trial.

J Immunother Cancer 2021 Oct;9(10)

Department of Medical Oncology, Lille University & Oscar Lambret Cancer Center, Lille, France.

Background: Recurrent and/or metastatic (R/M) disease develops in approximately 65% of patients with squamous cell carcinoma of the head and neck (SCCHN) and is associated with a poor prognosis. Immune checkpoint inhibitors have proven effective in multiple tumor types, including R/M SCCHN. We report the efficacy and safety of avelumab (antiprogrammed death ligand 1 antibody) in an expansion cohort of patients with platinum-refractory/ineligible R/M SCCHN enrolled in the phase I JAVELIN Solid Tumor trial (NCT01772004).

Methods: Eligible patients with R/M SCCHN were aged ≥18 years and had received ≥1 line of platinum-based chemotherapy with disease progression or recurrence within 6 months of the last dose or were ineligible for platinum-based chemotherapy. All patients received avelumab 10 mg/kg every 2 weeks. Tumor assessments were carried out by a blinded independent review committee (IRC) and investigators according to Response Evaluation Criteria in Solid Tumors V.1.1 (RECIST 1.1). Key endpoints included best overall response, duration of response (DOR) and progression-free survival (PFS) assessed by IRC and investigator per RECIST 1.1, overall survival (OS), and safety.

Results: Between April 24, 2015, and November 13, 2015, 153 patients were enrolled. Patients had a median of two prior lines of therapy for metastatic or locally advanced disease (range 0-6); 12 patients (7.8%) were not eligible for platinum-based chemotherapy. At data cut-off (December 31, 2017), the confirmed objective response rate was 9.2% (95% CI 5.1% to 14.9%) assessed by IRC and 13.1% (95% CI 8.2% to 19.5%) assessed by investigator. Median DOR was not reached (95% CI 4.2 to not estimable) based on IRC assessment. Median PFS was 1.4 months (95% CI 1.4 to 2.6) assessed by IRC and 1.8 months (95% CI 1.4 to 2.7) assessed by investigator; median OS was 8.0 months (95% CI 6.5 to 10.2). Any-grade treatment-related adverse events (TRAEs) occurred in 83 patients (54.2%) and were grade ≥3 in 10 patients (6.5%). The most common TRAEs were fatigue (n=19, 12.4%), fever (n=14, 9.2%), pruritus (n=12, 7.8%), and chills (n=11, 7.2%), and there were no treatment-related deaths.

Conclusion: Avelumab showed clinical activity and was associated with a low rate of grade ≥3 TRAEs in heavily pretreated patients with platinum-refractory/ineligible R/M SCCHN.
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http://dx.doi.org/10.1136/jitc-2021-002998DOI Listing
October 2021

Combining immune checkpoint inhibitors with chemotherapy in advanced solid tumours: A review.

Eur J Cancer 2021 Oct 13;158:47-62. Epub 2021 Oct 13.

Department of Medical Oncology, Hôpital Saint-André, Bordeaux University Hospital-CHU, Bordeaux, France. Electronic address:

The use of immune checkpoint inhibitors (ICIs), especially anti-programmed cell death 1 (PD1) and anti-programmed cell death ligand 1 (PD-L1), has changed practices in oncology, becoming a new standard of care in first or subsequent lines for several cancer subtypes. Recent data have highlighted the ability of standard chemotherapy to enhance immunogenicity and/or to break immunoresistance of the tumour and its microenvironment, leading to a rationale for the use of ICIs in combination with the standard chemotherapy regimen to improve efficacy of cancer treatment. Here, we propose to review randomised clinical trials evaluating concomitant administration of ICIs and chemotherapy, to assess clinical efficacy and safety profiles in advanced solid tumours. Association of these two modes of action on treatments has shown improved overall survival and better objective response rates than standard chemotherapy, especially in first-line treatment of non-small cell lung cancer (NSCLC) and for PD1/PD-L1 enriched tumours, highlighting a potential synergistic effect of this treatment combination in certain tumour types. However, improved survival results with the use of anti-PD-L1 avelumab as a maintenance schedule for bladder cancer raises the question of the most appropriate approach between sequential and concomitant administration of chemoimmunotherapy. To date, no trials have compared in a head-to-head protocol the administration of concomitant chemoimmunotherapy with chemotherapy, used for tumour debulking, followed by administration of ICIs. Regarding the tolerance profile, no new safety signals were found with the combination tested to date. Interestingly, recent results have shown an improved Progression Free survival 2 (PFS2) (defined as the progression after the next line of therapy) in head-and-neck cancers or NSCLC after a first-line pembrolizumab-chemotherapy combination, suggesting a potential long-lasting effect of ICIs when used in combination in the first-line setting.
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http://dx.doi.org/10.1016/j.ejca.2021.09.013DOI Listing
October 2021

Baseline co-medications may alter the anti-tumoural effect of checkpoint inhibitors as well as the risk of immune-related adverse events.

Eur J Cancer 2021 Oct 11;157:474-484. Epub 2021 Oct 11.

Department of Rheumatology, Bordeaux University Hospital, Bordeaux, France.

Purpose: As gut microbiota composition is an important determinant of response to immune checkpoint inhibitors (ICIs), we examined the effect of various co-medications known for their interaction with microbiota, when given at ICI initiation.

Patients And Methods: We identified patients with advanced cancer treated with ICI between May 2015 and September 2017 in our institution. Co-medications given within 1 month before or 1 month after the first administration of ICI were reviewed from medical records. Survival data were analysed with univariable Cox regression, and the combined effect of multiple factors was assessed with factor analysis of mixed data (FAMD). The impact of co-medications on immune-related adverse events (irAEs) occurrence was also assessed.

Results: A total of 635 patients were included. Psychotropic drugs (41%), proton pump inhibitors (PPIs; 38%), angiotensin-converting enzyme (ACE) inhibitors and/or angiotensin II receptor blockers (ARBs; 32%), glucocorticoids (26%), antibiotics (24%), statins (21%) and morphine (20%) were the most prescribed co-medications. Baseline use of antibiotics, glucocorticoids >10 mg/day, PPIs, psychotropic drugs, morphine and insulin was associated with significantly shortened overall survival and decreased tumour response, whereas coadministration of statins, ACEs and/or ARBs, non-steroidal anti-inflammatory drugs, aspirin and oral antidiabetic drugs did not impact patient outcomes. Treatments that altered the response to ICI were also associated with a decreased incidence of irAEs. FAMD revealed the respective weight of each factor or co-medication on the oncological outcomes.

Conclusion: Co-medications must be carefully assessed at the time of ICI initiation and clinicians aware of their possible deleterious effect, notably for PPIs, glucocorticoids, antibiotics and psychotropic drugs.
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http://dx.doi.org/10.1016/j.ejca.2021.08.036DOI Listing
October 2021

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

The impact of sarcopenia on the efficacy and safety of immune checkpoint inhibitors in patients with solid tumours.

Acta Oncol 2021 Sep 22:1-7. Epub 2021 Sep 22.

Department of Medical Oncology, Hôpital Saint-André, CHU Bordeaux-University of Bordeaux, Bordeaux, France.

Background: Evidence suggests that sarcopenia is a significant predictive factor of worst outcomes and treatment-associated toxicities in patients with metastatic solid tumours. The aim of this study was to explore the relationship between low muscle mass and clinical outcomes and immune-related severe toxicities (IrST) in patients treated with immune checkpoint inhibitors (ICIs).

Methods: A retrospective cohort of 261 consecutive metastatic solid tumour patients treated with ICIs were included in our study. Low muscle mass was defined as skeletal muscle index <41 cm/m for females and <43 cm/m for males if body mass index (BMI) <25 kg/m or <53 cm/m if BMI ≥ 25 kg/m. Severe toxicities (ST), including grade III-IV toxicities and side effects leading to treatment interruption, were recorded.

Results: The majority of patients ( = 179; 69%) included in this study had metastatic lung cancer. The prevalence of low muscle mass was 47%. The median progression-free survival (PFS) was 32.2 weeks for low muscle mass patients and 24.3 weeks for non-low muscle mass patients (adjusted HR, 0.80; 95% CI, 0.60-1.055;  = 0.11). For low muscle mass and non-low muscle mass lung cancer patients, median PFS was 24.0 weeks and 18.8 weeks (adjusted HR, 0.70; 95% CI, 0.50-0.98;  = 0.04) and median overall survival was 50.7 weeks and 41.1 weeks (adjusted HR, 0.77; 95% CI, 0.54-1.10,  = 0.15) respectively. Immune-related severe toxicities occurred in 3.3% and 9.4% of low muscle mass and non-low muscle mass patients respectively (adjusted OR, 0.69; 95% CI: 0.31-1.49;  = 0.35).

Conclusion: No difference in outcomes and safety was observed for low muscle mass and non-low muscle mass patients treated with ICIs.
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http://dx.doi.org/10.1080/0284186X.2021.1978540DOI 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

Cetuximab combined with paclitaxel or paclitaxel alone for patients with recurrent or metastatic head and neck squamous cell carcinoma progressing after EXTREME.

Cancer Med 2021 06 25;10(12):3952-3963. Epub 2021 May 25.

Department of Medical Oncology, CHU la Timone, AP-HM, Marseille, France.

Background: Prognosis of recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) remains poor. The addition of cetuximab, to platinum and fluorouracil chemotherapy (EXTREME regimen) has been shown to improve patients' outcomes in first-line settings.

Methods: We conducted a retrospective, multicenter study, including HNSCC that progressed after a first line of platinum-based chemotherapy and cetuximab, treated either by paclitaxel + cetuximab (PC) or paclitaxel alone (P), between January 2010 and April 2018. The end points were overall survival (OS), progression-free survival (PFS), and overall response rates (ORR). Patients were matched according to their propensity scores, estimated with a logistic regression model. The secondary objectives were to study the safety profile and to look for prognostic and predictive factors of effectiveness.

Results: Of the 340 identified patients, 262 were included in the analysis, 165 received PC, and 97 received P. In unmatched population, ORR was 16.4% with PC and 6.2% for P. Median PFS was 2.9 months [95% Confidence Interval 2.7-3.0] for PC versus 2.5 months [2.2-2.7] for P, hazard ratio (HR) = 0.770 [0.596-0.996]. Median OS was 5.5 months [4.4-6.9] for PC versus 4.2 months [3.4-4.8] for P, HR = 0.774 [0.590-1.015]. In multivariate analysis, PC was associated with better PFS and OS. These results were consistent in matched-paired population. Previous cetuximab maintenance for more than 3 months was predictive of better OS with PC.

Conclusion: Although the continuation of cetuximab in combination with paclitaxel after EXTREME provides moderate benefit, it could be an interesting option for selected patients.
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http://dx.doi.org/10.1002/cam4.3953DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8209557PMC
June 2021

Colitis presenting 5 months after the final dose of anti-PD-1: long-term monitoring is warranted after adjuvant therapy.

Immunotherapy 2021 06 28;13(9):741-744. Epub 2021 Apr 28.

Department of Medical Oncology, Hôpital Saint-André, CHU Bordeaux-University of Bordeaux, Bordeaux, France.

Immune checkpoint inhibitors have been approved as adjuvant therapy. Adverse immune events occurred during the administration of treatment, and delayed immune-related events have low incidence. A 66-year-old man was treated for hypopharynx cancer in 2012. In 2019, he was treated for a new oropharynx cancer. After undergoing surgery and complete response, the patient received nivolumab as adjuvant treatment. 5 months after the last dose of nivolumab, he presented with grade III diarrhea and abdominal pain for 3 weeks. Rectoscopy showed infiltration of mucous by lymphocytes. Corticosteroid was started resulting in a rapid decrease in symptom severity. With the increasing immune checkpoint inhibitors in adjuvant therapy, strict surveillance and education of patient in remission is necessary.
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http://dx.doi.org/10.2217/imt-2020-0282DOI Listing
June 2021

Systemic treatment of metastatic squamous cell carcinoma of the head and neck: proposal for management changes.

Curr Opin Oncol 2021 05;33(3):160-167

Centre Antoine Lacassagne, Nice.

Purpose Of Review: Worldwide, head and neck carcinomas account for 5% of all malignancies. Two-thirds of patients relapse after initial multimodal therapy. Until early 2010, the median overall survival (OS) of metastatic patients was about 10 months.

Recent Findings: New drugs have been incorporated in patient management, thus enabling an increase in OS. Several first and second line protocols are now available but the lack of direct comparison makes the choice difficult between them.

Summary: This work aims to define the comprehensive medical management of patients with relapsing head and neck carcinoma. In September 2020, the French head and neck groups GORTEC, Unicancer head and Neck group, GROCC and GETTEC decided to promote a one-day meeting to propose how to incorporate these new regimens in first and second line treatment for recurrent and metastatic head and neck cancer (R/M SCCHNC). Twelve French medical oncologist involved in the management of R/M SCCHNC for more than 10 years examined the literature and proposed a simple and practical management based on five criteria: age, delay from last platinum injection, combined positive score expression level, FIT or UNFIT patient according to physician decision, fast response needed or not.
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http://dx.doi.org/10.1097/CCO.0000000000000738DOI Listing
May 2021

Management of Immune Checkpoint Inhibitor Toxicities.

Cancer Manag Res 2020 28;12:9139-9158. Epub 2020 Sep 28.

Department of Medical Oncology, Hôpital Saint-André, CHU Bordeaux-University of Bordeaux, Bordeaux, France.

Immune checkpoint inhibitors (ICIs) have radically changed the clinical outcome of several cancers with durable responses. CTLA-4 (cytotoxic T lymphocyte antigen-4), PD-1 (programmed cell death protein 1) or PDL-1 (programmed cell death ligand protein 1) represent ICIs that can be used as monotherapy or in combination with other agents. The toxicity p\rofiles of ICIs differ from the side effects of cytotoxic agents and come with new toxicities like immune-related adverse events. Typically, these toxicities occur in all organs. However, the main organs affected are the skin, digestive, hepatic, lungs, rheumatologic, and endocrine. Most of the immune toxicity that occurs is low grade but some more severe toxicities can occur that require a rapid diagnosis and appropriate treatment. The recognition of symptoms by physicians and patient is necessary to resolve them rapidly and adapt treatment to allow the toxicity to resolve.
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http://dx.doi.org/10.2147/CMAR.S218756DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7533913PMC
September 2020

Current management and future perspectives of penile cancer: An updated review.

Cancer Treat Rev 2020 Nov 7;90:102087. Epub 2020 Aug 7.

Department of Medical Oncology, Bordeaux University Hospital, Bordeaux, France; Bordeaux University, Bordeaux, France. Electronic address:

Penile cancer (PeCa) is a rare disease worldwide, accounting for less than one percent of all malignancies in men. It usually presents as a painless ulcer or lump on the head of the penis. Squamous cell carcinoma represents the most common histological subtype of PeCa, with pathogenesis intimately linked to chronic Human Papilloma Virus (HPV) infection. Surgery is the cornerstone for the treatment of primary PeCa with potential mutilating outcome depending on the nodal extension of the disease. However, in case of extensive lymph node involvement, multidisciplinary treatment including perioperative chemotherapy and inclusion in clinical trial should be considered. To date, advanced or metastatic disease still have poor prognosis and are a therapeutic challenge with limited options, highlighting the need of new treatments and further investigations. Growing efforts to identify molecular alterations, understand the role of HPV and characterize immune contexture have expanded over the past years, providing further perspectives in prognostication, predictive biomarkers and therapeutic intervention. In this review, we provide an updated overview of current management of PeCa focusing on perioperative strategy. We discuss about new insights of the biology of PeCa and comment future directions in the field.
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http://dx.doi.org/10.1016/j.ctrv.2020.102087DOI Listing
November 2020

Bintrafusp alfa, a bifunctional fusion protein targeting TGF-β and PD-L1, in advanced squamous cell carcinoma of the head and neck: results from a phase I cohort.

J Immunother Cancer 2020 07;8(2)

Department of Medical Oncology, Centre Oscar Lambret and Lille University Hospital, Lille, France.

Background: We report the clinical activity and safety of bintrafusp alfa, a first-in-class bifunctional fusion protein composed of the extracellular domain of the transforming growth factor β (TGF-β)RII receptor (a TGF-β 'trap') fused to a human IgG1 monoclonal antibody blocking programmed death-ligand 1 (PD-L1), in patients with heavily pretreated squamous cell carcinoma of the head and neck (SCCHN).

Methods: In this phase I dose-expansion cohort, patients with advanced SCCHN not amenable to curative therapy that progressed/recurred after platinum therapy in the recurrent/metastatic setting, or <6 months after platinum therapy in the locally advanced setting, received bintrafusp alfa 1200 mg intravenously every 2 weeks. The primary endpoint was confirmed best overall response (BOR; Response Evaluation Criteria for Solid Tumors (RECIST) 1.1) per independent review committee (IRC); other endpoints included BOR per investigator and safety.

Results: As of August 24, 2018, 32 patients had received bintrafusp alfa (median follow-up 86.4 weeks; range 2-97). Per IRC, the confirmed objective response rate (ORR) was 13% (95% CI 4% to 29%; 4 partial responses (PR)); 4 patients had stable disease (SD) (disease control rate 34%; 95% CI 12% to 43%). Per investigator, there were 5 PRs (ORR, 16%), including 2 patients who developed delayed PRs after initial disease increase (total clinical response rate 22%). Responses (ORRs) were observed in patients with PD-L1-positive (12%), PD-L1-negative (17%; 73-10 antibody for immunohistochemistry), human papillomavirus (HPV)-positive (33%) and HPV-negative tumors (5%). Grade 3 treatment-related adverse events (TRAEs) were reported in 11 patients (34%), with no grade 4 TRAEs or treatment-related deaths.

Conclusions: Bintrafusp alfa showed clinical activity across subgroups of PD-L1 expression and in HPV-positive tumors and had a manageable safety profile in patients with heavily pretreated advanced SCCHN. Activity in HPV-positive tumors is favorable compared with historical data from PD-L1 inhibitors and is being further investigated in an ongoing study of HPV-associated tumors.

Trial Registration Number: NCT02517398.
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http://dx.doi.org/10.1136/jitc-2020-000664DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7342865PMC
July 2020

Adaptation of multidisciplinary meeting decisions in a medical oncology department during the COVID epidemic in a less affected region of France: a prospective analysis from Bordeaux University Hospital.

Eur J Cancer 2020 08 17;135:98-100. Epub 2020 Jun 17.

Department of Medical Oncology, Hôpital Saint-André, Bordeaux University Hospital, Bordeaux, France; Bordeaux University, France. Electronic address:

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http://dx.doi.org/10.1016/j.ejca.2020.04.039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7298500PMC
August 2020

Safety of sunitinib in patients with renal cell carcinoma following nephrectomy.

Expert Opin Drug Saf 2020 Jul 10;19(7):799-806. Epub 2020 Jun 10.

Department of Medical Oncology, Bordeaux University Hospital , Saint-André, France.

Introduction: The safety profile characteristics of sunitinib were evaluated in patients who underwent nephrectomy for kidney cancer.

Areas Covered: In this literature review, safety data were evaluated from phase III trials investigating sunitinib following nephrectomy, either in the more recent adjuvant setting after nephrectomy or in the metastatic setting, with a focus on new data from the CARMENA and SURTIME trials. In particular, the aim was to determine the specificity of toxicity in the adjuvant setting.

Expert Opinion: In the adjuvant setting, even if the toxicity profile of sunitinib does not differ significantly from that in the metastatic setting, the importance of the dose intensity and, thus, exposure has been emphasized. Consequently, as described mainly in the metastatic setting, management of the adverse effects of sunitinib remains critical.
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http://dx.doi.org/10.1080/14740338.2020.1774551DOI Listing
July 2020

Atezolizumab for the treatment of renal cell carcinoma.

Expert Opin Biol Ther 2020 07 13;20(7):679-686. Epub 2020 Apr 13.

Department of Medical Oncology, Bordeaux University Hospital , Bordeaux, France.

Introduction: The therapeutic landscape of renal cell cancer has evolved rapidly over the past 2 years with nivolumab and ipilimumab for patients with metastatic disease and an intermediate or poor prognosis, in the first line setting. More recently, data from trials combining antiangiogenic agents and immune checkpoint inhibitors demonstrated a major benefit of this treatment approach for all patients.

Areas Covered: One of three recent trials evaluated the combination of atezolizumab, an anti-programmed death ligand 1 antibody, with bevacizumab, an anti-vascular endothelial growth factor monoclonal antibody. In this manuscript, we summarize the preclinical, clinical, and safety data on atezolizumab for treatment of renal cell carcinoma and describe ongoing trials.

Expert Opinion: Atezolizumab was evaluated in combination with an antiangiogenic agent. These trials were designed based on the hypothesis that selecting patients according to the expression of programmed death ligand 1 would increase the benefit of the treatment combination. Despite positive effects on the primary endpoints progression-free survival and response rate in this selected population, overall survival in the global population did not meet the criteria for significance at the time of the intermediate analysis. The major information was a proposed tumor gene expression signature. The signature was predictive of the sensitivity to anti-angiogenic and/or immune checkpoint inhibitor therapy.
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http://dx.doi.org/10.1080/14712598.2020.1751113DOI Listing
July 2020

Prognostic factors for cancer patient admitted to a medical intensive care unit.

Acta Oncol 2020 Apr 16;59(4):458-461. Epub 2020 Jan 16.

Department of Medical Oncology, Hôpital Saint-André, CHU Bordeaux, Bordeaux, France.

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http://dx.doi.org/10.1080/0284186X.2019.1711171DOI Listing
April 2020

Response to salvage chemotherapy after progression on immune checkpoint inhibitors in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck.

Eur J Cancer 2019 11 28;121:123-129. Epub 2019 Sep 28.

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

Background: Immune checkpoint inhibitors (ICI) are active in patients with recurrent/metastatic squamous cell carcinoma of the head and neck (R/M SCCHN). Recent data suggest that exposure to ICI improves response to salvage chemotherapy (SCT) in advanced non-small-cell lung cancer. We evaluated response to chemotherapy in patients who had progressed on ICI in patients with R/M SCCHN.

Patients And Methods: A retrospective study was conducted at 4 French centres. Eligibility criteria were patients who progressed after treatment with ICI for R/M SCCHN and received SCT and for whom efficacy data were available between September 2014 and January 2018.

Results: Of 232 patients treated with ICI, 82 met eligibility criteria: 84% were male. ICI was given as monotherapy in 45% of patients or as combination in 55%. SCT included taxanes (56.1%), cetuximab in combination with taxanes or platinum (50%), platinum-based regimen (36.6%). The median number of treatment lines before SCT was 2 (range 1-6). The objective response rate (ORR) to SCT was 30%. Three patients (4%) presented complete response and 22 patients (27%) had partial response. Median progression-free survival was 3.6 months and median overall survival was 7.8 months. The age at SCT, initial tumour location, number of prior chemotherapy regimens, type of chemotherapy before ICI, best response to ICI, site of relapse and Eastern Cooperative Oncology Group at SCT were not associated with response to SCT on univariate analysis.

Conclusion: In R/M SCCHN, the ORR to SCT was high (30%) suggesting that exposure to ICI may increase tumour sensitivity to chemotherapy.
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http://dx.doi.org/10.1016/j.ejca.2019.08.026DOI Listing
November 2019

Which place for avelumab in the management of urothelial carcinoma?

Expert Opin Biol Ther 2019 09 9;19(9):863-870. Epub 2019 Jul 9.

a Department of Medical Oncology, Bordeaux University Hospital , Bordeaux , France.

: Urothelial carcinoma (UC) has a poor prognosis, with the only standard first-line metastatic treatment being platinum-based chemotherapy. Until 2018, there was no Food and Drug Administration (FDA)-approved drug for second-line setting, and only vinflunine was approved by the European Medicines Agency (EMEA) in Europe. However, targeting the programmed cell-death 1 (PD-1)/PD-ligand 1 (PD-L1) pathway with immune checkpoint inhibitor (ICI) agents has shown encouraging results. Avelumab is a human anti-PD-L1 antibody that is currently being investigated in several trials. : In this review article, we summarise preclinical, clinical, and safety data on avelumab for UC, and describeongoing trials that are evaluating avelumab for local or advanced diseases. We also compare its place in the management of UC. : Avelumab has shown clinical efficacy for metastatic and advanced UC in phase I studies after the failure of platinum-based therapy with a well-tolerated safety profile. This anti-PD-L1 targeting agent has the capacity to induce antibody-dependant cellular cytotoxicity (ADCC)-mediated tumor cell lysis compared to other ICI. These results led to FDA approval of avelumab as a second-line treatment for locally advanced and metastatic UC. Avelumab is also investigated in phase II and in a randomized phase III trial as a maintenance therapy in UC as well for combination use with chemotherapy.
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http://dx.doi.org/10.1080/14712598.2019.1637412DOI Listing
September 2019

Long-term prognosis of septic shock in cancer patients.

Support Care Cancer 2020 Mar 26;28(3):1325-1333. Epub 2019 Jun 26.

Intensive Care and Infectious Disease Unit, CHU Bordeaux, 33000, Bordeaux, France.

Objectives: In the last decades, the number of cancer patients admitted in intensive care units (ICUs) for septic shock has dramatically increased. However, prognosis data remain scarce.

Methods: To assess the 180-day mortality rate in cancer patients admitted to the ICU for septic shock, a 5-year prospective study was performed. All adult patients admitted for septic shock were included and categorized into the following two groups and four subgroups: cancer patients (solid tumor or hematological malignancy) and non-cancer patients (immunocompromised or not). Data were collected and compared between the groups. Upon early ICU admission, the decision to forgo life-sustaining therapy (DFLST) or not was made by consultation among hematologists, oncologists, and the patients or their relatives.

Results: During the study period, 496 patients were admitted for septic shock: 252 cancer patients (119 hematological malignancies and 133 solid tumors) and 244 non-cancer patients. A DFLST was made for 39% of the non-cancer patients and 52% of the cancer patients. The 180-day mortality rate among the cancer patients was 51% and 68% for those with hematological malignancies and solid cancers, respectively. The mortality rate among the non-cancer patients was 44%. In a multivariate analysis, the performance status, Charlson comorbidity index, simplified acute physiology score 2, sequential organ failure assessment score, and DFLST were independent predictors of 180-day mortality.

Conclusions: Despite early admission to the ICU, the 180-day mortality rate due to septic shock was higher in cancer patients compared with non-cancer patients, due to excess mortality in the patients with solid tumors. The long-term prognosis of cancer patients with septic shock is modulated by their general state, severity of organ failure, and DFLST.
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http://dx.doi.org/10.1007/s00520-019-04937-4DOI Listing
March 2020

The interest of sequential treatment with immune check point inhibitors followed chemotherapy: A case report.

Oral Oncol 2019 07 8;94:125-127. Epub 2019 May 8.

Department of Medical Oncology, Hôpital Saint-André, Bordeaux University Hospital-CHU, Bordeaux, France. Electronic address:

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http://dx.doi.org/10.1016/j.oraloncology.2019.05.001DOI Listing
July 2019

Dramatic response under combination of immune-oncology in head & neck cancer included in the Condor study: A case report.

Oral Oncol 2019 02 11;89:150-152. Epub 2019 Jan 11.

Department of Medical Oncology, Hôpital Saint-André, Bordeaux University Hospital-CHU Bordeaux, France; University of Bordeaux, Bordeaux, France; ImmunoConcEpt, CNRS UMR 5164, Bordeaux University, Bordeaux 33076, France.

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http://dx.doi.org/10.1016/j.oraloncology.2019.01.002DOI Listing
February 2019

Safety and Efficacy of Durvalumab With or Without Tremelimumab in Patients With PD-L1-Low/Negative Recurrent or Metastatic HNSCC: The Phase 2 CONDOR Randomized Clinical Trial.

JAMA Oncol 2019 02;5(2):195-203

Clinical Oncology, Cancer Center Centre Léon Bérard, University of Lyon, Lyon, France.

Importance: Dual blockade of programmed death ligand 1 (PD-L1) and cytotoxic T-lymphocyte associated protein 4 (CTLA-4) may overcome immune checkpoint inhibition. It is unknown whether dual blockade can potentiate antitumor activity without compromising safety in patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) and low or no PD-L1 tumor cell expression.

Objective: To assess safety and objective response rate of durvalumab combined with tremelimumab.

Design, Setting, And Participants: The CONDOR study was a phase 2, randomized, open-label study of Durvalumab, Tremelimumab, and Durvalumab in Combination With Tremelimumab in Patients With R/M HNSCC. Eligibility criteria included PD-L1-low/negative disease that had progressed after 1 platinum-containing regimen in the R/M setting. Patients were randomized (N = 267) from April 15, 2015, to March 16, 2016, at 127 sites in North America, Europe, and Asia Pacific.

Interventions: Durvalumab (20 mg/kg every 4 weeks) + tremelimumab (1 mg/kg every 4 weeks) for 4 cycles, followed by durvalumab (10 mg/kg every 2 weeks), or durvalumab (10 mg/kg every 2 weeks) monotherapy, or tremelimumab (10 mg/kg every 4 weeks for 7 doses then every 12 weeks for 2 doses) monotherapy.

Main Outcomes And Measures: Safety and tolerability and efficacy measured by objective response rate.

Results: Among the 267 patients (220 men [82.4%]), median age (range) of patients was 61.0 (23-82) years. Grade 3/4 treatment-related adverse events occurred in 21 patients (15.8%) treated with durvalumab + tremelimumab, 8 (12.3%) treated with durvalumab, and 11 (16.9%) treated with tremelimumab. Grade 3/4 immune-mediated adverse events occurred in 8 patients (6.0%) in the combination arm only. Objective response rate (95% CI) was 7.8% (3.78%-13.79%) in the combination arm (n = 129), 9.2% (3.46%-19.02%) for durvalumab monotherapy (n = 65), and 1.6% (0.04%-8.53%) for tremelimumab monotherapy (n = 63); median overall survival (95% CI) for all patients treated was 7.6 (4.9-10.6), 6.0 (4.0-11.3), and 5.5 (3.9-7.0) months, respectively.

Conclusions And Relevance: In patients with R/M HNSCC and low or no PD-L1 tumor cell expression, all 3 regimens exhibited a manageable toxicity profile. Durvalumab and durvalumab + tremelimumab resulted in clinical benefit, with minimal observed difference between the two. A phase 3 study is under way.

Trial Registration: clinicaltrials.gov Identifier: NCT02319044.
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http://dx.doi.org/10.1001/jamaoncol.2018.4628DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6439564PMC
February 2019

Dramatic response after anti PD1 treatment failure in a squamous cell carcinoma of the maxillary sinus.

Oral Oncol 2018 12 18;87:207-209. Epub 2018 Oct 18.

Department of Medical Oncology, Hôpital Saint-André, Bordeaux University Hospital-CHU, Bordeaux, France. Electronic address:

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http://dx.doi.org/10.1016/j.oraloncology.2018.10.017DOI Listing
December 2018

Progression beyond nivolumab: Stop or repeat? Dramatic responses with salvage chemotherapy.

Oral Oncol 2018 06 24;81:116-118. Epub 2018 Apr 24.

Department of Medical Oncology, Hôpital Saint-André, Bordeaux University Hospital-CHU Bordeaux, France; University of Bordeaux, Bordeaux, France; ImmunoConcEpt, CNRS UMR 5164, Bordeaux University, Bordeaux 33076, France.

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http://dx.doi.org/10.1016/j.oraloncology.2018.04.013DOI Listing
June 2018

Treatment of spinal metastases in renal cell carcinoma: A critical review.

Crit Rev Oncol Hematol 2018 May 6;125:19-29. Epub 2018 Mar 6.

Department of Medical Oncology, Hôpital Saint-André, Bordeaux University Hospital-CHU Bordeaux, 1 Rue Jean Burguet, 33000 Bordeaux, France; University of Bordeaux, Bordeaux, France.

Kidney cancer is the 9th most common cancer in men and the 14th most common in women worldwide. Renal cell carcinoma (RCC) constitutes 90% of all malignancies of the kidney. RCC, is known to be highly vascular and relatively radioresistant. Bone metastases are one of the most common metastatic sites and occur in around 30% of RCCs. They significantly impact the quality of life of patients causing pain and pathological fractures. Spinal metastases represent a particular case with regard to symptoms and treatment. Indeed, neurological pain is often added to the nociceptive pain caused by metastases. More importantly, neurological impairment can be seen, caused by spinal cord or nerve root compression (MSCC). Due to close contact with the spinal cord, the treatment of spinal bone metastases is challenging and requires a multidisciplinary approach. Specific treatment is currently focused on 4 main avenues which are surgery, radiotherapy, interventional radiology and systemic treatment. In June 2017 we carried out an extensive search on PubMed, Web of Science, and Cochrane Library to review the various treatment options and to establish a treatment strategy. This article presents the result of our critical review of the literature, given our expertise in the field.
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http://dx.doi.org/10.1016/j.critrevonc.2018.02.017DOI Listing
May 2018

Induction chemotherapy with the EXTREME regimen in frail patients with locally advanced head and neck squamous cell carcinoma.

Target Oncol 2018 04;13(2):247-252

Department of Medical Oncology, Hôpital Saint-André, Bordeaux University Hospital-CHU Bordeaux, 1 Rue Jean Burguet, 33000, Bordeaux, France.

Background: Induction chemotherapy (IC) with TPF (docetaxel, cisplatin, 5FU) for locally advanced head and neck squamous cell carcinoma (LAHNSCC) is limited to fit patients.

Objective: We conducted a retrospective cohort study to assess the use of the EXTREME regimen (platinum-based therapy, 5FU, cetuximab) as IC in frail patients with LAHNSCC.

Patients And Methods: Retrospective analysis of all consecutive patients with unresectable LAHNSCC treated with the EXTREME regimen, with or without 5FU as IC, from two French centers from 2008 to 2015. We assessed the rate of completed sequence defined as at least two cycles of IC and definitive radiation therapy.

Results: We included 34 patients with a median age of 56 years [44-70]. The primary site of tumor development was the oropharynx (67%, n=23, all HPV negative), hypopharynx (21%, n=7) and the oral cavity (12%, n=4). At inclusion, patients presented: T4 76, 5% (n=26), N2c 41% (n=14), N3 26% (n=9), stage disease IVa 62% (n=21), IVb 38% (n=13), ECOG PS2 38% (n=13), decreased weight (10% in one month or 15% in 6 months) 74% (n=25). The sequence was achieved for 76% (n=26) of patients and 80% (n=27) presented a clinical response after the chemotherapy course with notably increased weight (40%, n=11) or general status (75%, n=26). Median PFS and OS were 5.7 and 15.5 months, respectively. Disease progression at 3 months was significantly associated with decreased median overall survival (13.6 versus 21.9 months, p=0.01).

Conclusion: This is the first study to report the use of the EXTREME regimen as induction chemotherapy, and although this IC was used in a very frail population, the majority completed the sequence with significant clinical benefit.
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http://dx.doi.org/10.1007/s11523-018-0552-7DOI Listing
April 2018

Rheumatic disorders associated with immune checkpoint inhibitors in patients with cancer-clinical aspects and relationship with tumour response: a single-centre prospective cohort study.

Ann Rheum Dis 2018 03 16;77(3):393-398. Epub 2017 Nov 16.

Rheumatology Department, Centre Hospitalier Universitaire, Bordeaux, Aquitaine, France.

Objectives: To evaluate the prevalence and type of rheumatic immune-related adverse events (irAEs) in patients receiving immune checkpoint inhibitors (ICIs), as well as the correlation with tumour response.

Methods: This was a single-centre prospective observational study including all cancer patients receiving ICIs. The occurrence of irAEs and tumour response was assessed on a regular basis. Patients who experienced musculoskeletal symptoms were referred to the department of rheumatology for clinical evaluation and management.

Results: From September 2015 to May 2017, 524 patients received ICIs and 35 were referred to the department of rheumatology (6.6%). All but one of the rheumatic irAEs occurred with anti-programmed cell death protein 1(PD-1)/PD-1 ligand 1(PD-L1) antibodies, with a median exposure time of 70 days. There were two distinct clinical presentations: (1) inflammatory arthritis (3.8%) mimicking either rheumatoid arthritis (n=7), polymyalgia rheumatica (n=11) or psoriatic arthritis (n=2) and (2) non-inflammatory musculoskeletal conditions (2.8%; n=15). One patient with rheumatoid arthritis was anti-cyclic citrullinated peptide (anti-CCP) positive. Nineteen patients required glucocorticoids, and methotrexate was started in two patients. Non-inflammatory disorders were managed with non-steroidal anti-inflammatory drugs, analgesics and/or physiotherapy. ICI treatment was pursued in all but one patient. Patients with rheumatic irAEs had a higher tumour response rate compared with patients without irAEs (85.7% vs 35.3%; P<0.0001).

Conclusion: Since ICIs are used with increasing frequency, knowledge of rheumatic irAEs and their management is of major interest. All patients were responsive either to low-to-moderate doses of prednisone or symptomatic therapies and did not require ICI discontinuation. Furthermore, tumour response was significantly higher in patients who experienced rheumatic irAEs.
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http://dx.doi.org/10.1136/annrheumdis-2017-212257DOI Listing
March 2018

Phase I study of axitinib and everolimus in metastatic solid tumours and extension to metastatic renal cell carcinoma: Results of EVAX study.

Eur J Cancer 2017 11 5;85:39-48. Epub 2017 Sep 5.

Department of Medical Oncology, Cancer University Institute of Toulouse Oncopole, Toulouse, France.

Purpose: Anti-angiogenic and mammalian target of rapamycin inhibitors have shown efficacy in solid tumours. Reported combination of both drugs was deemed to be too toxic. Due to a potential favourable safety profile of axitinib (AX), a phase I study combining everolimus (EV) and AX for solid tumours was explored.

Experimental Design: Patients (pts) with advanced cancers were enrolled in an escalation phase I study to investigate the safety of the combination. Pharmacokinetic profile and functional vascular imaging were performed. An extension to pts with naive metastatic renal cell carcinoma (MRCC) was explored.

Results: 15 pts were included over three different dose levels (DLs); DL 0: AX 3 mg BID (twice daily)/EV 5 mg OD (once daily); DL 1: AX 5 mg BID/EV 5 mg OD and DL 2: AX 5 mg BID/EV 10 mg OD for 28 d. One dose-limiting toxicity (DLT) was reported at DL 0: grade (Gr) III diarrhoea and one DLT at DL 2: Gr III asthenia. Three severe adverse events (AEs) in two pts were unexpected: jaw osteonecrosis, recurrent renal failure and cardiomyopathy. Maximum tolerated dose (MTD) was level 2. After 1st cycle, Gr III or Gr II AEs of interest were mainly asthenia, diarrhoea and anorexia. All pts but one showed tumour shrinkage. Partial responses (PRs) were seen in one pt with bladder carcinoma and in one pt in 1st line MRCC in the escalating phase. In the extension phase in naive MRCC treated at MTD, five pts had a PR and one pt had a prolonged stable disease.

Conclusion: The recommended dose for phase II is AX 5 mg BID/EV 10 mg OD.
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http://dx.doi.org/10.1016/j.ejca.2017.07.031DOI Listing
November 2017

Immune checkpoint inhibitors and elderly people: A review.

Eur J Cancer 2017 09 6;82:155-166. Epub 2017 Jul 6.

Department of Medical Oncology, Hôpital Saint-André, Bordeaux University Hospital-CHU Bordeaux, France; University of Bordeaux, Bordeaux, France; Clinical Investigational Center, CIC, INSERM CIC 1401, Bordeaux University Hospital, Bordeaux, France.

Immune checkpoint inhibitors, including targeting programmed cell death 1, programmed cell death ligand 1, and cytotoxic T lymphocyte antigen 4 pathways, are a new type of cancer treatment. This approach of targeting the immune system has demonstrated dramatic efficacy for several cancers, and various drugs have been approved by health authorities and are used in clinical practice. Elderly patients (≥65 years) represent most of the cancers diagnosed and deaths by age group, with an increase expected over the next decade. However, this subgroup of patients is under-represented in clinical trials. Ageing is also associated with a decrease in the effectiveness of the immune system and in alterations to it. Few specific trials have been carried out for immunotherapy in elderly people, with most patients considered to be fit. In this review, we discuss the impact of ageing and immunosenescence on immune system functions, and we assess the safety and efficacy of immune checkpoint inhibitors in elderly patients, principally from the data of pivotal clinical trials with subgroup analysis. Tolerance in elderly patients seems similar to younger people, but efficacy seems different between younger and elderly patients according to the type of cancer, some showing no difference and others less efficacy in the elderly subgroup. However, the numbers in elderly groups are small and more investigation is needed, with specific clinical trials for elderly cancer patients.
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http://dx.doi.org/10.1016/j.ejca.2017.05.044DOI Listing
September 2017

Pulmonary arterial hypertension due to an intratumoral shunt: an unexpected side effect of sunitinib.

Future Oncol 2017 Jun 13;13(14):1219-1221. Epub 2017 Jun 13.

Department of Medical Oncology, Saint-André Hospital, University Hospital, CHU Bordeaux, France.

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http://dx.doi.org/10.2217/fon-2017-0012DOI Listing
June 2017
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