Publications by authors named "Aude Fléchon"

97 Publications

Pembrolizumab alone or combined with chemotherapy versus chemotherapy as first-line therapy for advanced urothelial carcinoma (KEYNOTE-361): a randomised, open-label, phase 3 trial.

Lancet Oncol 2021 May 26. Epub 2021 May 26.

University of Michigan Health System, Ann Arbor, MI, USA.

Background: PD-1 and PD-L1 inhibitors are active in metastatic urothelial carcinoma, but positive randomised data supporting their use as a first-line treatment are lacking. In this study we assessed outcomes with first-line pembrolizumab alone or combined with chemotherapy versus chemotherapy for patients with previously untreated advanced urothelial carcinoma.

Methods: KEYNOTE-361 is a randomised, open-label, phase 3 trial of patients aged at least 18 years, with untreated, locally advanced, unresectable, or metastatic urothelial carcinoma, with an Eastern Cooperative Oncology Group performance status of up to 2. Eligible patients were enrolled from 201 medical centres in 21 countries and randomly allocated (1:1:1) via an interactive voice-web response system to intravenous pembrolizumab 200 mg every 3 weeks for a maximum of 35 cycles plus intravenous chemotherapy (gemcitabine [1000 mg/m] on days 1 and 8 and investigator's choice of cisplatin [70 mg/m] or carboplatin [area under the curve 5] on day 1 of every 3-week cycle) for a maximum of six cycles, pembrolizumab alone, or chemotherapy alone, stratified by choice of platinum therapy and PD-L1 combined positive score (CPS). Neither patients nor investigators were masked to the treatment assignment or CPS. At protocol-specified final analysis, sequential hypothesis testing began with superiority of pembrolizumab plus chemotherapy versus chemotherapy alone in the total population (all patients randomly allocated to a treatment) for the dual primary endpoints of progression-free survival (p value boundary 0·0019), assessed by masked, independent central review, and overall survival (p value boundary 0·0142), followed by non-inferiority and superiority of overall survival for pembrolizumab versus chemotherapy in the patient population with CPS of at least 10 and in the total population (also a primary endpoint). Safety was assessed in the as-treated population (all patients who received at least one dose of study treatment). This study is completed and is no longer enrolling patients, and is registered at ClinicalTrials.gov, number NCT02853305.

Findings: Between Oct 19, 2016 and June 29, 2018, 1010 patients were enrolled and allocated to receive pembrolizumab plus chemotherapy (n=351), pembrolizumab monotherapy (n=307), or chemotherapy alone (n=352). Median follow-up was 31·7 months (IQR 27·7-36·0). Pembrolizumab plus chemotherapy versus chemotherapy did not significantly improve progression-free survival, with a median progression-free survival of 8·3 months (95% CI 7·5-8·5) in the pembrolizumab plus chemotherapy group versus 7·1 months (6·4-7·9) in the chemotherapy group (hazard ratio [HR] 0·78, 95% CI 0·65-0·93; p=0·0033), or overall survival, with a median overall survival of 17·0 months (14·5-19·5) in the pembrolizumab plus chemotherapy group versus 14·3 months (12·3-16·7) in the chemotherapy group (0·86, 0·72-1·02; p=0·0407). No further formal statistical hypothesis testing was done. In analyses of overall survival with pembrolizumab versus chemotherapy (now exploratory based on hierarchical statistical testing), overall survival was similar between these treatment groups, both in the total population (15·6 months [95% CI 12·1-17·9] with pembrolizumab vs 14·3 months [12·3-16·7] with chemotherapy; HR 0·92, 95% CI 0·77-1·11) and the population with CPS of at least 10 (16·1 months [13·6-19·9] with pembrolizumab vs 15·2 months [11·6-23·3] with chemotherapy; 1·01, 0·77-1·32). The most common grade 3 or 4 adverse event attributed to study treatment was anaemia with pembrolizumab plus chemotherapy (104 [30%] of 349 patients) or chemotherapy alone (112 [33%] of 342 patients), and diarrhoea, fatigue, and hyponatraemia (each affecting four [1%] of 302 patients) with pembrolizumab alone. Six (1%) of 1010 patients died due to an adverse event attributed to study treatment; two patients in each treatment group. One each occurred due to cardiac arrest and device-related sepsis in the pembrolizumab plus chemotherapy group, one each due to cardiac failure and malignant neoplasm progression in the pembrolizumab group, and one each due to myocardial infarction and ischaemic colitis in the chemotherapy group.

Interpretation: The addition of pembrolizumab to first-line platinum-based chemotherapy did not significantly improve efficacy and should not be widely adopted for treatment of advanced urothelial carcinoma.

Funding: Merck Sharp and Dohme, a subsidiary of Merck, Kenilworth, NJ, USA.
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http://dx.doi.org/10.1016/S1470-2045(21)00152-2DOI Listing
May 2021

Response to systemic therapy in fumarate hydratase-deficient renal cell carcinoma.

Eur J Cancer 2021 Jul 8;151:106-114. Epub 2021 May 8.

Department of Medical Oncology, Gustave Roussy, Villejuif, France; Réseau National de Référence pour Cancers Rares de l'Adulte PREDIR labellisé par l'INCa, Hôpital Bicêtre, AP-HP, Le Kremlin Bicêtre, France. Electronic address:

Purpose: Fumarate hydratase-deficient (FHdef) renal cell carcinoma (RCC) is a rare entity associated with the hereditary leiomyomatosis and RCC syndrome with no standard therapy approved. The aim of this retrospective study was to evaluate the efficacy of different systemic treatments in this population.

Methods: We performed a multicentre retrospective analysis of Fhdef RCC patients to determine the response to systemic treatments. The endpoints were objective response rate (ORR), time-to-treatment failure (TTF), and overall survival (OS). The two latter were estimated using the Kaplan-Meier method.

Results: Twenty-four Fhdef RCC patients were identified, and 21 under systemic therapy were included in the analysis: ten received cabozantinib, 14 received sunitinib, nine received "other antiangiogenics" (sorafenib, pazopanib, and axitinib), three received erlotinib-bevacizumab (E-B), three received mTOR inhibitors, and 11 received immune checkpoint blockers (ICBs). ORR for treatments were 50% for cabozantinib, 43% for sunitinib, 63% for "other antiangiogenics," and 30% for E-B, whereas ORR was 0% for mTOR inhibitors and 18% for ICBs. The median TTF (mTTF) was significantly higher with antiangiogenics (11.6 months) than with mTOR inhibitors (4.4 months) or ICBs (2.7 months). In the first-line setting, antiangiogenics presented a higher ORR compared with nivolumab-ipilimumab (64% versus 25%) and a significantly superior mTTF (11.0 months vs 2.5 months; p = 0.0027). The median OS from the start of the first systemic treatment was 44.0 months (95% confidence interval: 13.0-95.0).

Conclusions: We report the first European retrospective study of Fhdef RCC patients treated with systemic therapy with a remarkably long median OS of 44.0 months. Our results suggest that antiangiogenics may be superior to ICB/mTOR inhibitors in this population.
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http://dx.doi.org/10.1016/j.ejca.2021.04.009DOI Listing
July 2021

An adaptive, biomarker-directed platform study of durvalumab in combination with targeted therapies in advanced urothelial cancer.

Nat Med 2021 05 3;27(5):793-801. Epub 2021 May 3.

CRUK Manchester Institute Cancer Biomarker Centre, Manchester, UK.

Durvalumab is a programmed death-ligand 1 (PD-L1) inhibitor with clinical activity in advanced urothelial cancer (AUC). AUC is characterized by several recurrent targetable genomic alterations. This study ( NCT02546661 , BISCAY) combined durvalumab with relevant targeted therapies in biomarker-selected chemotherapy-refractory AUC populations including: (1) fibroblast growth factor receptor (FGFR) inhibitors in tumors with FGFR DNA alterations (FGFRm); (2) pharmacological inhibitor of the enzyme poly-ADP ribose polymerase (PARP) in tumors with and without DNA homologous recombination repair deficiency (HRRm); and (3) TORC1/2 inhibitors in tumors with DNA alteration to the mTOR/PI3K pathway.This trial adopted a new, biomarker-driven, multiarm adaptive design. Safety, efficacy and relevant biomarkers were evaluated. Overall, 391 patients were screened of whom 135 were allocated to one of six study arms. Response rates (RRs) ranged 9-36% across the study arms, which did not meet efficacy criteria for further development. Overall survival (OS) and progression-free survival (PFS) were similar in the combination arms and durvalumab monotherapy arm. Biomarker analysis showed a correlation between circulating plasma-based DNA (ctDNA) and tissue for FGFRm. Sequential circulating tumor DNA analysis showed that changes to FGFRm correlated with clinical outcome. Our data support the clinical activity of FGFR inhibition and durvalumab monotherapy but do not show increased activity for any of the combinations. These findings question the targeted/immune therapy approach in AUC.
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http://dx.doi.org/10.1038/s41591-021-01317-6DOI Listing
May 2021

TROPHY-U-01: A Phase II Open-Label Study of Sacituzumab Govitecan in Patients With Metastatic Urothelial Carcinoma Progressing After Platinum-Based Chemotherapy and Checkpoint Inhibitors.

J Clin Oncol 2021 Apr 30:JCO2003489. Epub 2021 Apr 30.

Fred Hutchinson Cancer Research Center, University of Washington, Seattle Cancer Care Alliance, Seattle, WA.

Purpose: Patients with metastatic urothelial carcinoma (mUC) who progress on platinum-based combination chemotherapy (PLT) and checkpoint inhibitors (CPIs) have limited options that offer objective response rates (ORRs) of approximately 10% with a median overall survival (OS) of 7-8 months. Sacituzumab govitecan (SG) is a TROP-2-directed antibody-drug conjugate with an SN-38 payload that has shown preliminary activity in mUC.

Methods: TROPHY-U-01 (ClinicalTrials.gov identifier: NCT03547973) is a multicohort, open-label, phase II, registrational study. Cohort 1 includes patients with locally advanced or unresectable or mUC who had progressed after prior PLT and CPI. Patients received SG 10 mg/kg on days 1 and 8 of 21-day cycles. The primary outcome was centrally reviewed ORR; secondary outcomes were progression-free survival, OS, duration of response, and safety.

Results: Cohort 1 included 113 patients (78% men; median age, 66 years; 66.4% visceral metastases; median of three [range, 1-8] prior therapies). At a median follow-up of 9.1 months, the ORR was 27% (31 of 113; 95% CI, 19.5 to 36.6); 77% had decrease in measurable disease. Median duration of response was 7.2 months (95% CI, 4.7 to 8.6 months), with median progression-free survival and OS of 5.4 months (95% CI, 3.5 to 7.2 months) and 10.9 months (95% CI, 9.0 to 13.8 months), respectively. Key grade ≥ 3 treatment-related adverse events included neutropenia (35%), leukopenia (18%), anemia (14%), diarrhea (10%), and febrile neutropenia (10%), with 6% discontinuing treatment because of treatment-related adverse events.

Conclusion: SG is an active drug with a manageable safety profile with most common toxicities of neutropenia and diarrhea. SG has notable efficacy compared with historical controls in pretreated mUC that has progressed on both prior PLT regimens and CPI. The results from this study supported accelerated approval of SG in this population.
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http://dx.doi.org/10.1200/JCO.20.03489DOI Listing
April 2021

Synchronous brain metastases as a poor prognosis factor in clear cell renal carcinoma: a strong argument for systematic brain screening.

J Neurooncol 2021 May 10;153(1):133-141. Epub 2021 Apr 10.

Centre Léon Bérard, 28 Prom. Lea et Napoleon Bullukian, 69008, Lyon, France.

Purpose: Brain metastases (BM) usually represent a poor prognostic factor in solid tumors. About 10% of patients with renal cancer (RCC) will present BM. Local therapies such as stereotactic radiotherapy (SRT), whole brain radiotherapy (WBRT), and surgery are used to achieve brain control. We compared survival between patients with synchronous BM (SynBM group) and metachronous BM (MetaBM group).

Methods: It is a retrospective study of patients with clear cell renal cell carcinoma (ccRCC) and BM treated with TKI between 2005 and 2019 at the Centre Léon Bérard in Lyon. We collected prognostic factors: The International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk score, the TNM stage, the histological subtypes and the Fuhrman grade. Overall survival (OS) was defined from diagnosis of metastatic ccRCC to death. Brain progression-free survival (B-PFS) was defined from focal brain therapy to brain progression or death.

Results: 99 patients were analyzed, 44 in the SynBM group and 55 in the MetaBM group. OS in the MetaBM group was 49.4 months versus 19.6 months in the SynBM group, p = 0.0002. The median time from diagnosis of metastasic disease to apparition of BM in the MetaBM group was 22.9 months (4.3; 125.7). SRT was used for 101 lesions (66.4%), WBRT for 25 patients (16.4%), surgery for 21 lesions (13.8%), surgery followed by radiation for 5 lesions (3.3%). B-PFS for all patients was 7 months (IC95% [5.0-10.5]).

Conclusions: Survival of patients with synchronous BM is inferior to that of patients with metachronous BM. Outcome is poor in both cases after diagnosis of BM. Brain screening should be encouraged at time of diagnosis of metastatis in ccRCC.
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http://dx.doi.org/10.1007/s11060-021-03751-5DOI Listing
May 2021

Dose-Dense Methotrexate, Vinblastine, Doxorubicin, and Cisplatin With or Without Panitumumab in Patients With Advanced Urothelial Carcinoma: Multicenter, Randomized, French Unicancer GETUG/AFU 19 Study.

Clin Genitourin Cancer 2021 Feb 24. Epub 2021 Feb 24.

Department of Pathology, René Huguenin Curie Institute, Saint Cloud, France.

This study looked at whether epidermal growth factor receptor inhibition by the monoclonal antibody panitumumab could increase the efficacy of standard chemotherapy in advanced urothelial cancer. Results were disappointing, with higher toxicity and no improvement in efficacy in the combination arm.

Background: Epidermal growth factor receptor (EGFR) overexpression is frequent and associated with poor outcome in urothelial carcinoma. EGFR inhibition could improve the antitumor activity of chemotherapy.

Patients And Methods: Patients with advanced, treatment-naïve, histologically confirmed advanced urothelial carcinoma and no HRAS or KRAS mutation in the primary tumor received dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (dd-MVAC) without or with the anti-EGFR monoclonal antibody panitumumab (Pmab). A randomized (1:2) phase II design was used with progression-free survival (PFS) as the primary endpoint.

Results: Ninety-seven eligible patients were randomized; 96 patients were evaluable for toxicity and 87 for efficacy. The median PFS were 6.8 months (95% confidence interval [CI], 6.3-9.2) for dd-MVAC and 5.7 months (95% CI, 4.6-6.4 months) for dd-MVAC+Pmab. For both immunohistochemical and molecular definition of basal/squamous-like (BASQ) tumors, no difference was observed in objective response rates or PFS between the two arms in BASQ and non-BASQ tumors.

Conclusion: dd-MVAC+Pmab was associated with more serious adverse events and no improvement in efficacy outcomes.
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http://dx.doi.org/10.1016/j.clgc.2021.02.005DOI Listing
February 2021

Multicentric phase II trial of TI-CE high-dose chemotherapy with therapeutic drug monitoring of carboplatin in patients with relapsed advanced germ cell tumors.

Cancer Med 2021 04 5;10(7):2250-2258. Epub 2021 Mar 5.

Institut Claudius Regaud, IUCT-Oncopole, Toulouse, France.

Background: High-dose chemotherapy (HDCT) with TI-CE regimen is a valid option for the treatment of relapsed advanced germ cell tumors (GCT). We report a phase II trial with therapeutic drug monitoring of carboplatin for optimizing area under the curve (AUC) of this drug.

Methods: Patients with unfavorable relapsed GCT were treated according to TI-CE regimen: two cycles combining paclitaxel and ifosfamide followed by three cycles of HD carboplatin plus etoposide administered on 3 days. Carboplatin dose was adapted on day 3 based on carboplatin clearance (CL) at day 1 in order to reach a target AUC of 24 mg.min/mL per cycle. The primary endpoint was the complete response (CR) rate.

Results: Eighty-nine patients who received HDCT were included in the modified intent-to-treat (mITT) analysis. Measured mean AUC was 24.4 mg.min/mL per cycle (22.4 and 26.8 mg.min/mL for 10th and 90th percentiles). Thirty-five (44.3%) patients achieved a CR with or without surgery of residual masses and 20 patients achieved a partial response with negative tumor markers. With a median follow-up of 44 months (m), median PFS was 12.3 m (95% CI: 7.5-25.9) and OS was 46.3 m (95% CI: 18.6-not reached). For high- and very high-risk patients, according to the International Prognostic Score at first relapse or treated after at least one salvage treatment (n = 51), 2-year PFS rate was 41.1%.

Conclusion: The rates of complete and favorable responses were clinically relevant in this very poor risk population. Individual monitoring of carboplatin plasma concentration permitted to control more accurately the target AUC and avoided both underexposure and overexposure to the drug.
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http://dx.doi.org/10.1002/cam4.3687DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7982623PMC
April 2021

Real-world evidence of cabozantinib in patients with metastatic renal cell carcinoma: Results from the CABOREAL Early Access Program.

Eur J Cancer 2021 01 27;142:102-111. Epub 2020 Nov 27.

Centre Hospitalier Universitaire Saint-André, Bordeaux, France.

Background: Real-world data on cabozantinib in metastatic renal cell carcinoma (mRCC) is limited. This study (CABOREAL) reports treatment patterns and outcomes for patients treated with cabozantinib through the French Early Access Program.

Patients And Methods: This multicentre (n = 26), observational, retrospective study enrolled patients with mRCC who had received ≥1 dose of cabozantinib. Overall survival (OS) was estimated using the Kaplan-Meier method; subgroups were compared using the log-rank test. A multiple Cox regression model assessed predictive factors of OS after cabozantinib initiation.

Results: Four hundred and ten recruited patients started treatment between September 2016 and February 2018: the Eastern Cooperative Oncology Group Performance Status ≥2, 39.3%; poor International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk, 31.7%; 0-1, 2 and ≥3 previous treatment lines, 25.3%, 33.4% and 41.2%, respectively; bone metastases, 55.9%; brain metastases, 16.8%. Median (min-max) follow-up was 14.4 (0-30) months. Overall, 57.0% of patients had a dose reduction, 15.6% an alternative dose schedule. The median average daily dose was 40.0 mg. Median (quartile [Q]1-Q3) treatment duration was 7.6 (0.1-29.1) months, median OS was 14.4 months, and the 12-month OS rate was 56.5% (95% confidence interval: 51.5-61.2). Most patients (54.4%) received subsequent treatment. Predictive factors associated with longer OS were body mass index ≥25 kg/m (p = 0.0021), prior nephrectomy (p = 0.0109), favourable or intermediate IMDC risk (p < 0.0001) and cabozantinib initiation at 60 mg/day (p = 0.0486).

Conclusions: In the largest real-world study to date, cabozantinib was effective in unselected, heavily pretreated patients with mRCC. Initiation at 60 mg/day was associated with improved outcomes. CLINICALTRIALS.

Gov Identifier: NCT03744585.
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http://dx.doi.org/10.1016/j.ejca.2020.09.030DOI Listing
January 2021

A Risk-benefit Analysis of Prophylactic Anticoagulation for Patients with Metastatic Germ Cell Tumours Undergoing First-line Chemotherapy.

Eur Urol Focus 2020 Oct 6. Epub 2020 Oct 6.

Hematology Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. Electronic address:

Background: It remains unclear which patients with metastatic germ cell tumours (mGCTs) need prophylactic anticoagulation to prevent venous thromboembolic events (VTEs).

Objective: To assess the risk and onset of VTEs stratified by risk factors.

Design, Setting, And Participants: This multi-institutional retrospective dataset included mGCT patients treated with first-line platinum-based chemotherapy.

Intervention: Patients with prophylactic anticoagulation were excluded.

Outcome Measurements And Statistical Analysis: A regression analysis was performed to select risk factors for VTEs. The simulated number needed to treat (NNT) and the number needed to harm (NNH) with prophylactic anticoagulation were calculated based on the cumulative incidences retrieved from this study and hazard rates of recently published trials describing the efficacy of prophylactic anticoagulation to prevent VTEs and the risk of bleeding events.

Results And Limitations: From 1120 patients, 121 (11%) had a VTE, which occurred prior to chemotherapy in 49 (4%) and on or after chemotherapy in 72 (6%). Six patients (<1%) had a bleeding event without anticoagulation. After backward regression, the one risk factor for a VTE during or after chemotherapy was the use of a venous access device. The simulated cumulative VTE incidence from prophylactic anticoagulation for patients on or after chemotherapy would translate into an NNT of 45 (95% confidence interval [CI] 36-56) and an NNH of 186 (95% CI 87-506). Limitations are mainly related to the retrospective nature of the study.

Conclusions: The mGCTs associated VTEs are most common before and during, but not after, chemotherapy. Avoiding venous access device and/or prophylactic anticoagulation with an acceptable risk-benefit profile may decrease VTE occurring on chemotherapy.

Patient Summary: We found that venous thromboembolic events (VTEs) occur rarely after chemotherapy. Based on experience of prophylactic anticoagulation in other cancers, we conclude that the risk of VTE in men undergoing chemotherapy for metastatic germ cell tumours can be decreased by thromboprophylaxis with a reasonable risk-benefit profile and by avoidance of venous access devices.
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http://dx.doi.org/10.1016/j.euf.2020.09.017DOI Listing
October 2020

Could Aberrant Migration Explain Metachronous Germ Cell Tumors?

Cancer Invest 2021 Feb 6;39(2):195-201. Epub 2020 Nov 6.

Institut d'Hématologie et d'Oncologie Pédiatrique, Lyon, France.

Background: Extragonadal germ cell tumors (GCTs) are thought to arise as a result of local transformation of primordial gonadal cells (PGCs) that become misplaced during embryogenesis. With the exception of bilateral testis tumors, metachronous GCT (i.e., occurring at a site classically described for primary GCTs) are rare events.

Patients And Methods: The clinical, radiological, and molecular data (if available) of patients with metachronous GCT were analyzed.

Results: Three Caucasian males were identified: case 1 presented with a pineal germinoma 19 years after a mediastinal seminoma that had been treated with chemotherapy, case 2 presented with a pineal non-seminomatous GCT (NSGCT) that occurred three years after a mediastinal seminoma treated with chemotherapy, and case 3 presented with a mediastinal seminoma concomitant with a suprasellar germinoma that occurred two years after a stage I testicular NSGCT treated exclusively with surgery. None of these patients had a positive family history or disorder of sex development. Molecular data were available for cases 2 and 3. In case 2, a gene biallelic inactivation in the second tumor suggested chemoresistance to cisplatin. This was further confirmed by tumor progression during second-line treatment. In case 3, the molecular analysis revealed different profiles in the three tumors, thus suggesting distinct tumor cell origins.

Conclusion: These rare cases should alert clinicians of the possibility of multiple GCTs that should not be considered to be relapses. The underlying physiopathology is unknown, but multiple PGC mismigrations is a likely cause. Initial treatment with cisplatin may select chemo-resistant clones, thereby making the subsequent treatment more of a challenge.
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http://dx.doi.org/10.1080/07357907.2020.1828447DOI Listing
February 2021

Nivolumab Plus Ipilimumab for Metastatic Castration-Resistant Prostate Cancer: Preliminary Analysis of Patients in the CheckMate 650 Trial.

Cancer Cell 2020 10 10;38(4):489-499.e3. Epub 2020 Sep 10.

Department of Cancer Medicine, Gustave Roussy, University of Paris Saclay, 94800 Villejuif, France.

Metastatic castration-resistant prostate cancer (mCRPC) is immunologically "cold" and predominantly resistant to immune checkpoint therapy due to few tumor-infiltrating T cells. Ipilimumab (anti-CTLA-4) or anti-PD-1/PD-L1 monotherapy failed to show a significant benefit. Although the PD-1/PD-L1 pathway is minimally expressed in prostate tumors, we previously demonstrated that PD-1/PD-L1 expression increases as a compensatory inhibitory pathway in parallel with an ipilimumab-induced increase in tumor-infiltrating T cells. Here, we report the largest trial to date in mCRPC with anti-CTLA-4 plus anti-PD-1 (nivolumab 1 mg/kg plus ipilimumab 3 mg/kg; CheckMate 650, NCT02985957). With median follow-ups of 11.9 and 13.5 months in cohorts 1 (pre-chemotherapy; n = 45) and 2 (post-chemotherapy; n = 45), objective response rate was 25% and 10%, and median overall survival was 19.0 and 15.2 months, respectively. Four patients, two in each cohort, had complete responses. Exploratory studies identify potential biomarkers of response. Grade 3-4 treatment-related adverse events have occurred in ∼42%-53% of patients, with four treatment-related deaths. Therefore, dose/schedule modifications have been implemented.
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http://dx.doi.org/10.1016/j.ccell.2020.08.007DOI Listing
October 2020

Randomized Phase III Trial of Dose-dense Methotrexate, Vinblastine, Doxorubicin, and Cisplatin, or Gemcitabine and Cisplatin as Perioperative Chemotherapy for Patients with Muscle-invasive Bladder Cancer. Analysis of the GETUG/AFU V05 VESPER Trial Secondary Endpoints: Chemotherapy Toxicity and Pathological Responses.

Eur Urol 2021 02 28;79(2):214-221. Epub 2020 Aug 28.

Department of Medical Oncology, Saint-Louis-APHP, Faculté de Paris, France.

Background: Perioperative chemotherapy (neoadjuvant or adjuvant) has been developed to increase overall survival for nonmetastatic muscle-invasive bladder cancer (MIBC). Retrospective studies or prospective phase II trials have been reported to use dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (dd-MVAC) or gemcitabine and cisplatin (GC). As dd-MVAC has shown higher response rates in metastatic disease, better efficacy is expected in the perioperative setting.

Objective: We designed a randomized phase III trial to compare the efficacy of dd-MVAC or GC in MIBC perioperative (neoadjuvant or adjuvant) setting.

Design, Setting And Participants: A total of 500 patients were randomized from February 2013 to March 2018 in 28 centers and received either six cycles of dd-MVAC every 2 wk or four cycles of GC every 3 wk.

Outcome Measurements And Statistical Analysis: The primary endpoint (progression-free survival at 3 yr) was not reported. We focused on secondary endpoints: chemotherapy toxicity and pathological responses.

Results And Limitations: In the neoadjuvant group, 218 patients received dd-MVAC and 219 received GC. Of the patients, 60% received six cycles in the dd-MVAC arm and 84% received four cycles in the GC arm; 199 (91%) and 198 (90%) patients underwent surgery, respectively. Complete pathological response (ypT0pN0) was observed in 84 (42%) and 71 (36%) patients, respectively (p=0.2). An organ-confined status (
Conclusions: The toxicity of dd-MVAC was manageable with more severe asthenia and GI side effects than that of GC in perioperative chemotherapy. A higher local control rate (complete pathological response, tumor downstaging, or organ confined) was observed in the dd-MVAC arm (p=0.021). However, such data have to be confirmed on progression-free survival, with primary endpoint data expected in mid-2021.

Patient Summary: The authors have designed a randomized phase III controlled study comparing the efficacy of gemcitabine and cisplatin, and dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (dd-MVAC) in patients for whom chemotherapy has been decided, before or after radical cystectomy. Higher toxicity regarding asthenia and gastrointestinal side effects along with a better bladder control rate were observed in the dd-MVAC arm. However, such data have to be confirmed on progression-free survival, with primary endpoint data expected in mid-2021.
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http://dx.doi.org/10.1016/j.eururo.2020.08.024DOI Listing
February 2021

Pharmacokinetic and Pharmacogenetic Study of Etoposide in High-Dose Protocol (TI-CE) for Advanced Germ Cell Tumors.

Pharm Res 2020 Jul 16;37(7):147. Epub 2020 Jul 16.

Institut Claudius-Regaud, IUCT-Oncopole, Toulouse, France.

Background: Etoposide dosing is based on body surface area. We evaluated if further dose individualization would be required for high dose (HD) etoposide within the TI-CE (taxol, ifosfamide, carboplatin, and etoposide) protocol.

Methods: Eighty-eight patients received 400 mg/m/day of etoposide as a 1-hour IV infusion on 3 consecutive days over 3 cycles as part of a phase II trial evaluating efficacy of therapeutic drug monitoring (TDM) of carboplatin in the TI-CE HD protocol. Pharmacokinetic (PK) data were analyzed using population PK model on NONMEM to quantify inter- and intra-individual variabilities. Relationship between etoposide exposure and pharmacodynamic (PD) endpoints, and between selected genetic polymorphisms and tumor response or toxicity were evaluated.

Results: The inter-patient, inter- and intra-cycle variabilities of clearance were 16%, 9% and 0.1%, respectively. The PK-PD relationship was not significant despite a trend toward higher etoposide exposure in patients responding to treatment. A significant correlation was found between exposure and extended neutropenia at cycle 3. A significant association between UGT1A1*28 polymorphism and late neutropenia was observed but needs further evaluation.

Conclusions: The present study suggests that neither a priori dose individualization nor dose adaptation using TDM is required validating body surface area dosing of etoposide in the TI-CE protocol.
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http://dx.doi.org/10.1007/s11095-020-02861-5DOI Listing
July 2020

[Treatment of testicular germ cell tumors relapse].

Bull Cancer 2020 Sep 8;107(9):912-924. Epub 2020 Jul 8.

Département d'oncologie médicale, centre Léon-Bérard, 28, rue Laennec, 69337 Lyon cedex 08, France.

Seminomatous (SGCT) and non-seminomatous (NSGCT) germ cell tumors (GCT) are rare but their incidence are increasing. We will discuss different therapeutic strategies in relapse disease: patients with stage I germ cell tumor have an excellent prognosis with a cure rate approaching 98-99 %, whatever the histology and the chosen treatment (surveillance strategy or adjuvant treatment). Relapses are observed among 20% of patients with stage I SGCT or low risk NSGCT and 50 % of patients with high risk NSGCT. Patients are treated according to the international prognosis group (IGCCCG) for SGCT and low risk NSGCT, naïve of chemotherapy. After an adjuvant treatment, the protocol must be adapted to the number of previous cycles (1 or 2 BEP) and to the prognosis group. Five to 50% of patients relapse after a first line of metastatic chemotherapy according to initial prognosis group. Dose-dense chemotherapy according to the GETUG13 protocol reduces the risk of relapse for the patients with poor-risk group NSGCT and unfavorable tumor marker decline. The prognosis of patients with relapsed or refractory GCT after a first line is more negative since only half of them will be cured by salvage standard chemotherapy. An international therapeutic trial (TIGER) is ongoing in first line salvage treatment evaluating high-dose chemotherapy (HDCT) with hematopoietic stem cell transplantation (HSCT). Finally, developing biomarkers for predicting clinical relapse, the management in expert centers of these patients and participation in therapeutic innovation are important perspectives for a better understanding and treatment of these patients with a poorer prognosis.
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http://dx.doi.org/10.1016/j.bulcan.2020.03.012DOI Listing
September 2020

[Intensification by high dose chemotherapy for germ-cell tumors, still an ongoing subject?]

Bull Cancer 2020 Jun;107(5S):S41-S48

Département de cancérologie médicale, centre Léon-Bérard, 28, rue Laennec, 69008 Lyon, France.

More than 80 % of patient with metastatic germ cell tumor are cured with first line chemotherapy. Twenty to 30 % of patients will experience relapse or refractory disease with a very poor long-term prognosis. Most of them had metastatic germ cell tumors with a poor prognosis according to the international germ cell classification collaborative group (IGCCCG). The role of treatment intensification by high dose chemotherapy (HDCT) followed by stem cell rescue has not been demonstrated yet in the first line setting compared to standard chemotherapy. The role of HDCT in first or second salvage is also not yet demonstrated, many studies have been published in this situation with a lot of different regimen. Outside clinical trial, HDCT remains an option in salvage therapy, depending on many factors including prognostics factors, previous therapy, general condition and reference center consideration to select eligible patient who could benefit the most of this approach. Results from the international randomized trial TIGER will provide evidence-based information for HDCT strategy.
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http://dx.doi.org/10.1016/S0007-4551(20)30277-0DOI Listing
June 2020

Brain metastases from germ cell tumor: time to reconsider radiotherapy?

Crit Rev Oncol Hematol 2020 Jun 16;150:102946. Epub 2020 Apr 16.

Department of Medical Oncology, Institut Claudius Regaud / Institut Universitaire du Cancer de Toulouse - Oncopole, 1 avenue Irène Joliot-Curie, 31000, Toulouse, France. Electronic address:

The presence of brain metastases (BMs) from germ cell tumor (GCT) remains a rare situation. BMs predominantly occur among patients with testis primary tumor site, and are almost exclusively associated with non-seminomatous (NS) histologies. Two situations must be distinguished, which differ in terms of clinical presentation, overall prognostic and management. At diagnosis, BMs are almost systematically associated with extra-cerebral metastases and the cornerstone of treatment is chemotherapy, while the role of local treatment remains controversial. In the metachronous setting, BMs more frequently constitute an isolated site of relapse, the outcome is poorer, and the role of local treatment is more consensual. However, all these data widely come from old reports, with outdated radiation techniques. The recent advances in radiation oncology, especially the rising use of stereotactic radiotherapy, could lead to the reconsideration of ancient dogmas regarding the "radiosensitivity" of (NS)GCT and the role of radiotherapy among patients with BMs.
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http://dx.doi.org/10.1016/j.critrevonc.2020.102946DOI Listing
June 2020

Axitinib in first-line for patients with metastatic papillary renal cell carcinoma: Results of the multicentre, open-label, single-arm, phase II AXIPAP trial.

Eur J Cancer 2020 04 5;129:107-116. Epub 2020 Mar 5.

Medical Oncology, Gustave Roussy, Villejuif, France.

Introduction: Papillary renal cell carcinoma (PRCC) represents 10%-15% of renal carcinomas. No standard treatments exist for metastatic PRCC (mPRCC) patients. Axitinib is indicated as second-line treatment in metastatic clear cell renal carcinoma, and we aim to assess the efficacy of this vascular endothelial growth factor receptor inhibitor in front line for mPRCC.

Methods: This French multicentre phase II study AXIPAP enrolled untreated mPRCC patients, with measurable disease, Eastern Cooperative Oncology Group performance status ≤ 1 and adequate organ functions. PRCC had to be confirmed by histology expert central review. Axitinib was administered orally 5 mg twice daily. Primary end-point was progression-free rate at 24 weeks (24w-PFR) by central review.

Results: Fifty-six patients were screened, and 44 included (13 type 1, 30 type 2 and 1 non-specified). The median follow-up was 32.0 (13.1-39.9) months. The 24w-PFR was 45.2% (95% confidence interval [CI], 32.6% to +∞), the objective response rate was 28.6% (95% CI, 15.7%-44.6%) (type 1: 7.7%; type 2: 35.7%). The overall median progression free survival was 6.6 months (95% CI, 5.5-9.2), 6.7 months (95% CI, 5.5-9.2) and 6.2 months (95% CI, 5.4-9.2) for type 1 and 2, respectively. Median overall survival was 18.9 months (95% CI, 12.8-not reached). Adverse events were as expected; grade 3-4 treatment-related adverse events were rare except hypertension (27%).

Conclusions: Axitinib demonstrated encouraging efficacy in mPRCC patients, especially in type 2 PRCC. Toxicity was manageable. Axitinib appears as an interesting option for first-line treatment and to be worth further investigation in combination with immunotherapy in these patients. Expert pathology review should be recommended in this setting.

Clinical Trial Registration: ClinicalTrials.gov, NCT02489695.
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http://dx.doi.org/10.1016/j.ejca.2020.02.001DOI Listing
April 2020

[Docetaxel for octogerian metastatic castration-resistant prostate cancer patient: A multicentric ten years' experience].

Bull Cancer 2020 Feb 31;107(2):171-180. Epub 2019 Dec 31.

Institut de cancérologie Lucien-Neuwirth, département d'oncologie médicale, 108, bis avenue Albert-Raimond, BP60008, 42271 Saint-Priest-en-Jarez cedex, France.

Introduction: There is very few data about the management of elderly patients with metastatic castration-resistant prostate cancer (mCRPC). The aim of this study was to analyze the management of patients aged 80 and over treated with docetaxel for a mCRPC.

Methods And Materials: Clinical and pathological characteristics of octogerians treated with docetaxel were collected retrospectively from 3 French centers from 2009 to 2019. Patient's outcome, treatments administered before and/or after docetaxel were also analyzed.

Results: Data of 89 patients could be analyzed. A total of 20.2 % of patients received the standard regimen and 79.8 % received an adapted one. Patients in the adapted group were significantly older than in standard one. Other patient's characteristics - including the geriatric scales - were similar. Dose reductions for toxicity were more frequent in the standard group (P=0.04). The median overall survival of the total population was 13.3 months. It was longer in the standard group than in the adapted group (26.1 months vs 12.4 months=0.01). In multivariate analysis, the type of docetaxel regimen (standard versus adapted) was an independent predictor of survival.

Conclusion: This study suggests the benefit of the standard management even in oldest patients. A geriatric evaluation should certainly be processed in patients with poor oncogeriatric scale in order to select the sub-population able to receive the full dose standard docetaxel regimen.
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http://dx.doi.org/10.1016/j.bulcan.2019.11.006DOI Listing
February 2020

Neuroendocrine Carcinoma of the Urinary Bladder: A Large, Retrospective Study From the French Genito-Urinary Tumor Group.

Clin Genitourin Cancer 2020 08 5;18(4):295-303.e3. Epub 2019 Dec 5.

Department of Pathology, Hôpital Foch, Suresnes, France; Department of Pathology, Institut Curie, Saint-Cloud, France.

Background: Neuroendocrine carcinoma of the urinary bladder (NCUB) is rare, accounting for < 1% of bladder cancer cases, with scarce reported data available.

Materials And Methods: We retrospectively reviewed the data from patients with NCUB treated at French institutions. The objectives were to describe the patient characteristics, treatments received, and outcomes (ie, disease-free survival [DFS], progression-free survival, overall survival [OS]) and investigate the prognostic factors.

Results: From 1997 to 2017, we included 236 patients, 173 with early-stage NCUB and 63 with advanced-stage NCUB. For those with early-stage disease, the median DFS was better for the patients who had received cisplatin-based chemotherapy compared with carboplatin (hazard ratio [HR], 1.95; 95% confidence interval [CI], 1.1-3.46), with no difference found between the neoadjuvant and adjuvant settings (HR, 1.1; 95% CI, 0.61-1.97). The median OS was 36 months (95% CI, 29-43 months) for stage I and II, 26 months (95% CI, 18 months to not reached) for stage IIIA, 16 months (95% CI, 12-21 months) for stage IIIB. The HR for stage IIIB compared with stage I/II was 2.6 (95% CI, 1.5-4.4). The DFS at 6 months was associated with OS (HR, 7.8; 95% CI, 4.1-15.0). For patients with metastases at diagnosis who had received chemotherapy, the median progression-free survival was 9 months (95% CI, 8-11) for first-line cisplatin and 6 months (95% CI, 4-13 months) for carboplatin; the median OS was 13 months (95% CI, 9-15 months). A high-risk Bajorin score (HR, 11.5; 95% CI, 1.2-112.6) and the use of carboplatin (HR, 2.26; 95% CI, 1.03-4.96) were associated with worse outcomes.

Conclusions: In early-stage disease, a shorter DFS was associated with worse OS, and the use of cisplatin was associated with better OS. For the patients with metastases at diagnosis, a high-risk Bajorin score and the use of carboplatin were associated with worse outcomes.
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http://dx.doi.org/10.1016/j.clgc.2019.11.014DOI Listing
August 2020

Clinical progression is associated with poor prognosis whatever the treatment line in metastatic castration resistant prostate cancer: The CATS international database.

Eur J Cancer 2020 01 29;125:153-163. Epub 2019 Nov 29.

Hôpital Civil, Strasbourg, France.

Aim Of The Study: Our goal was to evaluate the impact of progression type (prostate-specific antigen [PSA] only, radiological or clinical) at initiation of first-, second- and third life-extending therapy (LET) on treatment outcomes in metastatic castration-resistant prostate cancer (mCRPC) patients, by performing a post-hoc analysis using data from the CATS international registry.

Methods: The 669 consecutive mCRPC patients of the CATS registry were classified according to their type of progression at initiation of each LET: PSA only (PSA-p), radiological (±PSA) (Radio-p); or clinical (±PSA, ±radiological) progression (Clin-p). Overall survival (OS), the primary endpoint, was calculated from initiation of the first-, second- and third-LET to death for each sequence.

Results: Median OS was shorter in the Clin-p group compared with the PSA-p group (14-month difference in first line; around 7-month difference in second- and third line). Shorter progression-free survival (PFS) was also observed in Clin-p patients, whatever the treatment is. Clinical progression seemed to be associated with a shorter duration of therapy with androgen receptor-targeted therapy (ART) compared with taxanes.

Conclusions: Clinical progression at initiation of a LET is associated with poor outcomes including shorter PFS and OS as well as clinical and biological features of aggressive disease. Stratifying patients in clinical trials according to disease progression type may prevent selection bias and data heterogeneity. In daily practice, first signs of clinical progression may prompt physicians to consider starting a new LET, independently of PSA levels.
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http://dx.doi.org/10.1016/j.ejca.2019.10.030DOI Listing
January 2020

Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE): overall survival and updated results of a randomised, double-blind, phase 3 trial.

Lancet Oncol 2020 01 18;21(1):105-120. Epub 2019 Nov 18.

Institut Català d'Oncologia L'Hospitalet, Institut d'Investigacio Biomedica de Bellvitge, University of Barcelona, Barcelona, Spain.

Background: Ramucirumab-an IgG1 vascular endothelial growth factor receptor 2 antagonist-plus docetaxel was previously reported to improve progression-free survival in platinum-refractory, advanced urothelial carcinoma. Here, we report the secondary endpoint of overall survival results for the RANGE trial.

Methods: We did a randomised, double-blind, phase 3 trial in patients with advanced or metastatic urothelial carcinoma who progressed during or after platinum-based chemotherapy. Patients were enrolled from 124 investigative sites (hospitals, clinics, and academic centres) in 23 countries. Previous treatment with one immune checkpoint inhibitor was permitted. Patients were randomly assigned (1:1) using an interactive web response system to receive intravenous ramucirumab 10 mg/kg or placebo 10 mg/kg volume equivalent followed by intravenous docetaxel 75 mg/m (60 mg/m in Korea, Taiwan, and Japan) on day 1 of a 21-day cycle. Treatment continued until disease progression, unacceptable toxicity, or other discontinuation criteria were met. Randomisation was stratified by geographical region, Eastern Cooperative Oncology Group performance status at baseline, and visceral metastasis. Progression-free survival (the primary endpoint) and overall survival (a key secondary endpoint) were assessed in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT02426125; patient enrolment is complete and the last patient on treatment is being followed up for safety issues.

Findings: Between July 20, 2015, and April 4, 2017, 530 patients were randomly allocated to ramucirumab plus docetaxel (n=263) or placebo plus docetaxel (n=267) and comprised the intention-to-treat population. At database lock (March 21, 2018) for the final overall survival analysis, median follow-up was 7·4 months (IQR 3·5-13·9). In our sensitivity analysis of investigator-assessed progression-free survival at the overall survival database lock, median progression-free survival remained significantly improved with ramucirumab compared with placebo (4·1 months [95% CI 3·3-4·8] vs 2·8 months [2·6-2·9]; HR 0·696 [95% CI 0·573-0·845]; p=0·0002). Median overall survival was 9·4 months (95% CI 7·9-11·4) in the ramucirumab group versus 7·9 months (7·0-9·3) in the placebo group (stratified HR 0·887 [95% CI 0·724-1·086]; p=0·25). Grade 3 or worse treatment-related treatment-emergent adverse events in 5% or more of patients and with an incidence more than 2% higher with ramucirumab than with placebo were febrile neutropenia (24 [9%] of 258 patients in the ramucirumab group vs 16 [6%] of 265 patients in the placebo group) and neutropenia (17 [7%] of 258 vs six [2%] of 265). Serious adverse events were similar between groups (112 [43%] of 258 patients in the ramucirumab group vs 107 [40%] of 265 patients in the placebo group). Adverse events related to study treatment and leading to death occurred in eight (3%) patients in the ramucirumab group versus five (2%) patients in the placebo group.

Interpretation: Additional follow-up supports that ramucirumab plus docetaxel significantly improves progression-free survival, without a significant improvement in overall survival, for patients with platinum-refractory advanced urothelial carcinoma. Clinically meaningful benefit might be restricted in an unselected population.

Funding: Eli Lilly and Company.
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http://dx.doi.org/10.1016/S1470-2045(19)30668-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6946880PMC
January 2020

Large retroperitoneal lymphadenopathy and increased risk of venous thromboembolism in patients receiving first-line chemotherapy for metastatic germ cell tumors: A study by the global germ cell cancer group (G3).

Cancer Med 2020 01 12;9(1):116-124. Epub 2019 Nov 12.

Division of Medical Oncology and Hematology, Department of Medicine, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada.

Background: Metastatic germ cell tumor (mGCT) patients receiving chemotherapy have increased risk of life-threatening venous thromboembolism (VTE). Identifying VTE risk factors may guide thromboprophylaxis in this highly curable population.

Methods: Data were collected from mGCT patients receiving first-line platinum-based chemotherapy at 22 centers. Predefined variables included International Germ Cell Cancer Collaborative Group (IGCCCG) risk classification, long-axis diameter of largest retroperitoneal lymph node (RPLN), Khorana score, and use of indwelling vascular access device (VAD). VTE occurring at baseline, during chemotherapy and within 90 days, was analyzed.

Results: Data from 1135 patients were collected. Median age was 31 years (range 10-74). IGCCCG risk was 64% good, 20% intermediate, and 16% poor. VTE occurred in 150 (13%) patients. RPLN >3.5 cm demonstrated highest discriminatory accuracy for VTE (AUC 0.632, P < .001) and was associated with significantly higher risk of VTE in univariable analysis (22% vs 8%, OR 3.0, P < .001) and multivariable analysis (OR 1.8, P = .02). Other significant risk factors included, Khorana score ≥3 (OR 2.6, P = .008) and VAD use (OR 2.7, P < .001).

Conclusions: Large RPLN and VAD use are independent risk factors for VTE in mGCT patients receiving chemotherapy. VAD use should be minimized in this population and thromboprophylaxis might be considered for large RPLN.
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http://dx.doi.org/10.1002/cam4.2674DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6943085PMC
January 2020

Sequencing of Taxanes and New Androgen-targeted Therapies in Metastatic Castration-resistant Prostate Cancer: Results of the International Multicentre Retrospective CATS Database.

Eur Urol Oncol 2018 12 8;1(6):467-475. Epub 2018 Jun 8.

Hôpital Civil, Strasbourg, France.

Background: The optimal sequence of life-extending therapies in metastatic castration-resistant prostate cancer (mCRPC) is unknown.

Objective: To evaluate outcomes among mCRPC patients treated with docetaxel (DOC), cabazitaxel (CABA), and a novel androgen receptor-targeted agent (ART; abiraterone acetate or enzalutamide) according to three different sequences.

Design, Setting, And Participants: Data from 669 consecutive mCRPC patients were retrospectively collected between November 2012 and October 2016.

Outcome Measurements And Statistical Analysis: The primary endpoint was the prostate-specific antigen (PSA) response (decrease ≥50% from baseline) to each therapy. Secondary endpoints included best clinical benefit, time to PSA progression, radiological progression-free survival (rPFS), overall survival (OS), and toxicity.

Results And Limitations: A total of 158 patients received DOC→CABA→ART (group 1), 456 received DOC→ART→CABA (group 2), and 55 received ART→DOC→CABA (group 3). At baseline, PSA progression only and Gleason <8 were more common in group 3. PSA response on DOC was lower in group 3 than in other groups (p=0.02) and PSA response on CABA was higher in the second than in the third line (p=0.001). In Group 3, rPFS on ART (6.6 mo) and DOC (9.2 mo) was also shorter than in the other groups. OS calculated from the first life-extending therapy reached 34.8, 35.8, and 28.9 mo in groups 1, 2 and 3, respectively (p=0.007). Toxicity was comparable between the arms. The main limitations of the trial are its retrospective design and the low number of patients in group 3.

Conclusions: In this retrospective trial, sequencing of DOC, CABA, and one ART, was associated with median OS of up to 35.8 mo. CABA seemed to retain its activity regardless of treatment sequence. DOC activity after ART appeared to be reduced, but the data are insufficient to conclude that cross-resistance occurs.

Patient Summary: The order of drugs administered to patients with metastatic castration-resistant prostate cancer could impact their efficacy, with cabazitaxel appearing to retain its activity whatever the therapeutic sequence.
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http://dx.doi.org/10.1016/j.euo.2018.05.009DOI Listing
December 2018

[Securing patients pathways treated by oral antitumoral: Guidelines for better organization of departments and management of incoming calls].

Bull Cancer 2019 Jun 21;106(6):514-526. Epub 2019 May 21.

CHU Henri-Mondor, 51, avenue Mal-De-Lattre-De-Tassigny, 94000 Créteil, France; Centre François-Baclesse, 3, avenue du Général-Harris, 14076 Caen, France.

The emergence of oral cancer treatment in oncology has shifted patient follow-up from the hospital to the home. This trend has resulted in an increase in phone and e-mail interactions initiated by patients, but also by pharmacists, by liberal nurses, by general practitioners, and an increase in calls to the emergency response services (SAMU) both for real or perceived emergencies. This increased volume of patient and pharmacist communication has caused significant disruption in the daily activity of affected oncology departments and in particular of the secretariats. The procedures for formulating and securing appropriate responses within a short time frame are generally not established, and as a result, there is a risk that decisions made could be inappropriate for the patient's situation, especially in the case of complications.. Tracking responses to phone calls is necessary and answers should be noted in the medical file, including side effects, in particular the serious AEs for a good quality of care. This guideline describes best practices for oncologists who manage "incoming" calls from patients or professionals involved in the care pathway.
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http://dx.doi.org/10.1016/j.bulcan.2019.03.015DOI Listing
June 2019

Estimation of Unbound Carboplatin Clearance From Total Plasma Concentrations as a Means of Facilitating Therapeutic Drug Monitoring.

Ther Drug Monit 2019 02;41(1):66-74

Institut Claudius-Regaud, IUCT-Oncopole, Toulouse.

Background: Therapeutic drug monitoring of carboplatin is based on its unbound clearance (CLU) determined by Bayesian analysis on unbound (U) concentrations. However, the ultrafiltration of plasma samples presents technical and time constraints. Therefore, this study aims to estimate CLU using total plasma (P) concentrations.

Methods: U and P concentration data of 407 patients were obtained from 2 clinical studies in which actual CLU had been determined for each patient. The patients were then split into development (277 patients) and prospective data sets (130 patients). Two approaches were evaluated. PK-model-only approach: a 3-compartment pharmacokinetic (PK) model based on U and P concentrations and taking into account the protein binding process was developed. The model with patient covariates was also evaluated. Linear regression approach: an equation (CLU = aCLP + b) was obtained by linear regression analysis between actual CLU and CLP, which is the total plasma clearance obtained by analyzing P concentrations according to a 2-compartment PK model. Predictive performance was then assessed within the prospective data set by estimating CLU from P concentrations using each approach and computing the relative percentage error (PE) between estimated CLU and actual CLU.

Results: The linear regression equation was CLU (L/h) = 1.15 CLP (L/h) + 0.13. The mean PE (MPE) between CLU (estimated using the equation) and the actual CLU was +1.2% (ranging from -31% to +33%) and the mean absolute PE (MAPE) was 9.7%. With the 3-compartment PK model, the MPE was +2.3% (ranging from -41% to +31%) and the MAPE was 11.1%. Inclusion of covariates in the 3-compartment model did not improve the estimation of CLU [MPE = +6.3% (from -33% to +37%); MAPE = 11.4%].

Conclusions: The linear equation gives a relatively good estimation of CLU based on P concentrations, making PK-based carboplatin dose adaptation possible for centers without ultrafiltration facilities.
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http://dx.doi.org/10.1097/FTD.0000000000000569DOI Listing
February 2019

Olaparib combined with abiraterone in patients with metastatic castration-resistant prostate cancer: a randomised, double-blind, placebo-controlled, phase 2 trial.

Lancet Oncol 2018 07 4;19(7):975-986. Epub 2018 Jun 4.

Centre Hospitalier de l'Université de Montréal, Montréal, QC, Canada.

Background: Patients with metastatic castration-resistant prostate cancer and homologous recombination repair (HRR) mutations have a better response to treatment with the poly(ADP-ribose) polymerase inhibitor olaparib than patients without HRR mutations. Preclinical data suggest synergy between olaparib and androgen pathway inhibitors. We aimed to assess the efficacy of olaparib plus the androgen pathway inhibitor abiraterone in patients with metastatic castration-resistant prostate cancer regardless of HRR mutation status.

Methods: We carried out this double-blind, randomised, placebo-controlled phase 2 trial at 41 urological oncology sites in 11 countries across Europe and North America. Eligible male patients were aged 18 years or older with metastatic castration-resistant prostate cancer who had previously received docetaxel and were candidates for abiraterone treatment. Patients were excluded if they had received more than two previous lines of chemotherapy, or had previous exposure to second-generation antihormonal drugs. Patients were randomly assigned (1:1) using an interactive voice or web response system, without stratification, to receive oral olaparib 300 mg twice daily or placebo. All patients received oral abiraterone 1000 mg once daily and prednisone or prednisolone 5 mg twice daily. Patients and investigators were masked to treatment allocation. The primary endpoint was investigator-assessed radiographic progression-free survival (rPFS; based on Response Evaluation Criteria in Solid Tumors version 1.1 and Prostate Cancer Clinical Trials Working Group 2 criteria). Efficacy analyses were done in the intention-to-treat population, which included all randomly assigned patients, and safety analyses included all patients who received at least one dose of olaparib or placebo. This trial is registered with ClinicalTrials.gov, number NCT01972217, and is no longer recruiting patients.

Findings: Between Nov 25, 2014, and July 14, 2015, 171 patients were assessed for eligibility. Of those, 142 patients were randomly assigned to receive olaparib and abiraterone (n=71) or placebo and abiraterone (n=71). The clinical cutoff date for the final analysis was Sept 22, 2017. Median rPFS was 13·8 months (95% CI 10·8-20·4) with olaparib and abiraterone and 8·2 months (5·5-9·7) with placebo and abiraterone (hazard ratio [HR] 0·65, 95% CI 0·44-0·97, p=0·034). The most common grade 1-2 adverse events were nausea (26 [37%] patients in the olaparib group vs 13 [18%] patients in the placebo group), constipation (18 [25%] vs eight [11%]), and back pain (17 [24%] vs 13 [18%]). 38 (54%) of 71 patients in the olaparib and abiraterone group and 20 (28%) of 71 patients in the placebo and abiraterone group had grade 3 or worse adverse events, including anaemia (in 15 [21%] of 71 patients vs none of 71), pneumonia (four [6%] vs three [4%]), and myocardial infarction (four [6%] vs none). Serious adverse events were reported by 24 (34%) of 71 patients receiving olaparib and abiraterone (seven of which were related to treatment) and 13 (18%) of 71 patients receiving placebo and abiraterone (one of which was related to treatment). One treatment-related death (pneumonitis) occurred in the olaparib and abiraterone group.

Interpretation: Olaparib in combination with abiraterone provided clinical efficacy benefit for patients with metastatic castration-resistant prostate cancer compared with abiraterone alone. More serious adverse events were observed in patients who received olaparib and abiraterone than abiraterone alone. Our data suggest that the combination of olaparib and abiraterone might provide an additional clinical benefit to a broad population of patients with metastatic castration-resistant prostate cancer.

Funding: AstraZeneca.
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http://dx.doi.org/10.1016/S1470-2045(18)30365-6DOI Listing
July 2018

Efficacy of cabazitaxel rechallenge in heavily treated patients with metastatic castration-resistant prostate cancer.

Eur J Cancer 2018 07 7;97:41-48. Epub 2018 Apr 7.

European Georges Pompidou Hospital, Paris, France; René Descartes University, Paris V, France. Electronic address:

Background: Treatment option in patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with docetaxel (DOC), cabazitaxel (CABA) and new hormone therapy (NHT) is limited. Rechallenge with DOC is limited because of cumulative toxicities. This study investigated the activity and safety of CABA rechallenge in mCRPC.

Patients And Methods: Clinical data were collected retrospectively in 17 centres in Europe. Eligible patients had undergone rechallenge with cabazitaxel after three previous lines of treatment (DOC, NHT and CABA, in any order). Overall survival (OS) and progression-free survival (PFS) were estimated by the Kaplan-Meier method. Data on toxicities were collected.

Results: A total of 69 of 562 patients (Eastern Cooperative Oncology Group performance status 0-1 69%) were rechallenged with CABA (25 mg/m q3w, 58%; 20 mg/m q3w, 27.5%; other, 14.5%) for 1-10 (median 6) cycles; 76.8% received prophylactic granulocyte colony-stimulating factor. Median radiological or clinical PFS with CABA rechallenge was 7.8 months and 11.9 months with initial CABA therapy. OS was 13.7 months (95% confidence interval [CI]: 9.3-15.7) from the first CABA rechallenge cycle, 59.9 months (47.8-67.1) from the first life-extending therapy in mCRPC and 78.3 months (66.4-90.7) from mCRPC diagnosis. Best clinical benefit was improved (34.3%) or stable (47.8%). Lack of response to rechallenge occurred in 17.9% of patients (3.1% with initial CABA). The level of prostate-specific antigen decreased by ≥ 50% in 24% of patients at rechallenge (71% with initial CABA). There was no grade ≥III peripheral neuropathy or nail disorders.

Conclusions: CABA rechallenge may be a treatment option without cumulative toxicity in heavily pretreated patients with mCRPC who are still fit and had a progression >3 months after the last CABA injections.
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http://dx.doi.org/10.1016/j.ejca.2018.03.008DOI Listing
July 2018

Results of the FLAC European Database of Metastatic Castration-Resistant Prostate Cancer Patients Treated With Docetaxel, Cabazitaxel, and Androgen Receptor-Targeted Agents.

Clin Genitourin Cancer 2018 08 23;16(4):e777-e784. Epub 2018 Feb 23.

Department of Medical Oncology, Georges Pompidou European Hospital, Paris, France; Université Paris Descartes Sorbonne Paris-Cité, Paris, France. Electronic address:

Background: Several agents have demonstrated an overall survival (OS) benefit in patients with metastatic castration-resistant prostate cancer (mCRPC); however, the optimal sequencing of these therapies is unknown as a result of a lack of prospective randomized controlled trials. This retrospective study aimed to identify clinical factors influencing outcomes and to determine optimal treatment sequencing in patients with mCRPC treated with cabazitaxel (CABA) and/or androgen receptor-targeted agents (ART) after androgen-deprivation therapy (ADT) and docetaxel (DOC).

Patients And Methods: Records of 574 consecutive patients treated (2012-2016) at 44 centers in 6 countries were retrospectively examined.

Results: A total of 267 patients received ADT → DOC → CABA (group 1), 183 patients ADT → DOC → ART → CABA (group 2), and 124 patients ADT → DOC → CABA → ART (group 3), with respective median OS from diagnosis of mCRPC of 38.3, 44.45, and 53.9 months (P = .012 for group 3 vs. group 1). Multivariate analysis showed response to first ADT ≤ 12 months, Gleason score of 8 to 10, clinical progression, and high prostate-specific antigen levels at mCRPC diagnosis were associated with worse OS. Prior receipt of ART did not influence activity of CABA.

Conclusion: OS appeared to increase with the number of life-extending therapies, with a sequence including DOC, CABA, and an ART providing the greatest OS benefit.
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http://dx.doi.org/10.1016/j.clgc.2018.02.016DOI Listing
August 2018