Abstract
Background
Abiraterone (Abi), enzalutamide (Enz) and docetaxel (Doc) are all approved first-line (1L) treatment options for mCRPC. However, the optimal treatment sequence has not been ...established yet. In the present analysis, we explored the outcomes of pts treated with 1L Doc or Abi/Enz in the prospective PROREPAIR-B cohort study (NCT03075735).
Methods
We assessed the impact of 1L treatment options (Doc vs Abi/Enz) on progression-free survival to 1L therapy (PFS) and overall survival (OS). Uni- (UV) and multivariable (MV) Cox-regression models were used. MV model covariates included age (≥75 years), local therapy, Gleason Score, visceral metastases, metastases at diagnosis, phosphatase alkaline (ALP) (≥ULN), lactate dehydrogenase (LDH) (≥ULN), haemoglobin (Hb) (≤LNL), albumin (≤LNL) and ECOG performance status.
Results
Of 419 pts enrolled in the study, 406 received 1L Doc (n = 188) or Abi/Enz (n = 218). Overall, pts receiving Doc were younger (p = 0.002), had higher rates of visceral metastases (17.6% vs 8.7%, p = 0.008), ALP (52.1% vs 40.4%, p = 0.018), LDH (48.1% vs 31.2%, p < 0.001), lower Hb (7.4% vs 2.8%, p = 0.029) and albumin (11.3% vs 4.6%). The median follow-up was 40 months. PFS was longer in pts receiving 1L Abi/Enz vs Doc (10.8 vs 8.3 months, HR: 0.5, p < 0.001). 123/188 pts treated with 1L-Doc received second-line (2L) Abi/Enz: 30 received other 2L and 35 had not started 2L. 111/216 pts treated with 1L-Abi/Enz received 2L Doc, 26 were started on other 2L and 79 had not initiated 2L. Choice of first-line agent was not associated with OS in the MV model. Similar results were found in the elderly population. Of 137 aged ≥ 75 years, 48 received Doc and 88 Abi/Enza as first-line therapy. PFS favoured 1L Abi/Enz vs Doc (9.6 vs 8.3m, HR: 0.52, p = 0.001), whereas no difference was found in terms of OS (28.2 vs 24.8m, respectively, HR: 1.18, p = 0.474).
Conclusions
Pts treated with 1L Doc had worse baseline prognostic features. Despite a longer PFS was observed in pts treated with 1L Abi/Enz vs Doc, no difference in OS was found between the treatment sequences. Similar results were observed in the elderly population. Biomarker-driven pts selection is needed to identify the optimal sequence.
Clinical trial identification
NCT03075735.
Legal entity responsible for the study
Centro Nacional de Investigaciones Oncológicas (CNIO).
Funding
Unrestricted grant from Fundación Cris Contra el Cancer; three investigator awards from the Prostate Cancer Foundation (C.C.P. 2013, D.O. 2014, and E.C. 2017); and three grants from Fondo de Investigación Sanitaria, Instituto de Salud Carlos III (No. PI13/01287 and PI16/01565 to D.O. and No. PI15/01471 to P.L.). During the conduct of this study, E.C., D.O., P.N., and L.M-P. were supported by grants from Ministerio de Economía, Industria y Competitividad (No. JCI-2014-19129 E.C., No. RYC-2015-18625 D.O., No. SVP-2013-067937 P.N., No. SVP-2014-068895 L.M.); D.O. was also funded by a Return fellowship from Fundación Científica de la Asociación Española Contra el Cancer, 2012-2015; N.R.L. and R.L., by grants from Instituto de Salud Carlos III (No. CM14-00200 to N.R.L. and No. CM17-00221 R.L.); and Y.C., by a grant from Ministerio de Educación, Cultura y Deportes (No. FPU15/05126). C.C.P. was supported by a congressional-designated medical research program award (No. CMRP-PC131820).
Disclosure
C. Cattrini: Travel / Accommodation / Expenses: Novartis, Ipsen. N. Romero Laorden: Honoraria (self): MSD, Sanofi-Aventis, Astellas, Janssen-Cilag; Travel / Accommodation / Expenses: Bayer, Janssen-Cilag, Roche, PharmaMar; Research grant / Funding (institution): Bayer, Astellas, Janssen, Sanofi. E. Castro: Honoraria (self): Astellas Pharma, Janssen-Cilag, AstraZeneca, Bayer, Pfizer; Advisory / Consultancy: Bayer, Janssen-Cilag; Research grant / Funding (institution): Janssen-Cilag, AstraZeneca, Bayer; Travel / Accommodation / Expenses: Bayer, Janssen-Cilag, Roche, Astellas Pharma. I. García-Carbonero: Advisory / Consultancy: Janssen Oncology, Astellas Pharma, Bayer, Sanofi; Travel / Accommodation / Expenses: Astellas Pharma, Janssen, Sanofi, Bayer. J.M. Piulats: Advisory / Consultancy: Janssen Oncology, Astellas Pharma, VCN Biosciences, Clovis Oncology, Roche, Genentech, Bristol-Myers Squibb, Merck Sharp & Dohme; Research grant / Funding (institution): Bristol-Myers Squibb, AstraZeneca, MedImmune, Merck Sharp & Dohme, Pfizer, EMD Serono, Incyte, Janssen Oncology; Travel / Accommodation / Expenses: Janssen Oncology, Roche, Bristol-Myers Squibb. J. Puente: Advisory / Consultancy: Pfizer, Astellas Pharma, Janssen-Cilag, Merck Sharp & Dohme, Bayer, Roche, Bristol-Myers Squibb, AstraZeneca, Boehringer Ingelheim, Clovis Oncology, Ipsen, Eisai, EUSA Pharma, Sanofi; Speaker Bureau / Expert testimony: Pierre Fabre, Celgene, Kiowa, Novartis, Lilly; Research grant / Funding (institution): Astellas Pharma, Pfizer; Research grant / Funding (institution): Pfizer, Roche, Janssen-Cilag. B. P. Valderrama: Honoraria (self): Pierre Fabre, Astellas Pharma, Novartis, Bristol-Myers Squibb, Ipsen; Advisory / Consultancy: Astellas Pharma, Novartis, Pfizer, Pierre Fabre, Bayer, Sanofi, Bristol-Myers Squibb, Roche, Ipsen; Travel / Accommodation / Expenses: Janssen-Cilag, Bristol-Myers Squibb. E. Gonzalez Billalabeitia: Travel / Accommodation / Expenses: Bristol-Myers Squibb, Pfizer, Janssen-Cilag, Astellas Pharma, Sanofi. R. Morales Barrera: Honoraria (self): MSD, Sanofi, AstraZeneca, Asofarma, Johnson and Johnson, Roche/Genentech; Advisory / Consultancy: MSD, Sanofi, AstraZeneca, Asofarma, Johnson and Johnson, Roche/Genentech; Speaker Bureau / Expert testimony: MSD. Sanofi, AstraZeneca, Asofarma, Johnson and Johnson; Research grant / Funding (institution): AB Science, Aragon Pharmaceuticals, Arog Pharmaceuticals, INC, Astellas Pharma., AstraZeneca AB, Aveo Pharmaceuticals INC, Bayer AG, Blueprint Medicines Corporation, BN Immunotherapeutics INC, Boehringer Ingelheim España, S.A., Bristol-Myers Squibb Intern; Travel / Accommodation / Expenses: MSD, Roche/Genentech, Lilly, Clovis Oncology, Bayer, Johnson and Johnson, Astellas Pharma, AstraZeneca. R. Lozano Mejorada: Honoraria (self): Roche, Janssen-Cilag, Bayer; Research grant / Funding (institution): Bayer, Janssen-Cilag; Travel / Accommodation / Expenses: Roche, Janssen-Cilag, Astellas Pharma. R. Luque: Honoraria (self), Travel / Accommodation / Expenses: Janssen-Cilag, Sanofi Aventis, Astellas Medivation, Roche, Novartis, Pfizer, Bristol-Myers Squibb, EUSA Pharma. E. Martinez Ortega: Honoraria (self), Travel / Accommodation / Expenses: Sanofi Aventis, Roche, Pfizer Bristol Mayers Squibb, EUSA Pharma and IPSEN. J.A. Arranz Arija: Honoraria (self): Novartis MSD Oncology Janssen-Cilag EUSA Pharma Astellas Pharma Bristol-Myers Squibb; Advisory / Consultancy: Pfizer Astellas Pharma Janssen-Cilag Novartis Bayer Ipsen MSD Oncology Bristol-Myers Squibb EUSA Pharma; Research grant / Funding (institution): Novartis Pierre Fabre Bristol-Myers Squibb; Travel / Accommodation / Expenses: Bristol-Myers Squibb Janssen-Cilag MSD Oncology Pfizer. E. Gallardo Diaz: Honoraria (self): Astellas Pharma, Roche, Bristol-Myers Squibb, Novartis; Advisory / Consultancy: Pfizer, Bayer Schering Pharma, Janssen Oncology, Astellas Pharma, Roche, Bristol-Myers Squibb, Sanofi, Ipsen, Eisai, Rovi, Daiichi Sankyo, EUSA Pharma; Speaker Bureau / Expert testimony: Rovi, LEO Pharma, Menarini, Bristol-Myers Squibb, Ipsen, Astellas Pharma, Roche, Daiichi Sankyo; Travel / Accommodation / Expenses: Pfizer, Astellas Pharma, Pierre Fabre, Bayer Schering Pharma, Bristol-Myers Squibb, Eisai, Janssen, Roche. E. Almagro Casado: Speaker Bureau / Expert testimony: MSD; Travel / Accommodation / Expenses: Bristol-Myers Squibb. M.J. Mendez Vidal: Advisory / Consultancy: Janssen-Cilag, Pfizer, Astellas Pharma, Sanofi, Bayer, Bristol-Myers Squibb, Novartis, Roche; Travel / Accommodation / Expenses: Janssen-Cilag, Pfizer, Astellas Pharma, Bristol-Myers Squibb. D. Olmos Hidalgo: Speaker Bureau / Expert testimony: Astellas, Bayer, Janssen, Sanofi; Advisory / Consultancy: Astellas, AstraZeneca, Bayer, Genentech, Janssen, Clovis; Research grant / Funding (institution): Astellas, AstraZeneca, Bayer, Genentech/Roche, Janssen (Incl.Aragon), Medivation/Pfizer, Tokai, MSD, GSK; Travel / Accommodation / Expenses: Bayer, Janssen-Cilag, Ipsen. D. Lorente: Honoraria (self): Janssen-Cilag, Bayer, Astellas Pharma, Sanofi; Advisory / Consultancy: Janssen-Cilag, Bayer, Sanofi; Travel / Accommodation / Expenses: Sanofi, Astellas, Janssen-Cilag, Celgene. All other authors have declared no conflicts of interest.
Abstract
Background
Ra223 is a life-prolonging alpha-emitter bone targeted therapy for mCRPC patients with bone metastases. However, evidence on biomarkers that may help us in patient selection are ...lacking. Total ALP (tALP) appeared to be a potential marker of Ra223 effect in early studies (Sartor, Ann Oncol, 2017). Other bone-related markers, as bone-specific ALP (BALP), have demonstrated its prognostic value in mCRPC patients with bone metastases (Fizazi K, Eur Urol, 2015; Lara PN, J Natl Cancer Inst, 2014).
Methods
PRORADIUM (NCT022925702) is a prospective multicentre cohort study in mCRPC patients treated with Ra223. The primary aim was to assess the impact of baseline serum biomarkers of bone formation (BALP and C-terminal of type 1 collagen propeptide CICP) on overall survival (OS). Secondary aims include the correlation of progression-free survival (PFS), time to PSA progression (TTPP) and skeletal-related events free-survival (SRE-FS) with serum bone markers.
Results
142 out of 168 pts enrolled in the study were included in this preliminary analysis. Median age was 74 yrs, 85.5% pts had ECOG 0-1, 52% pts completed 5-6 cycles of Ra223. Higher baseline levels of BALP and CICP were associated to number of metastases in bone-scan (p = 0.007 and p = 0.016, respectively) and baseline pain (p = 0.014 and p = 0.050, respectively). After a median follow-up of 18 months, 91 deaths were observed, with a median OS of 11.5 months (95%CI: 9.1-13.9). Patients with baseline BALP and CICP values above the median showed a trend to shorter TTPP (BALP: 2.8 vs 3.1 m, p = 0.016; CICP: 2.8 vs 3.0 m, p = 0.091) and PFS (BALP: 4.4 vs 5.1 m, p = 0.070; CICP: 4.2 vs 5.5 m, p = 0.281), respectively. The elevation of bone markers above the median was significantly associated with worse OS (BALP: 8.8 vs 17.9 m, p < 0.001; CICP: 9.4 vs 16.8 m, p = 0.001). There were not associations found with SRE-FS.
Conclusions
Our results suggest that baseline serum markers of bone formation may serve as biomarkers for prognosis in mCRPC patients treated with Ra233.
Clinical trial identification
NCT022925702.
Legal entity responsible for the study
IBIMA and CNIO.
Funding
Bayer, CRIS Cancer Foundation, Grant from Instituto de Salud Carlos III (PI16/01565).
Disclosure
N. Romero Laorden: Honoraria (self), Travel / Accommodation / Expenses: Bayer, Astellas Pharma, Janssen-Cilag, Sanofi-Aventis, PharmaMar, MSD, Roche. R. Lozano Mejorada: Honoraria (self): Roche, Janssen-Cilag, Bayer; Research grant / Funding (institution): Bayer, Janssen-Cilag; Travel / Accommodation / Expenses: Roche, Janssen-Cilag, Astellas Pharma. E. Almagro Casado: Honoraria (self): MSD; Travel / Accommodation / Expenses: BMS. E. Gonzalez Billalabeitia: Travel / Accommodation / Expenses: BMS, Pfizer, Janssen-Cilag, Astellas Pharma, Sanofi. A. Montesa: Advisory / Consultancy: Janssen-Cilag, Pfizer, Sanofi, Astellas Pharma; Travel / Accommodation / Expenses: Pfizer. G.A. De Velasco Oria de Rueda: Honoraria (self), Advisory / Consultancy: Pfizer, Novartis, Ipsen, Astellas Pharma, BMS, Bayer, MSD, Roche. R. Morales Barrera: Honoraria (self): MSD, Sanofi, AstraZeneca, Janssen, Roche/Genentech; Advisory / Consultancy: MSD, Sanofi, AstraZeneca, Janssen, Roche/Genentech; Speaker Bureau / Expert testimony: MSD, Sanofi, AstraZeneca, Asofarma, Janssen; Research grant / Funding (institution): AB Science, Aragon Pharmaceuticals, INC, Astellas Pharma, AstraZeneca, Aveo Pharmaceuticals, Bayer, Blueprint Medicines Corporation, BN Immunotherapeutics, Boehringer Ingelheim España, BMS, Clovis Oncology, Cougar Technology, Deciphera Pharmaceuticals LL; Travel / Accommodation / Expenses: MSD, Roche, Lilly, Clovis Oncology, Bayer, Janssen-Cilag, Astellas Pharma, AstraZeneca. D. Lorente: Honoraria (self): Janssen-Cilag, Bayer, Astellas Pharma, Sanofi; Advisory / Consultancy: Janssen-Cilag, Bayer, Sanofi; Travel / Accommodation / Expenses: Sanofi, Astellas, Janssen-Cilag, Celgene. E. Castro: Honoraria (self): Astellas Pharma, Janssen-Cilag, AstraZeneca, Bayer, Pfizer; Advisory / Consultancy: Bayer, Janssen-Cilag; Research grant / Funding (institution): Janssen-Cilag, AstraZeneca, Bayer, Genentech, Roche, Pfizer, Astellas Medivation, Tokai Pharmaceuticals; Travel / Accommodation / Expenses: Bayer, Janssen-Cilag, Roche, Astellas Pharma. D. Olmos Hidalgo: Honoraria (self): Janssen-Cilag, Bayer, Sanofi; Advisory / Consultancy: Bayer, Janssen-Cilag, AstraZeneca, Clovis Oncology; Research grant / Funding (institution): Bayer, Janssen, AstraZeneca, Roche/Genentech, Medivation/Pfizer, Astellas, Tokai, MSD, GSK; Travel / Accommodation / Expenses: Bayer, Janssen-Cilag, Ipsen. All other authors have declared no conflicts of interest.
Abstract
Background
There are currently no good indicators of which patients with cancer will respond or not to immunotherapy. Novel computational analysis of computed tomography scans (CT) (i.e. ...radiomics) provides information about the tumour-infiltrating CD8 and predict response to immunotherapy. We aim to validate in an external cohort the VHIO CT-radiomics signature and to develop a combined radiomics-clinical signature that predicts the response to immune checkpoint inhibitors in patients with advanced solid tumours.
Methods
The VHIO CT-radiomics signature was developed in a population of 115 consecutive patients treated with immune checkpoint inhibitors (programmed-death protein 1 PD-1 or programmed-death ligand 1 PD-L1 inhibitors) monotherapy in phase I clinical trials (Cohort 1). The external validation included 62 consecutive patients with urinary bladder cancer treated with anti-PD-1 or PD-L1 monotherapy (Cohort 2). From the baseline CT, a target lesion per patient was delineated. Radiomics variables of first-order, shape, and texture were extracted. An elastic-net model combining radiomics and clinical features was implemented. The association between the radiomics score and changes in tumour shrinkage was assessed using Mann-Whitney analysis.
Results
In the Cohort 1 the CT-radiomics signature associates with response (area under the curve AUC of 0.81, p-value=2.74x10-5 and 0.72, p = 0.001 in the training and internal validation sets, respectively). In the external validation set (Cohort 2), the CT-radiomics signature predicts a response with an AUC of and 0.76 (p = 0.001). The model combining radiomics and clinical features has an AUC of 0.84 (p-value=5.04x10-9) for response prediction. Tumour homogeneity, hypodensity and spherical shape together with high lymphocytes and albumin and low neutrophils, corresponding to a high clinical-radiomics signature score, are indicators of tumour response. A higher CT-radiomics signature score is associated with a larger tumour shrinkage (p < 0.05).
Conclusions
CT-radiomics signature at baseline predicts the response to immune checkpoint inhibitors. Integrating radiomics and clinical data improved the response prediction capacity.
Legal entity responsible for the study
The authors.
Funding
This study was supported by the Banco Bilbao Vizcaya Argentaria and Fundacio La Caixa. RPL is supported by a Prostate Cancer Foundation Young Investigator award.
Disclosure
J. Martín Liberal: Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Novartis; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: MSD; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Ipsen; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Pierre Fabre; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Astellas; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Bristol-Myers Squibb. R. Morales Barrera: Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Sanofi Aventis; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Bayer; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Janssen; Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Merck Sharp & Dohme; Advisory / Consultancy, Speaker Bureau / Expert testimony: Asofarm; Travel / Accommodation / Expenses: Roche; Travel / Accommodation / Expenses: Astellas; Travel / Accommodation / Expenses: Pharmacyclics; Travel / Accommodation / Expenses: Clovis Oncology; Travel / Accommodation / Expenses: Lilly. E. Elez: Travel / Accommodation / Expenses: Merck; Travel / Accommodation / Expenses: Sanofi; Travel / Accommodation / Expenses: Roche; Travel / Accommodation / Expenses: Servier and Amge ; Research grant / Funding (self): Merck. E. Felip: Honoraria (self): AbbVie; Honoraria (self): AstraZeneca; Honoraria (self): Blue Print Medicines; Honoraria (self): Boehringer Ingelheim; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Celgene; Honoraria (self): Eli Lilly; Honoraria (self): Guardant Health; Honoraria (self): Janssen; Honoraria (self): Medscape; Honoraria (self): Merck KGaA; Honoraria (self): MSD; Honoraria (self): Novartis; Honoraria (self): Pfizer; Honoraria (self): Takeda; Honoraria (self): Touchtime. J. Tabernero: Advisory / Consultancy: Array Biopharma; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Bayer; Advisory / Consultancy: BeiGene; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: Chugai; Advisory / Consultancy: Genentech, Inc; Advisory / Consultancy: Genmab A/S; Advisory / Consultancy: Halozyme; Advisory / Consultancy: Imugene Limited; Advisory / Consultancy: Inflection Biosciences Limited; Advisory / Consultancy: Ipsen; Advisory / Consultancy: Kura Oncology; Advisory / Consultancy: Lilly; Advisory / Consultancy: MSD; Advisory / Consultancy: Menarini; Advisory / Consultancy: Merck Serono; Advisory / Consultancy: Merus; Advisory / Consultancy: Molecular Partners; Advisory / Consultancy: Novartis; Advisory / Consultancy: Peptomyc; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Pharmacyclics; Advisory / Consultancy: ProteoDesign SL; Advisory / Consultancy: F. Hoffmann-La Roche Ltd; Advisory / Consultancy: Sanofi; Advisory / Consultancy: SeaGen; Advisory / Consultancy: Seattle Genetics; Advisory / Consultancy: Servier; Advisory / Consultancy: Symphogen; Advisory / Consultancy: Taiho; Advisory / Consultancy: VCN Biosciences; Advisory / Consultancy: Biocartis; Advisory / Consultancy: Foundation Medicine; Advisory / Consultancy: HalioDX SAS. R. Dienstmann: Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Speaker Bureau / Expert testimony: Symphogen; Speaker Bureau / Expert testimony: Ipsen; Speaker Bureau / Expert testimony: Amgen; Speaker Bureau / Expert testimony: Sanofi; Speaker Bureau / Expert testimony: MSD; Speaker Bureau / Expert testimony: Servier; Research grant / Funding (self): Merck. All other authors have declared no conflicts of interest.
In cancer, regional lymph node (LN) cells are one of the first components of the immune system to have contact with tumor cells or their products. Therefore, the phenotype and functional properties ...of hematopoietic cells present within the tumor-draining LN are important to understanding their role in the control of malignant cells. Based on the locoregional metastatic behavior of squamous cell carcinoma of the head and neck (SCCH&N) region, we analyzed tumor-draining lymph nodes from SCCH&N patients to obtain insights into regional tumor immunity. Using a three-color fluorescent labeling technique, surface antigen expression was visualized in mononuclear cells of lymph nodes that were obtained from head and neck cancer patients and compared to mononuclear cells of normal lymph nodes. Cell cycle analyses were performed using propidium iodide. Proliferation after phytohemagglutinin stimulation was measured by a sodium tetrazolium-based assay. LN histology was correlated with flow cytometric findings. Regional lymph nodes of head and neck cancer patients undergo morphologic and functional changes. Flow cytometry revealed a decrease in CD8+ T cells and in some lymph nodes the presence of second or third populations of larger cells with distinct size and granularity that expressed both T (γδ/αβ) and different natural killer cell markers. Moreover, cell cycle analyses and proliferation assays showed a diminished response to mitogenic stimuli. These changes were found in both metastatic and hyperplastic lymph nodes from head and neck cancer patients; however, no alterations were found in control lymph nodes or peripheral blood mononuclear cells from noncancer patients. The immune alterations detected in lymphocytes present within the draining lymph nodes of head and neck cancer patients may improve our understanding of how tumor cells escape host immunosurveillance. However, this dysfunction in local draining lymph nodes may not be detected systemically.
The incidence of testicular germ cell tumours (TGCT) is increasing and the improvement in survival may lead to an increased incidence of bilateral tumours. We examined the incidence, prognosis, ...clinical and histological characteristics, treatment and outcome of patients with bilateral TGCTs based on 15 years of experience from a single institution.
We reviewed the charts from all patients treated for a testicular tumour germ cell at Hospital Vall d'Hebron in Barcelona, Spain. The information was retrospectively obtained from the patients' hospital. All the patients were evaluated with clinical history, physical exam, serum markers (alphaFP, LDH and betahCG), ultrasonographic evaluation of the testicles, computed tomography (CT) scans of the chest, abdomen and pelvis, surgery, location and histology of first and second tumour, treatment after the surgery and follow-up.
Of 151 patients with TGCT, 8 (5.3%) developed bilateral tumours, seven (4.6%) were metachronous and one (0.7%) synchronous tumours. Two patients underwent testis-sparing surgery for the second tumour. All the patients are alive without evidence of disease based on physical exam, tumour markers and CT scan.
Survival in patients with bilateral testicular germ cell tumours (BTGCT) is similar to that of patients with unilateral TGCT. There is no standard therapy to treat BTGCT and each patient requires a tailored therapeutic treatment.
Abstract
Background
Prognostic factors for survival in metastatic urothelial carcinoma (mUC) have been established in patients (pts) treated with chemotherapy. However, their role has not been ...clearly defined in the era of immune-checkpoint inhibitors (ICIs). We have previously reported the Vall d’Hebron immuno-oncology prognostic index (VIO score) for refractory pts treated in phase I clinical trials with ICIs (Hierro C, et al ESMO 2018). In this retrospective study, we assessed VIO in pts with mUC treated with ICIs.
Methods
Pts with mUC enrolled from May 2015 to May 2018 in clinical trials at the Vall d’Hebron University Hospital were analysed. VIO score includes: albumin < 3.5 g/dl; LDH> upper limit of normal; neutrophil/leukocytes minus neutrophils ratio (dNLR) > 3; more than 2 sites of metastasis; and presence of liver metastasis. The following VIO clusters were defined: good prognosis (0-1), intermediate prognosis (2) and poor prognosis (³3 variables). Median overall survival (OS) was calculated using Kaplan-Meier method, long rank test was used for statistical comparison. All analyses were performed using SPSS v25; IBM Inc.
Results
Overall, 86 mUC pts received therapy with ICIs and 72 pts with complete annotation for VIO index were included in our analysis. Median age was 67.4 years, 62 (86.1%) pts were male, 66 pts (91.7%) had ECOG PS 0-1, 17 pts (23.6%) had liver metastasis and 8 pts (72%) had >2 sites of metastasis. Forty-eight pts (66.6%) were treated with ICIs as monotherapy and 24 pts (33.3%) in combination regimens. Follow-up was 13.2 moths (m) (95% CI; 10.5-15.9) and median OS was 11.3 m (95% CI; 7.1-15.4) in the evaluable population. Estimated mOS in good prognosis (62.5% of all pts), intermediate prognosis (23.6%) and poor prognosis (13.9%) were 19.3 m (95% CI; 5.1-33.6), 8.2 m (95% CI; 3.3-13.1) and 2.9 m (95% CI;0.1-7.7), respectively (p < 0.001). 3-m OS rates were 95.6%, 82.4% and 50% for good, intermediate and poor prognosis, respectively (p = 0.001).
Conclusions
VIO score is a powerful tool for predicting outcome in mUC pts treated with ICI and objectively estimating their life expectative at 3 m, which can help prioritize alternative therapies in clinical trials.
Legal entity responsible for the study
Vall d’Hebron Institute of Oncology, Vall d’ Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain.
Funding
Has not received any funding.
Disclosure
R. Morales Barrera: Honoraria (self), Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: MSD; Honoraria (self), Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Sanofi; Honoraria (self), Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: AstraZeneca; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Asofarma; Honoraria (self), Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Astellas; Honoraria (self), Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Johnson & Johnson; Honoraria (institution), Travel / Accommodation / Expenses: Bayer; Honoraria (institution), Travel / Accommodation / Expenses: Clovis Oncology; Honoraria (institution), Travel / Accommodation / Expenses: Lilly; Honoraria (self), Honoraria (institution), Advisory / Consultancy, Travel / Accommodation / Expenses: Roche/Genentech; Research grant / Funding (institution): AB Science; Research grant / Funding (institution): Aragon Pharmaceuticals; Research grant / Funding (institution): Arog Pharmaceuticals; Research grant / Funding (institution): INC; Research grant / Funding (institution): Aveo Pharmaceuticals INC; Research grant / Funding (institution): Blueprint Medicines Corporation; Research grant / Funding (institution): BN Immunotherapeutics INC; Research grant / Funding (institution): Boehringer Ingelheim España, S.A.; Research grant / Funding (institution): Cougar Biotechnology INC; Research grant / Funding (institution): Deciphera Pharmaceuticals LLC; Research grant / Funding (institution): Exelixis INC; Research grant / Funding (institution): Glaxosmithkline; Research grant / Funding (institution): Incyte Corporation; Research grant / Funding (institution): Karyopharm Therapeutics INC; Research grant / Funding (institution): Laboratoires Leurquin Mediolanum SAS; Research grant / Funding (institution): Medimmune; Research grant / Funding (institution): Millennium Pharmaceuticals; Research grant / Funding (institution): Nanobiotix SA; Research grant / Funding (institution): Novartis Farmacéutica, S.A; Research grant / Funding (institution): Pfizer, S.L.U; Research grant / Funding (institution): Puma Biotechnology; Research grant / Funding (institution): SFJ Pharma LTD; Research grant / Funding (institution): Teva Pharma S.L.U. M. Gonzalez: Travel / Accommodation / Expenses: Roche; Travel / Accommodation / Expenses: Astellas; Travel / Accommodation / Expenses: Bayer; Travel / Accommodation / Expenses: Novartis. C. Suárez: Research grant / Funding (institution): AB Science; Research grant / Funding (institution): Aragon Pharmaceuticals; Research grant / Funding (institution): Arog Pharmaceuticals; Advisory / Consultancy, Research grant / Funding (institution): Astellas Pharma; Speaker Bureau / Expert testimony, Research grant / Funding (institution): AstraZeneca AB; Research grant / Funding (institution): Aveo Pharmaceuticals INC; Research grant / Funding (institution): Bayer AG; Research grant / Funding (institution): Blueprint Medicines Corporation; Research grant / Funding (institution): BN Immunotherapeutics INC; Research grant / Funding (institution): Boehringer Ingelheim España, S.A.,; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Bristol-Myers Squibb International Corporation (BMS),; Research grant / Funding (institution): Clovis Oncology; Research grant / Funding (institution): Cougar Biotechnology INC; Research grant / Funding (institution): Deciphera Pharmaceuticals LLC; Research grant / Funding (institution): Exelixis INC; Research grant / Funding (institution), Travel / Accommodation / Expenses: Hoffmann-La Roche LTD; Research grant / Funding (institution): Genentech INC; Research grant / Funding (institution): Genentech INC; Research grant / Funding (institution): GlaxoSmithKline, SA; Research grant / Funding (institution): Incyte Corporation; Research grant / Funding (institution): Janssen-Cilag International NV; Research grant / Funding (institution): Karyopharm Therapeutics INC; Research grant / Funding (institution): Lilly, S.A; Research grant / Funding (institution): Millennium Pharmaceuticals, INC; Research grant / Funding (institution): Nanobiotix SA; Research grant / Funding (institution): Novartis Farmacéutica, S.A; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Pfizer; Research grant / Funding (institution): Puma Biotechnology; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Sanofi-Aventis, S.A; Research grant / Funding (institution): SFJ Pharma LTD. II; Research grant / Funding (institution): Teva Pharma S.L.U.; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self), Travel / Accommodation / Expenses: Ipsen; Advisory / Consultancy: Eusa; Advisory / Consultancy: Novartis. C. Fernandez: Travel / Accommodation / Expenses: AstraZeneca. C. Hierro: Research grant / Funding (self): Bayer; Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Travel / Accommodation / Expenses: Lilly; Advisory / Consultancy, Travel / Accommodation / Expenses: Ignyta. E. Serra: Travel / Accommodation / Expenses: Clovis Oncology; Travel / Accommodation / Expenses: Bayer. J. Mateo: Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy, Travel / Accommodation / Expenses: Janssen; Advisory / Consultancy: Roche; Advisory / Consultancy: Amgen; Speaker Bureau / Expert testimony: Sanofi. J. Martín Liberal: Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Novartis; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: BMS; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Pierre Fabre; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Roche; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Pfizer; Travel / Accommodation / Expenses: Ipsen. A. Quintana: Honoraria (self): Fundación Respira; Travel / Accommodation / Expenses: MSD. R. Dienstmann: Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Speaker Bureau / Expert testimony: Symphogen; Speaker Bureau / Expert testimony: Ipsen; Speaker Bureau / Expert testimony: Amgen; Speaker Bureau / Expert testimony: MSD; Speaker Bureau / Expert testimony: Servier; Research grant / Funding (self): Merck. C. Serrano: Advisory / Consultancy, Research grant / Funding (institution): Deciphera; Research grant / Funding (institution), Travel / Accommodation / Expenses: Pfizer; Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Bayer; Advisory / Consultancy: Blueprint; Travel / Accommodation / Expenses: PharmaMar; Travel / Accommodation / Expenses: Novartis; Travel / Accommodation / Expenses: Lilly. E. Garralda: Advisory / Consultancy, Research grant / Funding (institution): Roche/Genentech; Advisory / Consultancy: Ellipses Pharma; Advisory / Consultancy: Neomed Therapeutics; Advisory / Consult
Abstract
Background
Activation of the mTOR pathway is associated with shorter overall survival (OS) in patients (p) with metastatic renal cell carcinoma (mRCC). This outcome could be reversed with ...mTOR inhibitors (mTORi).
Methods
We retrospectively analized by amplicon-seq mutations in mTOR, VEGF, and cell cycle pathways in 90 mRCC p who had received mTORi. A multivariate Cox model including sex, age, non-clear or sarcomatoide component, metastatic sites, IMDC subgroup, and line of mTORi was adjusted to isolate the effect of having mTORi mutations on progression-free survival (PFS), death form diagnosis (OS1) and death from mTORi treatment (OS2).
Results
We identified 33% of p having mutations in the mTOR pathway: mTOR (17.8%), PIK3CA (5.6%), PTEN (3.3%), TSC1 (5.6%) and TSC2 (4%). No mutations were found in AKT (AKT1, AKT2, AKT3). OS for favorable, intermediate and poor prognosis of the IMDC were 43.7, 22.2 and 8.7 months respectively. As summarized in the table, in the best adjusted model there were no statistically differences in the hazard ratios (HR) of PFS, OS1 or OS2, between patient with and without mutations (M/NotM). Four long-term responders to mTORi (> 7 years) harboured mutations in one or more genes of this pathway (p53, PTEN and mTOR). Upon progression one patient adquired an LRPB1 mutation.
Table:975PAdjusted HR (Cox)PFSOS1OS 2M/NoM1.121.021.1895% CI0.67 – 1.890.61 – 1.690.63 – 2.21p0.6600.9460.607
Conclusions
In a multivariate adjusted model in patients with mRCC treated with mTORi, we did not find the expected worse prognosis associated with mTOR mutations. This finding can be considered as an indirect signal of the effect of mTORi on PFS and OS in patients with mTOR mutations. Although, not the most effective treatment in the overall population, some patients with specific alterations in the mTOR pathway should be considered for an mTORi.
Legal entity responsible for the study
Vall d´Hebron Institute of Oncology.
Funding
Has not received any funding.
Disclosure
C. Suarez Rodriguez: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Astellas; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): BMS; Advisory / Consultancy: Eusa; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Ipsen; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy: Sanofi-Aventis; Research grant / Funding (institution), Travel / Accommodation / Expenses, Non-remunerated activity/ies: Roche; Research grant / Funding (institution): AB Science; Research grant / Funding (institution): Aragon Pharmaceuticals; Research grant / Funding (institution): AstraZeneca AB; Research grant / Funding (institution): Aveo Pharmaceuticals INC; Research grant / Funding (institution): Bayer AG; Research grant / Funding (institution): Blueprint Medicines Corporation; Research grant / Funding (institution): BN Immunotherapeutics INC; Research grant / Funding (institution): Boehringer Ingelheim España, S.A; Research grant / Funding (institution): Clovis Oncology; Research grant / Funding (institution): Cougar Biotechnology INC; Research grant / Funding (institution): Deciphera Pharmaceuticals LLC; Research grant / Funding (institution): Exelixis INC; Research grant / Funding (institution):, F. Hoffmann-La Roche LTD; Research grant / Funding (institution): Genentech INC; Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution): Incyte Corporation; Research grant / Funding (institution): Janssen-Cilag International NV; Research grant / Funding (institution): Karyopharm Therapeutics INC; Research grant / Funding (institution): Laboratoires Leurquin Mediolanum SAS; Research grant / Funding (institution): Lilly, S.A; Research grant / Funding (institution): Medimmune; Research grant / Funding (institution): Millennium Pharmaceuticals; Research grant / Funding (institution): Nanobiotix SA. J.A. Arranz Arija: Advisory / Consultancy, Research grant / Funding (institution): BMS; Research grant / Funding (institution): Pierre-Fabre; Research grant / Funding (institution): Novartis; Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Advisory / Consultancy: Pfizer; Travel / Accommodation / Expenses: Janssen-Cilag. R. Morales Barrera: Research grant / Funding (institution): AB Science; Research grant / Funding (institution): Aragon Pharmaceuticals; Research grant / Funding (institution): Arog Pharmaceuticals, INC; Research grant / Funding (institution), Travel / Accommodation / Expenses: Astellas Pharma.; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca AB; Research grant / Funding (institution): Aveo Pharmaceuticals INC; Research grant / Funding (institution), Travel / Accommodation / Expenses: Bayer AG; Research grant / Funding (institution): Blueprint Medicines Corporation; Research grant / Funding (institution): BN Immunotherapeutics INC; Research grant / Funding (institution): Boehringer Ingelheim España, S.A.; Research grant / Funding (institution): Bristol-Myers Squibb International Corporation (BMS); Research grant / Funding (institution), Travel / Accommodation / Expenses: Clovis Oncology, INC,; Research grant / Funding (institution): Cougar Biotechnology INC; Research grant / Funding (institution): Deciphera Pharmaceuticals LLC; Research grant / Funding (institution): Exelixis INC; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: F. Hoffmann-La Roche LTD/Genentech,; Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution): Incyte Corporation; Research grant / Funding (institution): Janssen-Cilag International NV; Advisory / Consultancy: Johnson and Johnson; Research grant / Funding (institution): Karyopharm Therapeutics INC.,; Research grant / Funding (institution): Laboratoires Leurquin Mediolanum SAS; Research grant / Funding (institution), Travel / Accommodation / Expenses: Lilly; Research grant / Funding (institution): Medimmune, Millennium Pharmaceuticals, INC.; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Shareholder / Stockholder / Stock options: MSD; Research grant / Funding (institution): Nanobiotix SA,; Research grant / Funding (institution): Novartis Farmacéutica, S.A; Research grant / Funding (institution): Puma Biotechnology; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Sanofi-Aventis; Research grant / Funding (institution): Pharma LTD; Research grant / Funding (institution): Teva Pharma S.L.U.; Advisory / Consultancy, Speaker Bureau / Expert testimony: Asofarma. J. Puente: Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy, Research grant / Funding (self): Astellas; Advisory / Consultancy, Travel / Accommodation / Expenses: Janssen-Cilag; Advisory / Consultancy: Merck Sharp & Dohme; Advisory / Consultancy: Bayer; Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Travel / Accommodation / Expenses: BMS; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Boehringer; Advisory / Consultancy: Clovis; Advisory / Consultancy: Ipsen; Advisory / Consultancy: Eisai; Advisory / Consultancy: Eusa; Advisory / Consultancy: Sanofi-Aventis; Speaker Bureau / Expert testimony: Pierre-Fabre; Speaker Bureau / Expert testimony: Celgene; Speaker Bureau / Expert testimony: Kiowa; Speaker Bureau / Expert testimony: Novartis; Speaker Bureau / Expert testimony: Lilly. O. Reig: Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Ipsen; Speaker Bureau / Expert testimony: BMS; Speaker Bureau / Expert testimony: Pfizer. L. Faez: Travel / Accommodation / Expenses: AstraZeneca; Travel / Accommodation / Expenses: Amgen; Travel / Accommodation / Expenses: Pfizer. A. González del Alba: Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Astellas; Advisory / Consultancy, Speaker Bureau / Expert testimony: Janssen; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Bayer; Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Ipsen; Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy: Pierre Fabre; Advisory / Consultancy: Novartis; Advisory / Consultancy: Eusa; Advisory / Consultancy: Eisai; Advisory / Consultancy, Travel / Accommodation / Expenses: BMS; Travel / Accommodation / Expenses: MSD. B. P. Valderrama: Honoraria (self), Advisory / Consultancy: Pierre-Fabre; Honoraria (self), Advisory / Consultancy: Astellas; Honoraria (self): Novartis; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: BMS; Honoraria (self): Ipsen; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Bayer; Advisory / Consultancy: Sanofi-Aventis; Advisory / Consultancy: Ipsen; Advisory / Consultancy: MSD; Travel / Accommodation / Expenses: Janssen-Cilag; Travel / Accommodation / Expenses: Pfizer. E. Gallardo: Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Astellas; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Janssen; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommo
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