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Background : Axitinib monotherapy obtained approval in pre-treated metastatic renal cell carcinoma (mRCC) patients and recently in combination with pembrolizumab or avelumab in the first-line setting. However, patient profiles that may obtain increased benefit from this drug and its combinations still need to be identified. Patients and Methods : Retrospective multicentre analysis describing clinical characteristics associated with axitinib long-responder (LR) population by comparing two extreme-response sub-groups (progression-free survival [PFS] ≥9 months versus disease progression/refractory patients [RP]). A multivariate logistic-regression model was used to analyse clinical factors. Efficacy and safety were also analysed. Results : In total, 157 patients who received axitinib in second or subsequent line were evaluated (91 LR and 66 RP). Older age at start of axitinib and haemoglobin levels > LLN were independent predictive factors for LR in multivariate analyses. In LR patients, median (m) PFS was 18.1 months, median overall survival (OS) was 36.0 months and objective response rate (ORR) was 45.5%. In 59 LR patients receiving axitinib in second-line, mPFS was 18.7 months, mOS was 44.8 months and ORR was 43.9%. mOS was significantly longer in second line compared to subsequent lines (44.8 versus 26.5 months; P=0.009). In LR versus RP, mPFS with sunitinib in first-line was correlated with mPFS with axitinib in second-line (27.2 versus 10.9 months P Conclusions : This study confirms the long-term benefits of axitinib in a selected population, helping clinicians to select the best sequential approach and patients who could obtain a greater benefit from axitinib. Microabstract Patients with metastatic renal cell carcinoma (mRCC) who may benefit most from axitinib still need to be identified. AXILONG study confirms long-term benefits in a selected population in which age at axitinib initiation and haemoglobin baseline levels were significantly associated although further validation may be required. First-line sunitinib outcomes were also correlated with prolonged response. These results might be helpful in real-life management of mRCC patients.

Purpose: Germ cell tumors (GCT) of the testis are highly curable, but those patients who are refractory to cisplatin (CDDP)-based combination chemotherapy have a poor prognosis. Therefore, identifying new alternatives for treatment remains a priority. Several studies support an important role for angiogenesis in GCTs, suggesting that antiangiogenic treatment might be a good alternative. Sunitinib is an oral multitarget tyrosine kinase receptor inhibitor with antiangiogenic and antitumor activities. In the present study, we evaluated the effect of sunitinib, CDDP, or the combination of both drugs using an orthotopic model of human testicular GCT.Experimental Design: Mice were implanted with four different testicular tumors: a yolk sac, two choriocarcinomas, and a CDDP-resistant choriocarcinoma variant induced in mice by continuous exposure to CDDP. Mice were treated with vehicle, CDDP, sunitinib, or the combination of both drugs and their effects on tumors were analyzed.Results: We observed a significant inhibition in tumor growth accompanied by longer survival after sunitinib treatment. Combination therapy with CDDP significantly enhanced these effects. Sunitinib induced apoptosis, reduced tumor cell proliferation and tumor vasculature, and inhibited vascular endothelial growth factor receptor 1, 2, and 3 and platelet-derived growth factor receptor α phosphorylation without affecting phosphorylation of other tyrosine kinase receptors. More importantly, tumor growth inhibition induced by sunitinib was also observed in the induced CDDP-resistant choriocarcinoma model.Conclusions: Taken together, these results suggest that sunitinib might be a new alternative for treatment of CDDP-refractory patients.

Supplementary Data from Sunitinib Inhibits Tumor Growth and Synergizes with Cisplatin in Orthotopic Models of Cisplatin-Sensitive and Cisplatin-Resistant Human Testicular Germ Cell Tumors

It remains unclear which patients with metastatic germ cell tumours (mGCTs) need prophylactic anticoagulation to prevent venous thromboembolic events (VTEs).To assess the risk and onset of VTEs stratified by risk factors.This multi-institutional retrospective dataset included mGCT patients treated with first-line platinum-based chemotherapy.Patients with prophylactic anticoagulation were excluded.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.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.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.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.

PURPOSE The classification of the International Germ Cell Cancer Collaborative Group (IGCCCG) plays a pivotal role in the management of metastatic germ cell tumors but relies on data of patients treated between 1975 and 1990. MATERIALS AND METHODS Data on 9,728 men with metastatic nonseminomatous germ cell tumors treated with cisplatin- and etoposide-based first-line chemotherapy between 1990 and 2013 were collected from 30 institutions or collaborative groups in Europe, North America, and Australia. Clinical trial and registry data were included. Primary end points were progression-free survival (PFS) and overall survival (OS). The survival estimates were updated for the current era. Additionally, a novel prognostic model for PFS was developed in 3,542 patients with complete information on potentially relevant variables. The results were validated in an independent data set. RESULTS Compared with the original IGCCCG publication, 5-year PFS remained similar in patients with good prognosis with 89% (87%-91%) versus 90% (95% CI, 89 to 91), but the 5-year OS increased from 92% (90%-94%) to 96% (95%-96%). In patients with intermediate prognosis, PFS remained similar with 75% (71%-79%) versus 78% (76%-80%) and the OS increased from 80% (76%-84%) to 89% (88%-91%). In patients with poor prognosis, the PFS increased from 41% (95% CI, 35 to 47) to 54% (95% CI, 52 to 56) and the OS from 48% (95% CI, 42 to 54) to 67% (95% CI, 65 to 69). A more granular prognostic model was developed and independently validated. This model identified a new cutoff of lactate dehydrogenase at a 2.5 upper limit of normal and increasing age and presence of lung metastases as additional adverse prognostic factors. An online calculator is provided ( https://www.eortc.org/IGCCCG-Update ). CONCLUSION The IGCCCG Update model improves individual prognostication in metastatic nonseminomatous germ cell tumors. Increasing age and lung metastases add granularity to the original IGCCCG classification as adverse prognostic factors.

PURPOSE Antitumor activity in preclinical models and a phase I study of patients with dedifferentiated liposarcoma (DD-LPS) was observed with selinexor. We evaluated the clinical benefit of selinexor in patients with previously treated DD-LPS whose sarcoma progressed on approved agents. METHODS SEAL was a phase II-III, multicenter, randomized, double-blind, placebo-controlled study. Patients age 12 years or older with advanced DD-LPS who had received two-five lines of therapy were randomly assigned (2:1) to selinexor (60 mg) or placebo twice weekly in 6-week cycles (crossover permitted). The primary end point was progression-free survival (PFS). Patients who received at least one dose of study treatment were included for safety analysis (ClinicalTrials.gov identifier: NCT02606461 ). RESULTS Two hundred eighty-five patients were enrolled (selinexor, n = 188; placebo, n = 97). PFS was significantly longer with selinexor versus placebo: hazard ratio (HR) 0.70 (95% CI, 0.52 to 0.95; one-sided P = .011; medians 2.8 v 2.1 months), as was time to next treatment: HR 0.50 (95% CI, 0.37 to 0.66; one-sided P < .0001; medians 5.8 v 3.2 months). With crossover, no difference was observed in overall survival. The most common treatment-emergent adverse events of any grade versus grade 3 or 4 with selinexor were nausea (151 [80.7%] v 11 [5.9]), decreased appetite (113 [60.4%] v 14 [7.5%]), and fatigue (96 [51.3%] v 12 [6.4%]). Four (2.1%) and three (3.1%) patients died in the selinexor and placebo arms, respectively. Exploratory RNA sequencing analysis identified that the absence of CALB1 expression was associated with longer PFS with selinexor compared with placebo (median 6.9 v 2.2 months; HR, 0.19; P = .001). CONCLUSION Patients with advanced, refractory DD-LPS showed improved PFS and time to next treatment with selinexor compared with placebo. Supportive care and dose reductions mitigated side effects of selinexor. Prospective validation of CALB1 expression as a predictive biomarker for selinexor in DD-LPS is warranted.

Background The coronavirus disease 2019 (COVID-19) pandemic has become a public health emergency affecting frail populations, including patients with cancer. This poses the question of whether cancer treatments can be postponed or modified without compromising their efficacy, especially for highly curable cancers such as germ cell tumors (GCTs). Materials and Methods To depict the state-of-the-art management of GCTs during the COVID-19 pandemic, a survey including 26 questions was circulated by e-mail among the physicians belonging to three cooperative groups: (a) Italian Germ Cell Cancer Group; (b) European Reference Network–Rare Adult Solid Cancers, Domain G3 (rare male genitourinary cancers); and (c) Genitourinary Medical Oncologists of Canada. Percentages of agreement between Italian respondents (I) versus Canadian respondents (C), I versus European respondents (E), and E versus C were compared by using Fisher's exact tests for dichotomous answers and chi square test for trends for the questions with three or more options. Results Fifty-three GCT experts responded to the survey: 20 Italian, 6 in other European countries, and 27 from Canada. Telemedicine was broadly used; there was high consensus to interrupt chemotherapy in COVID-19–positive patients (I = 75%, C = 55%, and E = 83.3%) and for use of granulocyte colony-stimulating factor primary prophylaxis for neutropenia (I = 65%, C = 62.9%, and E = 50%). The main differences emerged regarding the management of stage I and stage IIA disease, likely because of cultural and geographical differences. Conclusion Our study highlights the common efforts of GCT experts in Europe and Canada to maintain high standards of treatment for patients with GCT with few changes in their management during the COVID-19 pandemic.

Management of first-line advanced urothelial carcinoma (UC) has consisted during the past three decades in the administration of platinum-based chemotherapy followed by observation. Despite moderate to high response rates to first-line treatment, most patients will relapse shortly after and the outcomes with subsequent therapies are poor with 5-year overall survival rates of 5% in the pre-immunotherapy era. Nonetheless, recent therapeutic developments including the paradigm shift of first-line maintenance therapy with avelumab after response or stabilization on platinum-based chemotherapy, along with the incorporation of new drug classes in further lines of treatment such as antibody drug-conjugates and fibroblast growth factor receptor inhibitors have reshaped the field leading to better outcomes in this patient population. This article reviews the current state of the art with an overview on UC management, recent advances, and the upcoming strategies currently in development in advanced UC with an insight into the biology of this disease.

410 Background: Between 4%- 30% of patients with clinical stage 1 (CS I) seminoma testis (ST) in active surveillance (AS) relapse depending on pathological risk factors tumor size (TS) and rete testis invasion (RTI). The level of evidence supporting these pathological risk factors in clinical decision-making is low due to heterogeneous study design and reporting and the difficulty to analyze patient subgroups according to combination of these factors. The objectives of the present study were to identify the most important pathological prognostic factors predicting relapse in CS I seminoma patients with normal post-orchidectomy serum tumor marker (STM) levels in AS and to construct risk-groups for guiding treatment decision-making and follow-up. Methods: Individual patient data from 1016 CS I-ST patients diagnosed between February 1994 and January 2019 in AS were collected from 9 institutions. Central pathology review was not routinely performed in all institutions; therefore, pagetoid and stromal RTI were not differentiated explicitly in most cases. Assessing patient age, pre-orchidectomy STM b-human chorionic gonadotropin and lactate dehydrogenase, pathological TS, RTI, lympho-vascular invasion (LVI), multi-focality, and GCNIS, multivariable Cox proportional hazards regression models were fit to identify the most important prognostic factors for the time to first relapse by imaging and/or markers (primary endpoint). Probabilities of relapse were estimated using Kaplan-Meier curves. Results: After median follow-up of 7.7 years, 149 (14.7%) patients relapsed, 104 identified by imaging alone, 44 by imaging with elevated STMs and 1 by elevated STMs alone. Excluding 18 patients with unknown LVI from the multivariable analyses, TS (≤ 2 cm, between 2 and 5 cm, > 5 cm), presence of RTI and presence of LVI were used to form three risk groups: very low, low and high-risk (Table). Five-years probability of relapse varied from 8% in the very low risk-group to 44% in the high risk-group. The new model outperformed the current model with TS < 4cm vs ≥ 4 and RTI (Harrell's C index 0.65 vs 0.61) and identifies a subgroup of patients with a higher risk of relapse. Conclusions: The new risk-group stratification for CS I -ST patients in AS outperforms the histopathological model based on TS and RTI. It will serve to better inform patients on the risk of relapse during follow-up after orchidectomy but requires an independent validation. [Table: see text]

LBA441 Background: Two interim OS analyses from IMvigor130 demonstrated non-statistically significant OS benefit with atezo monotherapy (Arm B) vs placebo + platinum (investigator [INV] choice of carboplatin or cisplatin [carbo or cis])/gemcitabine (plt/gem; Arm C) in patients (pts) with PD-L1–high (IC2/3) mUC, as well as a favorable safety profile vs chemo (Galsky Lancet 2020, Davis AACR 2021). Exploratory data showed clinical benefit with atezo monotherapy in cis-ineligible pts with IC2/3 tumors. Here, we report the final OS analysis from IMvigor130 Arms B and C. Methods: Pts were randomly assigned 1:1:1 to Arm A (atezo + plt/gem; not reported here), B or C. Due to the statistical testing hierarchy, no formal comparison of OS (co-primary endpoint) in Arm B vs C was performed in ITT and IC2/3 pts. ORR and DOR, both per INV-assessed RECIST 1.1 (secondary endpoints), and safety were assessed. Subgroup analyses of OS in cis-ineligible pts and disease control rate (DCR, confirmed CR, PR or [SD ≥6 mo]) were exploratory. Results: As of data cutoff Aug 31, 2022, time since last pt randomly assigned was 49 mo. OS data (Table) did not show benefit for ITT pts, while an HR of 0.56 (0.34, 0.91) was seen in the cis-ineligible IC2/3 subgroup. In the ITT population, the 24-mo OS rates were 34% in Arm B and 32% in Arm C. ORR was 24% (87/359; 38% DCR) in Arm B and 44% (158/356; 59% DCR) in Arm C; median DOR was 29.6 and 8.1 mo, respectively. In cis-ineligible IC2/3 pts, ORR was 40% (20/50) in Arm B and 33% (14/43) in Arm C. Median DOR was not evaluable in Arm B and 6.2 mo in Arm C. Of safety-evaluable pts, 57 of 354 in Arm B (16%) and 312 of 389 in Arm C (80%) had a Gr 3/4 treatment-related AE (TRAE); 3 (1%) and 4 (1%), respectively, had a Gr 5 TRAE. Gr 3/4 AEs of special interest occurred in 36 pts (10%) in Arm B and 17 (4%) in Arm C. Conclusions: The final OS analysis was consistent with previous data. Atezo monotherapy continued to show better tolerability vs chemo with no new safety concerns. These exploratory data support the benefit-risk ratio of atezo monotherapy vs chemo for first-line cis-ineligible IC2/3 mUC. Clinical trial information: NCT02807636 . [Table: see text]

463 Background: Real-world evidence on la/mUC management in Europe is limited. This study describes patient (pt) characteristics, treatment patterns, survival, and HCRU for pts with la/mUC in Spain. Methods: A retrospective chart review was conducted using electronic medical records from 9 university hospitals in Spain. The study population included all pts aged ≥18 y with a first diagnosis/record of la/mUC from 1/1/2015–12/31/2020 (study period). Date of first la/mUC record/diagnosis during the study period was the index date. Pts with urachus carcinoma or other nonurothelial cancers were excluded. Pt characteristics are described for the full study population. Treatment patterns, survival, and la/mUC-associated HCRU are described for the follow-up cohort: a subset of the study cohort with a first la/mUC diagnosis/record from 1/1/2015–6/30/2020 (ie, to allow for ≥6 mo follow-up). Pts were followed from index date to death, loss to follow-up, or end of study. Median overall survival (OS) and progression-free survival (PFS; evaluated in a real-world setting) were determined using Kaplan–Meier curves. Time to progression, excluding pts who died and were censored at death, was also estimated. HCRU included inpatient admissions, outpatient visits, and emergency visits. Results: Overall, 903 pts were included. Median age at la/mUC diagnosis was 70 y; 79.6% were men. Most (71.0%) had ≥1 comorbidity, most commonly cardiovascular disease (54.2%). Primary tumor sites were the bladder (83.7%), urethra (7.0%), and upper tract (6.6%). De novo la/mUC (41.9%) was the most common initial UC diagnosis. In the follow-up cohort (n = 829), median follow-up was 12.7 mo. Most (84.7% [n = 702]) pts received first-line (1L) systemic treatment; of these, 46.9% (n = 329) received second-line (2L) and 16.6% (n = 116) received third-line (3L) therapy. Chemotherapy was the most common treatment (1L: 77.8% [n = 546]; 2L: 49.8% [n = 164]; 3L: 74.1% [n = 86]), followed by PD-1/L1 inhibitors (1L: 28.3% [n = 199]; 2L: 47.7% [n = 157]; 3L: 19.0% [n = 22]). From index la/mUC diagnosis, estimated median (95% CI) OS was 18.8 (17.5–21.5), PFS was 9.9 (8.9–10.5), and time to progression was 12.7 (11.3–14.6) mo. From the start of 1L, 2L and 3L therapy, estimated median (95% CI) OS were 16.9 (14.3–18.9), 11.6 (9.6–14.3), and 9.9 (7.9–12.6) mo. For HCRU, 71.8% (n = 595) of pts had ≥1 outpatient visit (mean: 2.2/mo), 56.6% (n = 469) had ≥1 inpatient admission (0.4/mo; median duration: 8.0 d), and 56.5% (n = 468) had ≥1 emergency visit (0.4/mo). Conclusions: This retrospective study of university hospital data describes pt characteristics and real-world treatment patterns, survival, and HCRU for pts with la/mUC in Spain. Advances in immunotherapy are shifting the treatment landscape for targeted groups of pts with la/mUC, but a need remains for innovative treatments that could improve pt outcomes.

LBA440 Background: The IMvigor130 primary analysis demonstrated statistically significant PFS benefit with 1L atezo + plt/gem (Arm A) vs placebo + plt/gem (Arm C) in pts with mUC (Galsky Lancet 2020). Interim data showed improved OS with Arm A vs C but did not cross the pre-specified threshold for significance (Galsky Lancet 2020; Galsky AACR 2021). In exploratory analyses, OS improved when atezo was combined with cisplatin (cis) vs carboplatin (carbo) regardless of PD-L1 status. Here, we report final OS data from Arms A and C. Methods: Pts were randomly assigned 1:1:1 to Arm A, B (atezo alone) or C. Arm A and C pts received cis or carbo per investigator (INV) choice. Co-primary endpoints were PFS per INV RECIST 1.1 and OS (Arm A vs C), and OS (Arm B vs C), tested hierarchically. Safety, ORR and DOR, disease control rate (DCR; confirmed CR, PR or [SD ≥ 6 mo]) and pre-specified exploratory OS data are also reported. Results: As of data cutoff Aug 31, 2022 (49 mo since last pt randomly assigned), in ITT pts, OS benefit was not statistically significant; in the cis subgroup, HR was 0.76 (95% CI 0.57, 1.01; Table). In ITT pts, DCR was 65% (290/447) in Arm A and 60% (239/397) in Arm C. 81% of safety-evaluable pts (370/454) in Arm A and 80% (312/389) in Arm C had a Gr 3/4 tx-related AE (TRAE). Gr 5 TRAEs occurred in 9 pts (2%) in Arm A and 4 (1%) in Arm C; Gr 3/4 AEs of special interest were seen in 41 pts (9%) in Arm A and 17 (4%) in Arm C. Conclusions: In this final analysis, improved OS with atezo + plt/gem vs placebo + plt/gem did not reach statistical significance in ITT pts with mUC. As seen with prior exploratory data, improved OS with atezo + plt/gem was greater when pts received cis vs carbo. No new safety signals were seen. Clinical trial information: NCT02807636 . [Table: see text]

Background Ramucirumab-an IgG1 vascular endothelial growth factor receptor 2 antagonistplus 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 2 (60 mg/m 2 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. Copyright (C) 2019 Elsevier Ltd. All rights reserved.

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, Venous thromboembolism can cause morbidity in germ cell tumor patients receiving chemotherapy; large retroperitoneal lymphadenopathy (RPLN) and indwelling vascular access devices (VAD) are significant VTE risk factors. VAD insertion should be avoided and thromboprophylaxis can be considered for large RPLN.

Objective: To assess the efficacy and tolerability of rechallenge with sunitinib and other targeted therapies (TTs) in patitents with relapsed recurrent renal cell carcinoma (RCC) in the advanced setting. Methods: In this multi-institutional retrospective study, patients with relapsed RCC were rechallenged with sunitinib or other systemic TTs as a first-line therapeutic approach after failed adjuvant sunitinib treatment. Patient characteristics, treatments and clinical outcomes were recorded. The primary endpoint was progression-free survival (PFS). Secondary endpoints were objective response rate (ORR) and overall survival (OS). Results: A total of 34 patients with relapses were recorded, and 25 of these (73.5%) were men. Twenty-five patients were treated with systemic TT: 65% of patients received TT against the vascular endothelial growth factor pathway (including sunitinib), 21.7% received mammalian target of rapamycin inhibitors and 13% received immunotherapy. The median (interquartile range) time to relapse was 20.3 (5.2–20.4) months from diagnosis, and 7.5 months (1.0–8.5) from the end of adjuvant suntinib treatment. At a median follow-up of 23.5 months, 24 of the 25 patients had progressed on first-line systemic therapy. The median PFS was 12.0 months (95% confidence interval [CI] 5.78–18.2). There were no statistical differences in PFS between different treatments or sunitinib rechallenge. PFS was not statistically different in patients relapsing on or after adjuvant suntinib treatment (≤ 6 or >6 months after adjuvant suntinib ending). The ORR was 20.5%. The median OS was 29.1 months (95% CI 16.4–41.8). Conclusions: Rechallenge with sunitinib or other systemic therapies is still a feasible therapeutic option that provides patients with advanced or metastastic RCC with additional clinical benefits with regard to PFS and OS after failed response to adjuvant sunitinib.

Among all Soft Tissue sarcomas there are some subtypes with low incidence and/or peculiar clinical behaviour, that need to be consider separately. Most of them are orphan diseases, whose biological characteristics imply a clearly different diagnostic and therapeutic approach from other more common sarcoma tumors. We present a brief and updated multidiciplinary review, focused on practical issues, aimed at helping clinicians in decision making. In this second part we review these subtypes: Alveolar Soft Part Sarcoma, Epithelioid Sarcoma, Clear Cell Sarcoma, Desmoplastic Small Round Cell Tumor, Rhabdoid Tumor, Phyllodes Tumor, Tenosynovial Giant Cell Tumors, Myoepithelial Tumor, Perivascular Epithelioid Cell Neoplasms (PEComas), Extraskeletal Myxoid Chondrosarcoma, NTRK-fusions Sarcomas. Most of them present their own radiological and histopathological feautures, that are essential to know in order to achieve early diagnosis. In some of them, molecular diagnosis is mandatory, not only in the diagnosis, but also to plan the treatment. On the other hand, and despite the low incidence, a great scientific research effort has been made to achieve new treatment opportunities for these patients even with approved indications. These include new treatments with targeted therapies and immunotherapy, which today represent possible therapeutic options. It is especially important to be attentive to new and potential avenues of research, and to promote the conduct of specific clinical trials for rare sarcomas.

Sarcomas are malignant soft tissue and bone tumours affecting adults, adolescents and children. They represent a morphologically heterogeneous class of tumours and some entities lack defining histopathological features. Therefore, the diagnosis of sarcomas is burdened with a high inter-observer variability and misclassification rate. Here, we demonstrate classification of soft tissue and bone tumours using a machine learning classifier algorithm based on array-generated DNA methylation data. This sarcoma classifier is trained using a dataset of 1077 methylation profiles from comprehensively pre-characterized cases comprising 62 tumour methylation classes constituting a broad range of soft tissue and bone sarcoma subtypes across the entire age spectrum. The performance is validated in a cohort of 428 sarcomatous tumours, of which 322 cases were classified by the sarcoma classifier. Our results demonstrate the potential of the DNA methylation-based sarcoma classification for research and future diagnostic applications., This work was funded by Deutsche Krebshilfe grant 70112499, the NCT Heidelberg and an Illumina Medical Research Grant. Part of this work was funded by the National Institute of Health Research (to S.B. and Z.J.) and to UCLH Biomedical research centre (BRC399/NS/RB/101410). Human tissues were obtained from University College London NHS Foundation Trust as part of the UK Brain Archive Information Network (BRAIN UK, Ref: 18/004) which is funded by the Medical Research Council and Brain Tumour Research UK. The methylation profiling at NYU is supported by a grant from the Friedberg Charitable Foundation (to M.Sn.). M.Mi. would like to thank the Luxembourg National Research Fond (FNR) for the support (FNR PEARL P16/BM/11192868 grant). Open Access funding enabled and organized by Projekt DEAL.

Soft-tissue sarcomas (STS) are an uncommon and heterogeneous group of malignancies that result in high mortality. Metastatic STS have very bad prognosis due to the lack of effective treatments. Dinaciclib is a model drug for the family of CDK inhibitors. Its main targets are cell cycle regulator CDK1 and protein synthesis controller CDK9. We present data supporting Dinaciclib ability to inactivate in vitro different STS models at nanomolar concentrations. Moreover, the different rhythms of cell death induction allow us to further study into the mechanism of action of the drug. Cell death was found to respond to the mitochondrial pathway of apoptosis. Anti-apoptotic Bcl-xL was identified as the key regulator of this process. Already natural low levels of pro-apoptotic proteins BIM and PUMA in tolerant cell lines were insufficient to inhibit Bcl-xL as this anti-apoptotic protein showed a slow decay curve after Dinaciclib-induced protein synthesis disruption. Combination of Dinaciclib with BH3-mimetics led to quick and massive apoptosis induction in vitro, but in vivo assessment was prevented due to liver toxicity. Additionally, Bcl-xL inhibitor A-1331852 also synergized with conventional chemotherapy drugs as Gemcitabine. Thus, Bcl-xL targeted therapy arises as a major opportunity to the treatment of STS.

Testicular germ cell tumors (TGCTs) are a clinically and pathologically heterogeneous disease, and little is known of its genetic basis. Only low susceptibility risk loci have been identified for both sporadic and familial cases. Therefore, we tried to identify new susceptibility genes responsible for familial testicular cancer that may contribute to increasing our knowledge about the genetic basis of the disease. Nineteen Spanish families with at least two affected individuals with TGCT were selected. WES was performed on those individuals using an Illumina Hiseq2000 sequencing platform. Data were analyzed under a monogenic and polygenic model of inheritance, and candidate variants were evaluated in a case-control association study performed on 391 Spanish sporadic cases and 1,170 healthy Spanish controls. Results were replicated in a second series consisting of 101 TGCTs from the Cancer Genome Atlas (TGCA) and 27,000 controls from the Exome Aggregation Consortium (ExAC) database. Logistic regression was carried out to analyze the association strength (risk) of candidate variants obtained among cases and controls in different populations. Despite the sample size, we detected a significant earlier age of onset in familial TGCT (28y) than sporadic cases (33y), using a Mann-Whitney U test. We identified significant variants in the comparative study of TGCT cases (391) versus controls (almost 1,170), and three of them [PLEC (OR = 6.28, p = 6.42 × 10-23 ) (p.Arg2016Trp), EXO5 (OR = 3.37, p = 4.82 × 10-09 ) (p.Arg344AlafsTer10) and DNAH7 (OR = 1.64, p = 0.048)] were replicated as potential candidates that may contribute to explaining the genetic basis of TGCT.

TPS8 Background: PSqCC is a rare tumor with poor prognosis and limited therapeutic options. The current standard of care for advanced disease has been palliative platinum-based chemotherapy, with only marginal survival benefit. Recent data has shown that the majority of PSqCC patients present high levels of programmed death-ligand 1 (PD-L1). The ORPHEUS trial is evaluating the efficacy and safety of INCMGA00012 –a programmed cell death 1 (PD-1) antagonist– in patients with unresectable, locally advanced or metastatic PSqCC. Methods: ORPHEUS is an international, multicenter, open-label, single-arm, phase 2 clinical trial. Eligible patients are male aged ≥18 years with locally advanced or metastatic PSqCC, ECOG performance status of 0-1, adequate organ function, a life expectancy of ≥12 weeks, and with no prior treatment with PD-1 or PD-L1/2 agents. A total of 18 patients will be enrolled to receive INCMGA00012 500 mg administered intravenously on day 1 of each 28-day cycle. Treatment will continue until progressive disease or unacceptable toxicity. Tumor assessments per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 and immune-related RECIST will be performed approximately every 8 weeks for the first 6 months and every 12 weeks thereafter until progressive disease. The primary endpoint is objective response rate. Secondary objectives include additional efficacy outcomes (clinical benefit rate, progression-free survival (PFS), 6-month PFS, duration of response, time to progression, overall survival, and maximum tumor shrinkage) and safety evaluated as per NCI-CTCAE 5.0. Exploratory objectives will evaluate efficacy based on immune-related RECIST; predictive and prognostic biomarkers; impact of INCMGA00012 on human immunodeficiency virus (HIV) control in patients known to be HIV-positive. The sample size calculation is based on an exact binomial test. At least 4 responders (22.2%) among 18 patients will be adequate to justify further investigation of this strategy. The analyses were designed to attain an 80% power, with a 10% dropout rate assumption, at a nominal one-sided α level of 5%. The response probabilities for null (H0) and alternative hypotheses (H1) were H0: ≤ 5% and H1: ≥ 25%, respectively. All 18 planned patients have been enrolled since the trial began in March 2020. Clinical trial information: NCT04231981.

Background Sorafenib is a potent targeted-therapy that blockades angiogenesis and has demonstrated activity against some sarcoma subtypes. Preclinical studies suggested that treatment with sorafenib plus cytotoxic agents could result in additive efficacy. Methods Patients with advanced soft tissue sarcoma, with or without anthracycline pretreatment were included. Patients received oral sorafenib 400 mg twice daily starting on Day +2, ifosfamide 2.0 g/m2 iv infusion lasting 4 h on days 1, 2 and 3 with concurrent mesna 400 mg/m2 every three weeks until disease progression or unacceptable toxicity or up to a maximum of 6 cycles of ifosfamide (sorafenib could be continued until progressive disease or unacceptable toxicity). Primary objective was progression-free rate (PFR) at 3 and 6 months; secondary objectives were overall response rate (ORR), Progression-free survival (PFS), Overall survival (OS) and safety. This article reports the phase II part of a phase I/II clinical trial. Results Thirty-five patients were enrolled. PFR at 3 and 6 months was 66% (95% CI 48–81) and 37% (95% CI 22–55). Six patients (17%) achieved partial response and 17 (49%) stable disease. Median PFS was 4.8 months (CI 95% 1.94–6.36) and overall survival 16.2 months (95% CI 8.75-NA). Conclusion Treatment with sorafenib plus ifosfamide achieved a significant clinical benefit with an acceptable safety profile in patients with advanced soft tissue sarcoma resistant to anthracyclines, which warrants a more detailed study in randomized clinical trials.

Objective: The aim of this study was to assess a risk-adapted strategy for stage I seminoma guided by the presence of rete testis invasion. Methods: Between January 2013 and December 2015, a total of 135 consecutive patients with stage I seminoma from 18 Spanish tertiary hospitals were included in a prospective multicenter study. Median patient age was 38 years (range 22–60). Preoperative beta-human chorionic gonadotropin was elevated in 9.6% of patients. Rete testis invasion was present in 47.4% of patients. After orchiectomy, subjects with rete testis invasion were treated with 2 courses of adjuvant carboplatin (area under the curve of 7, with 21-day interval). Those without this risk factor were managed by surveillance. Disease-free survival (DFS) and overall survival (OS) were estimated with the Kaplan-Meier method. Results: After a median follow-up time of 33 months, only 6 relapses were recorded (5 on surveillance, 1 after carboplatin). These cases were rescued with BEP or EP chemotherapy, and all 135 patients are currently disease free without sequelae. Three-year DFS was 92.0 and 98.2% for patients on surveillance and after carboplatin, respectively. Three-year OS was 100%. Conclusion: A risk-adapted approach based on rete testis invasion as a single risk factor is feasible and yielded an excellent outcome with a 3-year DFS of 94.9%.

Background: This multicentre phase II trial (DOVIGIST) evaluated the antitumour activity of dovitinib as second-line treatment of patients with gastrointestinal stromal tumour (GIST) refractory to imatinib or who do not tolerate imatinib. Methods: Patients received oral dovitinib 500 mg day(-1), 5 days on/2 days off, until GIST progression or unacceptable toxicity, with an objective to evaluate efficacy, assessed as the disease control rate (DCR) at 12 weeks. Tumour assessment and response to dovitinib therapy were evaluated by Response Evaluation Criteria In Solid Tumours (RECIST v1.1) and the Choi criteria. Secondary objectives included assessment of progression-free survival (PFS), safety and tolerability, and DCR at the end of treatment. Results: Thirty-eight of the 39 patients enrolled had histologically confirmed GIST. The DCR at 12 weeks was 52.6% (90% confidence interval (CI), 38.2-66.7%) meeting the preset efficacy criterion for the primary end point. The objective response rate (complete response+partial response) was 2.6% (1 of 38; 90% CI, 0.1-11.9%), and 5.3% (n = 2; 90% CI, 0.9-15.7%) at the end of the study. The median PFS was 4.6 months (90% CI, 2.8-7.4 months). Dose interruption was required in 26 patients (66.7%), of which 18 (69.2%) were due to adverse events. The most frequently observed grade 3 adverse events included hypertension (n = 7), fatigue (n = 5), vomiting (n = 4), hypertriglyceridaemia (n = 4), and gamma-glutamyltransferase increase (n = 4). Conclusions: Dovitinib is an active treatment for patients with GIST who are intolerant to imatinib or whose GIST progresses on imatinib.

Background High-dose chemotherapy (HDCT) has been studied in several clinical scenarios in advanced germ cell cancer (GCC). Objective To establish a clinical practice guideline for HDCT use in the treatment of GCC patients. Design, setting, and participants An expert panel reviewed information available from the literature. The panel addressed relevant issues concerning and related to HDCT. The guideline was externally reviewed by two international experts. Results and limitations The efficacy of HDCT has been demonstrated in selected GCC patients. The most conclusive evidence comes from retrospective analyses that need to be interpreted with caution. HDCT can cure a significant proportion of heavily treated GCC patients. When indicated, sequential HDCT with regimens containing carboplatin and etoposide, as well as peripheral stem-cell support, is recommended. There is no conclusive evidence to recommend HDCT as first-line therapy. According to a multinational retrospective pooled analysis, HDCT might be superior to conventional CT as first salvage treatment in selected patients. There is an urgent need for prospective clinical trials addressing the value of HDCT in GCC patients who experience failure on first-line cisplatin-based CT. In patients who progress on conventional-dose salvage CT, HDCT should be considered. Treatment of these patients at experienced centers is strongly recommended. Conclusions It has been demonstrated that HDCT cures selected GCC patients who experience disease progression on conventional rescue regimens. The panel recommends the inclusion of GCC patients in randomized clinical trials including HDCT. Patient summary This consensus establishes clinical practice guidelines for the use and study of high-dose chemotherapy in patients with germ cell cancer.

Sofia España,1 Maria Ochoa de Olza,2 Nuria Sala,3 Josep Maria Piulats,2 Ulises Ferrandiz,1 Olatz Etxaniz,1 Lucia Heras,2,4 Oscar Buisan,5 Juan Carlos Pardo,1 Jose F Suarez,6 Pilar Barretina,3 Josep Comet,7 Xavier Garcia del Muro,2 Lauro Sumoy,8 Albert Font1 1Catalan Institute of Oncology, Medical Oncology Department, University Hospital Germans Trias I Pujol, Badalona, Spain; 2Catalan Institute of Oncology, Medical Oncology Department, Bellvitge University Hospital, Hospitalet De Llobregat, Spain; 3Catalan Institute of Oncology, Medical Oncology Department, University Hospital Josep Trueta, Girona, Spain; 4Medical Oncology Department, Hospital Sant Joan Despí Moisès Broggi, Barcelona, Spain; 5Urology Department, University Hospital Germans Trias I Pujol, Badalona, Spain; 6Urology Department, Bellvitge University Hospital, Hospitalet de LLobregat, Spain; 7Urology Department, University Hospital Josep Trueta, Girona, Spain; 8High Content Genomics & Bioinformatics Unit, Germans Trias I Pujol Research Institute (IGTP), Program of Predictive and Personalized Medicine of Cancer (PMPPC), Campus Can Ruti, Badalona, SpainCorrespondence: Albert FontCatalan Institute of Oncology, Medical Oncology Department, University Hospital Germans Trias I Pujol, Ctra Canyet, s/n, Badalona 08916, SpainEmail afont@iconcologia.netBackground: Abiraterone acetate (AA) is widely used in the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC). However, a significant percentage of patients will still progress, highlighting the need to identify patients more likely to benefit from AA. Parameters linked to prostate-specific antigen (PSA) kinetics are promising prognostic markers. We have examined clinical and PSA-related factors potentially associated with overall survival (OS) in patients treated with AA.Methods: Between 2011 and 2014, 104 patients with mCRPC treated with AA after progression to docetaxel at centers of the Catalan Institute of Oncology were included in this retrospective study. Patients were assessed monthly. Baseline characteristics and variables related to PSA kinetics were included in univariate and multivariate analyses of OS.Results: Median OS was 16.4 months (range 12.4– 20.6) for all patients. The univariate analysis identified the following baseline characteristics as significantly associated with OS: ECOG PS, location of metastases, time between starting androgen deprivation therapy and starting AA, time between stopping docetaxel treatment and starting AA, neutrophil-lymphocyte ratio (NLR), alkaline phosphatase levels, and PSA levels. Factors related to PSA kinetics associated with longer OS were PSA response > 50%, early PSA response (> 30% decline at four weeks), PSA decline > 50% at week 12, PSA nadir < 2.4ng/mL, time to PSA nadir > 140 days, the combination of PSA nadir and time to PSA nadir, and low end-of-treatment PSA levels. The multivariate analysis identified ECOG PS (HR 37.46; p< 0.001), NLR (HR 3.7; p< 0.001), early PSA response (HR 1.22; p=0.002), and time to PSA nadir (HR 0.39; p=0.002) as independent prognostic markers.Conclusion: Our results indicate an association between PSA kinetics, especially early PSA response, and outcome to AA after progression to docetaxel. Taken together with other factors, lack of an early PSA response could identify patients who are unlikely to benefit from AA and who could be closely monitored with a view to offering alternative therapies.Keywords: castration-resistant prostate cancer, abiraterone, PSA kinetics, survival, early PSA response

Summary Background Atezolizumab can induce sustained responses in metastatic urothelial carcinoma. We report the results of IMvigor130, a phase 3 trial that compared atezolizumab with or without platinum-based chemotherapy versus placebo plus platinum-based chemotherapy in first-line metastatic urothelial carcinoma. Methods In this multicentre, phase 3, randomised trial, untreated patients aged 18 years or older with locally advanced or metastatic urothelial carcinoma, from 221 sites in 35 countries, were randomly assigned to receive atezolizumab plus platinum-based chemotherapy (group A), atezolizumab monotherapy (group B), or placebo plus platinum-based chemotherapy (group C). Patients received 21-day cycles of gemcitabine (1000 mg/m2 body surface area, administered intravenously on days 1 and 8 of each cycle), plus either carboplatin (area under the curve of 4·5 mg/mL per min administered intravenously) or cisplatin (70 mg/m2 body surface area administered intravenously) on day 1 of each cycle with either atezolizumab (1200 mg administered intravenously on day 1 of each cycle) or placebo. Group B patients received 1200 mg atezolizumab, administered intravenously on day 1 of each 21-day cycle. The co-primary efficacy endpoints for the intention-to-treat population were investigator-assessed Response Evaluation Criteria in Solid Tumours 1.1 progression-free survival and overall survival (group A vs group C) and overall survival (group B vs group C), which was to be formally tested only if overall survival was positive for group A versus group C. The trial is registered with ClinicalTrials.gov , NCT02807636 . Findings Between July 15, 2016, and July 20, 2018, we enrolled 1213 patients. 451 (37%) were randomly assigned to group A, 362 (30%) to group B, and 400 (33%) to group C. Median follow-up for survival was 11·8 months (IQR 6·1–17·2) for all patients. At the time of final progression-free survival analysis and interim overall survival analysis (May 31, 2019), median progression-free survival in the intention-to-treat population was 8·2 months (95% CI 6·5–8·3) in group A and 6·3 months (6·2–7·0) in group C (stratified hazard ratio [HR] 0·82, 95% CI 0·70–0·96; one-sided p=0·007). Median overall survival was 16·0 months (13·9–18·9) in group A and 13·4 months (12·0–15·2) in group C (0·83, 0·69–1·00; one-sided p=0·027). Median overall survival was 15·7 months (13·1–17·8) for group B and 13·1 months (11·7–15·1) for group C (1·02, 0·83–1·24). Adverse events that led to withdrawal of any agent occurred in 156 (34%) patients in group A, 22 (6%) patients in group B, and 132 (34%) patients in group C. 50 (11%) patients in group A, 21 (6%) patients in group B, and 27 (7%) patients in group C had adverse events that led to discontinuation of atezolizumab or placebo. Interpretation Addition of atezolizumab to platinum-based chemotherapy as first-line treatment prolonged progression-free survival in patients with metastatic urothelial carcinoma. The safety profile of the combination was consistent with that observed with the individual agents. These results support the use of atezolizumab plus platinum-based chemotherapy as a potential first-line treatment option for metastatic urothelial carcinoma. Funding F Hoffmann-La Roche and Genentech.

Background: The IMvigor130 primary analysis demonstrated a statistically significant progression-free survival (PFS) benefit and encouraging OS with atezo + plt/gem (Arm A) vs placebo + plt/gem (Arm C) as first-line mUC treatment, although interim OS results did not cross the pre-specified threshold for significance (Galsky Lancet 2020). Here we report the 2nd interim OS for Arm A vs C, including efficacy by type of chemotherapy (chemo) given. Methods: Pts were randomized 1:1:1 to Arm A, B (atezo monotherapy) or C. Investigators pre-specified the type of chemo pts would receive if assigned to Arms A or C (gem + either cisplatin or carboplatin). Co-primary endpoints (EPs) were RECIST 1.1 PFS and OS (Arm A vs C; ITT) and OS (Arm B vs C; ITT, IC2/3) tested using a hierarchical approach. Safety and secondary efficacy EPs (objective response rate and duration of response) are reported. Exploratory OS analyses by type of chemo were pre-specified. Results: As of data cutoff, June 14, 2020 (median follow-up, 13.3 mo), OS event rates were 67% in Arm A and 70% in Arm C. Efficacy data are shown (Table). Subsequent non-protocol immunotherapy use was 7% in Arm A vs 24% in Arm C. Of pts in the safety population (Arm A: 454; Arm C: 389), 81% and 80%, respectively, had a Gr 3/4 treatment-related AE (TRAE). No new Gr 5 TRAEs occurred since the 1st analysis (Gr 5 TRAEs: 2% in Arm A vs 1% in Arm C). Gr 3/4 AEs of special interest occurred in 9% in Arm A and 4% in Arm C. Conclusions: OS with atezo + plt/gem vs placebo + plt/gem in this updated analysis of IMvigor130 was consistent with the 1st interim analysis (not yet statistically significant). The impact of atezo plus chemo on outcomes may differ based on the specific platinum regimen; these exploratory findings warrant further investigation. OS follow-up is ongoing. Safety profile of atezo + plt/gem was consistent with each agent. IMvigor130 efficacy (second interim OS analysis)Arm A:Arm C:atezo + plt/gemplacebo + plt/gem(n=451)(n=400)OS HR (95% CI)aITT0.84 (0.71, 1.00); P=0.026bCisplatin (n=273)0.73 (0.54, 0.98)PD-L1 IC2/3 (n=69)c0.66 (0.32, 1.36)PD-L1 IC0/1 (n=204)c0.72 (0.52, 1.01)Carboplatin (n=578)0.91 (0.74, 1.10)PD-L1 IC2/3 (n=130)c0.80 (0.52, 1.23)PD-L1 IC0/1 (n=448)c0.94 (0.75, 1.18)Median OS (95% CI), moITT16.1 (14.2, 18.8)13.4 (11.9, 15.2)Cisplatin21.6 (17.5, 25.4)14.6 (11.7, 18.4)Carboplatin14.3 (12.0, 16.5)13.0 (10.6, 15.2)Objective response rate (95% CI), %ITT (n=844)d48 (43, 53)45 (40, 50)Cisplatin (n=271)d49 (40, 57)50 (41, 58)Carboplatin (n=573)d48 (42, 53)42 (36, 48)Complete response rate (95% CI), %ITT (n=844)d13 (10, 17)7 (5, 10)Cisplatin (n=271)d17 (11, 24)9 (5, 15)Carboplatin (n=573)d12 (9, 16)6 (4, 10)Median duration of response (95% CI), moeAll responders (n=391)9.3 (8.0, 10.7)8.2 (6.3, 8.5)Cisplatin (n=133)13.2 (10.4, 22.5)8.3 (6.3, 13.3)Carboplatin (n=258)8.1 (6.5, 10.2)7.1 (6.2, 8.5)IC, tumor-infiltrating immune cells; ITT, intention to treat.aHR for the ITT population is stratified by PD-L1 IC status (IC0 vs IC1 vs IC2/3), Bajorin risk factor score (0, 1, 2 and/or liver metastases), investigator's choice of cisplatin/gemcitabine vs carboplatin/gemcitabine and enrollment stage. HRs for subgroups are stratified by enrollment stage.bOne-sided; not statistically significant (O'Brien-Fleming stopping boundary P value 0.014).cPD-L1-expressing IC covering ≥5% (IC2/3) or Citation Format: Matthew D. Galsky, José Ángel Arranz, Enrique Grande, Maria De Santis, Ian D. Davis, Eiji Kikuchi, Xavier Garcia del Muro, Se Hoon Park, Ugo De Giorgi, Boris Alekseev, Marina Mencinger, Kouji Izumi, Javier Puente, Jian-Ri Li, Peter H. O'Donnell, Xiaodong Shen, Chooi Lee, Almut Mecke, Sanjeev Mariathasan, Aristotelis Bamias. Atezolizumab (atezo) + platinum/gemcitabine (plt/gem) vs placebo + plt/gem in patients (pts) with previously untreated locally advanced or metastatic urothelial carcinoma (mUC): Updated overall survival (OS) from the randomized phase III study IMvigor130 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT042.

Background: In the IMvigor130 primary analysis in patients (pts) with untreated locally advanced or mUC, a trend toward favorable OS with atezo (anti-PD-L1) monotherapy (Arm B) vs placebo + platinum/gemcitabine (plt/gem; Arm C) was seen in pts with PD-L1-expressing immune cells on ≥5% of the tumor area (IC2/3 per VENTANA SP142 IHC assay; Galsky Lancet 2020). We report clinical outcomes in Arm B vs C from the second interim OS analysis, including efficacy in cisplatin-ineligible pts. Methods: Pts were randomized 1:1:1 to Arm A (atezo + plt/gem [not reported here]), B or C. Co-primary endpoint OS was analyzed via hierarchical statistical testing. Since OS in Arm A vs C was not statistically significant, no formal comparison of Arm B vs C was performed in intention-to-treat (ITT) and IC2/3 pts. Objective response rate (ORR) and duration of response (DOR), both per RECIST 1.1 (secondary endpoints), and safety are reported; additional exploratory subgroup analyses of OS by PD-L1 status in ITT and cisplatin-ineligible pts were also done. Results: Efficacy from the updated OS analysis (June 14, 2020 cutoff; median follow-up, 13.3 mo) is shown in the Table. Exploratory subgroup analyses suggested that OS for IC2/3 pts may be higher in Arm B vs C. In ITT pts, ORR was higher in Arm C, but median DOR was longer in Arm B. In the safety population, Grade (Gr) 3/4 treatment-related adverse events (TRAEs) occurred in 16% and 80% of Arm B and C pts, respectively, and Gr 5 TRAEs in 1% of both arms. Gr 3/4 AEs of special interest (AESIs) occurred in 10% and 4%, respectively, and Gr 5 AESIs in Conclusions: These exploratory efficacy data from an updated OS analysis of IMvigor130 support the benefit of atezo monotherapy as first-line treatment for PD-L1 IC2/3 cisplatin-ineligible mUC. Atezo monotherapy showed a better tolerability profile than chemotherapy. With this longer follow-up, no new safety concerns arose. IMvigor130 efficacy (second interim OS analysis)Efficacy analysis populationArm B: atezoArm C: placebo + chemotherapyaITTOS events/pts (%)241/360 (66.9)246/359 (68.5)Median OS (95% CI), mo15.2 (13.1, 17.7)13.1 (11.7, 15.1)OS HR (95% CI)b0.99 (0.83, 1.19)Responders/ptsc84/359157/356ORR (95% CI), %23.4 (19.1, 28.1)44.1% (38.9, 49.4)Median DOR (95% CI), mod29.6 (15.9, NE)8.1 (6.3, 8.5)PD-L1 IC2/3 populationOS events/pts (%)43/88 (48.9)52/85 (61.2)Median OS (95% CI), mo27.5 (17.7, NE)16.7 (10.0, 26.1)OS HR (95% CI)b0.67 (0.45, 1.02)PD-L1 IC0/1 populationeOS events/pts (%)198/272 (72.8)194/274 (70.8)Median OS (95% CI), mo13.5 (11.1, 16.3)12.8 (11.3, 15.0)OS HR (95% CI)f1.05 (0.86, 1.28)Cisplatin-ineligible pts with PD-L1 IC2/3OS events/pts (%)28/50 (56)30/43 (70)Median OS (95% CI), mo18.6 (14.0, NE)10.0 (7.4, 18.1)OS HR (95% CI)f0.60 (0.36, 1.01)IC, tumor-infiltrating immune cells; NE, not estimable.aConcurrent control arm, which includes pts randomized in Stage 2 when Arm B was added to the study design.bStratified per randomization stratification factors: PD-L1 status (ITT only), Bajorin risk factor score/liver metastases, investigator's choice of platinum (cisplatin or carboplatin) before randomization.cPatients with measurable disease at baseline.dIn pts who had a confirmed response.eIC0/1 = PD-L1 IC Citation Format: Ian D. Davis, Matthew D. Galsky, Xavier Garcia del Muro, Se Hoon Park, Ugo De Giorgi, Boris Alekseev, Marina Mencinger, Kouji Izumi, Javier Puente, Jian-Ri Li, José Ángel Arranz, Aristotelis Bamias, Enrique Grande, Eiji Kikuchi, Almut Mecke, Sanjeev Mariathasan, Xiaodong Shen, Hannah (Xinhui) Huang, Maria De Santis. Updated overall survival (OS) analysis of atezolizumab (atezo) monotherapy vs chemotherapy in untreated locally advanced or metastatic urothelial carcinoma (mUC) in IMvigor130 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT040.

Background: IMvigor130 evaluated atezo + plt/gem (Arm A) vs placebo + plt/gem (Arm C) as 1L mUC treatment, allowing pts with at least SD to continue atezo or placebo “maintenance” after 4-6 cycles of plt/gem. The primary analysis showed statistically significant PFS benefit for Arm A vs C (Galsky Lancet 2020). The 1st interim OS data for Arm A vs C were encouraging but immature. This exploratory analysis used 2nd interim OS data (ITT median follow-up, 13.3 mo) to examine OS outcomes by response during atezo or placebo + chemo “induction” in Arm A vs C. Methods: Pts were randomized 1:1:1 to Arm A, B (atezo monotherapy) or C. In Arms A and C, chemo was gem + investigator's choice of cis or carbo. Co-primary EPs of PFS and OS in Arm A vs C (ITT) and OS in Arm B vs C (ITT and IC2/3) were tested hierarchically. This post hoc analysis evaluated post-induction (post-wk 18) OS in pts who completed 4-6 (but not >6) cycles of chemo without PD during induction (through wk 18), followed by ≥1 dose of atezo or placebo maintenance. Post-PD OS was evaluated in pts with PD during induction. HRs were adjusted to account for potential imbalances in known prognostic factors between arms. Results: Efficacy data are in the Table. Post-induction OS HR (95% CI) for pts with no PD was 0.86 (0.64, 1.16) (cis: 0.60 [0.35, 1.03], carbo: 0.97 [0.67, 1.41]). Post-progression OS HR for pts with PD was 0.74 (0.53, 1.03) (cis: 0.52 [0.28, 0.96], carbo: 0.78 [0.51, 1.18]). Conclusions: In this exploratory analysis from IMvigor130, OS benefit with atezo + plt/gem vs placebo + plt/gem in both pts with and without PD during induction was consistent with ITT results from the 1st interim analysis. Preliminary data suggest that cis-treated pts may derive greater OS benefit from adding atezo to chemo than carbo-treated pts, which warrants further investigation. OS follow-up is ongoing. IMvigor130 efficacy (second interim OS analysis)No PD during inductiona (post-induction OS)bPD during induction (post-progression OS)Arm A (n=166)Arm C (n=152)Arm A (n=91)Arm C (n=93)OS events, n (%)ITT97 (58.4)92 (60.5)82 (90.1)84 (90.3)Cisplatinc27/57 (47.4)35/59 (59.3)24/29 (82.8)30/33 (90.9)Carboplatinc70/109 (64.2)57/93 (61.3)58/62 (93.5)54/60 (90.0)Median OS (95% CI), moITT20.5 (17.6, 25.9)18.8 (14.4, 21.9)4.3 (3.5, 5.8)3.3 (2.5, 4.4)Cisplatin28.2 (19.8, NE)19.9 (11.0, 26.5)6.6 (4.8, 10.1)2.5 (1.6, 5.2)Carboplatin18.5 (12.9, 21.6)18.8 (12.9, 22.8)3.8 (3.2, 5.6)3.4 (2.6, 4.5)OS HR (95% CI)dITT0.86 (0.64, 1.16)0.74 (0.53, 1.03)Cisplatin0.60 (0.35, 1.03)0.52 (0.28, 0.96)Carboplatin0.97 (0.67, 1.41)0.78 (0.51, 1.18)Data cutoff: June 14, 2020. 1L, first-line; carbo, carboplatin; chemo, chemotherapy; cis, cisplatin; CR, complete response; EP, endpoint; HR; hazard ratio; ITT, intention to treat; mets, metastases; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease. a Pts who achieved at least SD (CR, PR, or SD without PD) during induction. b Post-week 18 OS. c Denominators refer to the number of pts in each chemotherapy subgroup/treatment arm. d Multivariable Cox proportional hazards model stratified by enrollment stage (1/2); adjusted for age, ECOG PS (0, 1, 2), cisplatin ineligibility (Y/N), liver mets (Y/N), lymph node mets only (Y/N), ≥3 metastatic sites (Y/N), renal impairment (Y/N), alkaline phosphatase ≥upper limit of normal (Y/N), glomerular filtration rate ( Citation Format: Enrique Grande, Aristotelis Bamias, Matthew D. Galsky, Eiji Kikuchi, Ian D. Davis, José Ángel Arranz, Arash Rezazadeh Kalebasty, Xavier Garcia del Muro, Se Hoon Park, Ugo De Giorgi, Boris Alekseev, Marina Mencinger, Kouji Izumi, Javier Puente, Jian-Ri Li, Xiaodong Shen, Beiying Ding, Qian Zhu, Jeremy Linsenmeier, Maria De Santis. Overall survival (OS) by response during “induction” from the global, randomized Phase III IMvigor130 study of atezolizumab (atezo) + platinum/gemcitabine (plt/gem) vs placebo + plt/gem in patients (pts) with previously untreated metastatic urothelial carcinoma (mUC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT187.

TPS4589 Background: First-line cisplatin-based chemotherapy (70 mg/m2) is the standard of care for LA/mUC patients (pts). However, about 50% will be ineligible for Cisplatin according to Galsky´s criteria. Moreover, a significant proportion of cisplatin-fit pts will receive carboplatin based on physician criteria. s-GC represents a feasible alternative in such situations, and could improve response rate compared to carboplatin regimens. Atezo is a programmed death-ligand 1 (PD-L1) inhibitor that is approved as first line treatment for cisplatin-ineligible LA/mUC pts with PD-L1 expression ≥5% (Ventana SP142). We present the study design of a phase II single arm trial of Atezo +s-GC in previously untreated pts with LA/mUC (NCT04602078). Methods: This single arm, open-label, multicenter study evaluates the efficacy and safety of Atezo +s-GC in previously untreated pts with LA/mUC. 66 pts will be enrolled and receive s-GC x 6 cycles (Cisplatin 35mg/m2 + Gemcitabine 1000mg/m2 on days 1 and 8 Q3W) and Atezo (1200 mg IV Q3W), followed by Atezo (1200 mg IV Q3W) until disease progression, toxicity or absence of clinical benefit. Eligibility criteria include histologically confirmed unresectable LA/mUC, measurable disease per RECIST 1.1 and adequate organ and marrow. Pts must be unfit for full cisplatin dose based on: age > 70 years, PS ECOG 0-2, creatinine Clearance >30 and 12 months prior to inclusion), prior autoimmune disease and uncontrolled significant illnesses. The primary endpoint is ORR per RECIST 1.1 assessed by investigator; the secondary endpoints are DoR, OS, PFS and safety. Biomarker analysis, including PD-L1 expression and microbiome relationship, will be an exploratory objective. The first two patients were enrolled in February 2021. Clinical trial information: NCT04602078.

11511 Background: Pazopanib (P) was assessed prospectively in a phase 2 study in SFT resulting in a longer progression free survival (PFS) and overall survival (OS) compared to historical controls treated with chemotherapy. No statistical correlation was found between angiogenic factors and P in its pivotal phase III sarcoma trial. In the last two years, a soaring interest on the prognostic and predictive value of inflammatory indexes such as neutrophil/lymphocyte (NLR) and platelet/lymphocyte (PLR) is emerging in sarcomas. A retrospective analysis of inflammatory indexes of patients who entered the GEIS-32 (NCT02066285) trial was performed. In that trial advanced SFT patients were treated with P from front-line. Methods: All eligible patients who entered in the typical- and malignant-SFT cohort of the GEIS-32 trial were included in this analysis. To determine NLR and PLR, baseline values of platelets (10e9/L), neutrophils (10e9/L) and lymphocytes (10e9/L) were obtained from complete blood count tests. Additionally, RDW (standardized as 1 = upper value of normal range) values at baseline were also determined. The impact of NLR, PLR and RDW on OS, PFS and Choi response were analyzed by univariate and multivariate analysis. MAXSTAT was used to determine optimal cut-off points for overall survival. Metastasis free interval (MFI), mitotic count and ECOG were also analyzed, among others. Results: Sixty-seven out of 70 enrolled SFT patients, median age 63-y and 57% female, were considered for this analysis. The median follow-up from treatment initiation was 20.0 months. High standardized RDW value at baseline (cut-off 1.03) was significantly associated with worse OS [10.7 months (95% CI 3.8-17.5) vs 49.8 months (95% CI 9.4-90.2), p < 0.001] and worse PFS [8.8 months (95% CI 0.9-7.0) vs 9.8 months (7.4-12.3), p = 0.001]. High PLR (cut-off 242) significantly correlated with worse OS [10.7 months (95% CI 5.2-16.2) vs 49.8 months (95% CI 14.6-85.0), p < 0.001] and worse PFS [4.5 months (95% CI 2.0-7.0) vs 10.1 months (95% CI 6.3-13.9), p = 0.005], and high NLR (cut-off 3.78) was significantly associated with worse OS [11.7 months (95% CI 3.5-19.8) vs NA, p < 0.001] and worse PFS [4.5 months (95% CI 1.9-7.0) vs 10.8 months (95% CI 8.7-12.9), p = 0.010]. Independent variables in multivariate analysis were NLR, RDW, MFI and mitosis for PFS; while RDW and ECOG for OS (see table). Further, NLR and mitosis were independent factors for Choi progressive disease (as best response). Conclusions: High NLR and RDW values were independent biomarkers of worse outcome in advanced SFT patients treated with pazopanib.[Table: see text]

4505 Background: Bladder-preserving combined-modality therapies constitute an alternative to radical cystectomy for selected pts with MIBC. In preclinical studies, combination of radiation and dual checkpoint blockade appears to activate non-redundant immune mechanisms, potentiating antitumor activity. The purpose of the present study is to explore feasibility, toxicity and activity of this approach in MIBC. Methods: Pts with localized MIBC in clinical stages T2-4a N0 M0, ECOG 0-1, without contraindications to immunotherapy, who either wished for bladder preservation or were ineligible for cystectomy, were included in this phase II study. Treatment consisted of initial transurethral resection (TUR) of the tumor, followed by durvalumab 1,500 mg i.v. plus tremelimumab 75 mg i.v., every 4 weeks for 3 doses. Normofractionated external-beam RT was started 2 weeks later, at doses of 46 Gy to minor pelvis and 64-66 Gy to bladder. Pts with either residual or relapsed MIBC were offered salvage cystectomy. The primary endpoint was complete response (CR) defined as absence of MIBC at post-treatment tumor site biopsy. A 2-stage sequential design was used (CR rate P0=5, P1=0.7, α=0.10, β=0.20) requiring at least 6 CR in the first 12 pts to expand to a second cohort of 20 pts. Results: From 1/2019 to 8/2020, 32 pts were enrolled at 6 centers. Median age was 71 years (49-91). PS was 0 in 24 pts,1 in 8. 25 were males. Clinical stage was T2 in 28 pts, T3 in 3 and T4a in 1. All pts received at least two immunotherapy cycles. The median dose of RT administered was 64 Gy (60-65). CR at post-treatment biopsy was documented in 26 (81%) pts, 2 pts had residual MIBC and 4 pts were not evaluated due to rejection (1), clinical impairment (1), death from COVID 19 (1) and a suspected treatment-related death from peritonitis (1). After a median follow up of 6.1 months (2.5 - 20.1), 2 pts underwent salvage cystectomy because of MIBC and T1 relapses, respectively. The estimated 6-months rates for disease-free survival (DFS) with bladder intact, DFS and overall survival were 76% (95%CI, 61%-95%), 80% (95%CI, 66%-98%) and 93% (95%CI, 85%-100%), respectively. A total of 31 (97%) pts experienced adverse events related to RT and/or immunotherapy, with diarrhea (41%) and urinary disorders (37.5%) as the most frequent. Grade 3 or 4 adverse events related to therapy were reported in 31% pts, being the most frequent gastrointestinal toxicity (12.5%), acute kidney failure (6%) and hepatitis (6%). Conclusions: A combined-modality approach including durvalumab + tremelimumab with concurrent RT is feasible and safe, showing high efficacy in terms of response and eliciting bladder preservation in a large number of pts. Further research on this approach as an alternative to cystectomy is warranted. Clinical trial information: NCT03702179.

Aim: We aimed to identify SNPs associated with cabazitaxel toxicity and response within a Phase II clinical trial using this compound in advanced transitional cell carcinoma after progression to a platinum-based regimen. Patients & methods: Eleven SNPs in CYP3A4, CYP3A5, CYP2C8, ABCB1 and TUBB1 were genotyped in 45 patients. Results: CYP3A5 rs776746 A allele was associated with protection against gastrointestinal toxicity (odds ratio: 0.06, 95% CI: 0.007–0.63, p = 0.018) and with reduced progression-free survival (hazard ratio: 5.1, 95% CI: 1.7–15.1, p = 0.0038, multivariable analysis). ABCB1 SNPs were associated with total number of grade 3–4 toxicity events (p-values of 0.009, 0.041 and 0.043, respectively). Conclusion: Polymorphisms in CYP3A5 and ABCB1 may define a subset of patients with different cabazitaxel toxicity and efficacy and therefore could be used as markers for treatment optimization.

434 Background: Atezo (anti–PD-L1) monotherapy is approved for cis-ineligible pts who have locally advanced or mUC with PD-L1–expressing immune cells on ≥ 5% of the tumor area (IC2/3 per VENTANA SP142 IHC assay). The IMvigor130 primary analysis demonstrated a significant PFS benefit with atezo + platinum/gemcitabine (plt/gem) (arm A) vs placebo (pbo) + plt/gem (arm C) as 1L treatment for mUC (Galsky Lancet 2020); at that time, interim OS data for arm A vs C were encouraging but immature. OS with atezo monotherapy (arm B) could not be formally tested, but favorable efficacy was seen in IC2/3 pts. In this exploratory analysis, we assess outcomes by PD-L1 status in cis-ineligible pts. Methods: Pts were randomized 1:1:1 to arms A, B or C (Galsky Lancet 2020). Evaluation of OS (co-primary EP) was performed via a hierarchical fixed sequence procedure: arm A vs C ITT pts; then, arm B vs C ITT and IC2/3 pts. No formal testing was performed in this exploratory subgroup analyses; OS and RECIST 1.1 ORR (per investigator [secondary EP]) were descriptively evaluated. Results: Efficacy data suggested OS and ORR benefit in atezo-treated cis-ineligible IC2/3 pts (Table). In the overall safety population, all-grade treatment-related AEs (TRAEs) had occurred in 60% and 96% of arm B and C pts, respectively; grade 3-4 TRAEs occurred in 15% and 81%, respectively. Biomarker data evaluating PD-L1 biology (assessed by SP142) and associated transcriptome analysis in arms B vs C will be presented. Conclusions: This exploratory analysis of IMvigor130 pts with 1L cis–ineligible IC2/3 mUC provides additional evidence for clinical benefit with single-agent atezo, a well-tolerated treatment with a distinct safety profile vs chemo. Analyses with longer OS follow-up are warranted. Clinical trial information: NCT02807636 . Research Sponsor: F. Hoffmann-La Roche Ltd[Table: see text]

Background Atezolizumab, a humanised monoclonal antibody targeting PD-L1, is approved for locally advanced/metastatic urothelial carcinoma. SAUL evaluated atezolizumab in a broader, pretreated population, including patients ineligible for the pivotal IMvigor211 phase 3 trial of atezolizumab. Objective To determine the safety and efficacy of atezolizumab in an international real-world setting. Design, setting, and participants Between November 2016 and March 2018 (median follow-up 12.7mo), 1004 patients with locally advanced or metastatic urothelial or nonurothelial urinary tract carcinoma who experienced progression during or after one to three prior therapies for inoperable, locally advanced, or metastatic disease were enrolled. Patients with renal impairment, treated central nervous system metastases, or stable controlled autoimmune disease were eligible; 10% had Eastern Cooperative Oncology Group performance status (ECOG PS) 2 and 98% were platinum pretreated (Clinicaltrials.gov: NCT02928406). Intervention Atezolizumab 1200mg every 3wk until progression or unacceptable toxicity. Outcome measurements and statistical analysis The primary endpoint was safety. Secondary efficacy endpoints included overall survival (OS), progression-free survival (PFS), and overall response rate (ORR). Results and limitations The median treatment duration was 2.8mo (range 0–19); 22% remained on treatment and 8% discontinued because of toxicity. Grade ≥3 adverse events occurred in 45% of patients. The most common grade ≥3 treatment-related adverse events were fatigue, asthenia, colitis, and hypertension (each in 1%). Median OS was 8.7mo (95% confidence interval [CI] 7.8–9.9). The 6-mo OS rate was 60% (95% CI 57–63%), median PFS was 2.2mo (95% CI 2.1–2.4), and the ORR was 13% (95% CI 11–16%; 3% complete responses). Among IMvigor211-like patients (excluding ECOG PS 2 and other IMvigor211 exclusion criteria), median OS was 10.0mo (95% CI 8.8–11.9) and 6-mo OS was 65% (95% CI 61–69%). Conclusions SAUL confirms the tolerability of atezolizumab in a real-world pretreated population with urinary tract carcinoma. Efficacy overall and in the IMvigor211-like subgroup is consistent with previous pivotal anti-PD-L1/PD-1 urothelial carcinoma trials. These results support the use of atezolizumab in urinary tract carcinoma, including patients with limited treatment options. Patient summary In this international study we investigated the efficacy and safety of atezolizumab treatment for advanced urinary tract cancer in a large population of pretreated patients, including those who would not normally be candidates for clinical trials. Patients tolerated the treatment well, even if they had autoimmune disease, were being treated with corticosteroids, or had disease that had spread to their brain. Life expectancy in this study for patients typical of everyday clinical practice was similar to that seen in trials that enrolled only selected fitter patients.

5012 Background: Cisplatin-based neoadjuvant chemotherapy (CT) followed by radical cystectomy (RC) is a standard treatment for MIBC. PD-1/L1 inhibitors as single agent induce pathological complete responses (pCR) in this setting. Predictors of response are still ill defined. DUTRENEO trial aimed to prospectively explore the activity of anti-PDL1 + anti-CTLA4 vs CT in pts selected according to a tumor pro-inflammatory IFN-gamma signature (tumor immune score, TIS). Methods: Cisplatin-eligible pts with urothelial MIBC (cT2-T4a, N≤1, M0) candidates to RC were classified as “hot” or “cold” according to a tumor TIS determined by Nanostring technology. Patients with "hot" tumors were randomized to DU 1500 mg + TRE 75 mg every 4 weeks x 3 cycles or standard cisplatin-based CT (GEMCIS or MVACdd). Pts in the “cold” arm received standard CT. Primary endpoint was to achieve ≥8 pCR in the DU+TRE arm. PDL1 expression was assessed using immunohistochemistry. Results: 61 pts were recruited in 10 sites between oct-2018 and dec-2019. Pts randomized in the “hot” arms received standard CT (n = 22) or DU+TRE (n = 23) and had a pCR rate of 8/22 pts (36.4%) vs 8/23 pts (34.8%), respectively [OR = 0.923 (0.26 – 3.24)]. In the “cold” arm, 16 pts received CT obtaining a pCR rate of 68.8% (11/16 pts). There were more PDL1 low tumors in the "cold" TIS arm (10/12, 83.3%). pCR rate by PDL1 status is shown in the table. One pt in the DU+TRE arm refused RC. Full treatment was delivered to 81.3% of CT "cold" vs 59.1% of CT "hot" vs 73.9% in the DU+TRE arm pts. Grade 3-4 toxicities were more frequent in the CT arms. Conclusions: The combination of DU+TRE is safe and active in MIBC patients in the neoadjuvant setting. Nevertheless prospective stratification by a pro-inflammatory IFN-gamma signature failed to select patients more likely to benefit from IO vs CT in this context. Further studies are required to guide treatment selection. Clinical trial information: NCT03472274 . [Table: see text]

TPS5097 Background: Several studies have shown that long-term bladder preservation is feasible in selected patients with muscle-invasive bladder cancer, using a multimodal treatment, including transurethral resection (TUR), radiotherapy and chemotherapy. Durvalumab, a fully human monoclonal antibody against PD-L1, has shown activity in patients with advanced pretreated urothelial cancer. A preclinical study showed that the combination of radiation, anti-CTLA4 and anti-PD-L1 overcome- adaptive immune resistance and has superior activity than either therapy alone (Twyman-Saint Victor et al. Nature 2015). The purpose of the present study is to explore feasibility, toxicity and activity in terms of response and bladder preservation of the integration of TUR, immune double checkpoint inhibition with durvalumab and tremelimumab (a fully human monoclonal antibody against CTLA-4), and radiotherapy in the treatment of localized muscle-invasive. Methods: This is a multicenter prospective phase II study of multimodal therapy in patients with localized urothelial carcinoma of the bladder in clinical stages T2-4a N0 M0, ECOG 0- 1, without contraindications to immunotherapy, who either wish for bladder preservation or are ineligible for cystectomy. The primary endpoint is pathological response (≤T1) at post-treatment biopsy. A 2-stage sequential design (response rate P0=5, P1=0.7, α=0.10, β=0.20) requires at least 6 responses in the first 12 pts to expand to a second cohort of 20 patients. The treatment consists of initial TUR of the tumor, followed by durvalumab 1500 mg i.v. plus tremelimumab 75 mg i.v., every 4 weeks for 3 doses. Normofractionated external-beam radiotherapy is started 2 weeks later, at doses of 46 Gy to the minor pelvis and 64-66 Gy to the bladder. Patients with pathological response will be candidates to bladder preservation, whereas those with residual muscle invasive tumor will be candidates to salvage cystectomy. At present time, prespecified activity goal for the first stage of accrual was met; second stage accrual began in December 2019. Clinical trial information: NCT03702179 .

5060 Background: Immunotherapy (IO)-based combinations have replaced tyrosine kinase inhibitors (TKI) as standard upfront treatment of metastatic RCC pts. Selection of 2L treatment after progression to novel combinations in 1st-line (1L) is mostly based on retrospective series or subgroups analysis of randomized trials. We aim to evaluate the activity and safety of sunitinib in advanced RCC after progression on an IO-based 1L approach. Methods: This is a prospective, non-randomized, open-label and multicenter phase II study. Pts with ECOG 0-2 and locally advanced or metastatic RCC after treatment in 1L with a prior PD-1 and/or PD-L1 and/or CTLA-4 inhibitor were included. Sunitinib was administered at 50 mg/day on a 4/2 schedule until disease progression. Primary endpoint was overall response rate (ORR) by RECIST v 1.1 criteria. Results: Twenty pts were enrolled in the study. Median age was 66 yo, 70% had intermediate prognosis by Heng's scale, and 88% ECOG 1. 45% of pts received atezolizumab, 30% pembrolizumab, 20% nivolumab and 15% ipilimumab-based regimens as 1L. ORR to 1L treatment was 45%. Median time from end of 1L to sunitinib onset date was 1.1 months (0.3-22.1). Two (10%) pts had partial response with sunitinib and 11 (55%) stable disease for a total disease control rate of 65%. With a median follow-up of 8.8 months, median PFS was 6.8 months (0.0-13.9) and median OS 13.6 months (10.5-16.6). Median duration of treatment was 4 months (0.9-16-2). Most common treatment-related adverse events, all grades, were asthenia (55%), dysgeusia (35%), diarrhea (30%), hypertension (30%), mucosal inflammation (25%), palmar-plantar erythrodysesthesia (25%), anemia (20%), neutropenia (20%) and nausea (15%); grade 3 were asthenia (15%), hypertension (10%) and neutropenia (10%). Conclusions: To our knowledge, the INMUNOSUN trial is the first study to evaluate prospectively the activity of a single agent TKI in a pure 2L setting of metastatic RCC pts treated with an IO-based approach upfront. ORR and PFS with sunitinib seem lower than expected when used as a 1L. Consistency in toxicity profile was observed. Clinical trial information: NCT03066427 .

[Background] A solitary fibrous tumour is a rare soft-tissue tumour with three clinicopathological variants: typical, malignant, and dedifferentiated. Preclinical experiments and retrospective studies have shown different sensitivities of solitary fibrous tumour to chemotherapy and antiangiogenics. We therefore designed a trial to assess the activity of pazopanib in a cohort of patients with malignant or dedifferentiated solitary fibrous tumour. The clinical and translational results are presented here., [Methods] In this single-arm, phase 2 trial, adult patients (aged ≥ 18 years) with histologically confirmed metastatic or unresectable malignant or dedifferentiated solitary fibrous tumour at any location, who had progressed (by RECIST and Choi criteria) in the previous 6 months and had an ECOG performance status of 0–2, were enrolled at 16 third-level hospitals with expertise in sarcoma care in Spain, Italy, and France. Patients received pazopanib 800 mg once daily, taken orally without food, at least 1 h before or 2 h after a meal, until progression or intolerance. The primary endpoint of the study was overall response measured by Choi criteria in the subset of the intention-to-treat population (patients who received at least 1 month of treatment with at least one radiological assessment). All patients who received at least one dose of the study drug were included in the safety analyses. This study is registered with ClinicalTrials.gov, number NCT02066285, and with the European Clinical Trials Database, EudraCT number 2013-005456-15., [Findings] From June 26, 2014, to Nov 24, 2016, of 40 patients assessed, 36 were enrolled (34 with malignant solitary fibrous tumour and two with dedifferentiated solitary fibrous tumour). Median follow-up was 27 months (IQR 16–31). Based on central radiology review, 18 (51%) of 35 evaluable patients had partial responses, nine (26%) had stable disease, and eight (23%) had progressive disease according to Choi criteria. Further enrolment of patients with dedifferentiated solitary fibrous tumour was stopped after detection of early and fast progressions in a planned interim analysis. 51% (95% CI 34–69) of 35 patients achieved an overall response according to Choi criteria. Ten (29%) of 35 patients died. There were no deaths related to adverse events and the most frequent grade 3 or higher adverse events were hypertension (11 [31%] of 36 patients), neutropenia (four [11%]), increased concentrations of alanine aminotransferase (four [11%]), and increased concentrations of bilirubin (three [8%])., [Interpretation] To our knowledge, this is the first trial of pazopanib for treatment of malignant solitary fibrous tumour showing activity in this patient group. The manageable toxicity profile and the activity shown by pazopanib suggests that this drug could be an option for systemic treatment of advanced malignant solitary fibrous tumour, and provides a benchmark for future trials., Spanish Group for Research on Sarcomas (GEIS), Italian Sarcoma Group (ISG), French Sarcoma Group (FSG), GlaxoSmithKline, and Novartis.

Background Oncogenic KIT/PDGFRA signaling inhibition with imatinib achieves disease control in most patients with advanced/metastatic gastrointestinal stromal tumor (GIST), but resistance eventually develops after 20-24 months. Notably, a small subset of these patients obtain durable benefit from imatinib therapy. Methods We analyzed clinical, pathological, and molecular characteristics and long-term outcomes in patients with metastatic GIST treated with continuous daily dosing of frontline imatinib in a cohort of patients benefiting for >= 5 years. A control group was obtained from the national Spanish Group for Sarcoma Research database and used as comparator. Results Sixty-four imatinib long-term responders (LTRs) and 70 control cases were identified. Compared with controls, LTRs at baseline had better performance status (PS) 0-1 (100% vs. 81%), lower mitotic count (median, 8 vs. 15), and tumor burden (number of metastases, 3 vs. 7). KIT exon 11 was the only region found mutated in LTRs. LTRs achieved 34% complete responses and a median progression-free survival of 11 years, compared with 4% and 2 years, respectively, in the control cohort. Prognostic factors that independently predicted long-term benefit with imatinib were PS, number of metastases prior to imatinib, and response to imatinib. Fifteen LTR patients developed new side effects attributable to imatinib after >= 5 years of continuous treatment. No resistance mutations were found in metastatic samples from three patients progressing on imatinib. Conclusion GISTs in LTRs are a distinctive entity with less aggressive behavior and marked sensitivity to KIT inhibition. Patients reaching 5 or more years on imatinib have a higher chance of remaining progression free over time. Implications for Practice This work demonstrates that clinical and inherent tumor characteristics define a subset of patients with gastrointestinal stromal tumor (GIST) with increased likelihood to achieve durable response to first-line imatinib therapy. Patients reaching >= 5 years on imatinib have a greater chance of remaining progression free over time, although the disease is unlikely to be cured. Imatinib is well tolerated for >5 years, and emergent toxicities are overall manageable. Resistance to imatinib emerging in patients with GISTs after long-term imatinib treatment does not involve polyclonal expansion of KIT secondary mutations.

Soft-tissue sarcomas (STS) are a heterogeneous group of diseases that are characterized by a historic lack of active treatment options. However, several new drugs and indications have become available in recent years.This article reviews the most relevant phase II studies that utilize chemotherapy agents (aldoxorubicin, amrubicin, trabectedin alone or in combination with doxorubicin, and gemcitabine plus docetaxel), targeted therapies (Imatinib, dasatinib, regorafenib, tivozanib, palbociclib and selinexor), a combination of chemotherapy plus targeted therapies (fucusing on doxorubicin plus olaratumab) and immunotherapies (pembrolizumab, combination of nivolumab plus ipilimumab and adaptive cell therapy) in STS (other than gastrointestinal stromal tumors) (GIST) published from 2015. Some of these strategies are under further clinical development or will likely be assessed in future phase III studies.A series of novel treatments have shown encouraging results in STS in recent years. The most important is the combination of the standard cytotoxic agent doxorubicin plus the platelet-derived growth factor receptor (PDGFR) inhibitor olaratumab, although definitive results from a phase III trial are expected. Immunotherapy has not been as successful in STS so far. However, further investigations are ongoing.

Health-related quality of life (HRQoL) is a patient-reported outcome that addresses patients' perceptions of symptoms across physical, emotional, cognitive and social domains. As HRQoL is currently rarely measured outside clinical trials in oncology, it must be inferred from patients' everyday performance during treatment. To gain insight into the HRQoL of advanced STS patients receiving palliative treatment in clinical practice, three case studies of patients treated with trabectedin are examined. Areas covered: The patient in Case 1 has maintained complete remission for more than 8 years after receiving nine cycles of second-line trabectedin followed by secondary surgery for recurrent myxoid liposarcoma, and was able to resume normal activities during trabectedin treatment. Case 2 describes 10 years' follow-up of a patient with myxoid liposarcoma who remains well after many lines of chemotherapy including extended use of trabectedin in the second line. The third case illustrates the feasibility of extending survival time in an elderly patient with metastatic leiomyosarcoma who was able to maintain a busy and active lifestyle while receiving second-line trabectedin. Expert commentary: Owing to its relatively benign safety profile, trabectedin frequently permits prolonged therapy and is generally well tolerated, often allowing patients to carry on with normal daily activities.

Patients with DICER1 predisposition syndrome have an increased risk to develop pleuropulmonary blastoma, cystic nephroma, embryonal rhabdomyosarcoma, and several other rare tumor entities. In this study, we identified 22 primary intracranial sarcomas, including 18 in pediatric patients, with a distinct methylation signature detected by array-based DNA-methylation profiling. In addition, two uterine rhabdomyosarcomas sharing identical features were identified. Gene panel sequencing of the 22 intracranial sarcomas revealed the almost unifying feature of DICER1 hotspot mutations (21/22; 95%) and a high frequency of co-occurring TP53 mutations (12/22; 55%). In addition, 17/22 (77%) sarcomas exhibited alterations in the mitogen-activated protein kinase pathway, most frequently affecting the mutational hotspots of KRAS (8/22; 36%) and mutations or deletions of NF1 (7/22; 32%), followed by mutations of FGFR4 (2/22; 9%), NRAS (2/22; 9%), and amplification of EGFR (1/22; 5%). A germline DICER1 mutation was detected in two of five cases with constitutional DNA available. Notably, none of the patients showed evidence of a cancer-related syndrome at the time of diagnosis. In contrast to the genetic findings, the morphological features of these tumors were less distinctive, although rhabdomyoblasts or rhabdomyoblast-like cells could retrospectively be detected in all cases. The identified combination of genetic events indicates a relationship between the intracranial tumors analyzed and DICER1 predisposition syndrome-associated sarcomas such as embryonal rhabdomyosarcoma or the recently described group of anaplastic sarcomas of the kidney. However, the intracranial tumors in our series were initially interpreted to represent various tumor types, but rhabdomyosarcoma was not among the typical differential diagnoses considered. Given the rarity of intracranial sarcomas, this molecularly clearly defined group comprises a considerable fraction thereof. We therefore propose the designation "spindle cell sarcoma with rhabdomyosarcoma-like features, DICER1 mutant" for this intriguing group.

In the original publication, the second name of the twentieth author was incorrect. It should read as 'Miguel Sáinz-Jaspeado'. The original publication of the article has been updated to reflect the change. This correction was authored by Ulrich Schüller on behalf of all authors of the original publication.

[Purpose] To investigate the genetic basis of cisplatin resistance as efficacy of cisplatin-based chemotherapy in the treatment of distinct malignancies is often hampered by intrinsic or acquired drug resistance of tumor cells., [Experimental Design] We produced 14 orthoxenograft transplanting human nonseminomatous testicular germ cell tumors (TGCT) in mice, keeping the primary tumor features in terms of genotype, phenotype, and sensitivity to cisplatin. Chromosomal and genetic alterations were evaluated in matched cisplatin-sensitive and their counterpart orthoxenografts that developed resistance to cisplatin in nude mice., [Results] Comparative genomic hybridization analyses of four matched orthoxenografts identified recurrent chromosomal rearrangements across cisplatin-resistant tumors in three of them, showing gains at 9q32-q33.1 region. We found a clinical correlation between the presence of 9q32-q33.1 gains in cisplatin-refractory patients and poorer overall survival (OS) in metastatic germ cell tumors. We studied the expression profile of the 60 genes located at that genomic region. POLE3 and AKNA were the only two genes deregulated in resistant tumors harboring the 9q32-q33.1 gain. Moreover, other four genes (GCS, ZNF883, CTR1, and FLJ31713) were deregulated in all five resistant tumors independently of the 9q32-q33.1 amplification. RT-PCRs in tumors and functional analyses in Caenorhabditis elegans (C. elegans) indicate that the influence of 9q32-q33.1 genes in cisplatin resistance can be driven by either up- or downregulation. We focused on glucosylceramide synthase (GCS) to demonstrate that the GCS inhibitor DL-threo-PDMP resensitizes cisplatin-resistant germline-derived orthoxenografts to cisplatin, [Conclusions] Orthoxenografts can be used preclinically not only to test the efficiency of drugs but also to identify prognosis markers and gene alterations acting as drivers of the acquired cisplatin resistance., Several authors are grateful recipients of predoctoral fellowships: J.M. Piulats from the AECC and F.J. García-Rodríguez from the Instituto de Salud Carlos III (ISCIII). This study was supported by grants from the Spanish Ministry of Economy and Competitiveness (SAF2002-02265 and FIS: BFU2007-67123; PI10-0222, PI13-01339, and PI16/01898, to A. Villanueva; PI15-00895, to J. Ceron; SAF2013-46063R, to F. Vi nals; PI030264, to ~ X. García-del-Muro), Fundacio La Marat o TV3 (051430, to F. Vi nals and X. ~ García-del-Muro), Generalitat de Catalunya (2014SGR364, to A. Villanueva and F. Vinals; FIS09/0059, to A. Morales), cofunded by FEDER funds/ ~ European Regional Development Fund (ERDF) — a way to Build Europe. A. Villanueva received a BAE11/00073 grant. We thank the staff of the Animal Core Facility of IDIBELL for mouse care and maintenance.

[Introduction] There are limited findings available on KIT-negative GIST-like (KNGL) population. Also, KIT expression may be post-transcriptionally regulated by miRNA221 and miRNA222. Hence, the aim of this study is to characterize KNGL population, by differential gene expression, and to analyze miRNA221/222 expression and their prognostic value in KNGL patients., [Methods] KIT, PDGFRA, DOG1, IGF1R, MIR221 and MIR222 expression levels were determined by qRT-PCR. We also analyzed KIT and PDGFRA mutations, DOG1 expression, by immunohistochemistry, along with clinical and pathological data. Disease-free survival (DFS) and overall survival (OS) differences were calculated using Log-rank test., [Results] Hierarchical cluster analyses from gene expression data identified two groups: group I had KIT, DOG1 and PDGFRA overexpression and IGF1R underexpression and group II had overexpression of IGF1R and low expression of KIT, DOG1 and PDGFRA. Group II had a significant worse OS (p = 0.013) in all the series, and showed a tendency for worse OS (p = 0.11), when analyzed only the localized cases. MiRNA222 expression was significantly lower in a control subset of KIT-positive GIST (p < 0.001). OS was significantly worse in KNGL cases with higher expression of MIR221 (p = 0.028) or MIR222 (p = 0.014)., [Conclusions] We identified two distinct KNGL subsets, with a different prognostic value. Increased levels of miRNA221/222, which are associated with worse OS, could explain the absence of KIT protein expression of most KNGL tumors., The project was funded by the Instituto de Salud Carlos III (ISCIII) - Fondo Europeo de Desarrollo Regional (FEDER), through a public competitive call (project reference PI15/01254; principal Investigator Javier Martín Broto), and the Spanish Group for Research on Sarcoma (GEIS).

Olfactory neuroblastoma/esthesioneuroblastoma (ONB) is an uncommon neuroectodermal neoplasm thought to arise from the olfactory epithelium. Little is known about its molecular pathogenesis. For this study, a retrospective cohort of n = 66 tumor samples with the institutional diagnosis of ONB was analyzed by immunohistochemistry, genome-wide DNA methylation profiling, copy number analysis, and in a subset, next-generation panel sequencing of 560 tumor-associated genes. DNA methylation profiles were compared to those of relevant differential diagnoses of ONB. Unsupervised hierarchical clustering analysis of DNA methylation data revealed four subgroups among institutionally diagnosed ONB. The largest group (n = 42, 64%, Core ONB) presented with classical ONB histology and no overlap with other classes upon methylation profiling-based t-distributed stochastic neighbor embedding (t-SNE) analysis. A second DNA methylation group (n = 7, 11%) with CpG island methylator phenotype (CIMP) consisted of cases with strong expression of cytokeratin, no or scarce chromogranin A expression and IDH2 hotspot mutation in all cases. T-SNE analysis clustered these cases together with sinonasal carcinoma with IDH2 mutation. Four cases (6%) formed a small group characterized by an overall high level of DNA methylation, but without CIMP. The fourth group consisted of 13 cases that had heterogeneous DNA methylation profiles and strong cytokeratin expression in most cases. In t-SNE analysis, these cases mostly grouped among sinonasal adenocarcinoma, squamous cell carcinoma, and undifferentiated carcinoma. Copy number analysis indicated highly recurrent chromosomal changes among Core ONB with a high frequency of combined loss of chromosome 1-4, 8-10, and 12. NGS sequencing did not reveal highly recurrent mutations in ONB, with the only recurrently mutated genes being TP53 and DNMT3A. In conclusion, we demonstrate that institutionally diagnosed ONB are a heterogeneous group of tumors. Expression of cytokeratin, chromogranin A, the mutational status of IDH2 as well as DNA methylation patterns may greatly aid in the precise classification of ONB.