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PURPOSE Rogaratinib, an oral pan-fibroblast growth factor receptor (FGFR1-4) inhibitor, showed promising phase I efficacy and safety in patients with advanced urothelial carcinoma (UC) with FGFR1-3 mRNA overexpression. We assessed rogaratinib efficacy and safety versus chemotherapy in patients with FGFR mRNA-positive advanced/metastatic UC previously treated with platinum chemotherapy. METHODS FORT-1 (ClinicalTrials.gov identifier: NCT03410693 ) was a phase II/III, randomized, open-label trial. Patients with FGFR1/ 3 mRNA-positive locally advanced or metastatic UC with ≥ 1 prior platinum-containing regimen were randomly assigned (1:1) to rogaratinib (800 mg orally twice daily, 3-week cycles; n = 87) or chemotherapy (docetaxel 75 mg/m2, paclitaxel 175 mg/m2, or vinflunine 320 mg/m2 intravenously once every 3 weeks; n = 88). The primary end point was overall survival, with objective response rate (ORR) analysis planned following phase II accrual. Because of comparable efficacy between treatments, enrollment was stopped before progression to phase III; a full interim analysis of phase II was completed. RESULTS ORRs were 20.7% (rogaratinib, 18/87; 95% CI, 12.7 to 30.7) and 19.3% (chemotherapy, 17/88; 95% CI, 11.7 to 29.1). Median overall survival was 8.3 months (95% CI, 6.5 to not estimable) and 9.8 months (95% CI, 6.8 to not estimable; hazard ratio, 1.11; 95% CI, 0.71 to 1.72; P = .67). Grade 3/4 events occurred in 37 (43.0%)/4 (4.7%) patients and 32 (39.0%)/15 (18.3%), respectively. No rogaratinib-related deaths occurred. Exploratory analysis of patients with FGFR3 DNA alterations showed ORRs of 52.4% (11/21; 95% CI, 29.8 to 74.3) for rogaratinib and 26.7% (4/15; 95% CI, 7.8 to 55.1) for chemotherapy. CONCLUSION To our knowledge, these are the first data to compare FGFR-directed therapy with chemotherapy in patients with FGFR-altered UC, showing comparable efficacy and manageable safety. Exploratory testing suggested FGFR3 DNA alterations in association with FGFR1/ 3 mRNA overexpression may be better predictors of rogaratinib response.

Treatment options for advanced vulvar cancer are limited. We evaluated pembrolizumab monotherapy in patients with advanced vulvar squamous cell carcinoma (SCC) enrolled in the phase 2 multicohort, open-label KEYNOTE-158 study (NCT02628067).Eligible patients had histologically or cytologically documented advanced vulvar SCC with prior treatment failure, measurable disease per RECIST v1.1, ECOG performance status 0-1, and a tumor sample available for biomarker analysis. Pembrolizumab 200 mg was administered intravenously Q3W for up to 35 cycles (approximately 2 years). The primary endpoint was objective response rate (ORR) per RECIST v1.1 by independent central radiologic review in all patients and subgroups based on PD-L1 combined positive score (≥1 [PD-L1-positive] versus1 [PD-L1-negative]).101 patients were enrolled. Median time from first dose to data cutoff was 36.0 months. The ORR (95% CI) was 10.9% (5.6%-18.7%) among all patients, 9.5% (4.2%-17.9%) among the 84 patients with PD-L1-positive tumors, and 28.6% (3.7%-71.0%) among the 7 patients with PD-L1-negative tumors. Among patients with a response, median DOR was 20.4 (range, 2.1+ to 28.0) months. Median (95% CI) PFS and OS were 2.1 (2.0-2.1) and 6.2 (4.9-9.4) months, respectively. Treatment-related AEs occurred in 50.5% of patients (grade 3-5, 11.9%) and led to discontinuation of treatment in 5.0% of patients. Two deaths were considered treatment-related (hepatitis, n = 2).Pembrolizumab monotherapy was associated with durable responses in a subset of patients with vulvar SCC. Responses occurred regardless of tumor PD-L1 status. No new safety signals emerged; overall, pembrolizumab was well tolerated.

In the KEYNOTE-158 study (NCT02628067), pembrolizumab showed a high objective response rate and durable clinical benefit for patients with previously treated, unresectable/metastatic microsatellite instability-high (MSI-H)/mismatch repair‒deficient (dMMR) non-colorectal solid tumours. We present health-related quality of life (HRQoL) results from the MSI-H/dMMR population (cohort K).Eligible patients had previously treated MSI-H/dMMR advanced non-colorectal solid tumours, measurable disease per RECIST v1.1, and ECOG performance status ≤1. Patients received pembrolizumab 200 mg Q3W for 35 cycles (2 years). The EORTC Quality of Life Questionnaire (QLQ-C30) and EQ-5D-3L were administered at baseline, at regular intervals throughout treatment, and 30 days after treatment discontinuation. Prespecified analyses (exploratory endpoints) included the magnitude of change from baseline to post-baseline timepoints in all patients and by the best overall response for QLQ-C30 global health status (GHS)/QoL, QLQ-C30 functional/symptom scales/items, and EQ-5D-3L visual analogue scale (VAS) score.At data cutoff (October 5, 2020), 351 patients were enrolled, of whom 311 and 315 completed baseline QLQ-C30 and EQ-5D-3L questionnaires, respectively. QLQ-C30 GHS/QoL scores improved from baseline to week 9 (mean [95% CI] change, 3.07 [0.19-5.94]), then remained stable or improved by week 111, with greater improvements observed in patients with a best response of complete response (CR) or partial response (PR) (10.85 [6.36-15.35]). Patients with CR/PR showed improvements in physical (5.58 [1.91-9.25]), role (9.88 [3.80-15.97]), emotional (5.62 [1.56-9.68]), and social (8.33 [2.70-13.97]) functioning, and stable cognitive functioning (1.74 [-1.45 to 4.94]).Pembrolizumab generally improved or preserved HRQoL in patients with previously treated MSI-H/dMMR advanced non-colorectal solid tumours.

Sarcomas are rare, heterogeneous, ubiquitously localized malignancies with many histologic subtypes and genomic patterns. The survival of patients with sarcoma has rarely been described based on this heterogeneity; therefore, the authors' objective was to estimate survival outcomes in patients who had sarcomas using the 2020 version of the World Health Organization classification of soft tissue and bone tumors.Patients older than 15 years who had incident sarcoma diagnosed between 2005 and 2010 were extracted from 14 French population-based cancer registries covering 18% of the French metropolitan population. Vital status for each patient was actively followed up to June 30, 2013. Net survival (NS) was estimated using the unbiased Pohar-Perme method.Overall, 4202 patients were included. NS declined with increasing age at diagnosis. According to topographic groups, large 5-year NS disparities were observed, ranging from 47% among women with gynecologic sarcomas to 89% among patients with skin sarcomas. Patients with soft tissue, bone, and gastrointestinal sarcomas had 5-year NS rates of 53%, 61%, and 70%, respectively. Similar heterogeneity was observed according to histologic subtypes, with 5-year NS ranging from 19% for patients with angiosarcomas to 96% for patients with dermatofibrosarcomas. Patients with sarcoma who displayed missense mutations had a better 5-year NS (74%); those with MDM2-amplified sarcomas had the worst NS (45%).NS rates in patients with sarcoma are presented here for the first time based on the 2020 World Health Organization classification applied to population-based registry data. Large prognostic heterogeneity was observed based on age, topographic and histologic groups, and genomic alteration profiles, constituting a benchmark for future studies and clinical trials.

PDF file - 23K, Kaplan-Meier curves of metastasis-free survival (A) and overall survival (B) for the overall population

Purpose: Data about the prognostic factors of soft-tissue leiomyosarcomas and their correlation with molecular profile are limited.Experimental Design: From 1990 to 2010, 586 adult patients with a primary soft-tissue leiomyosarcoma were included in the French Sarcoma Group (GSF) database after surgery of the primary tumor. Multivariate analyses were conducted by Cox regression model in a backward stepwise procedure. Genetic profiling was conducted for 73 cases.Results: Median age was 59 years (range, 21–98 years). The median follow-up of patients alive was 46 months. The 5-year metastasis-free survival (MFS) rate was 51% (95% location and grade > I were independent adverse prognostic factors for MFS). The 5-year overall survival (OS) rate was 63% [95% confidence interval (CI), 59–67]. On multivariate analysis, age ≥ 60 years old, tumor size > 5 cm, deep location, and grade > I were independent adverse prognostic factors for OS. Molecular profiling identified specific clusters with activation of different biologic pathways: retroperitoneal leiomyosarcomas are characterized by overexpression of genes involved in muscle differentiation and nonretroperitoneal leiomyosarcomas characterized by overexpression of genes mainly involved in extracellular matrix, wounding, and adhesion pathways. The CINSARC signature but not comparative genomic hybridization (CGH) profiling was predictive of outcome.Conclusion: Soft-tissue leiomyosarcomas represent a heterogeneous group of tumors with at least two categories, retroperitoneal and extremities leiomyosarcomas, having specific clinical outcome and molecular features. Future clinical trials should consider this heterogeneity for a better stratification of patients. Clin Cancer Res; 19(5); 1190–6. ©2013 AACR.

PDF file - 66K, Significant Prognostic Factors for Metastasis-free Survival (MFS) and Overall survival (OS) (univariate analysis)

PDF file - 55K, Kaplan-Meier curves of metastasis-free survival according to tumor site (A), tumor size (B), tumor location (C) and tumor grade (D)

Purpose:This prospective nationwide cohort study aimed to investigate desmoid-type fibromatosis (DF) outcomes, focusing on the prognostic value of CTNNB1 mutations.Experimental Design:ALTITUDES (NCT02867033) was a nationwide prospective cohort study of DF diagnosed between January 2016 and December 2020. At diagnosis, CTNNB1 molecular alterations were identified using next-generation sequencing or Sanger sequencing. The primary endpoint was event-free survival (EFS; progression, relapse, or death). We enrolled 628 patients managed by active surveillance, surgical resection, or systemic treatment as first-line therapy.Results:Overall, 516 (82.2%) patients [368 females (71.3%), median age 40.3 years (range, 1–89)] were eligible for analysis. In 435 (84.3%) cases, there was one CTNNB1 molecular alteration: p.T41A, p.S45F, or p.S45P. The first-line management was active surveillance in 352 (68.2%), surgical resection in 120 (23.3%), and systemic treatments in 44 (8.5%) patients. CTNNB1 mutation distribution was similar across the three therapeutic groups. The median follow-up period was 24.7 (range, 0.4–59.7) months. The estimated 3-year EFS rate was 66.2% [95% confidence interval (CI), 60.5%–71.2%]. DF harboring p.S45F was significantly associated with male sex (P = 0.03), non-abdominal wall sites (P = 0.05), pain (P = 0.007), and large tumor size (P = 0.025). CTNNB1 p.S45F mutation was not significantly associated with EFS, either in univariate (HR, 1.06; 95% CI, 0.65–1.73; P = 0.81) or in multivariate analysis (HR, 0.91; 95% CI, 0.55–1.49; P = 0.71).Conclusions:We found that CTNNB1 mutation profile was associated with unfavorable prognostic factors but was not a prognostic factor for EFS.See related commentary by Greene and Van Tine, p. 3911

Supplementary Figure 1. Study flowchart

Supplementary methods and results

Supplementary table 1. Main characteristics of patients receiving different dose levels

PDF file - 60K, Biological pathways overrepresented in "ARM" and internal trunk LMS

PDF file - 34K

Supplementary Data from Lack of Prognostic Value of CTNNB1 Mutation Profile in Desmoid-Type Fibromatosis

PDF file - 61K, Clinical characteristics of the molecular cohort (N=73)

PDF file - 60K, Biological pathways dysregulated in metastatic LMS

Supplementary Figure from Lack of Prognostic Value of CTNNB1 Mutation Profile in Desmoid-Type Fibromatosis

PDF file - 60K, Biological pathways overrepresented in "REARRANGED" LMS and LMS of the extremities

Supplementary table 3. Multivariate model for Overall Survival (Cytotoxic Agents)

Introduction: Because a dose–response relationship is characteristic of conventional chemotherapy, this concept is widely used for the development of novel cytotoxic (CTX) drugs. However, the need to reach the MTD to obtain optimal benefit with molecularly targeted agents (MTA) is controversial. In this study, we evaluated the relationship between dose and efficacy in a large cohort of phase I patients with solid tumors.Experimental Design: We collected data on 1,182 consecutive patients treated in phase I trials in 14 European institutions in 2005–2007. Inclusion criteria were: (i) patients treated within completed single-agent studies in which a maximum-administered dose was defined and (ii) RECIST/survival data available.Results: Seventy-two percent of patients were included in trials with MTA (N = 854) and 28% in trials with CTX (N = 328). The objective response (OR) rate was 3% and disease control at 6 months was 11%. OR for CTX was associated with higher doses (median 92% of MTD); this was not the case for MTA, where patients achieving OR received a median of 50% of MTD. For trials with MTA, patients treated at intermediate doses (40%–80%) had better survival compared with those receiving low or high doses (P = 0.038). On the contrary, there was a direct association between higher dose and better OS for CTX agents (P = 0.003).Conclusion: Although these results support the development of novel CTX based on MTD, we found no direct relationship between higher doses and response with MTA in unselected patients. However, the longest OS was seen in patients treated with MTA at intermediate doses (40%–80% of MTD). Clin Cancer Res; 20(22); 5663–71. ©2014 AACR.

Purpose:CDKN2A loss is frequent in gastrointestinal stromal tumors (GISTs) and associated with aggressive outcome. Palbociclib is a CDK4 inhibitor with preclinical antitumor efficacy in tumors with P16/CDKN2A loss.Patients and Methods:This is a multicenter single-arm phase II clinical trial assessing safety and efficacy of palbociclib in patients with advanced GIST bearing CDKN2A gene loss. Adults with unresectable locally advanced or metastatic, refractory to at least imatinib and sunitinib, measurable and documented progressive disease (PD) as per RECIST 1.1, and CDKN2A deletion centrally assessed were eligible. Patients received palbociclib 125 mg orally daily on a 21 days on/7 days off dosing schedule, until PD or unacceptable toxicity. The primary endpoint was 4-month non-PD rate according to RECIST 1.1.Results:As of May 2017, 71 patients had been included in the study, and 29 patients (40.3%) met the molecular eligibility requirement. Twenty-five patients (86.2%) had grade 1–2 adverse events (AEs) and 12 patients (41.4%) grade 3–4 AEs possibly related to the drug. The planned interim statistical analysis performed after central histologic and radiological review showed that 19 (86.4%) out of the first 22 evaluable patients had PD at 4 months. CDKN2A status had no impact either on overall survival or outcome on previous standard lines of treatment. Translational analysis suggested upregulation of CCNE1 or downregulation of CDKN1A/P21 or LRRC3B as potential mechanisms of resistance.Conclusions:Palbociclib has no significant clinical activity as a single agent in P16/CDKN2A–deleted GIST refractory to imatinib and sunitinib.

Supplementary table 2. Multivariate model for overall survival (Molecularly Targeted Agents).

PDF file - 52K, Kaplan-Meier curves of overall survival according to age (A), tumor size (B), tumor location (C) and tumor grade (D)

International audience; Background: Intracranial solitary fibrous tumour (iSFT) is an exceptional mesenchymal tumour with high recurrence rates. We aimed to analyse the clinical outcomes of newly diagnosed and recurrent iSFTs.Methods: We carried out a French retrospective multicentre (n = 16) study of histologically proven iSFT cases. Univariate and multivariate Cox models were used to estimate the prognosis value of the age, location, size, WHO grade, and surgical extent on overall survival (OS), progression-free survival (PFS), and local recurrence-free survival (LRFS).Results: Eighty-eight patients were included with a median age of 54.5 years. New iSFT cases were treated with gross tumour resection (GTR) (n = 75) or subtotal resection (STR) (n = 9) and postoperative radiotherapy (PORT) (n = 32, 57%). The median follow-up time was 7 years. The median OS, PFS, and LRFS were 13 years, 7 years, and 7 years, respectively. Forty-two patients experienced recurrence. Extracranial metastasis occurred in 16 patients. Median OS and PFS after the first recurrence were 6 years and 15.4 months, respectively. A higher histological grade was a prognosis factor for PFS (p = 0.04) and LRFS (p = 0.03). GTR influenced LRFS (p = 0.03).Conclusion: GTR provided benefits as a first treatment for iSFTs. However, approximately 40% of patients experienced relapse, which remains a challenging state.

Background The initial management of patients with sarcoma is a critical issue. We used the nationwide French National Cancer Institute-funded prospective sarcoma database NETSARC to report the management and oncologic outcomes in adolescents and young adults (AYAs) patients with sarcoma at the national level. Patients and methods NETSARC database gathers regularly monitored and updated data from patients with sarcoma. NETSARC was queried for patients (15–30 years) with sarcoma diagnosed from 2010 to 2017 for whom tumor resection had been performed. We reported management, locoregional recurrence-free survival (LRFS), progression-free survival (PFS), and overall survival (OS) in AYA treated in French reference sarcoma centers (RSC) and outside RSC (non-RSC) and conducted multivariable survival analyses adjusted for classical prognostic factors. Results Among 3,227 patients aged 15–30 years with sarcoma diagnosed between 2010 and 2017, the study included 2,227 patients with surgery data available, among whom 1,290 AYAs had been operated in RSC, and 937 AYAs in non-RSC. Significant differences in compliance to guidelines were observed including pre-treatment biopsy (RSC: 85.9%; non-RSC 48.1%), pre-treatment imaging (RSC: 86.8%; non-RSC: 56.5%) and R0 margins (RSC 57.6%; non-RSC: 20.2%) (p Conclusions This study highlights the importance for AYA patients with sarcoma to be managed in national sarcoma reference centers involving multidisciplinary medical teams with paediatric and adult oncologists.

International audience; The aim of this study is to evaluate the prevalence, determinants and prognostic value of pain at diagnosis in patients with desmoid-type fibromatosis (DF). We selected patients from the ALTITUDES cohort (NCT02867033), managed by surgery, active surveillance or systemic treatments, with pain assessment at diagnosis. Patients were invited to fill QLQ-C30 questionnaire and Hospital Anxiety Depression Scale. Determinants were identified using logistic models. Prognostic value on event-free survival (EFS) was evaluated using the Cox model. Overall, 382 patients were included in the current study (median age: 40.2 years; 117 men). The prevalence of pain was 36%, without significant difference according to first-line treatment (P =.18). In the multivariate analysis, pain was significantly associated with tumor size >50 mm (P =.013) and tumor site (P

Paraneoplastic neurological syndrome (PNS) is uncommon and not well known. PNS can reveal cancer, but its role in seminomas has not been described explicitly. We report the case of a 36-year-old man with unremarkable medical history and no comorbidities who was diagnosed with a retroperitoneal metastatic seminoma. The patient’s general condition deteriorated, and he developed progressive neurological palsy without other clinical anomalies. Electromyography revealed demyelinating, non-lengthy neuropathy. Guillain-Barré syndrome was initially suspected. However, a positron emission tomography scan revealed a retroperitoneal mass, and blood markers revealed increased human chorionic gonadotropin. The patient was diagnosed with PNS, and a computed tomography-guided biopsy revealed a metastatic seminoma without a primary tumor. No circulating neural antibodies were detected. Human polyvalent immunoglobulin was simultaneously administered with chemotherapy. After three cycles of a cisplatin-etoposide-bleomycin, a complete biological and metabolic response rate was observed, and his neurological symptoms rapidly improved. Four years later, the patient responded completely, without any neurological complaints. Paraneoplastic demyelinating inflammatory neuropathy can lead to advanced seminoma diagnosis. Prompt management of seminomas with cisplatin-based regimens provides the best chance of cure for both advanced seminoma and paraneoplastic syndrome.

Objectives Cancer patients with pre-existing autoimmune disease, such as systemic sclerosis (SSc), are excluded from clinical trials, so the data on tolerability and efficacy of immune checkpoint inhibitors in these patients are limited. This study investigated the tolerability and efficacy of anti–programmed death ligand 1 (PD (L)1) immunotherapies in patients with pre-existing SSc. Methods Scleronco-01 was a multicentre, nationwide, open-label, phase IV observational study, from 2019 to 2021. Results Seventeen SSc patients receiving treatment for lung carcinoma (n = 13, 77%), head and neck cancer (n = 2, 12%), melanoma (n = 1, 6%), and colorectal carcinoma (n = 1, 6%) were included. The median (interquartile range) patient age was 60 (34–82) years. Fifteen (88%) patients received anti-PD1 (nivolumab and pembrolizumab) and two (12%) anti-PD-L1 (durvalumab). The median follow-up duration was 12 (range, 2–38) months. Four patients (24%) experienced flare-up of SSc symptoms. Ten patients (59%) developed an immune-related adverse event (grade I–II in 11 patients [65%], grade III–IV in one [6%]) without grade V. The overall response rate was 41% (7/17 patients). The median overall survival was 15.8 (95% confidence interval: 7.3 to not reached) months. Conclusion Anti-PD1 or PD-L1 immunotherapies are suitable options for cancer patients with pre-existing SSc. Longer follow-up periods are required for long-term safety analyses.

BackgroundWe report the clinical activity, safety, and identification of a predictive biomarker for bintrafusp alfa, a first-in-class bifunctional fusion protein composed of the extracellular domain of TGFβRII (a TGF-β “trap”) fused to a human IgG1 mAb blocking PD-L1, in patients with advanced triple-negative breast cancer (TNBC).MethodsIn this expansion cohort of a global phase 1 study, patients with pretreated, advanced TNBC received bintrafusp alfa 1200 mg every 2 weeks intravenously until disease progression, unacceptable toxicity, or withdrawal. The primary objective was confirmed best overall response by RECIST 1.1 assessed per independent review committee (IRC).ResultsAs of May 15, 2020, a total of 33 patients had received bintrafusp alfa, for a median of 6.0 (range, 2.0-48.1) weeks. The objective response rate was 9.1% (95% CI, 1.9%-24.3%) by IRC and investigator assessment. The median progression-free survival per IRC was 1.3 (95% CI, 1.2-1.4) months, and median overall survival was 7.7 (95% CI, 2.1-10.9) months. Twenty-five patients (75.8%) experienced treatment-related adverse events (TRAEs). Grade 3 TRAEs occurred in 5 patients (15.2%); no patients had a grade 4 TRAE. There was 1 treatment-related death (dyspnea, hemolysis, and thrombocytopenia in a patient with extensive disease at trial entry). Responses occurred independently of PD-L1 expression, and tumor RNAseq data identified HMGA2 as a potential biomarker of response.ConclusionsBintrafusp alfa showed clinical activity and manageable safety in patients with heavily pretreated advanced TNBC. HMGA2 was identified as a potential predictive biomarker of response.ClinicalTrials.gov identifierNCT02517398

ObjectiveIdentifying new modifiable prognostic markers is important for ovarian cancer (OC). Low parasympathic activity is associated with inflammation, oxidative stress and sympathetic nervous system activation. Previous studies reported that low vagal nerve activity, measured by low heart rate variability (HRV), may predict poor cancer prognosis. We aimed to examine the prognostic value of HRV in OC.MethodsThis bicentric retrospective study included patients diagnosed with serous OC FIGO stage ≥IIB, between January 2015 and August 2019, with electrocardiograms (ECG) available around diagnosis. HRV was measured from ECG using the time domain parameter of standard deviation of all normal-to-normal heartbeat intervals (SDNN). Optimal SDNN cut-off was determined using the Youden index criteria of time-dependent ROC curves. We used multivariate cox proportional hazard models to investigate the association between HRV and overall survival (OS), while adjusting for well-known OC prognostic factors.ResultsThe 202 patients included were 65.7 years-old on average, 93% had stage FIGO IIIC/IV, 56% had complete surgical resection. Median OS was 38.6 months [95%CI:34.4-47.4]. The median SDNN was 11.1ms, with an optimal cut-off of 10ms to predict OS. OS was shorter for patients with low HRV compared to high HRV (26.4 vs 45.1 months; pConclusionLow HRV, was associated with worse OS in OC patients, supporting previous studies on the prognostic role of HRV in cancer. If replicated in prospective studies, vagal nerve activity may be a new therapeutic target in OC.

Rogaratinib, an oral pan-fibroblast growth factor receptor (FGFR1-4) inhibitor, showed promising phase I efficacy and safety in patients with advanced urothelial carcinoma (UC) withFORT-1 (ClinicalTrials.gov identifier: NCT03410693) was a phase II/III, randomized, open-label trial. Patients withORRs were 20.7% (rogaratinib, 18/87; 95% CI, 12.7 to 30.7) and 19.3% (chemotherapy, 17/88; 95% CI, 11.7 to 29.1). Median overall survival was 8.3 months (95% CI, 6.5 to not estimable) and 9.8 months (95% CI, 6.8 to not estimable; hazard ratio, 1.11; 95% CI, 0.71 to 1.72;To our knowledge, these are the first data to compare FGFR-directed therapy with chemotherapy in patients with

The French Sarcoma Group assessed the efficacy, safety, and quality of life (QoL) of trabectedin versus best supportive care (BSC) in patients with advanced soft tissue sarcoma (STS).This randomized, multicenter, open-label, phase III study included adults with STS who progressed after 1-3 prior treatment lines. Patients were randomized (1 : 1) to receive trabectedin 1.5 mg/mBetween 26 January 2015 and 5 November 2015, 103 heavily pre-treated patients (60.2% with L-STS) from 16 French centers were allocated to receive trabectedin (n = 52) or BSC (n = 51). Median PFS was 3.1 months [95% confidence interval (CI) 1.8-5.9 months] in the trabectedin arm versus 1.5 months (0.9-2.6 months) in the BSC arm (hazard ratio = 0.39, 95% CI 0.24-0.64, P0.001) with benefits observed across almost all analyzed subgroups, but particularly in patients with L-STS (5.1 versus 1.4 months, P = 0.0001). Seven patients (13.7%) in the trabectedin arm (all with L-STS) achieved a partial response, while no objective responses were observed in the BSC arm (P = 0.004). The most common grade 3/4 adverse events were neutropenia (44.2% of patients), leukopenia (34.6%), and transaminase increase (32.7%). Health-related 30-item core European Organization for the Research and Treatment of Cancer Quality-of-Life Questionnaire evidenced no statistical differences between the arms for any domain and at any time point. After progression, 91.8% of patients crossed over from BSC to trabectedin.Trabectedin demonstrates superior disease control to BSC without impairing QoL in patients with recurrent STS of multiple histologies, with greater impact in patients with L-STS.

Purpose: This prospective nationwide cohort study aimed to investigate desmoid-type fibromatosis (DF) outcomes, focusing on the prognostic value of CTNNB1 mutations. Experimental Design: ALTITUDES (NCT02867033) was a nationwide prospective cohort study of DF diagnosed between January 2016 and December 2020. At diagnosis, CTNNB1 molecular alterations were identified using next-generation sequencing or Sanger sequencing. The primary endpoint was event-free survival (EFS; progression, relapse, or death). We enrolled 628 patients managed by active surveillance, surgical resection, or systemic treatment as first-line therapy. Results: Overall, 516 (82.2%) patients [368 females (71.3%), median age 40.3 years (range, 1–89)] were eligible for analysis. In 435 (84.3%) cases, there was one CTNNB1 molecular alteration: p.T41A, p.S45F, or p.S45P. The first-line management was active surveillance in 352 (68.2%), surgical resection in 120 (23.3%), and systemic treatments in 44 (8.5%) patients. CTNNB1 mutation distribution was similar across the three therapeutic groups. The median follow-up period was 24.7 (range, 0.4–59.7) months. The estimated 3-year EFS rate was 66.2% [95% confidence interval (CI), 60.5%–71.2%]. DF harboring p.S45F was significantly associated with male sex (P = 0.03), non-abdominal wall sites (P = 0.05), pain (P = 0.007), and large tumor size (P = 0.025). CTNNB1 p.S45F mutation was not significantly associated with EFS, either in univariate (HR, 1.06; 95% CI, 0.65–1.73; P = 0.81) or in multivariate analysis (HR, 0.91; 95% CI, 0.55–1.49; P = 0.71). Conclusions: We found that CTNNB1 mutation profile was associated with unfavorable prognostic factors but was not a prognostic factor for EFS. See related commentary by Greene and Van Tine, p. 3911

Human epidermal growth factor 2 (HER2) alterations (protein overexpression, gene amplification and mutation) play a key role in oncogenesis and are more likely correlated to poorer outcome in solid tumors. We reviewed recently published studies in the last 18 months on novel treatment approaches for HER2 positive solid tumors (excluding breast cancer).Results of clinical studies assessing anti-HER2 therapies have been recently issued.One of the most promising drugs is transtuzumab deruxtecan, an antibody-drug conjugate which demonstrated clinically meaningful activity in gastric or gastroesophageal junction cancer and colorectal cancers.Small molecules such as poziotinib, pyrotinib, neratinib, which target both epidermal growth factor receptor (EGFR) and HER2 also showed promising activity, especially in heavily pretreated ERRB2-mutated non-small cell lung cancer (NSCLC) cancer patients. Yet, these findings need to be confirmed in confirmatory randomized trials with larger cohorts.Trastuzumab-based combinations with chemotherapy or immune checkpoint inhibitors are under development with promising results, but not in all HER2 tumors. Emerging adverse events with anti-HER2 are interstitial pneumopathy and diarrhea.Tyrosine kinase inhibitors, antibody drug conjugate in monotherapy and combinations are emerging strategies in many HER2-positive cancers; HER2 therapies are now part of standard of care of HER2-amplified gastric or gastroesophageal junction cancer. Data are pending on several unmet medical needs.

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.

We report the clinical activity, safety, and identification of a predictive biomarker for bintrafusp alfa, a first-in-class bifunctional fusion protein composed of the extracellular domain of TGFβRII (a TGF-β "trap") fused to a human IgG1 mAb blocking PD-L1, in patients with advanced triple-negative breast cancer (TNBC).In this expansion cohort of a global phase 1 study, patients with pretreated, advanced TNBC received bintrafusp alfa 1200 mg every 2 weeks intravenously until disease progression, unacceptable toxicity, or withdrawal. The primary objective was confirmed best overall response by RECIST 1.1 assessed per independent review committee (IRC).As of May 15, 2020, a total of 33 patients had received bintrafusp alfa, for a median of 6.0 (range, 2.0-48.1) weeks. The objective response rate was 9.1% (95% CI, 1.9%-24.3%) by IRC and investigator assessment. The median progression-free survival per IRC was 1.3 (95% CI, 1.2-1.4) months, and median overall survival was 7.7 (95% CI, 2.1-10.9) months. Twenty-five patients (75.8%) experienced treatment-related adverse events (TRAEs). Grade 3 TRAEs occurred in 5 patients (15.2%); no patients had a grade 4 TRAE. There was 1 treatment-related death (dyspnea, hemolysis, and thrombocytopenia in a patient with extensive disease at trial entry). Responses occurred independently of PD-L1 expression, and tumor RNAseq data identifiedBintrafusp alfa showed clinical activity and manageable safety in patients with heavily pretreated advanced TNBC.NCT02517398.

BACKGROUND According to guidelines, all sarcoma patients must be managed from initial diagnosis at expert sarcoma centers. However, in everyday practice, the time interval to an expert center visit can be long, which delays presentation to an expert multidisciplinary tumor board (MTB) and increases the risk of inappropriate management, negatively affecting local tumor control and prognosis. The advent of mobile health (mHealth) offers an easy way to facilitate communication and cooperation between general health care providers (e.g., general practitioners and radiologists) and sarcomas experts. We developed a mobile application (Sar’Connect) based on the algorithm designed by radiologists from French Sarcoma Group. Through a small number of easy-to-answer questions, Sar’Connect provides personalized advice for management of patients and contact information on the closest expert center. OBJECTIVE This retrospective study is the first to assess this mobile application’s benefits in reducing the time interval for patient referral to an expert center according to the initial clinical characteristics of the soft tissue tumor. METHODS We extracted tumor mass data for 78 patients discussed by MTBs of three centers of French Sarcoma Group. We applied the Sar’Connect algorithm to these data and estimated the time interval to expert center referral; then, we compared this estimated time interval with the observed time interval. RESULTS We found that the use of Sar’Connect shortened the time interval to a referral center by approximately 7.5 months. Moreover, for half of patients with a malignant soft tissue tumor, Sar’Connect avoided inappropriate management outside of the reference center. We did not identify a significant determinant for shortening the time interval for referral. CONCLUSIONS Overall, promoting the use of a simple mobile application is an innovative and straightforward means to accelerating both the referral and management of soft tissue sarcoma patients in expert centers.

Background According to guidelines, all patients with sarcoma must be managed from initial diagnosis at expert sarcoma centers. However, in everyday practice, the time interval to an expert center visit can be long, which delays presentation to an expert multidisciplinary tumor board and increases the risk of inappropriate management, negatively affecting local tumor control and prognosis. The advent of mobile health offers an easy way to facilitate communication and cooperation between general health care providers (eg, general practitioners and radiologists) and sarcomas experts. We developed a mobile app (Sar’Connect) based on the algorithm designed by radiologists from the French Sarcoma Group. Through a small number of easy-to-answer questions, Sar’Connect provides personalized advice for the management of patients and contact information for the closest expert center. Objective This retrospective study is the first to assess this mobile app’s potential benefits in reducing the time interval for patient referral to an expert center according to the initial clinical characteristics of the soft tissue tumor. Methods From May to December 2021, we extracted tumor mass data for 78 patients discussed by the multidisciplinary tumor boards at 3 centers of the French Sarcoma Group. We applied the Sar’Connect algorithm to these data and estimated the time interval between the first medical description of the soft tissue mass and the referral to expert center. We then compared this estimated time interval with the observed time interval. Results We found that the use of Sar’Connect could potentially shorten the time interval to an expert center by approximately 7.5 months (P Conclusions Overall, promoting the use of a simple mobile app is an innovative and straightforward means to potentially accelerate both the referral and management of patients with soft tissue sarcoma at expert centers.

Background: IMMUcan (SPECTA NCT02834884) is a European public-private effort to generate molecular and cellular profiling data of the human tumor microenvironment (TME) from up to 3,000 patients, to better understand how the immune system and tumors interact. Triple-negative breast cancer (TNBC) is a heterogenous disease with distinct molecular subtypes characterized by different gene expression, genomic profiles, and clinical outcomes. Here, we explored the association between molecular subtypes and response to neoadjuvant chemotherapy as well as levels of immune cell infiltration in the prospective IMMUcan TNBC cohort. Methods: At the cut-off date on June 29th, 2022, we identified a first cohort of 132 patients to perform preliminary analyses, of which 109 had pre-treatment RNAseq data available. Among those, pathological Complete Response (pCR) information was available for a total of 86 patients. Preliminary data included the density of CD3+, CD20+ and CD8+ immune cells from the stroma and tumor compartments from multiplex-immunofluorescence (mIF) for 69 patients. TNBC subtypes were computed as described by Bareche et al. Association of continuous variables with pCR was evaluated with logistic regression (univariate analysis). Results: The pCR rates differed across TNBC subtypes (Fisher’s test, P = 0.02). In detail, pCR was achieved in 88% (8/9) of basal like (BL), 63% (17/27) of immunomodulatory (IM) and 45% (16/35) of mesenchymal (M) tumors, while lower pCR rates were observed for the mesenchymal stem-like (MSL) and luminal androgen receptor (LAR) subtypes with 37% (3/8) and 14% (1/7), respectively, suggesting differences in the sensitivity to neoadjuvant chemotherapy in line with previous reports. When considered as continuous signature scores, pCR was positively associated to BL levels (OR = 2.7, 95% CI, 1.5-4.8; False Discovery Rate [FDR] = 0.0031), and negatively associated to MSL and LAR signature levels (OR = 0.53, 95% CI, 0.32-0.87; FDR = 0.019; OR = 0.30, 95% CI, 0.12-0.74; FDR= 0.019). In addition, CD3+ cell densities in the tumor and stroma were significantly higher in IM tumors (P = 0.002 and P < 0.001), while lower levels were found in M tumors (P = 0.005, P = 0.002). Similarly, stromal CD20+ levels were higher in IM tumors (P = 0.008) and lower in M tumors (P = 0.006), suggesting a more immunosuppressive TME in the M subtype. CD8+ cells levels were not significantly different between subtypes. Conclusions: These preliminary results show relevant differences in the pCR rates among TNBC subtypes, to be confirmed on a larger series of patients and further suggesting a substantial TNBC heterogeneity regarding treatment response. Of note, preliminary mIF results suggest a differential role of the immune response across molecular subtypes. Additional analyses integrating mIF and genomic data are currently ongoing. Funding: IMI2 JU grant agreement 821558, supported by EU’s Horizon 2020 and EFPIA. Citation Format: Andrea Joaquin Garcia, Mattia Rediti, Abdelkader Benyagoub, Stéphanie Tissot, Sylvie Rusakiewicz, Robin Liechti, Flavia Marzetta, Nicolas Penel, Julio Oliveira, Jean-Charles Goeminne, Pierre Fournel, Andreia Capela, Xiaoxiao Wang, Delphine Vincent, Françoise Rothe, Marie Morfouace, Henoch Hong, Donald Jackson, Christos Sotiriou, Laurence Buisseret. Pathologic complete response rate across triple negative breast cancer subtypes in the IMMUcan study. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4522.

Background This multi-cohort trial explored the efficacy and safety of regorafenib for patients with advanced sarcomas of bone origin; this report details the cohort of patients with metastatic or locally advanced chondrosarcoma (CS), progressing after prior chemotherapy. Patients and methods Patients with CS, progressing despite prior standard therapy, were randomised (2:1) to receive regorafenib or placebo. Patients on placebo could crossover to receive regorafenib after centrally confirmed progressive disease. The primary endpoint was progression-free rate (PFR) at 12 weeks. With one-sided α of 0.05, and 80% power, at least 16/24 progression-free patients at 12 weeks were needed for success (P0 = 50%, P1 = 75%). Results From September 2014 to February 2019, 46 patients were included in the CS cohort, and 40 patients were evaluable for efficacy: 16 on placebo and 24 on regorafenib. Thirteen patients (54.2%; 95% CI [35.8%-[) were non-progressive at 12 weeks on regorafenib versus 5 (31.3%; 95% CI [13.2%-[);) on placebo. Median PFS was 19.9 weeks on regorafenib, and 8.0 on placebo. Fourteen placebo patients crossed over to regorafenib after progression. The most common grade ≥3 treatment-related adverse events on regorafenib included hypertension (12%), asthenia (8%), thrombocytopenia (8%) and diarrhoea (8%). One episode of fatal liver dysfunction occurred on regorafenib. Conclusion Although the primary endpoint was not met statistically in this small randomised cohort, there is modest evidence to suggest that regorafenib might slow disease progression in patients with metastatic CS after the failure of prior chemotherapy. Clinical trial registration The trial is registered at ClinicalTrials.gov ( NCT02389244 ).

Objectives Continuous chemotherapy has been used to treat patients with metastatic esophageal squamous cell carcinoma (mESCC), despite weak evidence supporting a clinical benefit, associated side effects for the patients, and unjustified medical costs. In the French setting, we conducted a cost-utility analysis alongside the randomized E-DIS trial (NCT01248299), which compared first-line fluorouracil/platinum-based chemotherapy continuation (CT-CONT) to CT discontinuation (CT-DISC) in progressive-free patients after an initial 6-week treatment phase. Methods A partitioned survival analysis was performed using patient-level data collected during the trial for survival outcomes, quality of life (EQ-5D-3L), and medical costs. The mean quality-adjusted life-years (QALYs) and medical costs were estimated over an 18-month period to assess the incremental net monetary benefit and incremental cost-effectiveness ratio. Uncertainty was handled using the nonparametric bootstrap and univariate analysis. Sixty-seven patients with mESCC were randomized and included in the cost-utility analysis. Results On average, CT-CONT slightly decreased the number of QALYs (-0.038) and increased the cost per patient (+ €1177). At a willingness-to-pay threshold of €50 000/QALY, the incremental net monetary benefit was negative (-€3077 [95% confidence interval: -6564; 4359]), and the incremental cost-effectiveness ratio was -30 958€/QALY (CT-CONT dominated). The probability of the CT-CONT treatment option being cost-effective at a willingness-to-pay threshold of €50 000/QALY, compared to CT-DISC, was 29%. Conclusions CT-DISC may be considered as an alternative therapeutic option to CT-CONT in patients with mESCC who have stable disease after an initial chemotherapy treatment phase. A continuous chemotherapy could indeed reduce the number of QALYs because of the disutility associated with the continuous treatment.