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1522MO - Hormonal contraception and pregnancy and risk of progression or relapse in desmoid-type fibromatosis (DF)
- Marion DEBAUDRINGHIEN (Lille, France)
Abstract
Background
DF is a locally aggressive tumor with unpredictable course, but most relapses/progressions occur within 2 years. Some indirect arguments suggest that DF could be a hormone-dependent tumor, and that recent exposure to hormonal contraception or pregnancy could influence DF outcome.
Methods
ALTITUDES (NCT02867033) is a nationwide cohort of incident DF, diagnosed from January 2016 to February 2021 and confirmed by central pathological review (Penel, ASCO 2021). In the present study, we have selected women with childbearing age. The primary endpoint was event-free survival EFS (including progression during active surveillance -AS -or relapse after surgery -SUR-). We estimated EFS Kaplan-Meier curves, and modeled the risk in Cox models. We considered hormonal contraception or pregnancy within the 2 years before DF.
Results
We included 242 pts with a median age of 34.1 (range, 17.3-45.8). Abdominal wall is the most common tumor site (N=124, 51.5%). Pts were managed by AS (N=194) or SUR (N=48). Pregnancy occurred within 2 years before DF diagnosis, at the time of DF diagnosis and after DF diagnosis in 87 (36.0%), 12 (5.0%) and 24 cases (9.9%), respectively. Exposure to hormonal contraception within 2 years before diagnosis, at the time of diagnosis and after diagnosis concerned 107 (44.2%), 82 (33.9%) and 94 cases (38.8%). The median follow-up was 23.9 mo. (range, 0.4 to 59.7 mo.). The 2-year EFS rate was 74.5% (95%CI, 67.5-80.3%). We did not observe any association between pregnancy occurring within 2 years and EFS: 2-year EFS= 70.4% versus 76.9%, Hazard ratio=1.32 (0.77-2.28), p=0.31. We did not observe any association between exposure to hormonal contraception within 2 years and EFS: 2-year EFS= 78.5% versus 72.5%, Hazard ratio=0.84 (0.48-1.46), p=0.53. Results were stable in multivariate analysis. Subgroup analyses showed that effect of both pregnancy and hormonal contraception did not significantly differ according to primary site (abdominal wall versus other), age, tumor size and 1st-line strategy (AS versus SUR) (all interaction tests, p>0.15).
Conclusions
Pregnancy and exposure to hormonal contraception within 24 months did not influence DF outcome.
Clinical trial identification
NCT02867033.
Legal entity responsible for the study
Centre Oscar Lambret.
Funding
Ligue Nationale contre le Cancer, Fondation Institut Curie, InterSarc.
Disclosure
All authors have declared no conflicts of interest.
1523MO - Initial active surveillance strategy for patients with peripheral sporadic desmoids: A multicentre phase II observational trial
- Sylvie Bonvalot (Paris, CEDEX, France)
Abstract
Background
Desmoid tumors (DT) are characterized by an unpredictable course. Most of the existing literature consists of retrospective studies. In a previous double-blind phase 3 trial comparing sorafenib and placebo, the 2-year Progression Free Survival (PFS) rate of the placebo group was 36% (Gounder NEJM 2018). However, assigned patients had already progressive or recurrent DT. The primary endpoint of this observational phase 2 study was to evaluate PFS and treatments at progression of newly diagnosed sporadic DT. Secondary endpoints included pain evaluation and record of continued surveillance or treatments after progression.
Methods
NCT01801176 was conducted in 9 hospitals from the French Sarcoma Group. Adults with histologically documented, primary DT, located on superficial trunk or extremities, not previously treated were proposed to Active Surveillance (AS) after signed informed consent. MRI were performed at 1, 3 and then each 6 months, tumor size was centrally assessed (RECIST). Pain evaluation was scored by CTAV4.
Results
Between 2012 and 2015, 100 patients (pts) were enrolled. Female/male ratio was 8; median age was 35.5 years (IQR 26-45). Locations were: extremities n=28, abdominal wall n = 49, thoracic wall n = 23. Median follow up was 46.6 months (IQR 36.8–61.1). PFS at 2 and 3 years were 59.1% (49.2-68.4) and 53.4% (43.5-63.1). The best response was: CR: 8/90 pts (8.9%); PR: 20/90 pts (22.2%); SD: 60/90 pts (66.7%); Progression (P) = 2/90 pts (2.2 %), missing n =10 pts. Median Time to spontaneous response was 38.6 months (29.8-NA). Median TTP was 6.74 months (5.65-10.65). Median ratio of Tumor size/Tumor baseline size decreased after 9 months. Median visual pain score at 3-months was 0 (0-0.75). Age, location, tumor size and betacatenin mutations did not impact PFS in the Cox model. At progression (n = 48 patients), 25 continued AS, 4 received cryoablation, 4 received radiotherapy, 10 hormonal treatment, 4 chemotherapy, and 1 was operated.
Conclusions
Active surveillance of newly diagnosed DT is an effective strategy to better select indications for treatment and spare patients from aggressive treatments when unnecessary. The onset of the decrease of the ratio of median tumor size/baseline size may take 9 months.
Clinical trial identification
NCT01801176.
Legal entity responsible for the study
The authors.
Funding
National Grant from Institut National du Cancer, INCa, France.
Disclosure
All authors have declared no conflicts of interest.
Discussion 1522MO and 1523MO
- Bernd Kasper (Mannheim, Germany)
1524MO - Patterns of care and outcomes of 64 CIC-rearranged sarcoma: A retrospective multicentre case-series within the French Sarcoma Group (FSG)
- Brahmi Mehdi (Lyon, CEDEX, France)
Abstract
Background
CIC-DUX4 sarcoma (CDS) represent the second most prevalent subset of high grade round cell sarcomas after Ewing sarcomas. The natural history might be diverse and probably underscores a heterogeneous group. Moreover, treatment strategy can differ according to institutions. The main goals of this retrospective study was to describe characteristics, treatments and outcome for patients with CDS included in the French NETSARC database.
Methods
Pediatric and adult patients from 11 French centers with a diagnosis of CDS were registered from October 2008 to March 2021. Patients and tumors characteristics were collected from the national network NETSARC+ database. CDS diagnosis was histologically and molecularly confirmed with a central review by expert pathologists. Two groups of patients were studied: those treated similarly to classical Ewing sarcomas especially with multi-agent chemotherapy in neoadjuvant and adjuvant setting (cohort 1) and those treated as high-grade soft tissue sarcomas according to ESMO and/or EpSSG guidelines (cohort 2).
Results
Among the 64 patients with confirmed CDS, the sex ratio was 0.9 and the median age at diagnosis was 25 years (range 11-87) including 19 patients < 18. Three patients (5%) had a previous cancer history. Population and tumor characteristics were not statistically different between cohort 1 (N=38, 60%) and cohort 2 (N=26, 40%). With a median follow-up of 37 months (range 3-252), 32 patients (50%) died of the disease. Median overall survival from diagnosis was 4 years, with no significant difference between both cohorts (Log-rank test, P=0.99). Nevertheless, when focusing on patients with metastatic disease at diagnosis (N=18), all patients from cohort 2 (N=6) died due to progressive disease while 7 patients from cohort 1 are still alive and in complete remission, resulting in a significantly better OS (Log-rank test, P<0.05).
Conclusions
FSG experience confirms the aggressive clinical course of CDS patients regardless of chemotherapy regimen, even if this study suggests that metastatic patients should not benefit from a therapeutic de-escalation. Molecular studies are urgently needed to improve understanding and treatment of this orphan disease.
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.
1525MO - Phase I/II study of MAK683 in patients (pts) with advanced malignancies including epithelioid sarcoma
- Rastislav Bahleda (Villejuif, CEDEX, France)
Abstract
Background
EED is a core component of PRC2 which modifies the epigenetic status of target genes, including cell cycle control genes. Loss of SNF5 function in epithelioid sarcoma drives oncogenesis by imbalanced PRC2 activity. MAK683 is a potent, S-adenosyl-l-methionine, non-competitive PRC2 inhibitor that impairs EED binding to tri-methylated lysine 27 on histone H3 (H3K27me3), preventing allosteric activation of this complex. This is a phase I/II study of MAK683, in adult pts with advanced malignancies who have exhausted or have no effective standard treatment. The primary objective was to characterize safety and tolerability and determine the maximum tolerated dose and/or recommended phase II dose.
Methods
Pts received escalating doses of MAK683 in fasted conditions where appropriate. Eligible pts had specified advanced/metastatic hematological or solid malignancies. Here, we present data from a subset of pts with advanced epithelioid sarcoma. Pts were administered MAK683 120–300 mg twice daily (BID) or 500–800 mg once daily (QD) orally until unacceptable or dose-limiting toxicities (DLT) had developed, disease progression or death.
Results
As of Jan 15, 2021, 14 pts with a median of 1.5 prior lines of therapy (range: 0–5) had been treated. Four (29%) were ongoing and 10 (71%) discontinued, primarily due to progressive disease (PD) (43%). Nine (64%) pts reported ≥1 treatment-related adverse event (TRAE) of any grade, with the most common (≥20%) being alopecia (36%), nausea, neutropenia, thrombocytopenia (29% each), and diarrhea (21%). Grade 3/4 TRAEs were reported in 50% pts, with ≥20% reporting neutropenia and thrombocytopenia (21% each). DLT were reported in 2 pts receiving 120 and 300 mg BID, respectively. There were no treatment-related deaths. Partial response was observed in 2 pts (14%) receiving 120 mg BID and 500 mg QD respectively. Six (43%) pts had stable disease and 3 (21%) had PD. The overall response rate was 14% (95% CI: 1.8–42.8) and the disease control rate was 57% (95% CI: 28.9–82.3). Duration of response of the two responders were 16.5+ and 5.2+ months.
Conclusions
MAK683 was generally well-tolerated and there were preliminary signs of activity in pts with advanced epithelioid sarcoma.
Clinical trial identification
NCT02900651; Protocol number: CMAK683X2101; Release date: 27 June 2018.
Editorial acknowledgement
Writing and editorial assistance was provided by Sivanjaa Manoj of ArticulateScience, UK.
Legal entity responsible for the study
Novartis Pharmaceutical Corporation.
Funding
Novartis Pharmaceutical Corporation.
Disclosure
Z.A. Wainberg: Financial Interests, Personal, Other, Honoraria: Amgen, Astra Zeneca, Daiichi, Bayer, BMS, Merck, Ipsen, Five Prime, Gilead, Arcus, Astellas, Molecular Templates, Array; Financial Interests, Personal, Advisory Board: Amgen, Astra Zeneca, Daiichi, Bayer, BMS, Merck, Ipsen, Five Prime, Gilead, Arcus, Astellas, Molecular Templates, Array; Financial Interests, Institutional, Research Grant: Amgen, Astra Zeneca, Daiichi, Bayer, BMS, Merck, Ipsen, Five Prime, Gilead, Arcus, Astellas, Molecular Templates, Roche/Genentech, Array/Pfizer. A. Spreafico: Financial Interests, Institutional, Funding, Research Funding to support clinical trials: Novartis, Bristol-Myers Squibb, Symphogen AstraZeneca/Medimmune, Merck, Bayer, Surface Oncology, Northern Biologics, Janssen Oncology/Johnson & Johnson, Roche, Regeneron, Alkermes, Array Biopharma/Pfizer, GSK, Treadwell; Financial Interests, Personal, Advisory Board: Merck, Bristol-Myers Squibb, Oncorus, Janssen. B. Ma: Financial Interests, Personal, Invited Speaker: MSD, Taiho, Daichi; Financial Interests, Personal, Advisory Board: BMS; Financial Interests, Personal, Other, Pre-clinical: Boehringer Ingelheim, Novartis; Financial Interests, Personal, Other, Consultancy : Y-biologics. V. Subbiah: Financial Interests, Personal, Research Grant: Novartis; Financial Interests, Personal, Research Grant: LOXO Oncology; Financial Interests, Personal, Research Grant: BluePrint Medicines; Financial Interests, Personal, Advisory Board: Helsinn, Loxo Oncology/Eli Lilly, R-Pharma US, INCYTE, QED Pharma, Medimmune,and Novartis; Financial Interests, Personal, Other: Loxo Oncology/Eli Lilly, Novartis, Bayer, Berghealth, Incyte, Fujifilm, Pharmamar, D3, Pfizer, Multivir, Amgen, Abbvie, Alfa-sigma, Agensys, Boston Biomedical, Idera Pharma, Inhibrx, Exelixis, Blueprint Medicines, Medimmune, Altum, Dragonfly Therapeutics,. V. Ribrag: Financial Interests, Personal, Advisory Board: Gilead, Infinity, MSD, BMS, Nanostring, Incyte, Roche, AstraZeneca; Financial Interests, Personal, Other, Consulting: Servier; Non-Financial Interests, Personal, Research Grant: Astex. Y.Y. Fan: Financial Interests, Personal, Full or part-time Employment: Novartis. Y. Cheng: Financial Interests, Personal, Full or part-time Employment: Novartis. C. Lai: Financial Interests, Personal, Full or part-time Employment: Novartis; Financial Interests, Personal, Stocks/Shares: Novartis. F. De Braud: Financial Interests, Personal, Other, Honoraria: Roche, EMD Serono, NMS Nerviano Medical Science, Sanofi, Novartis, Incyte, Bristol-Myers Squibb, MSD, Servier, Merck Group, Amgen, Pfizer, Tesaro, Celgene. All other authors have declared no conflicts of interest.
Discussion 1524MO and 1525MO
- Anna Maria Frezza (Milan, Italy)
1526MO - GEMMK: A phase I study of gemcitabine (gem) and pembrolizumab (pem) in patients (pts) with leiomyosarcoma (LMS) and undifferentiated pleomorphic sarcoma UPS)
- Alannah Smrke (Vancouver, Canada)
Abstract
Background
Patients with advanced LMS and UPS have poor outcomes. Single agent immunotherapy (IO) results have been disappointing, whereas IO-cytotoxic combinations may improve outcomes. Gem-induced apoptosis may generate a more favourable immune microenvironment, providing rationale for the evaluation of gem in combination with a checkpoint inhibitor. The aim of this phase I trial (NCT03123276) was to determine the safety and maximum tolerated dose (MTD) of gem + pem.
Methods
Gem + pem were administered Day 1, gem Day 8 (6-8 cycles), followed by single agent pem 200mg Day 1 (to a max of 2 years) IV Q3weeks (wks) for pts with advanced LMS or UPS using a 3+3 design with 3 gem doses (800, 1000, 1200 mg/m2). Pre- and on treatment biopsies were mandated. The primary endpoint was safety (CTCAE v4.0) and secondary endpoints: radiological response (RECIST v1.1) at 9 wks and median progression-free survival (mPFS).
Results
Thirteen pts (2 UPS, 11 LMS) were enrolled. The median age was 51 yrs (range 40-67), 77% female, median of 1 (range 1-4) previous treatments. There was one dose-limiting toxicities (DLTs) observed at gem 1000, but not confirmed in the expanded cohort. The MTD of gem was not reached, recommended gem dose was 1200mg/m2. Detailed safety data will be presented. There were 16 SAE's, fever (n=10/16) was the most frequent. Common adverse events were neutropenia (n=11/13 pts; G3 n=2/13, G4 n=4/13), rash (n=10/13), fatigue (n=9/13), hypothyroidism (n=7/13), diarrhoea (n=7/13), nausea (n=6/13), fever (n=5/13). At 9 wks, 92% of pts (95%CI 57-99) were progression free. mPFS was 5.1m (95% CI 2-9); 11/13 pts had progressed at a median follow up of 5.1m. Best response at 9wks for LMS pts was SD (n=8/11) and PD (n=3/11); UPS PR (n=2/2). Most patients (n=10/13) discontinued due to PD, 2 remain on study (1 each on 1000 and 1200mg/m2) and 1 patient withdrew consent. Translational work is ongoing.
Conclusions
Gem-pem is safe and efficacy continues to be evaluated in the expansion cohort. A MTD dose expansion cohort is fully enrolled and follow-up is ongoing.
Clinical trial identification
NCT03123276.
Legal entity responsible for the study
The Royal Marsden NHS Foundation Trust.
Funding
Merck, Sharp & Dohme Corp.
Disclosure
N. Fotiadis: Other, Personal, Other, Consultation Fee: Johnson and Johnson; Other, Personal, Other, Consultation Fees: Boston Scientific; Other, Personal, Funding: Replimune. R.L. Jones: Other, Personal, Research Grant: MSD; Other, Personal, Research Grant: GSK; Other, Personal, Other, Consultation Fees: Adaptimmune, Athenex, Blueprint, Clinigen, Eisai, Epizyme, Daichii, Deciphera, Immunedesign, Lilly, Merck, Pharmamar, UptoDate. All other authors have declared no conflicts of interest.
1527MO - Biomarkers of response and hyperprogression in patients with sarcoma treated with checkpoint blockade
- Nicholas D. Klemen (New York, United States of America)
Abstract
Background
Checkpoint blockade with antibodies against PD-1 can mediate objective responses in selected sarcomas. There are few established predictors of response, and the incidence of hyperprogressive disease (HPD) is unknown.
Methods
We reviewed our experience treating sarcoma patients on prospective trials (RECIST v1.1) with nivolumab or pembrolizumab as monotherapy or combined with bempegaldesleukin, epacadostat, ipilimumab or Talimogene laherparepvec. HPD was an increased tumor growth rate of 50% or more post-treatment relative to pre-treatment (Ferrara
Results
134 patients with sarcoma received treatment from 2015 – 2019. Follow-up was 33 months, outcomes are in the table. One (3%) of 31 patients with liver metastases responded vs 8 (42%) of 19 with lymph node metastases (P < 0.001). ORR in lung, bone or other sites was 12-15%. Disease burden before CR/PR, SD, PD and HPD was 62 mm, 110 mm, 104 mm and 59 mm, respectively (CR/PR vs SD, P < 0.01; PD vs HPD, P = 0.035). Demographics, subtype, and outcomes of patients with PD and HPD were similar. TMB was similar across response groups; FGA was higher in responders. No genomic alterations associated with HPD and no relevant GSEA pathways were upregulated in HPD vs PD.
CR/PR SD PD HPD ORR (n, %) 21 (16%) 48 (36%) 50 (37%) 15 (11%) PFS (median, months) 15 mo 6 mo 2 mo 2 mo OS (median, months) NR 20 mo 8 mo 6 mo 3-year OS (%) 67% 30% 9% 10%
Conclusions
This study of patients with sarcoma treated with PD-1 blockade demonstrates an ORR of 16%. Low disease burden was associated with response. Patients with liver metastases were less likely to respond while those with nodal metastases were more likely. The incidence of HPD in sarcoma is comparable to other solid tumors, but we did not detect clinical or biological differences between PD and HPD tumors except disease burden at baseline. HPD does occur in sarcoma but its clinical significance remains uncertain.
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
C.M. Kelly: Financial Interests, Personal, Funding: Amgen; Financial Interests, Personal, Funding: Merck; Financial Interests, Personal, Funding: Agios; Financial Interests, Personal, Funding: Exicure; Financial Interests, Personal, Funding: Kartos; Financial Interests, Personal, Funding: Xencor; Financial Interests, Personal, Advisory Role: Exicure; Non-Financial Interests, Personal, Other, Family member employed: Daiichi Sankyo. S. Movva: Financial Interests, Institutional, Funding: Hutchinson Medipharma; Financial Interests, Institutional, Funding: Ascentage Pharma. B. Nacev: Non-Financial Interests, Personal, Other, Uncompensated provision of services: Delphi Diagnostics; Non-Financial Interests, Personal, Other, Uncompensated provision of services: QuadW Foundation; Non-Financial Interests, Personal, Other, Uncompensated provision of services: Rapafusyn Pharmaceuticals. J.E. Chan: Financial Interests, Personal, Royalties: WebMD; Financial Interests, Personal, Research Grant: Cytek Biosciences. S.P. D'Angelo: Financial Interests, Personal, Advisory Role, Also, travel/accommodations and research funding for MSKCC: EMD Serono; Financial Interests, Personal, Advisory Role, Also, research funding for MSKCC: Amgen; Financial Interests, Personal, Advisory Role, Also, travel/accommodations and research funding for MSKCC: Nektar; Financial Interests, Personal, Advisory Role: Immune design; Financial Interests, Personal, Advisory Role: GlaxoSmithKline; Financial Interests, Personal, Advisory Role, Also, research funding for MSKCC: Incyte; Financial Interests, Personal, Advisory Role, Also, research funding for MSKCC: Merck; Financial Interests, Personal, Advisory Role, Also, travel and accommodations: Adaptimmune; Financial Interests, Personal, Advisory Role: Immunocore; Financial Interests, Institutional, Funding: Bristol-Myers Squibb; Financial Interests, Institutional, Funding: Deciphera. All other authors have declared no conflicts of interest.
Discussion 1526MO and 1527MO
- Olivier Mir (Villejuif, France)