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- S. Bonvalot
- R. Maki
- M. Eriksson
1475PD - A randomized clinical trial of adjuvant chemotherapy with doxorubicin, ifosfamide and cisplatin (API), followed by radiotherapy versus radiotherapy alone in patients with localized uterine sarcomas (SARCGYN study). Update at 10 years (ID 3924)
- P. Pautier
Abstract
Background
There is no proven benefit of adjuvant treatment in uterine sarcoma (US). SARCGYN was a phase-III study which compared adjuvant polychemotherapy followed by pelvic radiotherapy (RT) (arm A)
Methods
Patients with FIGO stage ≤III US, and physiological age ≤65 years were randomized after complete surgery and normal thoracic, abdominal and pelvic CT scans between CT and no CT, with a stratification between carcinosarcomas (CS)
Results
Eighty-one patients were included: 39 in arm A and 42 in arm B; 52 stage I, 16 stage II, and 13 stage III; 53 leiomyosarcomas, 9 undifferenciated sarcomas, and 19 carcinosarcomas. API was toxic with two toxic deaths and one acute leukemia. After a median FU of 9.9 years [0.3-15.1], 42/81 patients relapsed, 16 in arm A, and 26 in arm B, and 38 died, 16 in arm A, and 22 in arm B. The 5-year OS is 74% in arm A and 60% in arm B, and the difference is not significant (p = 0.16).
Conclusions
In this trial interrupted at an early stage and with a longer follow-up, there is no statistical impact of API adjuvant CT on OS. The two toxic deaths and the integration of carcinosarcomas may have impacted on the global prognosis. A selection of a specific uterine population and a less toxic chemotherapy for future studies are mandatory.
Clinical trial identification
NCT00162721
Legal entity responsible for the study
Institut de Cancérologie Gustave Roussy
Funding
Association pour la Recherche contre le Cancer; Chugaï Pharma
Disclosure
P. Pautier: Advisory board: Roche and Pharmamar. S. Piperno-Neumann: Travel grants PharmaMar, Novartis. F. Bertucci: Traveling grants, PharmaMar, Novartis. F. Duffaud: Consultancy work: Lilly, Pharmamar, Bayer, Novartis Travel grants: Pfizer, Pharmamar. All other authors have declared no conflicts of interest.
1476PD - Tumour necrosis and clinical outcomes following neoadjuvant therapy in soft tissue sarcoma (STS) (ID 1424)
- J. Lewin
Abstract
Background
Tumour necrosis following chemotherapy is prognostic in bone sarcoma, but remains undefined in STS.
Methods
We searched MEDLINE, MEDLINE in progress, EMBASE and Cochrane to identify studies that investigated neoadjuvant therapy in STS. Eligible studies were required to have data on survival outcomes based on tumor necrosis in the resected specimen, or provided individual patient data. Hazard ratios (HR) for relapse free (RFS) and overall survival (OS) as well as odds ratios (OR) for recurrence at 3 years and for death at 5 years were pooled in a random effect meta-analysis. Association between patient characteristics and attainment of ≥ 90% necrosis were explored with logistic regression.
Results
21 studies comprising 1644 patients were included in this analysis. Location of the tumor included the extremities in the majority (n = 1459; 89%). Induction regimens included chemotherapy/radiation (n = 813; 49%), chemotherapy alone (n = 418; 25%), chemotherapy/caffeine (n = 81; 5%), radiotherapy alone (n = 78; 5%), isolated limb perfusion (ILP) with (n = 28; 2%) or without radiation (n = 208; 13%), and targeted therapy/radiotherapy (n = 18; 1%). Utilizing a cut-off of 90%, patients with ≥ 90% tumour necrosis had significantly reduced risk of recurrence at 3 years (OR0.30; 95% CI: 0.20-0.44; p < 0.0001) and had improved 5-year OS (OR 0.38; 95% CI: 0.23-0.63; p < 0.001). Limiting the analysis to studies with reported HR (n = 6), patients with ≥ 90% tumor necrosis also had a lower risk of recurrence (HR 0.68; 95% CI: 0.49-0.94; p = 0.02) and death (HR 0.54; 95% CI: 0.41-0.71; p < 0.001). There was no significant association between age, gender, and histologic subtype with attainment of ≥ 90% necrosis. Compared to other neoadjuvant modalities, ILP was associated with higher odds of achieving ≥ 90% necrosis (OR 12.1; 95% CI: 3.69-39.88; p < 0.001).
Conclusions
Tumour necrosis ≥ 90% following neoadjuvant therapy is associated with reduced recurrence risk and improved overall survival in patients with STS.
Legal entity responsible for the study
Princess Margaret Cancer Centre
Funding
None
Disclosure
All authors have declared no conflicts of interest.
1477PD - Prognosis of desmoid tumours initially managed with surveillance only at all anatomical locations (ID 3007)
- W. Van Houdt
Abstract
Background
Desmoid tumours are locally aggressive mesenchymal tumours that lack metastatic potential. Tumour behaviour is unpredictable and varies along a spectrum from remission to growth. Recently, active surveillance has been increasingly adopted as initial management. The aim of this study is to analyse the need and indications for treatment in desmoid patients initially managed with surveillance only.
Methods
Patients with a desmoid tumour at any anatomical location diagnosed between 1998 and 2016 were selected from a prospectively maintained database. Differences between patient groups were analysed with independent t-tests or Chi-square tests. Inverse univariate cox proportional hazard regression analyses were conducted to assess factors associated with start of treatment, tumour behaviour and pain.
Results
A total of 168 patients initially managed with surveillance only were identified. The tumours were located in an extremity (51), in the abdominal wall (61), intra-abdominally (15), in the chest wall (30) or at other locations (11). From these patients, 33% (n = 55) developed progressive disease, 38% (n = 64) had stable disease and 28% (n = 47) had a remission. Tumours in patients <50 years old were more likely to show progressive disease after surveillance in an univariate analysis (p = 0.046). A total of 78 patients (46%) eventually had some form of treatment, while 90 patients (54%) continued on surveillance only. Median time to treatment was 31 months. Patients with tumours >5 cm were more likely to undergo treatment (p < 0.01), while no significant differences were found between the different anatomical locations. Treatment consisted mainly of surgery (n = 40, 44%) or systemic therapy (n = 36, 40%). The indications to start treatment were pain (32%), growth (31%) or both (13%). Tumours located in the chest wall or upper extremity caused significantly more pain than other locations (p = 0.01), while pregnancy-associated desmoid tumours caused significantly less pain (p = 0.04).
Conclusions
Patients with desmoid tumours can be managed with surveillance only, but a large minority still needs treatment after an initial period of surveillance. Pain and tumour growth are the most common indications to start treatment after initial surveillance.
Legal entity responsible for the study
Winette van der Graaf
Funding
None
Disclosure
All authors have declared no conflicts of interest.
1478PD - Adult Translocation-related soft tissue sarcomas (TRS): Presentation, management and outcome of 2,143 cases confirmed by expert pathologists (ID 1260)
- N. Penel
Abstract
Background
To better characterize the TRS patterns compared to other sarcomas.
Methods
Retrospective multicenter study of 12,262 patients treated between 01/1980 and 12/2013 in one of 22 French Referral Sarcoma Center and enrolled in the “Conticabase”. Diagnoses were systematically reviewed by expert pathologists and entities classified according to the 2013 WHO Classification.
Results
The median follow-up was 4.9 years (95%-CI: 4.7-5.0). TRS included 13 entities: synovial S (760 cases; 7.4%/5-y OS: 64%), myxoid LPS (436; 4.2%/5-y OS:88%), PNET (205; 2.0%/5-y OS:58%), round cell LPS (183; 1.8%/5-yOS: 70%), alveolar RMS (122; 1.2%/5-yOS: 25%), malignant SFT (86; 0.8%/5-yOS: 77%), clear cell sarcoma (63; 0.6%/5-yOS: 67%), LGFMS (60; 0.6%/5-yOS: 82%), desmoplastic round cell tumor (56, 0.5%/5-y OS: 11%), ESMCS (54; 0.5%/5-yOS:78%), ASPS (48; 0.5%/5-yOS: 66%), EHE (42; 0.4%/5-yOS: 55%), and sclerosing epithelioid fibrosarcoma (28; 0.3%/5-y OS: 70%). All TRS (2,143 cases; 20.8%) are associated with younger age (40.6 versus 60.0; p < 0.0001), low rate of predisposing conditions (0.01% vs 22.3%, p < 0.0001), and higher rate of N involvement (4.7 vs 1.3%, p < 0.0001 and higher rate of synchronous metastasis (11.9 vs 6.7%, p < 0.001). R0 resection (41.6 versus 31.9%, p < 0.0001), use of (neo)adjuvant radiation therapy (62.6 vs 42.2%, p < 0.0001) and use of (neo)adjuvant CT (36.6 versus 22.3, p < 0.0001) were significantly more frequent. At the end, TRS are associated with a lower rate of local relapse (18.1 vs 26.0%, p < 0.0001) but a higher rate of metastasis relapse (42.0 vs 30.7%, p < 0.0001).
Conclusions
TRS display specific pattern compared to other sarcomas. Second opinion by expert pathologist and use of molecular biology confirmatory test are of major importance to recognize this population and discuss multimodal approach at early stage of the disease.
Legal entity responsible for the study
Centre Oscar Lambret, Lille, France
Funding
None
Disclosure
All authors have declared no conflicts of interest.
Invited Discussant 1475PD, 1476PD, 1477PD and 1478PD (ID 5906)
- S. Bonvalot
Q&A led by Discussant (ID 5907)
1479PD - Phase II study of TAS-116, an oral inhibitor of heat shock protein 90 (HSP90), in metastatic or unresectable gastrointestinal stromal tumor refractory to imatinib, sunitinib and regorafenib (ID 1811)
- Y. Kurokawa
Abstract
Background
Mutated KIT and PDGFRA in gastrointestinal stromal tumor (GIST) rely on HSP90 for their functional stability; therefore, HSP90 is a rational therapeutic target in treating GIST in patients (pts) acquired resistance to approved tyrosine kinase inhibitors. TAS-116 is an oral non-ansamycin, non-purine, non-resorcinol, highly selective inhibitor of HSP90α/β with antitumor activity in an imatinib-resistant human GIST xenograft mouse model. In a phase I study, TAS-116 demonstrated the acceptable safety and the efficacy signs in radiological imaging in pts with GIST including 1 partial response. Here, we conducted a phase II study to evaluate the safety and efficacy of TAS-116 in metastatic or unresectable GIST refractory to standard therapies.
Methods
This was a phase II, open label, single-arm, multi-center study. The key eligibility criteria were histologically confirmed GIST refractory to imatinib, sunitinib, and regorafenib; a measurable lesion per RECIST ver. 1.1; and adequate organ function. Pts received 160 mg/day TAS-116 on a 5-days-on/2-days-off schedule. The primary endpoint was progression-free survival (PFS); secondary endpoints included objective response rate, disease control rate, overall survival, and adverse events. An independent central review (ICR) committee assessed all responses. Sample size was 40 for full analysis set.
Results
From 12 May 2016 to 26 April 2017, 40 pts were enrolled in this study. The numbers of prior treatments was 3 in 24 pts, 4 in 9 pts, and ≥5 in 7 pts. In 34 pts evaluated as of 26 April 2017, the most common adverse events were diarrhea (82%), anorexia (50%), increased serum creatinine (44%), and eye disorders (21%). All eye disorders recovered or resolved following dose interruption, and were limited to Grade 1. There were no treatment-related deaths. According to ICR, median PFS was 4.5 months (95% CI, 2.9–6.1 months). Although none had a partial response, 27 out of 34 pts (79%) had stable disease for ≥6 weeks.
Conclusions
TAS-116 was well tolerated and the initial efficacy results in a ≥ 4th-line treatment setting for metastatic or unresectable GIST, are encouraging. Updated data will be presented at the meeting.
Clinical trial identification
JapicCTI-163182
Legal entity responsible for the study
Taiho Pharmaceutical co., LTD.
Funding
Taiho Pharmaceutical co., LTD.
Disclosure
Y. Kurokawa: Honoraria: Taiho Pharmaceutical, Yakult Honsha, Eli Lilly, Novartis, Pfizer, Chugai Pharma. T. Doi: Consulting/advisory role: Eli Lilly, Chugai, Kyowa Hakko Kirin, Novartis, MSD, Daiichi Sankyo, Amgen. Research funding: Taiho, Novartis, Merck Serono, Astellas, MSD, Janssen, Boehringer Ingelheim, Takeda, Pfizer, Eli Lilly, Sumitomo Group, Chugai, Bayer, Kyowa Hakko Kirin, Daiichi Sankyo, Celgene. A. Sawaki: Speakers’ Bureau: Novartis, Pfizer, Bayer, Taiho Pharmaceutical, Lilly, Eisai, Chugai Pharma, Yakult, Honsha, Research funding: Taiho Pharmaceutical. Y. Komatsu: Speakers’ Bureau: Taiho, Eli Lilly, Chugai Pharma, Merck Serono, Novartis, Pfizer, Bayer. Honoraria: Novartis, Pfizer, Bayer Research funding: Taiho, Eli Lilly, MSD, Ono Pharmaceutical, Novartis, Bayer, Chugai Pharma, Yakult Honsha. M. Ozaka: Honoraria: Taiho Pharmaceutical, Pfizer, Novartis, Bayer, Yakult Honsha. T. Takahashi: Speakers’ Bureau: Novartis, Pfizer, Bayer, SBI pharma. Research funding: SBI Pharma. Y. Naito: Speakers’ Bureau: Eisai, Chugai Pharma, Taiho Phamaceutical, Novartis, Eli Lilly, Meiji Seika Pharma, Bayer, Roche Diagnostics K.K. Research funding: Merck Serono, AstraZeneca, Eli Lilly, Nippon Kayaku. S. Okubo: Employment: Taiho Pharmaceutical Patents, Royalties, other intellectual property: Taiho Pharmaceutical. T. Nishida: Honoraria: Pfizer, Novartis, Bayer, Eisai, Sysmex.
1480PD - A phase 2 study of CMB305 and atezolizumab in NY-ESO-1+ soft tissue sarcoma: Interim analysis of immunogenicity, tumor control and survival (ID 4238)
- S. Chawla
Abstract
Background
CMB305 is an active immunotherapy designed to generate and expand anti-NY-ESO-1 immune response (IR). CMB305 consists of a dendritic cell-targeting lentiviral vector encoding NY-ESO-1 (LV305), and a boost with an NY-ESO-1 recombinant protein plus GLA-SE (G305), a TLR-4 agonist. Phase 1 studies of LV305 and CMB305 showed this approach is safe, generates IR and appears to impact survival with 81% 1-yr survival in NY-ESO-1+ sarcoma patients (pts) following LV305 treatment. We evaluated efficacy and IR for combination of CMB305 (C) and atezolizumab (A) or A alone in NY-ESO-1+ synovial sarcoma (SS) and myxoid round cell liposarcoma (MRCL).
Methods
A prospective randomized open label phase 2 study of C (LV305 Intradermal Days 0, 14, 42, 70 + G305 Intramuscular Days 28, 56, 84 then q6wk up to one year) + A (1200mg IV q3wk) vs. A alone in locally advanced or metastatic NY-ESO-1+ SS/MRCL. Primary endpoints are progression free survival (PFS) and overall survival (OS) with secondary endpoints of safety, IR, and response rate.
Results
As of December 30, 2016, 58 patients were enrolled. A prespecified interim analysis of PFS included the first 36 pts with median 7.0 mos follow up (Arm A+C: median age 47 yrs, 78% SS, 100% metastatic, 78% = >2 chemotherapy; Arm A: median age 44 yrs, 56% SS, 67% metastatic, 56% = >2 chemotherapy). Combination A+C was well tolerated. Clinical benefit was similar between arms (Arm A+C: 8/18 pts with SD, 1 pt unconfirmed PR, 6 mos PFS rate 17%; Arm A: 10/18 pts SD, 6 mos PFS rate 22%). In addition, anti-NY-ESO-1 IR seen in 10/19 (53%) pts Arm A+C vs. 3/12 (25%) pts Arm A by T Cell ELISpot, and 9/22 (41%) pts Arm A+C vs. 0% Arm A by antibody ELISA. Pts with IR had target lesion increase of 2% compared to 18% in pts without IR based on preliminary ANOVA-model based analysis. No deaths observed in pts with induced anti-NY-ESO-1 T cell IR (0/13 deaths IR+ pts vs. 5/18 deaths IR- pts).
Conclusions
In the interim analysis, Arm A+C resulted in a higher level of anti-NY-ESO-1 IR when compared to Arm A; pts with IR tend to have better target lesion control. Early data indicate that induction of anti-NY-ESO-1 IR may be associated with better survival.
Clinical trial identification
NCT02609984 First received: November 14, 2015 Last updated: February 28, 2017 Last verified: December 2016
Legal entity responsible for the study
Immune Design
Funding
Immune Design
Disclosure
S. Chawla: Board of Directors/Stock: Prana, Uptick Health, Counterpoint Biomedical. Honoraria: Amgen, Threshold, Cytrx, Pharmamar, J&J, Tracon, Morphetek. Research project: Amgen, Threshold, Cytrx, Pharmamar, J&J, Tracon, Morphotek, BMS, Etsai, Immune Design. B.A. Van Tine: Stock ownership: none Membership on Advisory Board Novartis Lilly Janseen Epizyme Karyopharm Diiachi Board of Directors none Corporate sponsored research Pfizer Merck Speakers Beuro Caris Janseen Lilly. K. Ganjoo: Compensation to author for Advisory board with both Daiichi Sanko and Novartis. R.F. Riedel: Sponsored Research/Advisory Board: AADi, Arog, Daiichi-Sankyo, Karyopharm, Lilly, Novartis, Oncternal, Plexxikon, SARC, Threshold, Tracon, Tokalas. Eisai, EMD-Serono, Ignyta, Immune Design, Janssen. Consultant: Lilly, The Oncology Consortium. S. Attia: Compensation (to Mayo Clinic) as Principal Investigator from: AB Science, Morphotek, Threshold Pharmaceuticals, Tracon Pharma, ZioPharm, CytRX, Bayer, Novartis, Daichii, Bayer, Lilly, Immune Design, Karyopharm Therapeutics, Epizyme. E. Choy: Consulting fees from Amgen, EMD Serono, Daiichi, Bayer. M. Agulnik: Advisory board: Novartis, Janssen, Eisai and Lilly. V. Keedy: Consultant Karyopharm Janssen Research funding to institution for sponsored research: Lilly, Plexxicon, CytRx, Daiichi, Threshold, Janssen, Roche, Astrazeneca, MedPacto, Immune Design, GSK. T. Philip: Consultant: Novartis. C. Bohac: Employed by Immune Design. Stock ownership with Amgen, Immune Design H. Lu: Employee of Immune Design and Stock ownership Immune Design. M. Chen: Employee of Immune Design and Stock Ownership Immune Design. R. Maki: Clinical Trial support (institution), consulting fees, travel: Immune Design. All other authors have declared no conflicts of interest.
1481PD - Efficacy and safety of palbociclib in patients with advanced gastrointestinal stromal tumors refractory to imatinib and sunitinib (ID 5361)
- A. Italiano
Abstract
Background
p16/CDKN2A loss play a crucial role in GIST progression. Therapeutic options after
Methods
This is a multicenter single-arm phase 2 clinical trial based on 2-stage Simon’s design which assesses safety and efficacy of palbociclib in patients (pts) with advanced GIST having failed at least on imatinib and sunitinib and with CDKN2A loss assessed by CGH array. All pts had to have documented progressive disease (PD) as per RECIST 1.1 before study entry. Pts receive palbocilcib 150mg day 1-day 21 (oral route), daily until PD or unacceptable toxicity. The primary endpoint is the 4-month non-PD rate according to RECIST 1.1. Based on the following hypotheses: 25% 4-month non-PD rate (H0), 45% acceptable 4-month non-PD rate (H1), 5% type I error rate, 90% power, a total of 57 assessable pts are necessary (22 for the first stage + 25 for the second stage). Following the inclusion of the first 22 pts, if ≥ 7 pts are progression-free at 4 months, the accrual will continue. In order to account for not assessable pts (+/- 10%), 63 pts will be of the French Sarcoma Group.
Results
As of May 2017, 72 pts (52 males, 20 females) have been included in the study. Median age is 66.0 years out of the first 22 first evaluable patients had progressive disease at 4 months indicating that palbocicilib had not reached the primary endpoint to justify continuing accrual after the 1st step of the study.
Conclusions
Palbociclib has no significant activity as a single agent in advanced GIST with p16/CDKN2A loss. Prognostic value of CDKN2A loss in the whole population will be presented at the meeting.
Clinical trial identification
NCT01907607
Legal entity responsible for the study
Institut Bergonié
Funding
INCA
Disclosure
All authors have declared no conflicts of interest.
1482PD - Notch pathway inhibition with LY3039478 in soft tissue sarcoma (STS) and gastrointestinal stromal tumours (GIST) (ID 1605)
- O. Mir
Abstract
Background
LY3039478 (LY) is an orally bioavailable selective Notch inhibitor (Notch 1-4). Here we report on safety, pharmacodynamics (PD), and anti-tumour activity of LY in patients (pts) with STS/GIST.
Methods
This ongoing, multi-part, phase 1 trial enrolled pts with refractory advanced or metastatic STS and GIST, measurable disease, ECOG score ≤1, and baseline tumour tissue. Eligible pts received LY 50 mg three times per week (TIW), for a 28-day cycle until disease progression. Safety assessments were based on CTCAE V4.0. Tumour responses were assessed using RECIST 1.1 and Choi criteria. Primary objectives are to confirm the recommended phase 2 dose of LY and document antitumour activity. Secondary objectives are safety and toxicity, PD, progression-free survival (PFS) and overall survival (OS).
Results
63 pts have been enrolled and received LY (24 males, 39 females; median age 58, range 31-76). 26 pts had leiomyosarcoma (LMS), 9 liposarcoma, 7 pleomorphic sarcoma, 6 angiosarcomas, 5 rhabdomyosarcoma and 10 GIST. 18 out of 39 (46%) pts with evaluable tumour samples were positive for Notch 1 ICD. 5% and 13% were positive for Notch 2 ICD, and Notch 3 respectively. Per RECIST, 2 out of 53 pts with STS had unconfirmed PR, and 20 SD. In GIST group, 4 pts had SD. Using Choi Criteria, 5 pts in STS had unconfirmed PR. Overall median PFS was 1.74 months (95% CI: 1.68-2.60) and consistent across histology groups (median PFS=2.23, 1.91 and 1.68 months for LMS, GIST and other STS, respectively). PFS rate at 3 months was 42% in LMS, 39% in GIST and 15% in other STS respectively. OS and biomarker/histologic analyses of pre and post treatment biopsies will be presented at the meeting. Most frequent related adverse events (all grades) occurring in ≥ 20% of pts included diarrhoea 44 (70%), vomiting 24 (38%), nausea 21 (33%), decreased appetite 17 (27%), fatigue 17 (27%) asthenia 16 (25%), hypophosphataemia 14 (22%).
Conclusions
LY suggested activity in pts with STS and GIST and had a manageable safety profile.
Clinical trial identification
Trial protocol number: Protocol I6F-MC-JJCA(e) Clinicaltrials.gov ID: NCT01695005 Release date: 08-July-2016
Legal entity responsible for the study
Eli Lilly and Company
Funding
Eli Lilly and Company
Disclosure
O. Mir: Speaker Bureau: Eli Lilly, Roche. Consulting/advisory board member: Amgen, Astra-Zeneca, Bayer, BMS, Eli Lilly, Netcancer, Novartis, Pfizer, Roche, Servier. A. Azaro: Member of Orion SMB. J.R. Merchan: Consulting/Advisory role: Exelixis. Research Funding: Rexahn, Eli Lilly, Novartis, Tocagen, Agensys, Tracon. R. Chugh: Stakeholder: Portala. Advisory board member: EMD Serano, Epizyme. Research funding: Eli Lilly, Novartis, Morphotek, Mabvax, Epizyme. J.C. Trent: Member of advisory board: Eli Lilly, Janssen, Eisai, Novartis, Eayer, Blueprint, Deciphera. J. Rodon: Advisor/board member: Eli Lilly, Novartis, and Servier. U. Ohnmacht: Stakeholder: Eli Lilly and Company. A. Le Cesne: Received honoraria: PharmaMar, Lilly, Amgen, Novartis, and Pfizer. J-C. Soria: Advisory board member: Eli Lilly and Company. C. Massard: Advisory board member, speaker, investigator: Amgen, Astellas, Astra Zeneca, Bayer, Celgene, Genentech, Ipsen, Janssen, Eli Lilly, Novartis, Pfizer, Roche, Sanofi, Orion. All other authors have declared no conflicts of interest.
Invited Discussant 1479PD, 1480PD, 1481PD and 1482PD (ID 5908)
- R. Maki
Q&A led by Discussant (ID 5909)
1483PD - Imatinib in combination with everolimus in patients with progressive advanced chordoma: results form an Italian phase 2 clinical trial (ID 4513)
- S. Stacchiotti
Abstract
Background
To evaluate the antitumor activity of imatinib in combination with everolimus in patients (pts) with advanced PDGFB- and/or PDGFRB-positive chordomas with evidence of mTOR and/or of its effectors (i.e. S6, 4EBP1) activation.
Methods
Within an Italian academic prospective phase II clinical study carried out from January 2011 to March 2015, 45 patients with advanced PDGFB/PDGFRB and mTOR/S6/4EBP1 positive chordoma received imatinib 400 mg/day in combination with everolimus at the starting dose of 2.5 mg/day, until progression or limiting toxicity. Eligible pts had to have evidence of progression in the 6 months prior to study entry. The primary endpoint was overall tumor response rate (ORR), defined by the Choi criteria applied also to MRI. Secondary endpoints were RECIST response, progression-free survival (PFS), overall survival (OS).
Results
Fifteen of 45 pts included in the study were pretreated with imatinib (as a single agent). All pts completed their treatment (22 progression; 16 toxicity; 7 other). Among 38/46 patients evaluable by Choi criteria, the best response was: 8 partial response (PR) (ORR, 21%), 23 stable disease (60%) and 7 progression. 42/46 pts were evaluable by RECIST with 1 PR (2%), 36 SD (85%) and 3. Median PFS by Choi criteria was 10 months (range 1-45), with 36% and 17% pts disease-free at 12 and 24 mos, respectively. Median PFS by RECIST was 13 months. At a median follow-up of 31 months, median OS was 47 months.
Conclusions
Although formally negative (the planned target was a Choi ORR ≥60%), this study showed that imatinib + everolimus is active in a proportion of progressive advanced chordoma pts. Major dimensional responses were uncommon but disease stabilization was apparently longer than observed with imatinib as a single agent. Toxicity was not negligible.
Clinical trial identification
EudraCT number: 2010-021755-34
Legal entity responsible for the study
Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
Funding
AIFA (Agenzia Italiana per il Farmaco)
Disclosure
S. Stacchiotti, E. Palassini, A.M. Frezza: Novartis, research funding to my Institution for clinical trial in which I am involved. A. Gronchi: Novartis: Advisory Board (compensated), Honoraria. P.G. Casali: Novartis, Advisory Board (compensated), Honoraria, Research funding to my Institution for clinical trial in which I am involved. All other authors have declared no conflicts of interest.
1484PD - A matching-adjusted indirect comparison of trabectedin and pazopanib for the treatment of advanced, metastatic, leiomyosarcomas (ID 2080)
- R. Jones
Abstract
Background
Trabectedin (T) and pazopanib (P) are approved treatments for locally advanced or metastatic leiomyosarcoma (L-mSTS). In the absence of head-to-head randomized controlled trials (RCTs); a matched indirect comparison (MAIC) was performed to assess potential differences in clinical efficacy between the treatment groups.
Methods
MAIC was performed by extracting baseline characteristics from two phase III RCTs: SAR 3007 (T) and PALETTE (P): individual patient level data (IPD) was available forT only aggregated was published for P. Excluding those T patients who did not meet inclusion criteria for PALETTE, a sample size of 372 L-mSTS patients (T = 263, P = 109) was generated. Of all baseline characteristics, only time since diagnosis (≥30 vs. < 30 months), age (≥65 vs. < 65 years), and body weight (≥77 vs. < 77 kilograms), were statistically significant outcome predictors with T. The generalized method of moments (GMM) was used to optimally match cohorts for evaluation of differences in overall survival (OS), progression-free survival (PFS), and safety. Statistical analysis was performed using “R”.
Results
There was no statistically significant difference in PFS [HR = 0.82, (95%CI 0.63-1.06, p = 0.13)], or OS [HR = 0.86, (95% CI 0.64-1.18, p = 0.36)]. The percentage of patients with post-progression therapies was higher in T (74.5%) vs. P (59%) group. In the subgroup with PFS ≥6 months, patients treated with T experienced significantly improved median PFS (11.2 months vs PFS 8.4 months HR: 0.47 (95% CI: 0.3007 – 0.7434), p = 0.002 and were significantly more likely to achieve long term survival (OS ≥ 18 months): 45.8% vs. 33.7% (95%CI: 23.5%-48.3%), p = 0.025. Increased myelosuppression and hepatotoxicity observed with T whereas diarrhea, hypertension, pulmonary toxicity/pneumothorax, and neurotoxicity were observed with P.
Conclusions
The MAIC model warrants further investigation and validation. No differences in mPFS or mOS were noted in a MAIC comparison. Among patients achieving long term disease control (PFS > 6 mo), T significantly increased mPFS and the proportion of patients achieving prolonged overall survival (OS ≥ 18 mo). Differences in the safety profile were highlighted by this indirect comparison.
Legal entity responsible for the study
Janssen Scientific Affairs, LLC, Pharma Mar S.A., LLC
Funding
Janssen Scientific Affairs, LLC, Pharma Mar S.A., LLC
Disclosure
R.L. Jones: Consultant for: Adaptimmune, Blueprint, Eisai, Epizyme, Daichii, Deciphera, Janssen Scientific Affairs, LLC, Immunedesign, Lilly, Merck, Pharmamar. J-Y. Blay: Research Funding and honoraria from Novartis, GSK and Pharmamar. A. Lecesne: Honoraria: Pfizer, Novartis, Pharmamar, Amgen, Lilly. J. Martin-Broto: Advisory boards for Novartis, Lilly, PharmaMar, Eisai, Bayer. M.J. Pontes, J.M. Fernandez Santos, B. García San Andrés: Employee of Pharma Mar S.A. and own stock in Pharma Mar S.A. G. Wang, S. Wang, C.R. Shin: Employee of Janssen and own stock in Johnson & Johnson. R. Maki: Consulting or advisory role: SARC, ASCO, AADX, ARCUS, Bayer, GSAI, GEM, Novartis, GSK, Immune Design, Janssen, Kyropharm, Lilly Tracon and Presage. Research Funding, travel and accommodations, expenses: Tracon, Immune Design, Lilly and SARC. S. Patel: Consultant to: Janssen, Eisai, Novartis, CytRx, Epizyme, Bayer, Eli Lilly. Grants for clinical trial from: Janssen, Eisai, Morphotek. G.D.S. Demetri: Consulting: Novartis, Janssen, PharmaMar, Daiichi-Sankyo, Adaptimmune, Eisai Patent licensed to Novartis from Dana-Farber with royalty paid to Dana-Farber. Research support to Dana-Farber: Novartis, Janssen.
LBA57 - Results of the LMS03 phase II study evaluating gemcitabine combined with pazopanib as a 2nd-line treatment for metastatic/relapsed leiomyosarcomas (uterine or soft tissue) after failure of anthracycline-based chemotherapy: The UNICANCER SARCOME 11 study (ID 4090)
- P. Pautier
Abstract
Background
Leiomyosarcomas (LMS) represent 10-15% of soft tissue and visceral sarcomas, most frequently uterine. LMS are moderately chemosensitive. Options in 2nd-line therapy after anthracycline-based chemotherapy for metastatic/advanced disease include Gemcitabine (G), trabectedin and pazopanib (P) monotherapy. Currently no combination therapy is better than monochemotherapy. LMS03 is an open-label multicentre single-group phase II study designed to assess the efficacy and tolerance of G+P in this 2nd-line setting.
Methods
Patients (pts) aged ≥18 years, ECOG ≤2 with metastatic or relapsed LMS (uterine or soft tissue) after 1st-line anthracycline chemotherapy failure were eligible. Pts were treated with G 1,000 mg/m2 on days 1 and 8 of each 21 day cycle (maximum 8 cycles), in combination with oral daily P (800 mg/day), until disease progression/unacceptable toxicity. Tumour response was assessed every 6 weeks (RECIST) with 9-month PFS rate as primary endpoint. Inacceptable and promising 9-month PFS rates were defined, in Intention-To-Treat (ITT), as 32% (Median PFS=5.5 months (mo)) and 44% (Median PFS=7.5 mo). Secondary objectives included control rate (CR/PR/SD), overall survival, toxicity.
Results
From 2011 to 2016, 18 French centres included 106 pts: mean age of 59.8 years, mainly women (85.8%), ECOG 0 (63.5%), and uterine LMS (61%). Pts were treated with P+G for a median of 3.8 mo; 40 pts (38%) completed the 8 cycles of combination. Pts were treated with P for a median of 4.2 mo. The 9-mo PFS was 32.1% (CI 95% 23.2-41.4; n = 105, ITT) and 34.6% (CI 95% 24.9-44.4; n = 95, per-protocol). Median PFS was 6.5 mo (CI 95% 5.6-8.2; n = 105, ITT) and 7.1 mo (CI 95% 5.7-8.3; n = 95, per-protocol). The 12-week control rate was 83.6% (11 PR and 45 SD; 67 pts evaluable). Grade 3-4 AE (>30%) with P+G were: neutropenia (76 [72.4%]), leucopenia (59 [56.2%]) and thrombocytopenia (40 [38.1%]).
Conclusions
The study results are negative in ITT with median PFS < 7.5 mo but nearly positive when considering per protocol results. In term of safety the combination P+G could be well managed, without unexpected toxicity.
Clinical trial identification
NCT01442662
Legal entity responsible for the study
UNICANCER R&D
Funding
GSK, Novartis
Disclosure
N. Isambert: Congress participations supported by PharmaMar, AZ, Roche, Novartis, Celgene. Board: Lilly. All other authors have declared no conflicts of interest.
Invited Discussant 1483PD, 1484PD and LBA57 (ID 5911)
- M. Eriksson