PDGFRA D842V-mutant GIST is highly resistant to all kinase inhibitors approved in the European Union for U/M GIST. Avapritinib, a novel KIT/PDGFRA kinase inhibitor, potently inhibits PDGFRA D842V mutants.
In the NAVIGATOR study, adult pts with U/M PDGFRA D842V-mutant GIST (regardless of prior therapy) received oral, once-daily avapritinib (dose escalation, 30–600 mg; dose expansion, 300 [recommended phase II dose, RP2D]/400 mg [maximum tolerated dose]). Long-term efficacy and safety in pts with PDGFRA D842V-mutant GIST treated at 300/400 mg from both phases are reported.
As of 9 March 2020 data cut-off (median follow-up, 26 months [mo]), 38 pts with PDGFRA D842V-mutant GIST treated at 300/400 mg achieved an overall response rate (ORR, modified Response Evaluation Criteria in Solid Tumours version 1.1) of 95%, with 5 (13%) complete responses (CR), and 31 (82%) partial responses (PR); of the 5 TKI-naïve pts, 2 had a CR and 3 a PR. Median duration of response was 22 mo (95% confidence interval [CI] 14–not reached [NR]). Median progression-free survival (PFS) was 24 mo (95% CI 18–NR), and median overall survival (OS) was NR; PFS and OS rates at 36 mo were 34% and 71%, respectively. In pts with PDGFRA D842V-mutant GIST who received less than the 300 mg RP2D (n=17), an ORR of 82% was still achieved, with 2 (12%) CR and 12 (71%) PR. Most common adverse events (AEs, any grade) in ≥10% of pts with PDGFRA D842V-mutant GIST treated at 300/400 mg were nausea (74%), anaemia (68%), diarrhoea (66%), fatigue (58%), memory impairment (47%), periorbital oedema (45%), decreased appetite (39%), increased lacrimation (34%), and vomiting, abdominal pain, hypokalaemia, increased blood bilirubin and peripheral oedema (all 32%). A total of 21% of pts discontinued treatment due to drug-related AEs. There were no treatment-related deaths.
In pts with U/M PDGFRA D842V-mutant GIST, avapritinib has clinical activity with durable responses and a tolerable safety profile, with no additional safety signals to those found in the NAVIGATOR study overall GIST population.
NCT02508532.
Medical writing support was provided by Cristina Tomas, and editorial support was provided by Sinead Stewart, all of Paragon, Knutsford, UK, supported by Blueprint Medicines Corporation, Cambridge, MA according to Good Publication Practice guidelines.
Blueprint Medicines Corporation.
Blueprint Medicines Corporation.
R.L. Jones: Research grant/Funding (self): MSD; Honoraria (self): Adaptimmune; Honoraria (self): Athenex; Honoraria (self): Blueprint Medicines Corporation; Honoraria (self): Clinigen; Honoraria (self): Eisai; Honoraria (self): Epizyme; Honoraria (self): Daichii; Honoraria (self): Helsinn; Honoraria (self): Deciphera; Honoraria (self): Immunedesign; Honoraria (self): Lilly; Honoraria (self): Merck; Honoraria (self): Pharmamar; Honoraria (self): Tracon. C. Serrano: Advisory/Consultancy, Research grant/Funding (self): Deciphera Pharmaceuticals; Honoraria (self), Research grant/Funding (self), Travel/Accommodation/Expenses: Bayer AG; Research grant/Funding (self), Travel/Accommodation/Expenses: Pfizer, Inc; Honoraria (self), Advisory/Consultancy: Blueprint Medicines Corporation; Travel/Accommodation/Expenses: PharmaMar; Travel/Accommodation/Expenses: Novartis; Travel/Accommodation/Expenses: Lilly. M. von Mehren: Advisory/Consultancy: Blueprint Medicines Corporation; Advisory/Consultancy: Arog Pharmaceuticals. S. George: Advisory/Consultancy, Research grant/Funding (institution): Blueprint Medicines Corporation; Advisory/Consultancy, Research grant/Funding (self): Deciphera Pharmaceuticals; Research grant/Funding (self): Pfizer; Research grant/Funding (self): Bayer; Research grant/Funding (self): Ariad; Research grant/Funding (self): Novartis; Advisory/Consultancy: Daiichi Sankyo; Advisory/Consultancy: Eli Lilly; Advisory/Consultancy: AstraZeneca. M. Heinrich: Honoraria (self), Research grant/Funding (self): Blueprint Medicines Corporation; Honoraria (self): Molecular MD; Honoraria (self): Novartis; Honoraria (self), Research grant/Funding (self): Deciphera Pharmaceuticals. Y-K. Kang: Honoraria (self): ALX Oncology; Honoraria (self): Zymeworks; Honoraria (self): Amgen; Honoraria (self): Novartis; Honoraria (self): Macrogenics; Honoraria (self): Daehwa; Honoraria (self): Surface Oncology; Honoraria (self): BMS. P. Schoeffski: Honoraria (self), Advisory/Consultancy: Deciphera Pharmaceuticals; Honoraria (self): Exelixis; Advisory/Consultancy: Plexxikon; Advisory/Consultancy: Eisai; Advisory/Consultancy: Loxo; Advisory/Consultancy: Lilly; Advisory/Consultancy: Blueprint Medicines Corporation; Advisory/Consultancy: Ellipses Pharma; Advisory/Consultancy: Merck; Advisory/Consultancy: Servier; Advisory/Consultancy: Genmab; Advisory/Consultancy: Adaptimmune; Advisory/Consultancy: Intellisphere; Advisory/Consultancy: Transgene; Research grant/Funding (self): MSD; Research grant/Funding (self): Ipsen. P. Cassier: Honoraria (self): Blueprint Medicines Corporation; Advisory/Consultancy: Abbvie; Advisory/Consultancy: Bayer; Advisory/Consultancy: BMS; Advisory/Consultancy: Merck Serono; Advisory/Consultancy: MSD; Advisory/Consultancy: Novartis; Advisory/Consultancy: Roche/Genentech; Advisory/Consultancy: GSK; Advisory/Consultancy: Janssen; Advisory/Consultancy: Lilly; Advisory/Consultancy: Amgen; Advisory/Consultancy, Research grant/Funding (self): Novartis. O. Mir: Advisory/Consultancy: Eli Lilly; Advisory/Consultancy: Janssen; Advisory/Consultancy: Lundbeck; Advisory/Consultancy: Pfizer; Advisory/Consultancy: Roche; Advisory/Consultancy: Servier; Advisory/Consultancy: Vifor Pharma; Shareholder/Stockholder/Stock options: Amplitude Surgical; Shareholder/Stockholder/Stock options: Transgene; Shareholder/Stockholder/Stock options: Ipsen. S.P. Chawla: Research grant/Funding (self): Amgen; Research grant/Funding (self): Roche; Research grant/Funding (self): Threshold Pharmaceuticals; Research grant/Funding (self): GSK; Research grant/Funding (self): CytRx Corporation; Research grant/Funding (self): Ignyta; Research grant/Funding (self): Immune Design; Research grant/Funding (self): Tracon Pharma; Research grant/Funding (self): SARC; Research grant/Funding (self): Karyopharm Therapeutics; Research grant/Funding (self): Jansen. P. Rutkowski: Honoraria (self): Novartis; Honoraria (self): BMS; Honoraria (self): MSD; Honoraria (self): Roche; Honoraria (self): Pierre Fabre; Honoraria (self): Pfizer; Honoraria (self): Blueprint Medicines Corporation. W.D. Tap: Honoraria (self), Advisory/Consultancy: Blueprint Medicines Corporation; Honoraria (self): Eli Lilly; Honoraria (self): EMD Serono; Honoraria (self): Eisai; Honoraria (self): Janssen; Honoraria (self): Immune Design; Honoraria (self): Daiichi Sankyo; Honoraria (self): Loxo; Honoraria (self): GSK; Honoraria (self): Agios Pharmaceuticals; Honoraria (self): NanoCarrier; Honoraria (self): Deciphera Pharmaceuticals; Advisory/Consultancy: Certis Oncology Solutions; Advisory/Consultancy, Shareholder/Stockholder/Stock options: Atropos Therapeutics; Advisory/Consultancy, Shareholder/Stockholder/Stock options: Daiichi Sankyo. T. Zhou: Shareholder/Stockholder/Stock options, Full/Part-time employment: Blueprint Medicines Corporation. M. Roche: Shareholder/Stockholder/Stock options, Full/Part-time employment: Blueprint Medicines Corporation. S. Bauer: Honoraria (self), Research grant/Funding (self): Blueprint Medicines Corporation; Research grant/Funding (self): Incyte; Research grant/Funding (self): Novartis; Honoraria (self): Deciphera Pharmaceuticals; Honoraria (self): Bayer; Honoraria (self): Exelixis; Honoraria (self): Novartis. All other authors have declared no conflicts of interest.
Ripretinib is an FDA-approved switch-control tyrosine kinase inhibitor (TKI) that broadly inhibits mutant KIT and PDGFRA kinase signaling. In INVICTUS, a randomized, double-blind, placebo-controlled trial in ≥4th-line advanced GIST, ripretinib compared with placebo (PBO) significantly improved progression-free survival (PFS, 6.3 vs. 1.0 months) reducing the risk of disease progression or death by 85% and showed a clinically meaningful improvement in overall survival (OS, 15.1 vs 6.6 months); data as of May 31, 2019 (ESMO 2019). Ripretinib is associated with a well-tolerated safety profile. Here, we report the updated results with an additional 9 months of follow-up.
Patients with advanced GIST previously treated with at least imatinib, sunitinib, and regorafenib were randomized (2:1) to ripretinib 150 mg QD or PBO. Upon disease progression determined by blinded independent central review (BICR), patients on PBO could cross over to ripretinib 150 mg QD. All patients who received 150 mg QD and progressed radiographically could receive 150 mg BID. Updated PFS by BICR, OS, and safety are reported here with data as of March 9, 2020.
Overall, 129 patients were randomized and 128 received treatment (ripretinib 150 mg QD, n=85; PBO, n=43). Patients randomized to ripretinib had a median PFS (mPFS) of 6.3 (95% CI 4.6−8.1) vs. 1.0 (95% CI 0.9−1.7) months for patients on PBO with a hazard ratio (HR) of 0.16. The median OS (mOS) in the ripretinib arm was not reached (95% CI 13.1–NE) vs. 6.3 (95% CI 4.1−10.0) months in the PBO arm with a HR of 0.43. No new safety concerns emerged with longer exposure to ripretinib.
Evaluation of mPFS and OS in the phase III randomized INVICTUS trial, with a cut-off date for analysis approximately 9 months after the primary results, has shown an improvement in the mOS in the ripretinib arm from 15.1 months to not reached (95% CI 13.1–NE) and a similar mPFS of 6.3 months in the ripretinib arm. These updated results confirm the clinically meaningful benefit in PFS and OS for ripretinib with a well-tolerated safety profile in patients with advanced GIST treated with at least 3 prior TKIs, including imatinib.
NCT03353753.
Medical writing and editorial support were provided by Lauren Hanlon, PhD; and Stefan Kolata, PhD, of AlphaBioCom, LLC (King of Prussia, PA).
Deciphera Pharmaceuticals, LLC.
Deciphera Pharmaceuticals, LLC.
J.R. Zalcberg: Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Pfizer; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Merck Serono; Honoraria (self), Research grant/Funding (institution): Specialized Therapeutics; Honoraria (self), Advisory/Consultancy: Targovax; Honoraria (self), Advisory/Consultancy: Halozyme; Honoraria (self), Shareholder/Stockholder/Stock options: Gilead Sciences; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: MSD; Advisory/Consultancy, Travel/Accommodation/Expenses: Sirtex Medical; Advisory/Consultancy: Lipotek; Advisory/Consultancy: Novella; Honoraria (self), Research grant/Funding (institution): Bayer; Research grant/Funding (institution): Roche; Research grant/Funding (institution): BMS; Research grant/Funding (institution), Travel/Accommodation/Expenses: AstraZeneca; Research grant/Funding (institution): Baxalta/Shire; Research grant/Funding (institution): Lilly; Research grant/Funding (institution): Boehringer-Ingelheim; Travel/Accommodation/Expenses: Deciphera; Travel/Accommodation/Expenses: Sirtex; Shareholder/Stockholder/Stock options: GW Pharmaceuticals; Shareholder/Stockholder/Stock options: Aimmune; Shareholder/Stockholder/Stock options: Vertex; Shareholder/Stockholder/Stock options: Bluebird Bio; Shareholder/Stockholder/Stock options: Alnylam; Shareholder/Stockholder/Stock options: Biomarin; Shareholder/Stockholder/Stock options: Sage Therapeutics; Shareholder/Stockholder/Stock options: Dova Pharmaceuticals; Shareholder/Stockholder/Stock options: Therapeutics MD; Shareholder/Stockholder/Stock options: Juno Therapeutics; Shareholder/Stockholder/Stock options: Kite Pharma; Shareholder/Stockholder/Stock options: Kiadis Pharma; Shareholder/Stockholder/Stock options: CSL Limited; Shareholder/Stockholder/Stock options: Cochlear; Non-remunerated activity/ies, Chair: Australian Clinical Trials Alliance; Non-remunerated activity/ies, Co-chair: National Oncology Alliance; Non-remunerated activity/ies, Co-chair: All.Can Australia; Shareholder/Stockholder/Stock options: Amarin; Shareholder/Stockholder/Stock options: Freq Therapeutics; Shareholder/Stockholder/Stock options: Global Blood Therapeutics; Shareholder/Stockholder/Stock options: Uniqure; Shareholder/Stockholder/Stock options: Sangamo; Shareholder/Stockholder/Stock options: Acceleron; Shareholder/Stockholder/Stock options: Zogenix. M. Heinrich: Advisory/Consultancy, Speaker Bureau/Expert testimony, Licensing/Royalties, Expert Testimony: Novartis; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Deciphera; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Blueprint; Advisory/Consultancy: MolecularMD. S. George: Advisory/Consultancy, Research grant/Funding (institution): Blueprint Medicines; Advisory/Consultancy, Research grant/Funding (institution): Deciphera; Advisory/Consultancy: Eli Lilly; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Bayer; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Daiichi Sankyo; Advisory/Consultancy: Exelixis; Leadership role: Alliance Foundation; Research grant/Funding (institution): Pfizer; Research grant/Funding (institution): Novartis; Shareholder/Stockholder/Stock options: Abbott Labs; Shareholder/Stockholder/Stock options: Allergan; Licensing/Royalties, UpToDate: Wolters Kluwer Health. S. Bauer: Honoraria (self), Advisory/Consultancy, Research grant/Funding (self), Research grant/Funding (institution): Novartis; Honoraria (self): Pfizer; Honoraria (self), Advisory/Consultancy: Bayer; Honoraria (self), Advisory/Consultancy: Lilly; Honoraria (self), Advisory/Consultancy: Pharmamar; Advisory/Consultancy, Research grant/Funding (institution): Blueprint Medicines; Advisory/Consultancy: ADC Therapeutics; Advisory/Consultancy: Daiichi Sankyo; Advisory/Consultancy: Plexxikon; Advisory/Consultancy: Nanobiotix; Advisory/Consultancy: Deciphera; Advisory/Consultancy: Exelixis; Advisory/Consultancy: Janssen-Cilag; Advisory/Consultancy: Roche; Research grant/Funding (institution): Incyte; Non-remunerated activity/ies, Member of external advisory board for \"off-label use in oncology\": Federal Ministry of Health. H. Gelderblom: Research grant/Funding (institution): Daiichi; Research grant/Funding (institution): Five Prime; Research grant/Funding (institution): Novartis; Research grant/Funding (institution): Deciphera; Research grant/Funding (institution): Lilly; Research grant/Funding (institution): Roche; Research grant/Funding (institution): Eisai; Research grant/Funding (institution): Debio; Research grant/Funding (institution): Boehringer; Research grant/Funding (institution): Pfizer; Research grant/Funding (institution): Amgen; Research grant/Funding (institution): TEVA. P. Schöffski: Advisory/Consultancy, Research grant/Funding (institution): Plexxikon; Advisory/Consultancy, Research grant/Funding (institution): Eisai; Advisory/Consultancy: Loxo; Advisory/Consultancy, Research grant/Funding (institution): Lilly; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Blueprint Medicines; Advisory/Consultancy: Ellipses Pharma; Advisory/Consultancy: Deciphera; Advisory/Consultancy: Merck; Advisory/Consultancy: Servier; Advisory/Consultancy: Genmab; Advisory/Consultancy: Adaptimmune; Advisory/Consultancy: Intellisphere LLC; Advisory/Consultancy: Transgene; Research grant/Funding (institution): Boehringer Ingelheim; Research grant/Funding (institution): CoBioRes NV; Research grant/Funding (institution): Exelixis; Research grant/Funding (institution): G1 Therapeutics; Research grant/Funding (institution): Novartis; Research grant/Funding (institution): Pharmamar. C. Serrano: Advisory/Consultancy, Research grant/Funding (self): Deciphera; Advisory/Consultancy, Speaker Bureau/Expert testimony: Blueprint Medicines; Speaker Bureau/Expert testimony, Research grant/Funding (self), Travel/Accommodation/Expenses: Bayer Healthcare; Research grant/Funding (self), Travel/Accommodation/Expenses: Pfizer; Travel/Accommodation/Expenses: Pharmamar; Travel/Accommodation/Expenses: Novartis; Travel/Accommodation/Expenses: Lilly. R.L. Jones: Honoraria (self), Advisory/Consultancy: Adaptimmune; Honoraria (self), Advisory/Consultancy: Athenex; Honoraria (self), Advisory/Consultancy: Blueprint; Honoraria (self), Advisory/Consultancy: Clinigen; Honoraria (self), Advisory/Consultancy: Eisai; Honoraria (self), Advisory/Consultancy: Epizyme; Honoraria (self), Advisory/Consultancy: Daiichi; Honoraria (self), Advisory/Consultancy: Deciphera; Honoraria (self), Advisory/Consultancy: Immunedesign; Honoraria (self), Advisory/Consultancy: Lilly; Honoraria (self), Advisory/Consultancy: Merck; Honoraria (self), Advisory/Consultancy: Pharmamar; Honoraria (self), Advisory/Consultancy: Upto Date; Advisory/Consultancy: Tracon; Research grant/Funding (institution), Clinical trial: MSD. S. Attia: Research grant/Funding (self): Desmoid Tumor Research Foundation; Research grant/Funding (institution): AB Science; Research grant/Funding (institution): Tracon Pharma; Research grant/Funding (institution): CytRx Corporation; Research grant/Funding (institution): Bayer; Research grant/Funding (institution): Novartis; Research grant/Funding (institution): Daiichi Sankyo; Research grant/Funding (institution): Lilly; Research grant/Funding (institution), Travel/Accommodation/Expenses: Immune Design; Research grant/Funding (institution): Karyopharm Therapeutics; Research grant/Funding (institution): Epizyme; Research grant/Funding (institution): Blueprint Medicines; Research grant/Funding (institution): Genmab; Research grant/Funding (institution): CBA Pharma; Research grant/Funding (institution): Merck; Research grant/Funding (institution): Philogen; Research grant/Funding (institution): Gradalis; Research grant/Funding (institution): Deciphera; Research grant/Funding (institution): Takeda; Research grant/Funding (institution): Incyte; Research grant/Funding (institution): Springworks; Research grant/Funding (institution): Adaptimmune; Research grant/Funding (institution): Advenchen Laboratories; Research grant/Funding (institution): Bavarian Nordic; Research grant/Funding (institution): BTG; Research grant/Funding (institution): PTC Therapeutics; Research grant/Funding (institution): GlaxoSmithKline; Research grant/Funding (institution): FORMA Therapeutics. G. D'Amato: Advisory/Consultancy, Speaker Bureau/Expert testimony: Lilly Pharmaceuticals; Advisory/Consultancy: Blueprint; Advisory/Consultancy, Speaker Bureau/Expert testimony: Janssen; Speaker Bureau/Expert testimony: Eisai; Advisory/Consultancy: Deciphera. P. Chi: Advisory/Consultancy, Research grant/Funding (institution), Clinical Research Support: Deciphera; Advisory/Consultancy: Exelixis; Research grant/Funding (institution), Clinical Research Support: Novartis; Research grant/Funding (institution), Clinical Research Support: Array. P. Reichardt: Honoraria (self), Research grant/Funding (institution): Novartis; Honoraria (self): Pfizer; Honoraria (self): PharmaMar; Honoraria (self): Lilly; Honoraria (self): Amgen; Advisory/Consultancy: Clinigen Group; Advisory/Consultancy: Roche; Advisory/Consultancy: Bayer; Advisory/Consultancy: Deciphera; Advisory/Consultancy: MSD; Advisory/Consultancy: Bristol-Myers Squibb. J.N. Meade: Travel/Accommodation/Expenses, Shareholder/Stockholder/Stock options, Full/Part-time employment, Sponser (of study) full time employee; granted stock options as a full time employee and sponser of study: Deciphera. V. Reichert: Shareholder/Stockholder/Stock options, Full/Part-time employment: Deciphera. K. Shi: Shareholder/Stockholder/Stock options: Alnylam; Shareholder/Stockholder/Stock options: Immunogen; Shareholder/Stockholder/Stock options: Karyopharm; Full/Part-time employment: Deciphera. R. Ruiz-Soto: Shareholder/Stockholder/Stock options, Full/Part-time employment, Employee: Deciphera. M. von Mehren: Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Deciphera; Advisory/Consultancy, Research grant/Funding (institution): Blueprint; Advisory/Consultancy: Exelexis; Research grant/Funding (institution): Arog; Research grant/Funding (institution): Novartis; Research grant/Funding (institution): Gradalis; Research grant/Funding (institution): GenMab; Travel/Accommodation/Expenses: NCCN. J-Y. Blay: Honoraria (self), Honoraria (institution), Advisory/Consultancy: Novartis; Honoraria (self), Honoraria (institution), Advisory/Consultancy: Bayer; Honoraria (self), Honoraria (institution), Advisory/Consultancy: Pfizer; Honoraria (self), Honoraria (institution), Advisory/Consultancy: Deciphera; Honoraria (self), Honoraria (institution), Advisory/Consultancy: Roche.
Ripretinib is an FDA-approved switch-control tyrosine kinase inhibitor (TKI) that broadly inhibits mutant KIT and PDGFRA kinase signaling. In the phase III study INVICTUS (NCT03353753), ripretinib significantly improved PFS vs placebo in patients (pts) with ≥4th-line GIST. Here, we report the phase I study (NCT02571036) IPDE experience in GIST pts across multiple lines of therapy.
In this dose-escalation and expansion phase I study, pts with 2nd, 3rd, and ≥4th-line GIST were treated with ripretinib 150 mg QD. Investigator-assessed RECIST response assessments were performed every 2 cycles and pts with progressive disease (PD) could dose escalate to ripretinib 150 mg twice a day (BID). PFS period 1 (PFS1; 150 mg QD) was calculated from Cycle 1, Day 1 to PD; PFS2 (150 mg BID) from date of IPDE to 2nd PD or death. Treatment-emergent adverse events (TEAEs) were summarized by PFS1 and PFS2 onset periods and compared descriptively.
In the phase I study, 142 GIST pts (2nd line, n=31; 3rd line, n=28; and ≥4th line, n=83) were enrolled in dose-escalation and expansion phases and received at least 1 dose of ripretinib 150 mg QD. In all lines, patients received additional benefit from ripretinib 150 mg BID (table; data as of Aug 31, 2019). TEAEs reported by the 64 pts in PFS1 and PFS2 periods were similar; the most common TEAEs (≥10%) were alopecia, myalgia, nausea, fatigue, palmar-plantar erythrodysesthesia, muscle spasms, rash, weight decreased, abdominal pain, diarrhea, back pain, vomiting and decreased appetite. In PFS2, anemia and dyspnea were also reported in ≥10% of pts.
Line of Therapy Ripretinib 150 mg QD (n=142) Ripretinib 150 mg BID (n=64) 2nd Line (n=31) 3rd Line (n=28) ≥4th Line (n=83) 2nd Line (n=8) 3rd Line (n=17) ≥4th Line (n=39) mPFS 10.7 mo 8.3 mo 5.5 mo PFS1, 8.3 mo PFS2, 5.6 mo PFS1, 8.3 mo PFS2, 3.7 mo PFS1, 5.5 mo PFS2, 3.7 mo mPFS2/mPFS1 67% 45% 67%
Ripretinib dose escalation to 150 mg BID after PD showed an additional PFS clinical benefit across all treatment lines with a similar safety profile compared to that observed with a 150 mg QD dosing regimen. The phase III INTRIGUE study (NCT03673501) in 2nd-line GIST is investigating ripretinib vs sunitinib.
NCT02571036.
Medical writing and editorial support were provided by Lauren Hanlon, PhD; and Stefan Kolata, PhD, of AlphaBioCom, LLC (King of Prussia, PA).
Deciphera Pharmaceuticals, LLC.
Deciphera Pharmaceuticals, LLC.
F. Janku: Research grant/Funding (institution): Novartis; Research grant/Funding (institution): Genentech; Research grant/Funding (institution): BioMed Valley Discoveries; Research grant/Funding (institution): Astellas; Research grant/Funding (institution): Agios; Research grant/Funding (institution): Plexxikon; Advisory/Consultancy, Research grant/Funding (institution): Deciphera; Research grant/Funding (institution): Piqur; Research grant/Funding (institution): Symphogen; Research grant/Funding (institution): Bristol-Myers Squibb; Advisory/Consultancy, Research grant/Funding (institution): Asana; Research grant/Funding (institution): Astex; Research grant/Funding (institution): SpringBank Pharma; Advisory/Consultancy, Research grant/Funding (institution): Synlogic; Advisory/Consultancy, Research grant/Funding (institution): Sotio; Research grant/Funding (institution): Sanofi; Research grant/Funding (institution): SynthoRx; Research grant/Funding (institution): Ideaya; Research grant/Funding (institution): FujiFilm; Research grant/Funding (institution): Merck; Advisory/Consultancy, Shareholder/Stockholder/Stock options: Cardiff Oncology; Advisory/Consultancy: Immunomet. P. Chi: Advisory/Consultancy, Research grant/Funding (institution), Clinical Research Support: Deciphera; Advisory/Consultancy: Exelixis; Research grant/Funding (institution), Clinical Research Support: Novartis; Research grant/Funding (institution), Clinical Research Support: Array. M. Heinrich: Advisory/Consultancy, Speaker Bureau/Expert testimony, Licensing/Royalties, Expert Testimony: Novartis; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Deciphera; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Blueprint; Advisory/Consultancy: Molecular MD. M. von Mehren: Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Deciphera; Advisory/Consultancy, Research grant/Funding (institution): Blueprint; Advisory/Consultancy: Exelexis; Research grant/Funding (institution): Arog; Research grant/Funding (institution): Novartis; Research grant/Funding (institution): Gradalis; Research grant/Funding (institution): GenMab; Travel/Accommodation/Expenses: NCCN. R.L. Jones: Honoraria (self), Advisory/Consultancy: Adaptimmune; Honoraria (self), Advisory/Consultancy: Athenex; Honoraria (self), Advisory/Consultancy: Blueprint; Honoraria (self), Advisory/Consultancy: Clinigen; Honoraria (self), Advisory/Consultancy: Eisai; Honoraria (self), Advisory/Consultancy: Epizyme; Honoraria (self), Advisory/Consultancy: Daiichi; Honoraria (self), Advisory/Consultancy: Deciphera; Honoraria (self), Advisory/Consultancy: Immunedesign; Honoraria (self), Advisory/Consultancy: Lilly; Honoraria (self), Advisory/Consultancy: Merck; Honoraria (self), Advisory/Consultancy: Pharmamar; Honoraria (self), Advisory/Consultancy: Upto Date; Advisory/Consultancy: Tracon; Research grant/Funding (institution), Clinical trial: MSD. K. Ganjoo: Advisory/Consultancy: Daiichi Sankyo; Advisory/Consultancy: Foundation Medicine; Research grant/Funding (institution): Deciphera. J. Trent: Advisory/Consultancy, Research grant/Funding (institution): Blueprint Medicines; Advisory/Consultancy, Research grant/Funding (institution): Deciphera ; Advisory/Consultancy: Daiichi-Sankyo; Advisory/Consultancy: Epizyme; Advisory/Consultancy, Research grant/Funding (institution): Agios; Research grant/Funding (institution): Plexxicon; Research grant/Funding (institution): Advanchen. H. Gelderblom: Research grant/Funding (institution): Daiichi; Research grant/Funding (institution): Five Prime; Research grant/Funding (institution): Novartis; Research grant/Funding (institution): Deciphera; Research grant/Funding (institution): Lilly; Research grant/Funding (institution): Roche; Research grant/Funding (institution): Eisai; Research grant/Funding (institution): Debio; Research grant/Funding (institution): Boehringer; Research grant/Funding (institution): Pfizer; Research grant/Funding (institution): Amgen; Research grant/Funding (institution): TEVA. A. Abdul Razak: Research grant/Funding (institution): Deciphera. M. Gordon: Advisory/Consultancy, Research grant/Funding (institution): Deciphera; Advisory/Consultancy, Research grant/Funding (institution): Tracon; Advisory/Consultancy, Research grant/Funding (institution): ImaginAB; Advisory/Consultancy: Imaging Endpoints; Advisory/Consultancy, Research grant/Funding (institution): Daiichi Sankyo; Advisory/Consultancy, Research grant/Funding (institution): Agenus; Advisory/Consultancy, Research grant/Funding (institution): Salarius; Advisory/Consultancy, Research grant/Funding (institution): RedHill Bipharma; Leadership role, Officer/Board of Directors: CareMission; Research grant/Funding (institution): Medimmune; Research grant/Funding (institution): Merck; Research grant/Funding (institution): BMS; Research grant/Funding (institution): Amgen; Research grant/Funding (institution): Tesaro; Research grant/Funding (institution): Beigene; Research grant/Funding (institution): ABBVIE; Research grant/Funding (institution): Aeglea; Research grant/Funding (institution): Arcus; Research grant/Funding (institution): Astex; Research grant/Funding (institution): Blueprint; Research grant/Funding (institution): Calithera; Research grant/Funding (institution): CellDex; Research grant/Funding (institution): Corcept; Research grant/Funding (institution): Clovis; Research grant/Funding (institution): Eli Lilly; Research grant/Funding (institution): Endocyte; Research grant/Funding (institution): Five Prime; Research grant/Funding (institution): Genocea; Research grant/Funding (institution): Neon; Research grant/Funding (institution): Plexxicon; Research grant/Funding (institution): Revolution Medicine; Research grant/Funding (institution): Seattle Genetics; Research grant/Funding (institution): Serono; Research grant/Funding (institution): SynDevRx; Research grant/Funding (institution): Tolero; Research grant/Funding (institution): Roche/Genentech; Research grant/Funding (institution): Syndax; Research grant/Funding (institution): FujiFilm; Research grant/Funding (institution): Veru; Shareholder/Stockholder/Stock options: Medelis. N. Somaiah: Honoraria (self), Advisory/Consultancy: Deciphera; Advisory/Consultancy: Blueprint. J. Jennings: Full/Part-time employment: Deciphera. K. Shi: Shareholder/Stockholder/Stock options: Alnylam; Shareholder/Stockholder/Stock options: Immunogen; Shareholder/Stockholder/Stock options: Karyopharm; Full/Part-time employment: Deciphera. R. Ruiz-Soto: Shareholder/Stockholder/Stock options, Full/Part-time employment: Deciphera. S. George: Advisory/Consultancy, Research grant/Funding (institution): Blueprint Medicines; Advisory/Consultancy, Research grant/Funding (institution): Deciphera; Advisory/Consultancy: Eli Lilly; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Bayer; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Daiichi Sankyo; Advisory/Consultancy: Exelixis; Leadership role: Alliance Foundation; Research grant/Funding (institution): Pfizer; Research grant/Funding (institution): Novartis; Shareholder/Stockholder/Stock options: Abbott Labs; Shareholder/Stockholder/Stock options: Allergan; Licensing/Royalties, UpToDate: Wolters Kluwer Health.
Desmoid tumors (DT) are locally aggressive tumors, which can significantly impact on patients’ quality of life and function. Systemic therapy can be considered in progressive cases or in symptomatic patients (pts). Regimens such as methotrexate-based schemes are usually administered for long periods. The aim of this phase II trial was to explore the activity of short-regimen of weekly nab-paclitaxel (nab-P) in DT.
Adult pts with clinically/radiologically progressive DT received 3 cycles of nab-P (125 or 240 mg/m2 days 1,8,15 every 28d in pts > 21y and 18-20 y, respectively). Primary combined end-point was overall response rate (ORR) by RECIST 1.1 and/or the proportion of pts with pain improvement in at least 2 points based on Brief Pain Inventory (BPI) scale. H0= ORR 20% or pain reduction 20%; H1= ORR 40% or pain reduction 40%. Central pathology and radiological review were mandatory.
From May 2017 to September 2019, 40 pts were enrolled in 8 sites: 26F/14M, median age 38y (18-76), site (limbs 14/40; trunk wall 13/40, abdominal cavity 7/40, head and neck 6/40). Reason of inclusion: RECIST PD in 13/40 (32.5%), symptomatic progression (SP) in 12/40 (30%), both RECIST and pain in 15/40 (37.5%). All but 1 pts completed therapy (1 pt stopped due to allergic reaction after 1 cycle). ORR by RECIST (central review) was 20.5% (8/39 evaluable pts had PR; 30/39 (76.9%) SD (19/39 with shrinkage), 1/39 (2.5%) PD. Median worst pain at baseline was 6.5 (0-10) and median worst pain at the end of therapy was 2 (0-6), with a median reduction in 4 points (0-8). 32/40 (80%) pts experienced at least reduction in 2 points in worst pain. 4 pts had G3 toxicities (2-G3 neutropenia, 1 G3 mucositis,1 G3 peripheral neuropathy). There were no G4 toxic effects. With a median of FU of 18 mos, there were 2 PD, 6 SP and 2 both, PD and SP. Neck and proximal upper-extremity sites had worse 18m-PFS: 24% vs 86% in other locations (p< 0.001).
Short-regimen nab-paclitaxel was safe and active in this cohort of DT, with 80% of pts having clinical improvement and 20.5% achieving a radiological response. In patients with DT in neck or proximal upper extremity this regimen was related with less efficacy in terms of 18m-PFS.
NCT03275818.
Spanish Group for Research on Sarcoma (GEIS).
Spanish Group for Research on Sarcoma (GEIS) and Celgene (Drug Supply).
J. Martin Broto: Research grant/Funding (institution): Celgene; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: PharmaMar; Advisory/Consultancy, Research grant/Funding (institution): Lilly; Research grant/Funding (institution): Novartis; Advisory/Consultancy, Research grant/Funding (institution): Eisai; Research grant/Funding (institution): Deciphera; Research grant/Funding (institution): Blueprint; Research grant/Funding (institution): Amgem; Research grant/Funding (institution): GSK; Research grant/Funding (institution): Adaptimmune; Advisory/Consultancy, Research grant/Funding (institution): Bayer; Research grant/Funding (institution): Karyopharm; Research grant/Funding (institution): Nektar; Research grant/Funding (institution): Daychii; Research grant/Funding (institution): Forma; Research grant/Funding (institution): Celgene. N. Hindi: Honoraria (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: PharmaMar; Research grant/Funding (institution): Novartis; Research grant/Funding (institution): Eisai; Honoraria (self), Research grant/Funding (institution): Lilly; Research grant/Funding (institution): Deciphera; Research grant/Funding (institution): Blueprint; Research grant/Funding (institution): Amgem; Research grant/Funding (institution): GSK; Research grant/Funding (institution): Adaptimmune; Research grant/Funding (institution): Celgene; Research grant/Funding (institution): Daychii; Research grant/Funding (institution): Karyopharm; Research grant/Funding (institution): Forma; Research grant/Funding (institution): Nektar; Research grant/Funding (institution): Bayer. A. Redondo: Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: PharmaMar; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Roche; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Astra-Zeneca; Honoraria (self): Novartis; Honoraria (self), Advisory/Consultancy: Amgem; Research grant/Funding (institution): Eisai; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: GSK; Honoraria (self), Advisory/Consultancy: Clovis. D. Marcilla: Travel/Accommodation/Expenses: PharmaMar. C. Valverde: Advisory/Consultancy, Research grant/Funding (institution): PharmaMar; Advisory/Consultancy, Research grant/Funding (institution): Lilly; Advisory/Consultancy, Research grant/Funding (institution): Pfizer; Advisory/Consultancy, Research grant/Funding (institution): Bayer; Advisory/Consultancy, Research grant/Funding (institution): Novartis; Research grant/Funding (institution): Incyte; Research grant/Funding (institution): Eisai. P. Luna: Advisory/Consultancy, Travel/Accommodation/Expenses: PharmaMar; Advisory/Consultancy: Lilly. All other authors have declared no conflicts of interest.
Overexpression of ABCB1/P-glycoprotein (Pgp) predicts poor outcome in retrospective osteosarcoma series. Two prospective trials with Pgp expression as stratification factor were activated in Italy and Spain.
Patients ≤ 40 years with extremity high-grade osteosarcoma were eligible. Pgp expression was centralized. Preoperatively, all patients received MAP (methotrexate, adriamycin, platinum). In case of Pgp overexpression (Pgp+), mifamurtide (2 mg/m2 twice/week for 3 months than weekly for 6 months) was added after surgery, with 4 consecutive cycles of ifosfamide 3 gr/m2/day, day 1-5 (HDIFO) in case of poor response (PR) to MAP. Patients without overexpression of Pgp (Pgp-) received MAP postoperatively, regardless the pathological response. From March 2013, an amendment increased high dose methotrexate (HDMTX) cumulative dose from 60 g/m2 (5 cycles) to 120 mg/m2 (10 cycles). In the same period, this regimen was adopted in an observational prospective study performed by the Spanish Sarcoma Group (GEIS) (NCT04383288).
From June 2011 to March 2018, 291 ISG patients were screened and 279 were included: 110 were Pgp-, 154 were Pgp+, while in 15 patients Pgp expression was not evaluable. With a median follow-up of 58 months (range 1.2 – 102.2), the 3-year EFS and OS were 65.5% (95% CI 59.4-70.9) and 85.8% (95% CI 81-89.6), respectively, with improved survival after 10 HDMTX cycles (table). °not evaluable in 15 patients
n % 3-yrs EFS (95% CI) Pgp° 0.0587 Negative (MAP) 110 59.9 (49.8-68.7) Positive (mifamurtide+HDIFO if PR) 154 70.1 (62.1-76.8) Necrosis <0.0001 Good response 116 80 (71.3-86.4) Poor response 163 55.1 (47-62.5) Amendment 0.009 Pre (5 HDMTX cycles) 74 57.6 (45.4–67.9) Post (10 HDMTX cycles) 205 68.4% (61.4-74.5)
In this prospective uncontrolled study, EFS compared favorably with all our previous series. With a limited number of HDMTX cycles, EFS was suboptimal, and significantly improved after an amendment increasing HDMTX cycles to 10. Pgp+ patients performed well in this study, in which they were added mifamurtide and HDIFO after a PR to MAP: a pre-planned merged analysis of this study with a twin GEIS observational series is ongoing.
NCT01459484; Eudract: 2011-001659-36.
Italian Sarcoma Group (ISG).
The Onlus Association “Il Pensatore - Matteo Amitrano”; Fondazione Carisbo Clinical and Translational Research Grant 2019.
E. Palmerini: Honoraria (institution), Advisory/Consultancy: Daiichi Sankyo; Advisory/Consultancy: Eusa Pharma ; Advisory/Consultancy: Deciphera; Honoraria (self), Travel/Accommodation/Expenses: Eli Lilly; Travel/Accommodation/Expenses: Takeda; Travel/Accommodation/Expenses, Non-remunerated activity/ies: PharmaMar; Honoraria (self), Honoraria (institution): Amgen; Non-remunerated activity/ies: Bristol Mayer Squibb; Non-remunerated activity/ies: Pfizer. M. Gambarotti: Honoraria (self), Honoraria (institution): Amgen. P.G. Casali: Honoraria (self): Bayer; Honoraria (self): Deciphera; Honoraria (self): Eisai; Honoraria (self): Eli Lilly; Honoraria (self): Nektar Therapeutics ; Honoraria (self): Pfizer; Honoraria (institution): Advencen Laboratories; Honoraria (institution): Amgen Dompé; Honoraria (institution): AROG Phaermaceuticals; Honoraria (institution): Bayer; Honoraria (institution): Blueprint medicines; Honoraria (institution): Daiichi Sankyo; Honoraria (institution): Deciphera; Honoraria (institution): Eisai; Honoraria (institution): Eli Lilly; Honoraria (institution): Epizyme Inc; Honoraria (institution): Glaxo; Honoraria (institution): Karyopharm Pharmaceuticals; Honoraria (institution): Novartis; Honoraria (institution): Pfizer; Honoraria (institution): PharmaMar. P. Picci: Honoraria (self), Travel/Accommodation/Expenses: Takeda; Honoraria (self), Honoraria (institution): Amgen. S. Ferrari: Honoraria (self): Takeda. All other authors have declared no conflicts of interest.
Palliative chemotherapy is the mainstay of treatment for patients with advanced soft tissue sarcomas (STS), however prognosis is limited (median overall survival 12-19 months). In this setting, patient values and preferences -though understudied- are central to treatment decisions. Our objectives were to explore priorities for quality versus quantity (length) of life (QoL vs. LoL) and treatment expectations in patients starting chemotherapy (CTx).
The HOLISTIC study is an international prospective cohort study assessing health-related quality of life in advanced STS patients receiving palliative CTx. Participants completed a baseline questionnaire before starting 1st-line CTx, including treatment expectations and preferences for QoL vs. LoL. Chi-squared and Fisher’s exact tests were used to evaluate associations between patient characteristics, preferences and expectations.
In total, 137 patients with advanced STS participated (U.K: n=72, Netherlands: n=65). Median age was 62 years (range 27-79). Preference for extended LoL (48%) was slightly more common than preference for QoL (41%); 9% valued LoL and QoL equally. Younger patients (aged<40 years;
These data show heterogenous preferences and expectations among advanced STS patients starting 1st line chemotherapy, supporting personalised decision making. Treatment regret will be a topic of further study.
NCT03621332.
Royal Marsden NHS Foundation Trust and Institute of Cancer Research.
Has not received any funding.
All authors have declared no conflicts of interest.
This observational, retrospective effort across Europe, US and Asia aims to assess the activity of systemic therapies in EHE, a ultra rare sarcoma, marked by
18 sarcoma reference centres contributed data. Patients with advanced EHE diagnosed 2000 onwords, treated with systemic therapies, were selected. Local pathological review and molecular confirmation was required. Radiological response was retrospectively assessed by local investigators according to RECIST. Progression free survival (PFS) and overall survival (OS) were estimated by Kaplan Meier method.
72 patients were included (characteristics in the table), 21 had more than one treatment. 33 patients received anthracycline-based regimens, achieving 1 (3%) partial response (PR), 25 (76%) stable disease (SD, 14 with prior PD), 7 (21%) progressive disease (PD). The median (m-) PFS and m-OS were 5 and 14 months respectively. 11 patients received weekly paclitaxel, achieving 1 (9%) PR, 6 (55%, 2 with prior PD) SD, 4 (36%) PD. The m-PFS and m-OS were 3 and 19 months respectively. 12 patients received pazopanib, achieving 3 (25%, 2 with prior PD) SD, 9 (75%) PD. The m-PFS and m-OS were.3 and 9 months respectively. 15 patients received INF-α 2b, achieving 1 (7%) PR, 11 (73%, 8 with prior PD) SD, 3 (20%) PD. The m-PFS and m-OS were 9 months and unreached respectively. Among 27 patients treated with other regimens, 1 PR (ifosfamide) and 9 SD (all with prior PD, 5 gemcitabine+docetaxel, 2 cyclophosphamide, 2 others) were reported. Population characteristics
Anthracycline based regimens Paclitaxel Pazopanib INFalfa2b Others 33 11 12 15 27 35.8 on 72 patients - - - - 69 (95%) 4 (5%) on 72 patients - - - - 49 38 43 46 48 15 (45%) 18 (55%) 4 (36%) 7 (64%) 4 (33%) 8 (67%) 7 (47%) 8 (53%) 12 (44%) 15 (56%) 6 (18%) 27 (82%) 1 (9%) 10 (91%) 1 (8%) 12 (92%) 3 (20%) 12 (80%) 4 (14%) 23 (86%) 19 (58%) 14 (42%) 6 (55%) 5 (45%) 10 (83%) 2 (17%) 12 (80%) 3 (20%) 24 (89%) 3 (11%) 29 (88%) 4 (12%) 0 8 (73%) 3 (27%) 0 5 (42%) 6 (50%) 1 (8%) 13 (86%) 1 (7%) 1 (7%) Not applicable
Systemic therapies available for advanced sarcomas exhibited limited activity in EHE. Although PFS should be interpreted with caution as non-progressive cases were included, m-PFS with chemotherapy and pazopanib was short (<6 months). The identification of new active compounds, especially for rapidly progressive cases, is needed.
Fondazione IRCCS Istituto Nazionale Tumori.
Has not received any funding.
A.M. Frezza: Research grant/Funding (institution): Amgen Dompè; Research grant/Funding (institution): Bayer; Research grant/Funding (institution): Daiichi Sankyo; Research grant/Funding (institution): Eli Lilly; Research grant/Funding (institution): Epizyme; Research grant/Funding (institution): Novartis; Research grant/Funding (institution), Travel/Accommodation/Expenses: Pharmamar; Research grant/Funding (institution): Pfizer; Research grant/Funding (institution): Eisai. G.G. Baldi: Honoraria (self), Travel/Accommodation/Expenses: Pharmamar; Honoraria (self), Travel/Accommodation/Expenses: Eli Lilly; Honoraria (self): Eisai. F. Duffaud: Honoraria (self): Bayer. N. Hindi: Honoraria (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: Pharmamar; Honoraria (self), Research grant/Funding (institution): Eli Lilly; Research grant/Funding (institution): Eisai; Honoraria (institution): Novartis; Research grant/Funding (institution): Deciphera; Research grant/Funding (institution): Blueprint; Research grant/Funding (institution): Karyopharm; Research grant/Funding (institution): Daychii; Research grant/Funding (institution): GSK; Research grant/Funding (institution): Adaptimmune; Research grant/Funding (institution): Amgen. W. Van Der Graaf: Research grant/Funding (institution): Novartis; Honoraria (institution): Bayer; Honoraria (institution): Springworks. S. Stacchiotti: Advisory/Consultancy: Adaptimmune; Advisory/Consultancy, Research grant/Funding (institution): Bayer; Advisory/Consultancy, Research grant/Funding (institution): Daiichi Sankyo; Advisory/Consultancy, Research grant/Funding (institution): Eli Lilly; Advisory/Consultancy, Research grant/Funding (institution): Epizyme; Advisory/Consultancy: Immunodesign; Advisory/Consultancy: Karyopharm; Advisory/Consultancy: Maxivax; Advisory/Consultancy, Research grant/Funding (institution): Pharmamar; Research grant/Funding (institution): Amgen Dompè; Advisory/Consultancy: Takeda; Research grant/Funding (institution): Novartis; Research grant/Funding (institution): Pfizer. All other authors have declared no conflicts of interest.
In 2002, the EORTC STBSG reported reference values for conducting phase II clinical trials (CTs) for STS with Progression-Free Rate as primary endpoint (Van Glabbeke et al. EJC 2002). These have been widely used since then. We aim to provide an update focusing on LMS.
CTs involving advanced or metastatic LMS were identified by literature review (published 2003-2018, ≥ 10 LMS patients). Endpoints of interest were 3- and 6-month PFS. When estimates could not be derived from the publication, data requests were sent out. Treatments (trt) were classified as recommended (R-T) or non-recommended (NR-T) according to the ESMO 2018 guideline. A random effects model was employed to pool trial-specific estimates and obtain overall PFS at 3 and 6 months for first line (1L) and pre-treated (2L+) patients separately. The ESMO Magnitude of Clinical Benefit Scale (ESMO-MCBS) was used to guide the choice of trt effect to target in future trials.
From 32 studies identified, we obtained information so far on 6 1L and 14 2L+ trials. Overall, for 1L, PFS at 3 and 6 months were 78% (95%CI 74-82) and 64% (95%CI 59-68), respectively. No difference was observed between R-T and NR-T due to considerable trial heterogeneity. For 2L+ patients, overall 3-month PFS was 50% (95%CI 44-56 – differences not significant between R-T and NR-T due to trial heterogeneity), and 37% (95%CI 29-44%) / 24% (95%CI 18-30) at 6 months for R/NR-T. Data collection continues. The ESMO-MCBS recommends a HR of at least 0.65 for PFS. The table below summarizes what this translates to for the null hypothesis (H0) and alternative hypothesis (H1) of a study assuming an exponential PFS curve.
3 months 6 months Ref (H0) Min target (H1) Ref (H0) Min target (H1) 1L 78% 85% 64% 75% 2L+ 50% 63% 30% 45%
This work provides updated thresholds for designing new studies for advanced or metastatic LMS. For 1L trt, a 6-month PFS of 64% can be considered as reference for H0. For 2L+ patients, a 3-month PFS > 50% or 6-month PFS > 30% would suggest drug activity.
EORTC-Soft Tissue and Bone Sarcoma Group (STBSG).
EORTC-Soft Tissue and Bone Sarcoma Group (STBSG).
L. D’Ambrosio: Advisory/Consultancy, Advisory Board: PSI; Advisory/Consultancy, Editorial Activity: Novartis; Travel/Accommodation/Expenses: PharmaMar; Travel/Accommodation/Expenses: Eli Lilly; Travel/Accommodation/Expenses: Celgene. W.T.A. Van Der Graaf: Research grant/Funding (institution): Novartis; Advisory/Consultancy, Advisory Board fee: Bayer. All other authors have declared no conflicts of interest.
WD/DD LPS usually arises in the abdomen, while other LPS subtypes mainly have an extra-abdominal origin. With the lack of prospective data on anthracycline-based CT in advanced WD/DD LPS, we conducted a retrospective analysis of the activity of cytotoxic regimens in patients (pts) with LPS of intrabdominal origin (IA-LPS) who had entered EORTC/STBSG clinical studies, assuming that the vast majority of LPS at this location are WD/DD LPS.
We searched for all adult pts treated with first-line CT for advanced IA-LPS in EORTC/STBSG phase II-III trials from 1970. Treatment was aggregated into 5 groups: anthracycline (A) alone (Doxorubicin (D) 75 mg/m2, Caelyx 50 mg/m2, Epirubicin 75 mg/m2, Epirubicin 150 mg/m2), Ifosfamide (IFO) alone (IFO 5 g/m2, IFO 9 g/m2, IFO 12 g/m2), D+IFO (D 50 mg/m2+IFO 5 g/m2, D 75 mg/m2+IFO 5 g/m2, DOX 75 mg/m2+IFO 10 g/m2), D+cyclophosphamide+vincristine+DTIC (CYVADIC), “other” (brostallicin, trabectedin). Response was assessed by RECIST or WHO criteria. Progression-free survival (PFS) and overall survival (OS) were computed by Kaplan-Meier method.
109 IA-LPS pts from 13 trials, enrolled between 1978 and 2012, were identified (median age 57 yrs). Overall, there were 10/109 (9.2%) responders to CT:
Response Treatment Total (N=109) A alone (N=48) IFO alone (N=15) D+IFO (N=18) CYVADIC (N=8) Other (N=20) CR 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) PR 3 (6.3) 2 (13.3) 4 (22.2) 1 (12.5) 0 (0.0) 10 (9.2) SD 24 (50.0) 10 (66.7) 5 (27.8) 4 (50.0) 14 (70.0) 57 (52.3) PD 20 (41.7) 3 (20.0) 6 (33.3) 3 (37.5) 6 (30.0) 38 (34.9) Not evaluable 1 (2.1) 0 (0.0) 3 (16.7) 0 (0.0) 0 (0.0) 4 (3.7)
At 10-mo median follow-up (IQR 6-24), m-OS was 19 mos (95%CI 15-21), m-PFS 4 mos (95%CI 3-6). D+IFO achieved a not statistically significant longer m-PFS (12 mos) and m-OS (31 mos) than observed with other regimens. Univariate and multivariate analysis of response to CT did not identify prognostic factors.
Cytotoxic CT, in particular D alone, had limited activity in advanced IA-LPS. Though IFO-containing regimens showed higher activity compared to A alone in a small number of cases. This series provides a benchmark for future trials on new drugs in WD/DD LPS.
EORTC Soft Tissue and Bone Sarcoma Group.
Has not received any funding.
S. Stacchiotti, B. Kasper: Honoraria (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: Pharmamar. R. Sanfilippo: Research grant/Funding (institution), Travel/Accommodation/Expenses: Pharmamar. All other authors have declared no conflicts of interest.