What is New in Front-line Treatment of Advanced / Metastatic Soft Tissue Sarcomas?

Transcription

1 What is New in Front-line Treatment of Advanced / Metastatic Soft Tissue Sarcomas? 14 th of December 2017, International Expert Time Grandangolo in Oncologia 2017, Genua, Italy Bernd Kasper University of Heidelberg Mannheim University Medical Center Interdisciplinary Tumor Center Sarcoma Unit German Interdisciplinary Sarcoma Group (GISG)

2 ft Tissue Sarcomas - Epidemiology ta from the European RARECARE project (n = ): Incidence of 5.6 / per year for all sarcomas 84 % Soft Tissue Sarcomas, 14 % Bone Sarcomas Age-standardized incidence for STS is / per year 5-year Overall Survival ~ 60 %; M1: median OS ~ 12+ months Stiller CA et al. Eur J Cancer 2013; 49:

3 ft Tissue Sarcomas - Histological Subtypes stribution of histological subtypes of all sarcomas diagnosed in 3 European regions quitaine + Rhône-Alpes in France, Veneto in Italy; ): 60 % of all sarcomas Mastrangelo G et al. Cancer 2012; 118:

4 ft Tissue Sarcomas - Survival and Prognosis Stojadinovic A et al. J Clin Oncol 2002; 20:

5 genda - Systemic Therapy in Metastatic STS 1 st line Treatment: Doxorubicin and More Beyond 1 st line: Which Approved Agents do we have? Outlook: New Compounds and Strategies

6 genda - Systemic Therapy in Metastatic STS 1 st line Treatment: Doxorubicin and More Beyond 1 st line: Which Approved Agents do we have? Outlook: New Compounds and Strategies

7 Benjamin RS et al. Cancer 1974; 33: 19-27

8 dvanced STS - Mono vs Poly Chemotherapy uthors Chemotherapy N Response Rate Survival uss et al A/AC 104 NS NS mura et al A/AD 146 NS NS orden et al A/AD 186 AD = 30 % (p = 0.02) NS erner et al A/AD 66 AD = 44 % (LMS) NS antoro et al A/AI/CYVADIC 449 NS NS orden et al A/AVd 295 NS NS dmonson et al A/AI/APM 262 AI = 34 % (p = 0.03) NS ntman et al AD/MAID 340 MAID = 32 % (p = 0.002) NS dson et al A/AI 415 AI = 26 % (A = 14 %) NS yan et al A/APal 447 APal = 28 % (A = 19 %) NS No survival benefit ð Doxorubicin (75 mg/m²) remained 1 st line Gold-Standard Muss H et al. Cancer 1985; 55: ; Omura G et al. Cancer 1983; 52: ; Borden E et al. J Clin Oncol 1987; 5: ; Santoro A et al. J Clin Oncol 1995; 13: ; Borden E et al. Cancer 1990; 66: ; Edmonson J et al. J Clin Oncol 1993; 11: ; Antman K et al. J Clin Oncol 1993; 11: ; Judson I et al. Lancet Oncol 2014; 15: ; Ryan CW et al. J Clin Oncol 2016 Sep 12.

9 RTC Study Design Doxorubicin 75 mg/m 2 d 1 or 72 h i.v. Con7nuous Infusion R Doxorubicin 25 mg/m 2 d Ifosfamid 2.5 g/m 2 d Neulasta 6 mg s.c. d 5 Judson I et al. Lancet Oncol 2014; 15:

10 RTC Overall Survival Judson I et al. Lancet Oncol 2014; 15:

11 RTC Results e Combination of Doxorubicin plus Ifosfamide: Doubled the Overall Response Rate ORR (27 % vs 14 %) Significantly improved the median PFS (7.4 vs 4.6 months) Could not significantly improve Survival (14.3 vs 12.8 months) Was far more toxic than Doxorubicin alone Doxorubicin remained Gold-Standard in 1 st line STS Treatment Judson I et al. Lancet Oncol 2014; 15:

12 Judson I et al. Lancet Oncol 2014; 15:

13 laratumab - Overall Survival (JGDG Phase 1b/2) Tap WD et al. Lancet 2016; 388:

14 laratumab - Overall Survival (JGDG Phase 1b/2) Tap WD et al. Lancet 2016; 388:

15 16 FDA Approvals for Metastatic Solid Tumors

16 laratumab - Study Design (JGDG Phase 1b) Phase 1b (N = 15) Primary endpoint: Safety Secondary endpoint: Pharmacokine7cs Advanced STS, not amenable to surgery or radiotherapy Age 18 years; ECOG PS 2 Any number of prior treatments; no prior anthracyclines Available tumor Dssue to determine PDGFRα status Olaratumab 15 mg/kg D1,8 + Doxorubicin 75 mg/m 2 D1 8 cycles (21 days) a Subsequent cycles: If benefit, olaratumab monotherapy undl disease progression a During Cycles 5-8, patients receiving Dox could receive Dexrazoxane prior to Dox on Day 1, at the investigator s discretion Tap WD et al. Lancet 2016; 388:

17 laratumab - Study Design (JGDG Phase 2) Phase 2 (N = 133) Same entry criteria as Phase 1b Stratification: PDGFRα (IHC) Lines of prior treatment ECOG PS Histology (leiomyosarcoma, synovial sarcoma, other) R A N D O M IZ E Olaratumab 15 mg/kg D1,8 + Doxorubicin 75 mg/m 2 D1 8 cycles (21 days) a Doxorubicin 75 mg/m 2 D1 8 cycles (21 days) Olaratumab monotherapy until progression Optional olaratumab monotherapy after progression Primary endpoint: Progression-free survival (PFS) (predefined statistical significance: 2-sided alpha = 0.2) Secondary endpoints: Overall survival (OS), objective response rate, PFS, safety and pharmacokinetics Biomarker: PDGFRα (IHC) and related ligands a During Cycles 5-8, patients receiving doxorubicin could receive Dexrazoxane, at the investigator s discretion Tap WD et al. Lancet 2016; 388:

18 laratumab - Histological Subtypes (JGDG Phase 1b/2) Histological type, n (%) Olara + Dox (N = 66) Dox (N = 67) Leiomyosarcoma 24 (36) 27 (40) Undifferentiated pleomorphic sarcoma 10 (15) 14 (21) Liposarcoma 8 (12) 15 (22) Angiosarcoma 4 (6) 3 (5) Synovial sarcoma 1 (2) 2 (3) Neurofibrosarcoma 1 (2) 0 Fibrosarcoma 1 (2) 0 Other 17 (26) 6 (9) Tap WD et al. Lancet 2016; 388:

19 laratumab - Histological Subtypes (JGDG Phase 1b/2) Histological type, n (%) Olara + Dox (N = 66) Dox (N = 67) Other Alveolar soft part sarcoma 1 (2) 0 Chondrosarcoma bone 0 2 (3) Clear cell sarcoma 1 (2) 0 Endometrial stromal sarcoma 1 (2) 0 Epithelioid sarcoma 2 (3) 0 Extraskeletal chondrosarcoma 0 1 (2) Extraskeletal myxoid chondrosarcoma 1 (2) 0 Fibromyxoid sarcoma 1 (2) 1 (2) Fibrosarcomatous transformation in a recurrent 1 (2) 0 dermatofibrosarcoma Hemangiopericytoma 1 (2) 1 (2) Malignant glomus tumor 1 (2) 0 Malignant peripheral nerve sheath tumor 1 (2) 0 Malignant solitary fibrous tumor 1 (2) 0 Myxofibrosarcoma 1 (2) 0 Myxoid chondrosarcoma 1 (2) 0 Myxoid sarcoma 0 1 (2) Soft tissue undifferentiated round cell carcoma negative 1 (2) 0 for EWS Undifferentiated neoplasm 1 (2) 0 Undifferentiated uterine sarcoma 1 (2) 0 Tap WD et al. Lancet 2016; 388:

20 laratumab - Progression-free Survival (JGDG Phase 1b/2) INVESTIGATOR assessment Olara + Dox Dox Patients/Events 66/55 67/48 Median, months (95% CI) 6.6 (4.1, 8.3) 4.1 (2.8, 5.4) HR (95% CI) 0.67 (0.44, 1.02) Stratified p-value.0615 INDEPENDENT assessment a Olara + Dox Dox Patients/Events 66/37 67/34 Median, months (95% CI) 8.2 (5.5, 9.8) 4.4 (3.1, 7.4) HR (95% CI) 0.67 (0.40, 1.12) Stratified p-value.1208 Olara + Dox Dox Number at Risk Olara + Dox Dox Tap WD et al. Lancet 2016; 388:

21 laratumab - Overall Survival (JGDG Phase 1b/2) Tap WD et al. Lancet 2016; 388:

22 laratumab - Response to Treatment (JGDG Phase 1b/2) Investigator Assessment Independent Assessment Olara + Dox (N = 66) Dox (N = 67) Olara + Dox (N = 66) Dox (N = 67) Variable Best overall response, n (%) Complete response (CR) 2 (3.0) 1 (1.5) 3 (4.5) 1 (1.5) Partial response (PR) 10 (15.2) 7 (10.4) 9 (13.6) 4 (6.0) Stable disease (SD) 39 (59.1) 34 (50.7) 37 (56.1) 36 (53.7) Progressive disease (PD) 11 (16.7) 15 (22.4) 11 (16.7) 15 (22.4) Not evaluable 4 (6.1) 10 (14.9) 6 (9.1) 11 (16.4) Disease control rate (CR + PR + SD) n (%) 51 (77.3) 42 (62.7) 49 (74.2) 41 (61.2) 95% CI (65.3, 86.7) (50.0, 74.2) (62.0, 84.2) (48.5, 72.9) Objective response rate (CR + PR) n (%) 12 (18.2) 8 (11.9) 12 (18.2) 5 (7.5) 95% CI (9.8, 29.6) (5.3, 22) (9.8, 29.6) (2.5, 16.6) p-value (Fisher s exact test) Duration of response, months Median % CI (2.7,12.7) (2.8, 14.5) Tap WD et al. Lancet 2016; 388:

23 laratumab - Safety Profile (JGDG Phase 2) l. Lancet 2016; 388: Tap WD et al. Lancet 2016; 388:

24 laratumab (Lartruvo ) in STS ropean Medicines Agency (2016): artruvo is indicated in combination with xorubicin for the treatment of adult patients th advanced soft tissue sarcoma who are not enable to curative treatment with surgery or iotherapy and who have not been previously ated with doxorubicin. Ø After > 40 years, Olaratumab in combination with doxorubicin is a new 1 st line treatment option for advanced STS patients!

25 laratumab - ANNOUNCE Study Design (JGDJ) NCT

26 laratumab - Case Study 1 ale *1957 n 12/2011 Leiomyosarcoma of the Retroperitoneum, G2 n 12/2011 Multivisceral Resection R1 (Nephrectomy right, ) n 02/2016 First diagnosis of liver metastases Q1

27 laratumab - Case Study 1 ale *1957 1: What would be your preferred 1 st line treatment option? 1) Doxorubicin single-agent? 2) Doxorubicin + Ifosfamide? 3) Doxorubicin + DTIC? 4) Doxorubicin + Olaratumab? 5) Gemcitabine + Docetaxel? 6) Study Inclusion?

28 laratumab - Case Study 1 ale * /2011 Leiomyosarcoma of the Retroperitoneum, G2 12/2011 Multivisceral Resection R1 (Nephrectomy right, ) 02/2016 First diagnosis of liver metastases 04/2016 Inclusion into ANNOUNCE trial (Phase III Doxorubicin + Olaratumab/Placebo) 10/2016 Patient completed the 8 cycles (incl. Dexrazoxane from the 5 th cycle); AE: nausea I o, fatigue I o, neutropenia I o 10/ /2017 Olaratumab/Placebo maintenance therapy 15 mg/kg d1 + 8 every 3 weeks 12/2016 Follow-up showed RECIST stable disease /2017 Further follow-up confirmed RECIST SD > continued maintenance therapy 05/2017 PD > switch to 2 nd line treatment with Trabectedin 1.5 mg/m² every 3 weeks 11/2017 SD after 6 cycles of Trabectedin > continue therapy

29 laratumab - Case Study 2 ale * /2016 Undifferentiated pleomorphic sarcoma (NOS) of the right thigh, G3 08/2016 Neoadjuvant Isolated Limb Perfusion (ILP) right thigh 09/2016 Tumor resection (R0) 11/2016 Local relapse and first diagnosis of pulmonal metastases Q1

30 laratumab - Case Study 2 ale *1956 1: What would be your preferred 1 st line treatment choice? 1) Doxorubicin single-agent? 2) Doxorubicin + Ifosfamide? 3) Doxorubicin + DTIC? 4) Doxorubicin + Olaratumab? 5) Gemcitabine + Docetaxel? 6) Study Inclusion?

31 laratumab - Case Study 2 ale * /2016 Undifferentiated pleomorphic sarcoma (NOS) of the right thigh, G3 08/2016 Neoadjuvant isolated limb perfusion (ILP) right thigh 09/2016 Tumor resection (R0) 11/2016 Local relapse and first diagnosis of pulmonal metastases 12/2016 Doxorubicin 75 mg/m² d1 + Olaratumab 15 mg/kg d /2017 Follow-up after 2 cycles showed RECIST progressive disease > treatment escalation to Doxorubicin plus Ifosfamide 02/ cycle Doxorubicin 60 mg/m² d1 + Ifosfamide 1500 mg/m² d1-5 03/2017 PD > Oral treatment with Pazopanib 800 mg daily 05/2017 Patient died due to further disease progression

32 A Randomized Phase 3, Multicenter, Open-label Study Comparing Evofosfamide (Evo) in Combination with Doxorubicin (Dox) v. Dox Alone in Patients with Advanced Soft Tissue Sarcoma: Study TH-CR-406/SARC021 William D. Tap, Zsuzsanna Papai, Brian A. Van Tine, Steven Attia, Kristen Ganjoo, Robin L. Jones, Scott Schuetze, Damon Reed, Sant P. Chawla, Richard F. Riedel, Anders Krarup-Hansen, Antoine Italiano, Peter Hohenberger, Giovanni Grignani, Lee D. Cranmer, Thierry Alcindor T, Antonio Lopez-Pousa, Tillman Pearce, Stew Kroll, Patrick Schöffski

33 ofosfamide (TH-302) - Results RFS OS N = 640 N = 640 Response Rate: Doxo 18 % Febrile Neutropenia: Doxo 11 % Doxo/Evo: 28 % (p = ) Doxo/Evo: 18 %

34 ofosfamide (TH-302) - Results Synovial Sarcoma (n = 34): 22 vs 9 months OS (HR: 0.32)

35 eddis: Gemcitabine + Docetaxel versus Doxorubicin alone line Randomised Controlled Phase III Trial of Gemcitabine + Docetaxel vs Doxorubicin N = 257 patients in 24 UK sites and 1 site in Switzerland (61 % female, median age 55 years) Histologies: uterine LMS 27 %, synovial sarcoma 4 %, pleomorphic sarcoma 12 %, others 56 % Primary endpoint: PFR 24wks 46.3 vs 46.4 % for Dox vs GemDoc Median PFS 23.3 vs 23.7 weeks (HR = 1.28, p = 0.06) Secondary endpoint: 74/129 (57 %) died in the doxorubicin group; 80/128 (63 %) in the GemDoc group Same PFR 24wks for Dox and GemDoc, but HR indicated superiority of Doxorubicin Doxorubicin was less toxic, easier to deliver and demonstrated a trend for a better OS and should, therefore, remain 1 st line standard treatment for most advanced STS Seddon B et al. Lancet Oncol 2017; 18:

36 genda - Systemic Therapy in Metastatic STS 1 st line Treatment: Doxorubicin and More Beyond 1 st line: Which Approved Agents do we have? Outlook: New Compounds and Strategies

37 pproved Agents for Advanced Pretreated STS Ø All STS (Europe) since 2007 Ø LMS + LPS (USA) since 2015 Ø All STS without LPS since 2012 Ø LPS only since 2016 Trabectedin Trabectedin Pazopanib Eribulin All STS (USA) Gemcitabine + Docetaxel (ESMO 2014) All STS Ifosfamide high dose (ESMO 2014) Leiomyosarcoma (Europe) Gemcitabine, DTIC (ESMO 2014) All STS Inclusion in Clinical Studies (ESMO 2014) Update 2017

38 abectedin in Pretreated STS ropean Medicines Agency (2007): rabectedin (Yondelis, q3wk 24-h) is indicated the treatment of patients with advanced soft sue sarcoma, after failure of anthracyclines and sfamide, or who are unsuited to receive these ents. ficacy data are based mainly on liposarcoma d leiomyosarcoma patients. Demetri GD et al. J Clin Oncol 2009; 27:

39 abectedin in Pretreated STS Trabectedin 1.5 mg/m² 24h q3wks Primary endpoint: OS Secondary endpoints: PFS, TTP, ORR, safety Statistical Assumptions: R 2:1 DTIC 1000 mg/m 2 20 min q3wks ratification: COG PS ines of prior therapy -sarcomas: Liposarcomas + Leiomyosarcomas DTIC, OS = 10.0 months Trabectedin, OS = 13.5 months 35 % improvement in median OS (HR = 0.74, 80 % power) Two-sided significance level of 0.05 Need ~ 570 patients to observe 376 deaths Interim analysis of OS ~ 188 death events (50 % events) Demetri GD et al. J Clin Oncol 2016; 34:

40 abectedin in Pretreated STS Demetri GD et al. J Clin Oncol 2016; 34:

41 ibulin Eribulin (E7389) is a synthetic analogue of Halichondrin B Blocks mitosis due to microtubule inhibition Leads to cell cycle arrest and tumor regression in preclinical models Administration: Eribulin 1.4 mg/m² i.v. day every 3 weeks Schöffski et al. Lancet Oncol 2011; 12:

42 ase III Eribulin vs DTIC Schöffski P et al. Lancet 2016; 387:

43 ase III Eribulin vs DTIC Schöffski P et al. Lancet 2016; 387:

44 ase III Eribulin vs DTIC Liposarcoma subgroup Median OS, months Halaven (n=71) 15.6 Dacarbazine (n=72) 8.4 HR % CI 0.346, Survival probability P value* Survival time (months) Patients at risk: Halaven Dacarbazine Schöffski P et al. Lancet 2016; 387:

45 genda - Systemic Therapy in Metastatic STS 1 st line Treatment: Doxorubicin and More Beyond 1 st line: Which Approved Agents do we have? Outlook: New Compounds and Strategies

46

47 Presented By Antoine Italiano at 2017 ASCO Annual Meeting

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49 mbrolizumab in Soft Tissue Sarcoma Pembrolizumab n = 4 x 10 Pembrolizumab demonstrates activity in UPS + DDLPS; Ø activity in LMS; Problem: Heterogeneity! Immunotherapy works in sarcoma in immune subsets of molecular subsets of histological subgroups! JY Blay Tawbi HA et al. Lancet Oncol 2017; Oct 4 [Epub ahead of print]

50 laratumab - Ongoing Clinical Studies Study JGDJ [ANNOUNCE; NCT ]: Phase 3 Doxorubicin combina7on in SoJ Tissue Sarcoma (STS) Objectives Efficacy and safety in the target popula7on (advanced / metasta7c SoJ Tissue Sarcoma) Efficacy across histologies Loading dose JGDL [ANNOUNCE 2; NCT ]: Phase 1b/2 Gemcitabine / Docetaxel combina7on in STS JGDQ [NCT ]: Phase 1 Pembrolizumab combina7on in STS JGDR [NCT ]: Phase 1 Doxorubicin / Ifosfamide combina7on in STS Safety data with Gem / Docetaxel Efficacy signals with Gem / Docetaxel Safe dose in combina7on with Pembrolizumab Safe dose in combina7on with Doxorubicin / Ifosfamide

51 laratumab - JGDL (ANNOUNCE 2) 1:1 ced soft tissue sarcoma, not amenable to ry or radiotherapy 16 years PS 1 ore than 2 lines prior systemic therapy for ced/ metastatic disease r tissue available R A N D O M IZ E Cycle 1: Olaratumab 20 mg/kg Day 1,8 Cycle 2-8: Olaratumab 15 mg/kg Day 1,8 + Gemcitabine Day 1,8 + Docetaxel Day 8 per cycle (21 days) Placebo Day 1,8 + Gemcitabine Day 1,8 + Docetaxel Day 8 per cycle (21 days) Continuation until progression Continuation until progression cation factors FRα s of prior treatment olaratumab G PS logy Primary objective Overall survival Secondary objectives Pharmacokinetics Progression-free survival Tumor response Patient pain Quality of life NCT

52 laratumab - JGDR (Doxorubicin / Ifosfamide) Inclusion Criteria stologically confirmed advanced STS propriate for treatment with doxorubicin + sfamide asurable/nonmeasurable disease per CIST OG PS 0-1 le to provide tumor tissue fe expectancy 3 months Phase 1b Dose escalation of olaratumab (with possible de-escalation of Ifosfamide if necessary) Olaratumab a Day 1, 8 Doxorubicin Day 1, 2, 3 Ifosfamide Day 1, 2, 3, 4 21-day Cycles Cycles 1-6: Olaratumab a plus Doxorubicin a Ifosfamide Primary objective Safety Secondary objectives Pharmacokinetics Immunogenicity Objective response rate Progression-free survival Duration of response Disease control rate Overall survival Cycle 7 and higher: Olaratumab alone for patient without disease progression NCT

53 linexor - KCP SEAL Study Design NCT

54 C105 ± Pazopanib in Angiosarcoma - TAPPAS Study Design NCT

55 ke-home-messages I Systemic Therapy for Soft Tissue Sarcomas (advanced / metastatic) Backbone Chemotherapy Doxorubicin (+ Ifosfamide / DTIC) + Olaratumab Approved Agents beyond 1 st line Trabectedin Pazopanib Eribulin Pipeline Selinexor (SEAL Phase II/III ongoing) TRC105 (TAPPAS Phase III ongoing) Immunotherapies (Phase I/II studies ongoing)

56 ke-home-messages II Doxorubicin-based CHT remains the Backbone in 1 st line for advanced STS patients. Most patients may benefit from Olaratumab in 1 st line (depends on final phase III data). Anthracycline candidates Olaratumab candidates (not the same for Ifosfamide!). Approved drugs for 2 nd line+ are Trabectedin, Pazopanib and Eribulin. Numerous new compounds and strategies are in the Pipeline.

57 Discussion & Questions Bernd Kasper, University of Heidelberg, Mannheim University Medical Center (UMM), Interdisciplinary Tumour Center, Sarcoma Unit, Mannheim, Germany; Secretary EORTC / SoJ Tissue and Bone Sarcoma Group