Perspectives in 2 nd line treatment of advanced Soft tissue Sarcoma treatment approaches Dr.Dana Stănculeanu Bucharest Institute of Oncology
Epidemiology of soft tissue sarcoma STS accounts for <1% of all malignant tumours 1 Incidence is often underestimated 1,2 For example, incidence estimates often only include sarcomas arising in soft tissue and not those arising in specific organs sites potentially underestimating the incidence by ~50% 2 In Europe, the estimated incidence of STS (assessed by histology) ranges from ~4 5 per 100,000 per year 3,4 1. NCCN Clinical Practice Guidelines in Oncology: Soft Tissue Sarcoma, v.2. 2014. http://www.nccn.org/professionals/physician_gls/pdf/sarcoma.pdf [accessed Nov 2014]; 2. Toro J et al. Int J Cancer 2006;119:2922; 3. Wibmer C et al. Ann Oncol 2010;21:1106; 4. ESMO guidelines 2014
5-year survival in soft tissue sarcoma varies depending on tumour stage 5-year survival in localized extremity STS according to tumour stage Stage N 5-year disease-free survival (%) 5-year overall survival (%) I 137 86 90 II 491 72 81 III 469 52 56 Data from Memorial Sloan-Kettering Cancer Centre (MSKCC) for the time period of 1 July 1982 to 30 June 2000 Morrison BA, Baylor University Medical Center Proceedings, 2003;12:285 3
Guidelines for the treatment of advanced soft tissue sarcoma
NCCN Guidelines reccomandationnccn guidelines: systemic therapies with activity in a STS Extremity, retroperitoneal, intra-abdominal Angiosarcoma Desmoid tumours GIST Combination Single agents Paclitaxel Doxorubicina, dacarbazina Doxorubicina, ifosfamida, mesna mesna, doxorubicina, ifosfamida, dacarbazina Ifosfamida, epirubicina, mesna Gemcitabina si docetaxel Gemcitabina si vinorelbina Doxorubicina Ifosfamida Epirubicina Gemcitabina Dacarbazina Doxorubicina lipozomala Temozolomida Vinorelbina Pazopanib* Eribulin Docetaxel Vinorelbina Sorafenib Sunitinib Bevacizumab All other systemic therapy options as per extremity sarcoma Sulindac or other NSAIDs, including celecoxib Tamoxifen ± sulindac Toremifene Methotrexate and vinblastine Low-dose interferon Doxorubicin-based regimens Imatinib Sorafenib Methotrexate and vinorelbine Liposomal doxorubicin Imatinib Sunitinib Disease progression after imatinib and sunitinib Nilotinib Dasatinib Sorafenib Pazopanib PEComa, angiomolipom recurent, limfangioleiomiomatoza Sirolimus Chordoma Inflammatory myofibroblastic tumour with ALK translocation Alveolar soft part sarcoma Solitary fibrous tumour/ haemangiopericytoma Pigmented villonodular synovitis/tenosynovial giant cell tumour Imatinib si cisplatin Imatinib si sirolimus Imatinib Sunitinib Crizotinib Sunitinib Bevacizumab si temozolomide Sunitinib Imatinib ALK, anaplastic lymphoma kinase; GIST, tumora stromala gastrointestinalas; NCCN, National Comprehensive Cancer Network; NSAID, non-steroidal antiinflammatory drug *Pazopanib should not be used for lipogenic sarcomas
ESMO guidelines: treatment of advanced soft tissue sarcoma First-line treatment Second-line treatment Anthracycline as monotherapy or in combination with ifosfamide Anthracycline plus ifosfamide* (if good performance status) Ifosfamide (at standard dose if not previously used) High-dose ifosfamide (if previously used)[ivc] Gemcitabine+Docetaxel [2C] Dacarbazine [IIB] Trabectedin (effective in leiomyosarcoma and liposarcoma) [IIB] Pazopanib [IB] Best supportive care is an option for patients with asts who have received prior chemotherapy Gemcitabine/docetaxel is more effective than gemcitabine alone in the second-line setting However, regimens have different toxicities and conflicting data Dacarbazine has some activity as second-line therapy (mostly in leiomyosarcoma) It can also be combined with gemcitabine If commercially available, pazopanib is an option in non-adipogenic STS asts, advanced soft tissue sarcoma; ESMO, European Society for Medical Oncology ESMO/European Sarcoma Network Working Group. Ann Oncol 2014;25(Suppl 3)2 6
Trabectedin Drug characteristics Molecule: Cytotoxic tetrahydroisoquinoline alkaloid isolated from the Caribbean marine tunicate, Ecteinascidia turbinata 1,2 MoA: DNA guanine-specific minor groove-binding agent that blocks the cell cycle in the late S and G phase 2 Dosing: 1.5 mg/m 2 once every 3 weeks 3 Administration: IV infusion over 24 hours 3 Designated as an orphan medicinal product on 30 May 2001 Indication 3 Treatment of patients with advanced STS, after failure of anthracyclines and ifosfamide, or who are unsuited to receive these agents Dose-limiting Neutropenia toxicities 3 Thrombocytopenia Elevated alanine transaminase Increased bilirubin and/or alkaline phosphatase IV, intravenous; MOA, mechanism of action; STS, soft tissue sarcoma 1. Demetri G et al. J Clin Oncol 2009;27:4188; 2. Izbika E et al. Ann Oncol 1998;9:981; 3. Yondelis. Pharma Mar, S.A., Summary of product characteristics, 2014 7
Phase II study with trabectedin in advanced leiomyosarcomas and liposarcomas Randomized Open-label Phase II STUDY POPULATION (n=270) Age 18 years Advanced and/or metastatic liposarcomas (34%) or leiomyosarcomas (66%) After failure of standard therapies 2 prior lines of therapy (median 1) PS 0 or 1 R A N D O M I Z A T I O N (q3wk 24-hour) Trabectedin 1.5 mg/m 2 24-hour infusion every 3 weeks n=130 Crossover on progression (qwk 3-hour) Trabectedin 0.58 mg/m 2 3-hour infusion 3 consecutive weeks 4-week cycle n=130 Primary endpoint TTP Secondary endpoint PFS OS ORR (RECIST) Duration of response OS, overall survival; ORR, objective response rate; PS, performance status; RECIST, Response Evaluation Criteria in Solid Tumours; TTP, time to progression Demetri G et al. J Clin Oncol 2009;27:4188 8
Phase II study with trabectedin in advanced leiomyosarcomas and liposarcomas Clinical efficacy Median TTP: 3.7 months (1.5 mg/m 2 24-hour) versus 2.3 months (0.58 mg/m 2 3-hour); hazard ratio 0.734; 95% CI 0.554, 0.974; p=0.0302 The independently assessed response rates by RECIST were 5.6% (q3wk 24-hour) versus 1.6% (qwk 3-hour) Cumulative probability of progression 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 Independent review q3w 24-hours (n=136, C=32) qw 3-hours (n=134, C=32) Censored p=0.0302 Cumulative probability of progression 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 Investigator s assessment q3w 24-hours (n=136, C=26) qw 3-hours (n=134, C=28) Censored p=0.042 0 2 4 6 8 10 12 14 16 18 20 22 24 Time (months) Time (months) C, censored; CI, confidence interval; RECIST, Response Evaluation Criteria in Solid Tumours; TTP, time to progression; qw, once a week; q3w, every 3 weeks Demetri G et al. J Clin Oncol 2009;27:4188 0 2 4 6 8 10 12 14 16 18 20 22 24 9
Phase II study with trabectedin in advanced leiomyosarcomas and liposarcomas Twelve patients (4.6%) discontinued owing to drug-related AEs No prophylactic use of haematopoietic growth factors Therapeutic use permitted Antiemetic prophylaxis was given (dexamethasone 20 mg IV) Grade 3/4 AEs Anaemia qw 3-hour q3w 24-hour Thrombocytopenia Neutropenia Vomiting Nausea Fatigue 0 10 20 30 40 50 Proportion of patients,% AE, adverse event; IV, intravenous; qw, once a week; q3w, every 3 weeks Demetri G et al. J Clin Oncol 2009;27:4188 10
Rationale for pazopanib usage in the 2nd line treatment of asts 11
Pazopanib Pazopanib is a selective oral tyrosine kinase inhibitor Pazopanib binds to the cytoplasmic kinase domain of VEGFR-1, -2 and -3, PDGFR-α, PDGFR-β and c-kit in vitro 1 4 Pazopanib also exhibits in vitro inhibition of: fibroblast growth factor receptors (FGFR-1 and -3); stem cell factor receptor (c-kit); interleukin-2 receptor inducible T-cell kinase (Itk); leukocyte-specific protein tyrosine kinase (Lck); and transmembrane glycoprotein receptor tyrosine kinase (c-fms) Pazopanib has exhibited minimal in vitro inhibition of Flt-3 (involved in the development of haematopoietic stem cells) 4 1. Kumar R et al. Mol Cancer Ther 2007;6:2012; 2. Sonpavde G & Hutson TE. Curr Oncol Rep 2007;9:115; 3. Novartis Votrient (pazopanib) SPC. 2015; 4. Kumar R et al. Br J Cancer 2009;101:1717 12
Phase I trial of pazopanib in patients with advanced solid tumours Open-label, non-randomized, dose-finding trial of pazopanib in patients with advanced-stage, refractory solid tumours Sequential dose-escalating cohorts (dose-escalation phase, n=43; dose expansion phase, n=20) receiving pazopanib 50 mg three times weekly to 2000 mg once daily and 300 mg to 400 mg twice daily Three patients had partial response (two confirmed, one unconfirmed) and 14 patients had stable disease 6 months Monotherapy dose of 800 mg once daily was selected for further trials Mean target trough concentration of 15 μg/ml (34 μmol/l) achieved at 800 mg once daily Four patients with sarcoma treated with pazopanib had stable disease 6 months Subtype Starting dose (mg) Final dose (mg) Duration of stable disease (months) Leiomyosarcoma 50 once daily 800 once daily 9.0 Chondrosarcoma 400 once daily 800 once daily 7.6 GIST 600 once daily 800 once daily 15.8 Chondrosarcoma 2000 once daily 800 once daily 19.8 GIST, gastrointestinal stromal tumour Hurwitz H et al. Clin Cancer Res 2009;15:4220 13
Pazopanib soft tissue sarcoma indications EU Pazopanib is indicated for the treatment of patients with advanced soft tissue sarcoma who have received prior chemotherapy for metastatic disease or who have progressed within 12 months after (neo) adjuvant therapy 1 1. Novartis Votrient (pazopanib) SPC 2015 14
The PALETTE study (PAzopanib explored in soft-tissue sarcoma a phase III study) A randomized, double-blind Phase III trial of pazopanib versus placebo in patients with soft tissue sarcoma whose disease has progressed during or following prior chemotherapy An EORTC STBSG and GlaxoSmithKline global network study (EORTC 62072; VEG110727)
PALETTE: study design n=369 R A N D O M I Z E 2:1 Pazopanib* (800 mg QD) (n=246) Matching placebo (n=123) Primary endpoint PFS by independent review (RECIST v 1.0) Secondary endpoints OS ORR QoL Safety TTR DoR *Until disease progression, unacceptable toxicity, withdrawal of consent for any reason or death Disease assessment At week 4, 8, 12, 20 and at 8-week intervals thereafter DoR, duration of response; ORR, overall response rate; PFS, progression-free survival; QoL, quality of life; QD, once daily; RECIST, Response Evaluation Criteria in Solid Tumors; TTR, time to response Van Der Graaf W et al. Lancet 2012;19:1879 16
PALETTE: key inclusion criteria Patients 18 years, WHO performance status (PS) 0 1 1 Progressive disease during the last 6 months (or 12 months in case of [neo]-adjuvant treatment only) 1 Up to four lines of prior treatment for advanced disease 1 (no more than two combination regimens) Patients whose disease had progressed on or after, or been intolerant to an anthracycline-based regimen 2 Measurable disease according to RECIST 1.0 2 Angiogenesis inhibitor-naïve 1 Adequate major organ function 1 No poorly controlled hypertension, bleeding diathesis or CNS involvement 2 Van Der Graaf W et al. Lancet 2012;19:1879; Van Der Graaf W et al. ASCO 2011; abstract LBA10002: oral presentation 17
PALETTE: included/excluded histological subtypes Included: 1,2 Fibroblastic Fibrohistiocytic Leiomyosarcoma Synovial sarcoma Malignant peripheral nerve sheath tumours Sarcoma not otherwise specified (NOS) Vascular STS Malignant glomus tumours Excluded: 1,2 Adipocytic sarcoma Osteosarcoma Inflammatory myofibroblastic sarcoma Chondrosarcoma Dermatofibrosarcoma protuberans Mixed mesodermal uterine tumour GIST Mesothelioma Ewing s sarcoma/pnet Non-alveolar and non-pleiomorphic rhabdomyosarcoma 1. Van Der Graaf W et al. Lancet 2012;19:1879; 2. Van Der Graaf W et al. ASCO 2011; abstract LBA10002: oral presentation 18
PALETTE: data analysis Two analyses were undertaken for the PALETTE study: Regulatory analysis conducted by GSK Analysis plan agreed with authorities for regulatory submission Academic analysis conducted by EORTC for publication purposes Rates and names of adverse events may differ between the regulatory and academic analysis due to differences in data handling Study VEG110727. 2011 19
PALETTE study: one study, two analyses Variable Regulatory analysis Academic analysis (EORTC) Median PFS Median OS 4.6 months versus 1.6 months for placebo; HR=0.35 (0.26, 0.48); p<0.001 1 12.6 months versus 10.7 months for placebo; HR=0.87 (0.67, 1.12); p=0.256* 1 4.6 months versus 1.6 months for placebo; HR=0.31 (0.24, 0.40); p<0.0001 2 12.5 months versus 10.7 months for placebo; HR=0.86 (0.67, 1.11); p=0.25 2 PFS by subtype Leiomyosarcoma: HR=0.37 (0.23, 0.60); p<0.001 1 Synovial: HR=0.43 (0.19,0.98); p=0.005 1 Others: HR=0.39 (0.25, 0.60); p<0.001 1 Leiomyosarcoma: HR=0.31 (0.20, 0.47); p<0.0001 3 Synovial: HR=0.19 (0.23, 0.60); p=0.0002 3 Others: HR=0.36 (0.25, 0.52); p<0.0001 3 Most common AEs Fatigue: 65% (13% G3; <1% G4) 1 Diarrhoea: 59% (5% G3; 0% G4) 1 Nausea: 56% (3% G3; 0% G4) 1 Weight loss: 48% (4% G3; 0% G4) 1 Hypertension: 42% (7% G3; 0% G4) 1 Fatigue: 65% (13% G3; <1% G4) 2 Diarrhoea: 58% (5% G3; 0% G4) 2 Nausea: 54% (3% G3; 0% G4) 2 Weight loss: 48% (0% G3; 0% G4) 2 Hypertension: 41% (7% G3; 0% G4) 2 EORTC: European Organisation for Research and Treatment of Cancer *Data consistent with the interim analysis 1.Study VEG110727 2011 2.Van Der Graaf W et al. Lancet 2012;379:1879; 3. Van Der Graaf W. ESMO 2012. Session 91IN 20
PALETTE: endpoints Primary endpoint: PFS: the analysis of the primary endpoint PFS was based on disease assessment by independent radiological review in the entire ITT study population Secondary endpoints OS PFS by histological subtype (leiomyosarcoma, synovial sarcoma and other eligible histologies) ORR Time to response Duration of response Safety and tolerability Study VEG110727. 2011 21
PALETTE: data analysis Efficacy results are based on the ITT population of 123 patients randomized to the placebo arm and 246 patients randomized to the pazopanib arm Patients were stratified by: WHO performance status (0 or 1 at baseline) Number of lines of prior systemic therapy for advanced disease (0 or 1 vs 2+) Study VEG110727. 2011 22
PALETTE: progression-free survival Estimated survival function 1.0 0.8 0.6 0.4 0.2 0.0 Placebo Pazopanib Regulatory analysis Placebo (n=123) Pazopanib (n=246) Median PFS (weeks) 7.0 20.0 Median PFS (months) 1.6 4.6 Hazard ratio (95% CI) CI, confidence interval; PFS, progression-free survival 0.35 (0.26, 0.48); p<0.001 0 20 40 60 80 100 Time since randomization (weeks) 1.Novartis Votrient (pazopanib) SPC. 2015 2.Study VEG110727. 2011 23
PALETTE: overall survival Estimated survival function 1.0 0.8 0.6 0.4 0.2 0.0 Placebo Pazopanib Regulatory analysis Placebo (n=123) Pazopanib (n=246) Median OS (weeks) 46.5 54.8 Hazard ratio (95% CI) CI, confidence interval; OS, overall survival 0.87 (0.67, 1.12); p=0.256 0 5 10 15 20 25 30 35 Time since randomization (months) 1. Novartis,Votrient (pazopanib) SPC. 2015; Sharma S et al. BMC Cancer 2013;13:385. Additional file 4. 24
PALETTE: overall survival Final OS data are mature; 76% of patients have died 1 OS was favoured in the pazopanib arm compared with the placebo arm, without a statistically significant difference (HR 0.87, p=0.256) 1 The observed OS is within the expected range if a 3-month median PFS difference translates into a 3-month median OS difference 1 Translating PFS treatment effect to OS is confounded when postprogression survival time is long relative to time to progression due to inherent variability during this period 2 Variations may come from high rates of post-progression therapies used to control progression The PALETTE study was not powered to detect a 3-month difference in OS 1 1. Study VEG110727. 2011 2. Broglio KR & Berry DA J Natl Cancer Inst 2009;101:1642 25
PALETTE: summary of efficacy Pazopanib demonstrated a significant improvement in PFS, with median PFS of 20 weeks (95% CI 17.9, 21.3) versus 7 weeks for placebo (95% CI 4.4, 8.1; HR 0.35; 95% CI 0.26, 0.48; p<0.001), in patients with asts* who have received prior chemotherapy 1,2 Pazopanib delivered a 65% reduction in the risk of progression or death compared with placebo Pazopanib provided significant improvement in PFS compared with placebo across multiple STS subtypes*: 1 Leiomyosarcoma (HR 0.37; 95% CI 0.23, 0.60; p<0.001; n=158) 20.1 weeks for pazopanib versus 8.1 weeks for placebo Synovial sarcoma (HR 0.43; 95% CI 0.19, 0.98; p=0.005; n=38) 17.9 weeks for pazopanib versus 4.1 weeks for placebo A collection of multiple asts subtypes (HR 0.39; 95% CI 0.25, 0.60; p<0.001; n=173) 20.1 weeks for pazopanib versus 4.3 weeks for placebo Pazopanib demonstrated an improvement in PFS versus placebo in patients with asts* that was consistent regardless of the number of lines of prior therapy 2 *Excluding GIST and adipocytic sarcoma 1. Novartis Votrient (pazopanib) SPC 2015 2. Study VEG110727. 2011 26
PALETTE: serious adverse events Serious adverse events (SAEs) most commonly reported ( 3%) in patients treated with pazopanib in the PALETTE trial: Dyspnea (4%) Alanine aminotransferase elevations (4%) Aspartate aminotransferase elevations (3%) Gamma glutamyl transferase elevations (3%) Haemoglobin decreased (3%) Pneumothorax (3%) Embolism (3%) Study VEG110727. 2011 27
PALETTE: AE summary The most common adverse reactions in patients with asts who received pazopanib (experienced by 40% of patients) are fatigue, diarrhoea, nausea, decreased weight, hypertension, and decreased appetite 1 The incidence of the following serious adverse reactions was higher in the asts population than in the arcc population: 1 3 Venous thromboembolic events (all grades 5% in the pazopanib arm versus 2% of patients in the placebo arm) Myocardial dysfunction (all grades 11% in the pazopanib arm versus 5% in the placebo arm) Pneumothorax (all grades 3% in pazopanib arm versus 0% in the placebo arm) Pazopanib is contraindicated in patients with severe hepatic impairment 1,3 Pazopanib use in patients with mild or moderate hepatic impairment should be undertaken with caution and with close monitoring 1. Novartis Votrient (pazopanib) SPC 2015 2. Study VEG110727. 2011 28
PALETTE: health-related quality of life (2) Change from baseline for QLQ-C30 Global Health Status/QoL score Adjusted mean (±SE) 20 10 0 10 20 Pazopanib Placebo MID MID Subjects with data (n) Baseline Week 4 Week 8 Week 12 Visit Pazopanib Placebo 246 123 187 93 148 54 128 32 MID, minimally important difference Study VEG110727 2011 29
PALETTE study summary: Pazopanib demonstrated a significant improvement in PFS, with median PFS of 20 weeks (95% CI 17.9, 21.3) versus 7 weeks for placebo (95% CI 4.4, 8.1; HR 0.35; 95% CI 0.26, 0.48; p<0.001), in patients with asts* who have received prior chemotherapy 1,2 Pazopanib delivered a 65% reduction in the risk of progression or death compared with placebo The most common adverse reactions in patients with asts who received pazopanib (experienced by 40% of patients) are fatigue, diarrhoea, nausea, decreased weight, hypertension, and decreased appetite 1 No significant deterioration in HRQoL for pazopanib versus placebo Consistency of global HRQoL observed across all three assessment timepoints (Weeks 4, 8 and 12) 30
Conclusions: Multiples subtypes of STS with multiples approaches: single or combination therapies ESMO recommendation for 2 nd line treatment of a STS is chemotherapy and also targeted therapy (ifosfamide/high dose for patients who have received standard dose ifosfamide [IVC],trabectedin[IIB],gemcitabine+docetaxel[IIC],dacarb azine[iib], pazopanib [Ib]) 31