Latest Advances in Targeted Therapy and Immunotherapy in Sarcomas. Robin L Jones Royal Marsden Hospital Institute of Cancer Research
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1 Latest Advances in Targeted Therapy and Immunotherapy in Sarcomas Robin L Jones Royal Marsden Hospital Institute of Cancer Research
2 Disclosures Consultant for: Adaptimmune Blueprint Clinigen Eisai Epizyme Daiichi Sankyo Deciphera Immunedesign Eli Lilly Merck PharmaMar
3 Plan Targeted Therapy GIST: Blu-285, DCC-2618 Olaratumab Angiosarcomas: TRC-105, anti-endoglin antibody Epithelioid sarcoma: EZH2 inhibitor Liposarcomas: CDK4 inhibitor + selinexor (NTRK inhibitors + crenolanib) Immunotherapy Ipilimumab: Synovial sarcoma Pembrolizumab Nivolumab: Leiomyosarcoma Nivolumab +/- ipilimumab
4 Targeted Therapy
5
6 BLU-285 Phase 1 study Key objectives Part 1: MTD, safety, pharmacokinetics, ctdna analyses and anti-tumor activity Part 2: response rate, duration of response and safety Part 1 Dose escalation completed Advanced GIST (n=46) MTD 3+3 design with enrichment MTD determined to be 400 mg PO QD RP2D determined to be 300 mg PO QD ctdna, circulating-tumour DNA; MTD, maximum tolerated dose; PDGFR, platelet-derived growth factor receptor; PO, orally; QD, once daily; RP2D, recommended Phase II dose; TKI, tyrosine kinase inhibitor. Part 2 Dose expansion enrolling Unresectable GIST after imatinib and 1 other TKI (n=50) PDGFRα D842V-mutant GIST (n=50)
7 Maximum reduction: sum of diameter change from baseline (%) Tumour reduction across multiple KIT genotypes (central radiology review) N=30; 300 mg (RP2D); 400 mg (MTD) * * * * 9 * 9 11 KIT mutation by exon PD SD PR * ctdna results pending; Per archival tumour and ctdna sample. ctdna, circulating-tumour DNA; KIT, mast/stem cell growth factor receptor Kit; MTD, maximum tolerated dose; PD, progressive disease; PR, partial response; RP2D, recommended Phase II dose; SD, stable disease. 20 of 30 (67%) patients with tumour shrinkage
8 Probability of progression-free survival (%) Prolonged PFS in heavily pre-treated KIT-mutant GIST (central radiology review) Best response (N=30) * Choi criteria n (%) RECIST 1.1 n (%) PR 16 (53) 5 (17) SD 7 (23) 18 (60) DCR (PR+SD) 23 (77) 23 (77) PD 7 (23) 7 (23) No approved therapies beyond third-line regorafenib ORR ~0% with imatinib retreatment in third-line KIT Imatinib retreatment median PFS, ~1.8 months Median PFS, 11.5 months; 95% CI, 9.3 NE; PFS at 6 months, 69% Months from first dose KIT mg Censored * 300 mg RP2D 200 mg MTD; Two pending confirmation. DCR, disease control rate; KIT, mast/stem cell growth factor receptor Kit; MTD, maximum tolerated dose; NE, not estimable; ORR, objective response rate; PD, progressive disease; PFS, progression-free disease; PR, partial response; RP2D, recommended Phase II dose; SD, stable disease. 1. Kang YK, et al. Lancet Oncol 2013;14(12):
9 Maximum reduction: sum of diameter change from baseline (%) D842V D842V D842V D842V D842V D842V D842V D842V D V D842V D842V D842-H845V D842V D842V D842V D842V D842V D842V D842V D842V D842V D842V D842V D842V D842V D842V D842V D842V D842V D842V D842V Remarkable activity in PDGFRα D842-mutant GIST (central radiology review) N=31 patients across all dose levels Numbers under bars indicate dose level 31 of 31 (100%) patients with tumor shrinkage Mutation status * PD SD PR CR * Per archival tumour and ctdna sample. CR, complete response; ctdna, circulating-tumour DNA; PD, progressive disease; PDGFR, platelet-derived growth factor receptor; PR, partial response.
10 Probability of progression-free survival (%) High response rate and prolonged PFS in PDGFRα D842-mutant GIST (central radiology review) Best response (N=31) * Choi criteria n (%) RECIST 1.1 n (%) CR 1 (3) 1 (3) PR 30 (97) 21 (68) CR + PR 31 (100) 22 (71) SD 0 9 (29) DCR (PR+SD) 31 (100) 31 (100) PD Median PFS, not reached PFS at 12 months, 78% Approved agents are ineffetive 1,2 median PFS, ~3 months 1 PDGFRα Censored ORR ~0% with currently approved agents 1,2 PDGFR Months from first dose * All dose levels included; PR from C3 to C13, CR at C16 and CR pending confirmation ; Three pending confirmation. CR, complete response; DCR, disease control rate; PD, progressive disease; PDGFR, platelet-derived growth factor; PFS, progression-free survival; PR, partial response; SD, stable disease. 1. Cassier PA, et al. Clin Cancer Res 2012;18: ; 2. Yoo C, et al. Cancer Res Treat 2016;48:
11 Treatment emergent AEs affecting 20% of patients Safety population (all patients) N=116 Severity Preferred term, n (%) Any AE Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 Nausea 65 (56) 41 (35) 17 (15) 7 (6) 0 0 Fatigue 62 (53) 23 (20) 31 (27) 8 (7) 0 0 Periorbital oedema 50 (43) 42 (36) 8 (7) Vomiting 48 (41) 36 (31) 9 (8) 3 (3) 0 0 Oedema peripheral 39 (34) 28 (24) 9 (8) 2 (2) 0 0 Anaemia 36 (31) 7 (6) 10 (9) 17 (15) 2 (2) 0 Diarrhoea 36 (31) 26 (22) 8 (7) 2 (2) 0 0 Cognitive effects * 35 (30) 20 (17) 10 (9) 4 (3) 1 (1) 0 Lacrimation increased 35 (30) 29 (25) 6 (5) Decreased appetite 33 (28) 24 (21) 6 (5) 3 (3) 0 0 Dizziness 27 (23) 21 (18) 6 (5) Constipation 25 (22) 18 (16) 6 (5) 0 1 (1) 0 Hair colour changes 25 (22) 24 (21) (34%) patients had Grade 3 treatment-related AEs: anaemia (9%), fatigue (7%), hypophosphataemia (4%), nausea (4%) and cognitive effects (3%) 67 patients still on treatment; 49 patients discontinued due to PD (n=40), AEs (n=6) and withdrawal of consent (n=3) * Consists of multiple similar AEs that have been aggregated into a single category, 42% of patients at 400 mg (MTD), 18% of patients at 300 mg (RP2D). AE, adverse event; PD, progressive disease.
12 DCC-2618, a novel pan-kit and PDGFRa kinase switch control inhibitor demonstrates encouraging activity in patients (pts) with Gastrointestinal Stromal Tumors (GIST) N. Somaiah, A. Razak, M. Gordon, F. Janku, D. Flynn, M. Kaufman, J. Pitman, R. Ruiz-Soto, B. Smith, D. Westwood, J. Jennings, D. Greensmith, J. Jacobson, O. Rosen, S. George
13 Study Design and Methods (NCT# ) Dose-escalation study of oral DCC-2618 (QD or BID for 28 days) followed by expansion cohorts (cut-off July 28 th 2017) Tumour assessment: CT scans every 2 cycles per local assessment Escalation phase only: FDG-PET at baseline and after 3 weeks of therapy NGS of plasma cfdna was performed throughout the study to quantify KIT, PDGFRα and other molecular alterations Tumour tissue was obtained at baseline for NGS analysis Patients (major eligibility criteria): Patients with advanced refractory cancers (KIT/PDGFRa mutated) with a focus on GIST ECOG PS 0 1; adequate end-organ function Prior KIT/PDGFRa inhibitors were allowed BID, twice daily; cfdna, circulating-free DNA; CT, computed tomography; ECOG PS, Eastern Cooperative Oncology Group performance status; FDG-PET, fludeoxyglucose-positron emission tomography; KIT, mast/stem cell growth factor receptor Kit; NGS, next generation sequencing; PDGFR, platelet-derived growth factor receptor; QD, once per day.
14 DCC-2618: GIST Patient characteristics (N=57) Median age: 62 years (range 28 85) ECOG PS: PS0: 18 (33% ) PS1: 37 (67%) [Note: 2 subjects missing screening ECOG] Baseline mutations (archival tissue *; N=57): KIT exon 9: 13 KIT exon 11: 27 KIT exon 17: 4 PDGRα exon18: 4 Other/UKN: 9 (2x KIT exon 13, 1x KIT UKN, 1x SDH, 5x not done) Mean prior number of agents: 3.3 (median 3; range 1 7) Imatinib: 49/49 (100%) Sunitinib: 43/49 (88%) Regorafenib: 36/49 (73%) Other: 35/49 (71%) DCC-2618 treatment doses: <100 mg/day: 5 (9%) 100 mg/day: 52 (91%) 150 mg QD: 21 (37%) * Various methods used per institutional standards. ECOG PS, Eastern Cooperative Oncology Group performance status; KIT, mast/stem cell growth factor receptor Kit; QD, once per day; SDH, sorbitol dehydrogenase.
15 DCC-2618: Safety Population summary of TEAEs (regardless of causality) reported in 10% of patients (N=70) GRADE GRADE TOTAL ADVERSE EVENT 1/2 3/4 (n=70) Lipase increased (47%) Fatigue (46%) Anemia (41%) Decreased appetite (29%) Diarrhea (23%) Alopecia (21%) Hypertension (21%) Amylase increased (20%) Myalgia (20%) Weight decreased (20%) Dyspnea (19%) Abdominal pain (16%) Constipation (16%) Nausea (16%) Palmar-plantar erythrodysaesthesia (16%) Arthralgia (14%) Blood bilirubin increased 8 2* 10 (14%) Rash (11%) All DLT events were not clinically significant: 2 G3 lipase at 100 mg & 200 mg BID and a G4 CPK at 150 mg QD. * Unconjugated bilirubin, both patients are homozygous for 28 (TA)7/(TA)7 UGT1A1 polymorphism per local assessment. BID, twice daily; DLT, dose-limiting toxicity; QD, once per day; TEAE, treatment-emergent adverse event. 150 mg QD GRADE GRADE TOTAL 1/2 3/4 (n=21) (24%) (24%) (5%) (14%) (0%) (19%) (0%) (5%) (10%) (5%) (5%) (0%) (10%) (5%) (10%) (0%) (5%) (5%)
16 Maximum reduction sum of diameters change from baseline (%) Waterfall plot of best response by RECIST in KIT/PDGFRα GIST patients (N=37) 40 DCC-2618 dose assigned <100 mg daily 100 mg daily 20 PD 0 * SD -20 PR -40 * 66% increase in tumour size; Patients treated at 150 mg QD (RP2D). KIT, mast/stem cell growth factor receptor Kit; PD, progressive disease; PDGFR, platelet-derived growth factor receptor; PR, partial response; SD, stable disease.
17 PFS (%) DCC-2618: PFS in patients treated at 100 mg/d compared with <100 mg/d mpfs not reached All patients treated at 100 mg daily (n=49) Number at risk 10 mg 49 <100 mg Despite small sample size results suggest that doses of 40 or 60 mg/d are insufficient All patients treated at <100 mg daily (n=4) mpfs is 15.2 weeks (95% CI, ) Time (weeks) The fact that 30 mg BID is an insufficient dose is supported by improvement in disease control in a patient with PD after 24 weeks following dose escalation (not shown) mpfs, median progression-free survival.
18 Invictus: Fourth-line GIST Phase 3 trial Patients with a confirmed diagnosis of GIST Who have received at least 3 prior lines of therapy Phase 3 trial in fourth-line GIST will be a 2:1 randomized, double-blind, placebo-controlled trial Primary endpoint: PFS determined by independent radiologic review of CT scans, as assessed by RECIST CT scans: every cycle for the first 3 cycles Then every two cycles thereafter, beginning with cycle 4 Secondary endpoint: overall survival DCC-2618 or placebo QD (150 mg) 28-day cycles with best supportive care Placebo: crossover to DCC-2618 upon PD with placebo DCC-2618: opportunity to remain on DCC-2618 upon PD CT, computed tomography; PD, progressive disease; QD, once per day; RECIST, Response Evaluation Criteria in Solid Tumors.
19 Invictus: Phase 3 trial design A Phase 3, INterVentional, Double-Blind Study to Assess Safety and Efficacy of DCC-2618 In Patients with Advanced c-kit/pdgfrα Gastrointestinal Stromal TUmourS Who Have Received Prior Treatment with Imatinib, Sunitinib, and Regorafenib Dose escalate to 150 mg BID Randomise 2:1 (N=120) DCC mg QD N=80 (28-day cycles) Placebo N=40 (28-day cycles) Disease progression by independent radiologic review/ unblinding DCC mg QD (28-day cycles) Placebo (28-day cycles) or Continue on same dose or Discontinue DCC-2618 Cross over to DCC mg QD or Primary endpoint: PFS Disease progression by investigator assessment Dose escalate to 150 mg BID or Continue on same dose or Discontinue DCC-2618 Discontinue study BID, twice daily; c-kit, mast/stem cell growth factor receptor proto-oncogene; PDGFR, plateletderived growth factor receptor; QD, once per day.
20 Intrigue: Phase 3 trial design Randomized, double-blind, multi-center trial comparing DCC-2816 with sunitinib Prior treatment with imatinib 500 patients 1:1 ratio: DCC-2816 and sunitinib Primary endpoint: PFS Randomization will be stratified by ECOG performance status (0 1 versus 2) Mutational status (KIT exon 9 versus exon 11 versus PDGFRα) Region (North America versus outside of North America) Time on imatinib ( 12 months versus >12 months) Patients randomized to sunitinib or DCC-2618 will be offered the opportunity to receive openlabel DCC-2618 upon disease progression ECOG, Eastern Cooperative Oncology Group; KIT, mast/stem cell growth factor receptor Kit; PDGFR, platelet-derived growth factor receptor; PFS, progression-free survival.
21
22 Olaratumab: Open-label, Phase 1b/2 Trial Phase 2 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 I Z E Olaratumab 15 mg/kg D1,8 + Dox 75 mg/m 2 D1 8 cycles (21 days)* Dox 75 mg/m 2 D1 8 cycles Olaratumab monotherapy until progression Optional olaratumab monotherapy after progression Primary endpoint: Progression-free survival (PFS) (predefined statistical significance: 2-sided alpha = 0.2) Secondary end points: Overall survival (OS), objective response rate, PFS at 3 months Biomarker: PDGFRα (IHC) and related ligands * During Cycles 5-8, patients receiving Dox could receive dexrazoxane, at the investigator s discretion. Tap W et al. Lancet 388(10043); : 2016
23 Clinical Characteristics of Patients Treated Within Olaratumab Phase II Trial Tap W et al. Lancet 388(10043); : 2016
24
25 Progression-Free Survival (ITT) (Phase 2) Tap W et al. Lancet 388(10043); : 2016
26 Olaratumab: Overall Survival (ITT) (Phase 2) Overall Survival Olaratumab + Dox Dox N Event 34 (51.5) 50 (74.6) Censored 32 (48.5) 17 (25.4) Median OS (95% CI) 25.0 (20.9, 30.9) 14.7 (9.2, 18.0) Stratified p-value Hazard ratio (95% CI) (0.277, 0.702) Olaratumab + Dox Dox Months Tap W et al. Lancet 388(10043); : 2016
27 Olaratumab Trials Phase NCT Drugs Geographic Location III NCT Doxorubicin + olaratumab vs doxorubicin + placebo I/ II Doxorubicin/ ifosfamide + olaratumab I/ II NCT Gemcitabine/ docetaxel + olaratumab Ib NCT Pre-operative olaratumab + doxorubicin I NCT Pembrolizumab + olaratumab USA/ Europe/ Asia USA, Europe USA, Europe USA, Europe USA, Europe
28 Endoglin Endoglin (CD105) Receptor expressed on proliferating endothelium Selectively expressed high density on angiogenic cells Upregulated by hypoxia through induction HIF-1-a Upregulated on tumor endothelial cells following inhibition of VEGF pathway TRC-105 Phase I/ II: Durable responses angiosarcoma
29 TAPPAS: TRC105 + Pazopanib vs Pazopanib in Angiosarcoma Angiosarcoma Stratification: cutaneous vs non-cutaneous, and prior chemotherapy (0 vs 1 or 2) Cycle: 21 days N = 124 (up to 200) R 1:1 TRC105 + Pazopanib 10 mg/kg weekly (TRC105) mg daily (pazopanib; adults 18 years of age), 600 mg (pazopanib; ages years) Pazopanib 800 mg daily (pazopanib; adults 18 years of age), 600 mg (pazopanib; ages years) TRC105 is an anti-endoglin antibody Jones RL et al. ASCO Abstract TPS11081.
30 Epithelioid Sarcoma 1970: Enzinger: 62 cases Distinct subtype Confused with chronic inflammatory process, necrotizing granuloma, squamous cell carcinoma 1961: Lakowski aponeurotic sarcoma Can occur at any age Peak incidence young adults Frequently males Classic-type Extremities Multiple local recurrences Proximal-type More aggressive clinical course Characterized by INI1 loss Etiology remains unknown Up to 27% associated with previous trauma Originating in scar tissue Thway K et al. Adv Anat Pathol 23; 41-29: 2016 Noujaim J et al. Front Oncol 5; 1-11: 2015
31 EZH2: Catalytic subunit PRC2 + responsible for methylation activity PRC2 Enzyme histone methylation Chromatin remodeling Transcriptional repression
32 Phase II EZH2 inhibitor Gounder MM et al. ASCO Abstract 11058
33 Epithelioid Sarcoma: EZH2 Inhibitor Gounder MM et al. ASCO Abstract 11058
34 Classic-type Epithelioid Sarcoma Gounder MM et al. ASCO Abstract 11058
35 Patient Selection: INI1 loss in Sarcomas Subtype INI1 loss Epithelioid Sarcoma 90% Epithelioid MPNST 50-67% Myoepithelial Carcinoma 10-40% Extraskeletal Myxoid Chondrosarcoma 17% Poorly Differentiated Chordoma Limited data Adapted from Hollmann TJ, Hornick JL. Am J Surg Pathol 35; 47-63: 2011
36 Phase 2 Trial of Palbociclib Single arm, phase 2, N = mg palbociclib per day for 14 days; 7 days off Eligibility: WDLS/DDLS, CDK4 amplification, and RB expression 1 prior systemic therapy Median PFS: 18 weeks 1 partial response Grade 3/ 4 AEs: Anemia (17%), Thrombocytopenia (30%) WDLS DDLS Neutropenia (50%), febrile neutropenia (3%) Dickson MA et al. J Clin Oncol 31; : 2013
37 Phase II Trial Palbociclib: Adverse Events Dickson MA et al. J Clin Oncol 31; : 2013
38 Palbociclib: Progression-Free Survival Phase 2, N = 60 Median PFS: 17.9 weeks Advanced WDLS/DDLS Palbociclib 125 mg/day in a 4-week cycle 3 weeks on, 1 week off Primary endpoint: PFS Median PFS: 17.9 weeks 2 sided 95%CI; weeks 1 complete response Dickson MA et al. JAMA Oncol 2; : 2016
39 Selective Inhibition of Nuclear Export (SINE) Selinexor: oral inhibitor of XPO-1 (nuclear exportin protein 1) Phase 2/3 study initiated based on early clinical activity in a phase 1b trial
40 Selinexor: Multicenter Trial Phase 2 Sarcoma measurable by RECIST v1.1 Radiographic progression 1 prior therapy ECOG PS 0-1 Adequate organ function N = 54 Selinexor 30 mg/m 2, d 1 and 3 n = 19 Selinexor 50 mg/m 2, d 1 and 3 n = 17 Selinexor 60 mg/m 2, d 1 and 3 n = 18 Continuous 3 weeks on, 1 week off Gounder MM et al. J Clin Oncol 34; : 2016
41 Selinexor: Change in Tumor Size Gounder MM et al. J Clin Oncol 34; : 2016
42 Selinexor: PFS and Time on Study Progression-Free Survival Time on Study Gounder MM et al. J Clin Oncol 34; : 2016
43 Selinexor: Toxicity Gounder MM et al. J Clin Oncol 34; : 2016
44 Phase 2/3 Trial (SEAL): SElinexor in Advanced Liposarcoma Phase 2: 57 patients randomized 1:1 to selinexor or placebo Phase 2 PFS data will inform adjustment of phase 3 sample size Primary outcome is PFS; HR = Phase 3 Advanced unresectable DDLS Estimated N = 195 Primary endpoints: PFS, TTP, QoL R 2:1 Selinexor 60 mg, 2x/wk Placebo
45 Immunotherapy
46 Ipilimumab in Synovial Sarcoma N=6 advanced synovial sarcoma Pre-treated doxorubicin/ ifosfamide 1-3 cycles of Ipilimumab Response rate: 0% Time to progression: Median 1.85 months (Range: ) Overall survival: Median 8.75 months (Range: ) Maki RG et al. Sarcoma : 2013
47 SARC 28 Trial: Pembrolizumab Multicenter open-label single arm Phase II trial Potent + highly selective humanized mab Blocks interaction between PD1 and PD-L1 + PD-L2 Well tolerated Sep 2014: FDA approval: Melanoma + NSCLC Study powered (>80%, α= 0.10) to detect Objective response rate from <10% to 25% 3-months PFS rate from 20% (historical control) to 40% Advanced sarcomas At least one prior Rx (1-3) Age 18 STS, or 12 for bone sarcomas Amenable to biopsy ECOG PS 0 or 1 Soft Tissue Sarcomas (n=40): Leiomyosarcoma Dedifferentiated liposarcoma Undifferentiated pleomorphic Synovial sarcoma Bone sarcomas (n=40): Ewing sarcoma Osteosarcoma Dedifferentiated chondrosarcoma Tawbi HA et al. Lancet Oncol 18; : 2017
48 SARC 28 Trial: Pembrolizumab Primary objective Response rate RECIST 1.1 Secondary objectives Safety and tolerability Response Rate by irrc Progression-Free Survival (RECIST 1.1) Overall Survival Correlation of pre-treatment PD-L1 with response Immune monitoring in the circulation and in the tumor while on therapy Tawbi HA et al. Lancet Oncol 18; : 2017
49 SARC28 Trial: Patient Characteristics Tawbi HA et al. Lancet Oncol 18; : 2017
50 SARC28 Trial: Toxicity Tawbi HA et al. Lancet Oncol 18; : 2017
51 SARC28 Trial: Response Evaluation Tawbi HA et al. Lancet Oncol 18; : 2017
52 SARC 28 Trial: Pembrolizumab Pembrolizumab 200 mg IV every 3 weeks STS Subtype Best Response CR PR SD PD Total LMS UPS 1 (10%) LPS 0 Synovial 0 Total 1 (2.5%) 3 (30%) 2 (20%) 1 (10%) 6 (15%) Tawbi HA et al. Lancet Oncol 18; : 2017
53 SARC 28 Trial: Pembrolizumab Soft tissue sarcomas: Median PFS: 18 weeks (95%CI: 8-21) Median OS: 49 weeks (95%CI: 34-73) 12 week PFS: 55% (95%CI: 40-70) Undifferentiated pleomorphic sarcoma: Median PFS: 30 weeks (95%CI: 8-68) Bone Sarcomas: Median PFS: 8 weeks (95%CI: 7-9) Median OS: 52 weeks (95%CI: 40-72) Tawbi HA et al. Lancet Oncol 18; : 2017
54 Phase II: Cyclophosphamide + Pembrolizumab 4 cohorts: LMS UPS Other GIST Cyclophosphamide 50 mg twice/ day 1 week on/ 1 week off Pembrolizumab 200 mg IV every 3 weeks 57 patients (50 assessable) Median age: 59.5 years Range: years 6-month non-progression rates: LMS: 0% UPS: 0% Other: 14.3% (95%CI: %) GIST: 11.1% (95%CI: %) Partial response: Solitary fibrous tumor Toulmonde M et al. JAMA Oncol 4; 93-97: 2018
55 Phase II Nivolumab Uterine leiomyosarcoma Single arm 2-stage Phase II NCI/ CTEP funded Advanced ulms 1 prior therapy or more Age >18 years, PS 0/1 Primary endpoint Response rate per RECIST 1.1 Secondary endpoint Toxicity profile PFS Immune correlates IHC: PD-L1, PD-L2, PD-1 Plan for serial biopsies in 10 patients RECIST 1.1 at 12 weeks Null hypothesis 5% response rate Ben-Ami E et al. Cancer 123; : 2017
56 Phase II Nivolumab N=12 Median age 54 years Median prior therapy = 3 N=12 gemcitabine/ docetaxel N=9 anthracycline Median 5 doses of nivolumab Response rate: 0% Median PFS 1.8 months Most off trial due to PD Nivolumab well tolerated N=1, Grade 3 abdominal pain N=1, Grade 4 amylase/ lipase increase IHC on archival tissue: PD-L1/ PD-1: low level/ 0 expression in tumor cells PD-L2: high expression in malignant cells N=1 sequential biopsy Inadequate tumor tissue Ben-Ami E et al. Cancer 123; : 2017
57 Phase II Trial: Nivolumab ± Ipilimumab Eligible patients with advanced sarcoma N = 96 R 1:1 N = 85 Nivolumab + Ipilimumab 3 mg/kg (nivo) + 1 mg/kg (ipi) n = 42 Nivolumab 75 mg/m 2 d 1 x 8 cycles n = 43 Nivolumab 3 mg/kg Every 3 wk x 4 Every 2 wk Every 2 wk Treatment until PD a Toxicity Up to 2 years a Treatment beyond PD allowed in first 12 weeks 4-week confirmation required to continue D Angelo SP et al. Lancet Oncol 19(3): : 2018
58 Phase II Trial of Nivolumab ± Ipilimumab Best Objective Status, n (%) CR PR SD PD Death/no assessment Nivolumab + Ipilimumab (n = 38) Nivolumab (n = 38) 2 (5) 5 (13) 19 (50) 10 (27) 2 (5) 0 3 (8) 15 (39) 20 (53) ORR (confirmed CR + PR) 6, 16% (90% CI, 7-29%) 2, 5% (90% CI, 1-15%) Clinical benefit rate (CR + PR + SD) 29% (90% CI, 17-43%) 18% (90% CI, 1-32%) Responses in Undifferentiated pleomorphic sarcoma Myxofibrosarcoma Angiosarcoma Leiomyosarcoma D Angelo SP et al. Lancet Oncol 19(3): :
59 CTOS 2017 Phase II 1 Durvalumab (PD-L1) + tremelimumab (CTLA-4) N=48: Lipo, LMS, UPS, SS, other Partial response: 5 (10%) ASPS: n=3 Angiosarcoma: n=1 UPS: n=1 Stable disease: 15 (31%) Phase II Axitinib/ pembrolizumab 2 29 evaluable Partial response: 5 (17%) Stable disease: 9 (31%) Median PFS: 15.9 weeks Partial response: ASPS: 4/ 9 1 Somiah N et al. CTOS Wilky B et al. CTOS 2017
60 CANCER TESTIS ANTIGENS ARE ATTRACTIVE IMMUNOTHERAPEUTIC TARGETS Proteins expressed in testis + many cancers NOT expressed in other normal tissues Immunogenic in cancer patients Includes NY-ESO-1, LAGE-1, PRAME, MAGE family antigens A: MAGE-A4 in tests; B: MAGE-C1 in fetal ovary C: MAGE-A in trophoblastic placenta; D: NY-ESO-1 in bladder cancer Pollack et al. Cancer 118; : 2012 Frequently map to chromosome X and exist as multigene families In vitro activation by hypomethylation +/or histone deacetylase inhibition
61 LV305 is a DC targeted lentivus encoding NY-ESO-1 LV305 Hybrid viral vector Target dendritic cells Induce NY-ESO-1 specific T cell response Potentially generate + expand anti cancer cytotoxic T cells Phase I Advanced/ Metastatic cancer NY-ESO-1 expression Somaiah N et al. ASCO 2015
62 CMB05 in NY-ESO-1 Positive STS Prime-boost strategy Prime with LV305: dendritic cell targeting NY-ESO-1 Boost with G305: Toll-like Receptor 4 (TLR4) agonist Activate innate immune system Co-formulated with NY-ESO-1 protein N = STS 14 synovial sarcoma 9 Myxoid liposarcoma 2 other Somaiah N et al. Abstract 11006; ASCO 2017 Median OS (95% CI), months Time, mo STS Patients (n = 25) NA (12.3-NA) 12-month OS rate, % month OS rate, % 76.2
63 Randomized Phase III trial (Synovate) Synovial sarcoma N=248 Maintenance therapy post 1st line (stable disease or response) Randomized 1:1 CMB-305 vs placebo Co-primary end-points PFS and OS Recruitment commenced 2018
64 Conclusion Targeted Therapy GIST: Phase III trials Blu DCC-2618 Olaratumab Phase III data 2019 Angiosarcomas: 1 st randomized Phase III trial (pazopanib +/- TRC-105) Epithelioid sarcoma: EZH2 inhibitor Liposarcomas: Randomized Phase III trial (Selinexor vs placebo) Immunotherapy Less promising or differential sensitivity of specific subtypes? PD1 inhibitors activity in Undifferentiated pleomorphic Angiosarcoma Alveolar soft part sarcoma Ongoing combination trials Increasing options but more emphasis on underlying biology Different drugs for different diseases
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