The hunting of the sarcoma

The hunting of the sarcoma Update of Recent Advances in Soft Tissue Sarcoma Treatment Lin Mei, MD Hematology-Oncology Fellow

Educational goal Anecdote of sarcoma (10 quiz) Review of pathology Neoadjuvant and adjuvant chemotherapy for early stage STS Traditional chemotherapy for advanced/metastatic STS Treatment for specific subtypes of sarcoma First-line treatment and second- or third-line chemotherapy New advances, e.g. immunotherapy

1.7-million-year old bone Dr. Aufberdeide found the first evidence of cancer inside of mummy at Chiribaya site, Peru Osteosarcoma

Joseph Lister and cancer In 1869, Lister removed a breast tumor from his sister with antiseptic approach. He performed amputation of a 13-year-old boy with sarcoma of thigh

Radium and cancer In late 1920s, it was found radium exposed workers easily developed sarcoma. Emil Grubbe assembled the first x-ray machine in Chicago in 1896 to treat a woman with breast cancer.

Father of cancer immunology William Coley In 1893, Dr. Coley found a sarcoma case (Fred Stein), whose tumor disappeared following high fever from Strep Pyogenes at MSKCC, which start the era of cancer immunology. Coley vaccine is from dead bacteria However, his idea majority disagreed from another famous person.

Small blue cell Cancer man: James Ewing In 1910, Ewing established a collaboration with a hospital called Memorial Hospital, which nowadays named MSKCC In 1919, he published a book: Neoplastic disease: a textbook on tumors, which established numerous oncological terms In 1920, he named a malignant osteoma: Ewing sarcoma

Starving cancer Otto Warburg and Paul Ehrlich studied starving sarcoma cells of metabolites, or tricking them into death by decoy molecules. Warburg effect

Cancer can be contagious? Peyton Rous: Nobel Prize in 1966 (40 years after his discovery) Cancer could be transmitted by a virus (now known as Rous Sarcoma Virus) and caused sarcoma of chicken. His son-in-law: Alan Hodgkin (1914-1998), Nobel prize in 1963.----Hodgkin s lymphoma? Thomas Hodgkin (1798-1866) was his ancestor.

Oncogene Harold Varmus and Michael Bishop won the Nobel Prize in 1989 due to the identification of c-src gene that gave rise to the v-src oncogene of Rous Sarcoma Virus (RSV), which was isolated by Peyton Rous in 1910.

Epidemiology In 2016, 1.6 million new cancer cases in US Only 1% of case present with sarcoma 12,310 cases of soft tissue sarcoma and 3,300 cases of bone/joint sarcoma Death rate increased from 2003 to 2012 Five-year survival is 80%. (In 1970s is around 70s). Siegel R, et al. CA Cancer J Clin, 2016; 66: 7-30.

Pathology Adipose tissue: liposarcoma Peripheral nervous tissue: nerve sheath tumor Smooth muscle: leiomyosarcoma Fibrous tissue: desmoid fibromatosis, fibrosarcoma, etc. Blood vessel: angiosarcomam etc. Skeletal muscle: rhabdomyosarcoma Unknown origin: synovial sarcoma, UPS, epithelioid sarcoma, extraskeletal- osteosarcoma, chondrosarcoma, Ewing sarcoma

Pathology

Heterogeneity

History: doxorubicin Gianni Bonadonna (1934-2015): breast cancer oncologist. He reported Adriamycin showed anti-tumor activity against a variety of solid tumor in 1970 Similar result was replicated at NCI by Dr. Robert Benjamin in 1975. Benjamin R. Tumori 2017; 103: 213.

Adjuvant chemotherapy OS benefit from doxorubin-based chemo is only 7% (Sarcoma Meta-analysis Collaboration 1997) Ifosfamide-containing regimen improved both PFS (48 vs. 16 mos)and OS (75 vs. 46 mos) [Frustaci S, et al. JCO, 2001; 19: 1239] Three cycles anthracycline-based regimen is non-inferior to 5 cycles. [Gronchi A et al. Ann Oncol 2016; 27: 2283.] Consider it in tumor size>5cm, highgrade histology and deep soft tissue involvement.

Adjuvant chemotherapy EORTC 62931 trial evaluate doxorubicin and ifosfamide for resected STS 351 pts were enrolled. Grade II-III STS, ECOG<2. Adjuvant chemotherapy(doxorubicin+ifosfamide q3w for 5 cycles) vs. observation OS: chemo (11.2 yr) vs. control (12.4 yr), no significant difference RFS: chemo (7.55 yr) vs. control (6.50 yr)no significant difference 5 yr OS rate: chemo (66.5%) vs. control (67.8%) Subgroup analysis showed limb STS, high grade and large tumor might be beneficial. Woll PJ et al. Lancet Oncol. 2012; 13: 1045.

Neoadjuvant treatment Gronchi A et al. reported equal efficacy of neo- and adjuvant chemotherapy. [Ann Oncol. 2016; 27: 2283.] What we are using at VCU is adopted from Stubbe F et al, using AIM plus concurrent radiotherapy with 100% local control rate in 1 year and 89.9% in 3 year. [Cancer Radiother, 2016; 20:6]

ISG-STS 1001 Trial Phase 3 histotype-tailored neoadjuvant chemotherapy vs. standard chemotherapy in high-risk STS Epirubicin+Ifos (standard), Trabectedin (myxoid liposarcoma), Gem+dacarbazine (leiomyosarcoma), synovial (high dose Ifos), Etoposide+Ifos (PNST), Gem+docetaxel (UPS). Postoperatively radiation DFS: 46 mos (62%) in standard vs. 22-25 mos (38%) in tailored group OS: at 46 months, 89% in standard vs.64% in tailored groups (P=0.03) Neutropenia: 86% in standard and 26% in tailored groups Conclusion: No benefit of histotype-tailored chemotherapy regimen over standard care. Lancet Oncol 2017; 18: 812-22.

ISG-STS 1001 Trial

Conclusion Adjuvant chemotherapy for early stage STS is controversial. Using anthracycline, the absolute benefit of OS is about 4% For extremity sarcoma, the benefit is about 7% Combined anthracycline+ifosfamide, the OS reduction is about 10% Visceral or abdominal sites STS seems not benefit from adjuvant treatment. Grade 1 or 2 STS is not benefit from adjuvant treatment. Neoadjuvant treatment Equal efficacy of neoadjuvant vs. adjuvant chemotherapy Anthracycline is the mainstay treatment. No benefit of histotype-tailored chemotherapy regimen Whether it helps local control still need further evidence.

Metastatic and advanced STS: First-line treatment

Doxorubicin Historically, combination with dacarbazine and ifosfamide improves responses but not PFS or OS. No RTC trials were done. Phase 3 trial (EORTC 62012), 455 pts from Europe: Dox+Ifos (25mg/m 2 /d D1-D3+2.5g/m 2 /d D1-D4) vs Dox alone (75mg/m 2 on D1) every 3 weeks (6 cycles) Dox+Ifos has higher response rate vs. Dox alone (26% vs. 14%) and longer PFS (7.4 vs. 4.6 mos). OS was not significantly different (14.3 vs. 12.8 months). 1 year survival rate: 60% vs. 51%. Authors called negative result. However Judson I et al. Lancet Oncol 2014; 15: 415

Doxorubicin

Palifosfamide and Evofosfamide PICASSO III trial: evaluate doxorubicin+palifosfamide vs. doxorubicin alone in advanced/metastatic STS (first line, phase 3) Palifosfamide: metabolite of ifos, not require prodrug activation, less toxicity 447 pts were assigned PFS: doxo (6.0 mos) vs. palifos+doxo (5.2 months) Median OS: doxo (16.9 mos) vs. palifos+doxo (15.9 mos) Higher grade 3-4 AE: 63.6% vs. 50.9% Neutropenic fever: 21.4% vs. 12.6% SARC 021 trial: evaluate doxorubicin+evofosfamide vs. doxorubicin alone in advanced/metastatic STS (first line, phase 3) Evofosfamide: hypoxia-activated prodrug 640 pts were assigned Median OS: doxo (19.0 mos) vs. Evo+doxo (18.4 mos) Ryan C et al. JCO. 2016; 34: 3898 Tap W et al. Lancet Oncol. 2017; 18: 1089

Gemticabine+docetaxel First reported from MSKCC in 2002 for leiomyosarcoma (LMS). First line or progressed after doxorubicin-based therapy The phase II trial extended to metastatic STS (sarcoma alliance study 002), including 122 pts Gemcitabine vs. Gemcitabine+docetaxel ORR was 8% (Gem) vs. 16% (Gem+docetaxel) PFS: 3.0 months (Gem) vs. 6.2 months (Gem+docetaxel) Median OS: 11.5 months (Gem) vs. 17.9 months (Gem+docetaxel) Toxicity: no significant higher rate in combination therapy than single agent Grade 3-4: Neutropenia (16 vs 28%), anemia (7 vs. 13%), Neutropenic fever (5 vs. 7%) Then the question is doxorubicin vs. Gem+docetaxel, which one is better? Hensley ML et al. JCO, 2002; 20: 2824 Maki RG et al. JCO, 2007; 25: 2755

Sarcoma alliance study 002 ECOG PS=0 ECOG PS>0 ECOG PS=0 ECOG PS>0

GeDDis Trial Phase III trial compared gem+docetaxel vs. doxorubicin as first-line treatment for advanced/metastatic STS. Dox 75mg/m 2 q3w; vs. Gem (675mg/m 2, D1, D8)+docetaxel (75mg/m 2 on D8), q3w 257 pts were enrolled (129 to dox and 128 to Gem+docetaxel), f/u 22 mos 6 months PFS: no difference (46.3% vs. 46.4%) Median PFS: no difference (23.3 weeks vs. 23.7 weeks) Toxicity Neutropenia (25% vs. 20%); fatigue (6% vs. 14%) Neutropenic fever (20% vs. 12%); mucositis (14% vs. 2%) Questions Lower than standard gemcitabine dose (900mg/m 2 ), capped at 6 cycles Many pts cross over to doxorubicin group, but less cross over to Gemcitabine group Seddon B, et al. Lancet Oncol. 2017; 18: 1397.

GeDDis Trial

Olaratumab Olaratumab: monoclonal antibody against PDGFRα Phase Ib/II open-label trial 133 pts were enrolled, advanced/metastatic STS not treated with anthracycline Doxorubicin (75mg/m 2 )+olaratumab (15mg/kg, D1, D8) vs. doxorubicin (D1) q3w Median PFS: 6.6 months (combination) vs. 4.1 months (single agent) Median OS: 26.5 months (combination) vs. 14.7 moths (single agent) p=0.0003 ORR: 18.2% (combination) vs. 11.9% (single agent) Toxicity: more neutropenia, mucositis, N/V/D. Similar rate of neutropenic fever Oct 2016, FDA approved olaratumab as first-line treatment in combination with doxorubicin. NCCN category 2A recommendation Tap W et al. Lancet. 2016; 388: 488

Olaratumab

Conclusion Doxorubicin remains the mainstay first-line treatment. Although EORTC 62012 trial is negative, however, adding ifosfamide shows increased ORR, PFS, and potential OS. It can be considered for large tumor burden, symptomatic and fit pt, or improve likelihood of tumor control from surgery or radiation. Gemcitabine+docetaxel has comparable efficacy with doxorubicin, though it is lack of clear evidence. It is better tolerate and can be use in prolonged duration. Olaratumab is a very promising agent which shows improved OS in combination with doxorubicin. However, we are still awaiting phase 3 result.

Specific subtypes of STS: 2nd-line treatment or more

Trabectedin and L-type STS Trabectedin: bind to DNA affect DNA synthesis Trabectedin plus doxorubicin didn t show superiority over doxorubicin alone as first-line treatment for STS Phase III trial evaluate efficacy and safety of trabectedin for metastatic liposarcoma(lps) or leiomyosarcoma (LMS) 518 pts were enrolled, compare trabectedin (n=345) vs. darcarbazine (n=173) After prior therapy with anthracycline and at least one additional regimen 45% reduction in the risk of disease progression or death Median PFS (trabectedin vs. dacarbazine): 4.2 vs. 1.5 months Median OS: 12.4 vs. 12.9 months Benefit all preplanned subgroup Toxicity: myelosuppression and transaminases FDA approved trabectedin for L-type STS after anthracycline treatment. Martin-Broto J et al. JCO; 2016: 34: 2294 Demetri GD et al. JCO; 2016: 34: 786

Trabectedin and L-type STS

Eribulin Eribulin: antimitotic agent inhibits microtubule. Phase 3 trail evaluate Eribulin vs. Dacarbazine in advanced LMS and LPS received at least two previous treatment. Eribulin 1.4mg/m 2 D1, D8/q3w (n=228), dacarbazine q3w (n=224) OS: Eribulin (13.5 months) vs. dacarbazine (11.5 months) Toxicity grade 3 or higher: Eribulin (67%) vs. dacarbazine (56%) More favor LPS renders FDA approval for LPS on Jan 2016 Subgroup analysis from the same trial reported in Oct 2017 In LPS group, OS: Eribulin (15.6 months) vs. dacarbazine (8.4 months) PFS: Eribulin (2.9 months) vs. dacarbazine (1.7 months) Toxicity: similar Not showing efficacy in other types of STS Eribulin approved for LPS after anthracycline treatment. Schoffski P et al. Lancet. 2016; 387:1629 Demetri GD et al. JCO. 2017; 35: 3433 Schoffski P et al. Lancet Oncol. 2011; 12: 1045

Eribulin

Pazopanib Pazopanib: multi-kinase inhibitor PALETTE trial: phase 3 trial, evaluate pazopanib for STS progressed from standard chemotherapy. 369 pts were assiagned: pazopanib (800mg qd) (n=246) vs. placebo (n=123) Median PFS: pazopanib (4.6 months) vs. placebo (1.6 months) OS: pazopanib (12.5 months) vs. placebo (10.7 months) LPS or GIST were not included FDA approved for non-adipocytic STS as 2 nd -line treatment on Apr 2012 Van der Graff WT, et al. Lancet. 2012; 379: 1879.

Pazopanib

Other Ifosfamide: active for synovial sarcoma and myxoid LPS, but less active for LMS Dacarbazine: modest activity against LMS Paclitaxel: active against angiosarcoma Sorafenib: against angiosarcoma and desmoid tumor Sunitinib: against alveolar soft part sarcoma Everolimus: approved for angiomyolipoma associated with tuberous sclerosis

New advanced in STS: immunotherapy and more

SARC028 trial Phase II trial, evaluate pembrolizumab for safety and activity in advanced STS or bone sarcoma Enrolled 86 pts 18% had ORR (40% for UPS, 20% for LPS, and 10% for synovial) None of the LMS had response 5% of bone sarcoma had ORR (5% of osteosarcoma and 20% chondrosarcoma) None of the Ewing sarcoma had response Toxicity: Hematological and prolonged PTT. 10% had severe irae Pembrolizumab showed more efficacy in UPS and LPS Pre-treatment PD-L1 and MSI status are investigated in the ongoing SARC028 and PembroSARC trials. Tawbi HA, et al. Lancet. 2017, Oct 4 th, epub

SARC028 trial

Immunotherapy A single center phase 2 study, Nivolumab single agent failed to show any response to previous treated advanced ulms, regardless of PD-L1 expression. A phase 2 study to evaluate pembrolizumab+ctx. 57 pts were included. Four cohorts: LMS, UPS, GIST and others Nonprogression rate: LMS (0%), UPS (0%), GIST (11%) and others (14%). Strong IDO1 expression on macrophage was observed in majority of STS. Combined IDO inhibition might need to be considered in the future Alliance A091401: phase 2 study of nivolumab +/- ipilimumab for metastatic sarcoma (ASCO 2017) 85 pts were enrolled. LMS (36%), LPS (4%), UPS (10%), Synovial (6%), bone (5%) and Ewing (5%), others (34%). Refractory to at least first-line treatment and >50% pts received three or more lines of treatment RR: N(2%) vs. N+I(6%); PFS: N(2.6) vs. N+I (4.5); OS: N(8.7) vs. N+I (11.2) 6 months PFS: N (16%) vs. N+I (36%) Ben-Ami E et al. Cancer. 2017; 123: 3285 Toulmonde M et al. JAMA Oncol. Jun 2017. epub

Aldoxorubicin Aldoxorubicin (INNO-206): prodrug of doxorubicin, bind to albumin, released in the acidic tumor environment. Phase 2b trial: evaluate first-line aldoxorubicin vs. doxorubicin in advanced STS. 140 pts were enrolled. Aldoxorubicin (350mg/m 2, equal to dox 260mg/m 2 ) or doxorubicin 75mg/m 2, q3w, for 6 cycles. Median PFS: Aldox (5.6 months) vs. dox (2.7 months) P=0.02 Median OS: Aldox (15.8 months) vs. dox (14.3 months) P=0.21 ORR: Aldox (25%) vs. Dox (0%) Toxicity: Gr 3 neutropenia: Aldox (29%) vs. Dox (12%), similar of febrile neutropenia, no EF reduced <50% in Aldox Chawla SP et al. JAMA Oncol. 2015; 1: 1272.

Conclusion 2 nd -line treatment Trabectedin for L-typed sarcoma progressed after anthracycline Eribulin for liposarcoma progressed after anthracycline Pazopanib for non-adipocytic (LPS) sarcoma Current immunotherapy result for STS is disappointing. Further study may need to investigate better biomarker and tumor environment (e.g. IDO).

Thank you!