Clinical Case Nº2 Dr. Javier Martín-Broto

Case description 49-year-old man 1 st symptom/sign: Mild pain in right buttock 1 st diagnosis: Core-biopsy: Monophasic Synovial Sarcoma Core-biopsy: Monophasic Synovial Sarcoma MRI: Heterogeneous mass deeply located in right gluteus (maximus and medius) MRI: Heterogeneous mass deeply located in right gluteus (maximus and medius) CT scan: Metastases ruled out CT scan: Metastases ruled out April 2008 August 2008 Synovial Sarcoma G3T2bN0M0

Neoadjuvant chemotherapy + radiotherapy: –Epirubicin 60 mg/m 2 /d d1-2+ Ifosfamide 3 g/m 2 /d d1-3/3 weeks GCSF x 3 cycles along with radiotherapy (44 Gy) Marginal surgery with in block resection of the tumor and maximus gluteus and partial medium gluteus. Microscopical margin 0.3 mm Boost of 16 Gy Case evolution: First treatment

In case of an early inoperable recurrence, what agents would you consider as options for the treatment of this synovial sarcoma patient? a.Gemcitabine+DTIC or plus Docetaxel b.HD Ifosfamide c.Trabectedin d.Pazopanib

Anthracyclines + ifosfamide is strongly recommended for this entity, which seems to be the histotype which benefits most from ifosfamide. 1 –High-dose ifosfamide as a single drug even after resistance to the combination, may be especially well suited for this entity. 1 Options after anthracyclines/ifosfamide: –Trabectedin: Several restrospective pooled analysis (N>100) showing an activity similar to that in leiomyosarcoma and liposarcoma 2-3 (Clinical benefit: 54%; median PFS: 3.0 months and median OS:13.9 months, with 2 years survival rate of 28%). 2 –Pazopanib: Prolonged progression-free survival over placebo in this population (N=38; 4.1 vs 1,0 months; HR=0.39 p=0.005). However, there was a trend towards lower survival with pazopanib vs placebo (8.7 vs 21.6 months; HR=1.62 p=0.115) for this subtype. 4-5 –Gemcitabine + docetaxel: In a retrospective review of 51 medical records, 43% achieved clinical benefit from the combination. 6 Synovial sarcoma (SS): Treatment options 1. Eriksson M. Ann Oncol. 2010; 21(7):vii270–6; 2. Le Cesne A, et al. Eur J Cancer. 2012;48(16): ; 3. Sanfilippo R, et al. CTOS 17th Annual Meeting. Prague, November 14-17, [Poster #107]; 4. Deeks E, et al. Drugs. 2012;72(16): ; 5. Votrient ® Summary of product characteristics. Available at: _Product_Information/human/001141/WC pdf ; 6. Sausan Abouharb et al. J Clin Oncol. 2014; 32:5s (suppl; abstr 10564). _Product_Information/human/001141/WC pdf

Bilateral lung metastases 4 nodules ranging between 3 and 9 mm. Treatment: HD Ifosfamide 12 g/m 2, 2 g/m 2 /d d1-6/ 21 d GCSF x 4 cycles. RECIST: SD Bilateral METASTASECTOMIES Case evolution: First recurrence June 2009 Oct & Nov 2009

Appearance of 4 nodules in right lung Gemcitabine (1,800 mg/m 2 ) + Dacarbazine (500 mg/m 2 ) 15 d x 9 cycles Best Response: SD Case evolution: Second recurrence Feb 2010

Bilateral lung metastases 4 nodules ranging between 3 and 9 mm. Case evolution: New progression June 2010 Jun 2010 Trabectedin 1.5 mg/m 2 every 3 weeks X 17 cycles (up to 07/2011) Outcome: PR Feb 2011

Four months after last cycle of trabectedin, there was a new progression, what therapeutic approach would you choose? a.Gemcitabine +/- docetaxel b.Pazopanib c.Best supportive care d.Rechallenge with trabectedin

Smaller time to progression with previous therapies: –HD Ifosfamide: 8 months –Gem/DTIC: 4 months –Trabectedin: 13 months Trabectedin safety profile allows long term treatment. In an analysis performed in more than a thousand of patients, no cumulative toxicities were apparent and it could be administered for up to 59 cycles. 1 Positive results of trabectedin rechallenge have been previously reported: 2 –The rechallenge therapeutic strategy with trabectedin resulted in clinical benefit (CR+PR+SD) for about two thirds of patients after the first rechallenge and one third of patients after the second rechallenge. What is the rationale supporting this decision? 1. Le Cesne A, et al. Invest New Drugs. 2012;30: ; Saada E, et al ASCO Annual Meeting. J Clin Oncol 30, 2012 (suppl; abstr 10062)

Trabectedin 1.5 mg/m 2 x 10 cycles Best Response: SD Case evolution: Trabectedin rechallenge Nov 2011 July Left paratracheal nodule. - Continue with trabectedin & RT 30 Gy targeting that nodule - Ongoing trabectedin - Best Response: PR New Progression:

Nodule in right middle lobe. Continue with Trabectedin & RT 30 Gy targeting that nodule Ongoing trabectedin Best Response: PR April 2013 Case evolution: Trabectedin rechallenge June 2013

Case evolution: Last treatments July 2013 Nov 2013 From November to February 2014: Epi+Ifos SD Patient died on May 2014 after liver and lung progression. From November to February 2014: Epi+Ifos SD Patient died on May 2014 after liver and lung progression. Bilateral nodules Pazopanib was started Bilateral nodules Pazopanib was started Up to Nov 2013 Best Response: SD Up to Nov 2013 Best Response: SD

Among the different treatments that this synovial patient received, trabectedin is the only agent able to bring partial responses and a long-term disease control. On the basis of this case report and findings from previous studies, trabectedin can be considered as an important therapeutic choice for the treatment of metastatic synovial sarcoma. Case timeline and conclusions 1st recurrence HD Ifo 4cy Metasta- sectomy Jun-Nov 2009 Feb 2010 Gem+DTIC 9cy SD June 2010 Trabectedin 17cy PR Nov 2011 Trabectedin 10cy SD July 2012 Continue Trabectedin + RTP 30gy PR April 2013 Continue Trabectedin + RTP 30gy PR July 2013 Nov 2013 May 2014 Pazopanib SD Epi + Ifo SD Death 8 months 4 months 37 months 4 months 6 months

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