Targeted therapies and immunotherapies show promise for certain subtypes of pediatric soft tissue sarcoma. Larotrectinib and entrectinib have response rates of 80-60% in infantile fibrosarcoma. Tazemetostat has response rates of 15% in epithelioid sarcoma. Anlotinib shows improved progression-free survival over dacarbazine in synovial sarcoma. MEK inhibitors and ALK inhibitors show activity in NF1-associated MPNST and inflammatory myofibroblastic tumor, respectively. Sorafenib and gamma secretase inhibitors demonstrate responses in desmoid tumors and fibromatosis. Immunotherapy may be effective for angios

1. Targeted therapy in pediatric
soft tissue sarcoma
Dr Sameer Rastogi
Dept of Medical oncology
Sarcoma Medical Oncology Clinic
AIIMS, New Delhi

2. Newer therapies
• Infantile fibrosarcoma – The ultimate success story
• Pazopanib and other VEGF inhibitors & Propanolol
• Tazemetostat – epithelioid sarcoma
• Anlotinib in synovial sarcoma
• ALK inhibitors – IMFT
• MEK inhibitor – NF1 with MPNST
• Gamma secretase inhibitor/ sorafenib – fibromatosis
• Immunotherapy- Potentially active – type of soft tissue tumors

3. 9 month old infant with IFS (Pre and post
surgery and chemotherapy)
17.6.21 14.1.22

4. Course in Bangladesh before presentation
• Patient received chemotherapy in Bangladesh / No imaging was done
• VAC chemotherapy
• Inj Vincristine 0.05mg/kg= 0.45mg weekly
•
• Inj Actinomycin 0.05mg/kg=0.45mg IV bolus 3 weekly
•
• Inj cyclophosphasmide 50mg/kg= 450mg , 3 weekly
• Landed up with veno
occlusive disease of liver
22/11/21 24/11/21 Between 22/11
and 27/11
20/12/21 26/12/21
Hb 7.0 5.8 9.8
TLC/DLC 4700 (N52L43) 1500 12,300
(N50L37)
Platelet 1.6 L 24,000 70,000
Ur/Cr
ALT/AST 5340(AST) 1885 4391/7349 1666 418
ALP 820
Bil(T/D) 4.8 5/1.8 7.3 6.6

5. Infantile Fibrosarcoma
H& E staining Myogenin negative

6. NTRK 3 and ETV6 Rearrangement by FISH in Infantile
fibrosarcoma

7. Drilon A et al. NEJM 2018
RR=80%

8. RR =60%

9. Larotrectinib Entrectinib
Inhibitor of all TRK isoforms Along with TRK isoforms , also against ROS1 and ALK
Approved for both pediatric and adult Most data from adults and children >12 years
Half life 3 hours Half life 20 hours
CNS penetration data is quite less Meaningful responses against intracranial solid tumors
and intracranial metastasis
100mg twice a day – Adults
100mg/ m2 BD in children with BSA <1
For pediatric patients (age 12 years or older)
with NTRK gene fusion–positive solid tumors, the
recommended daily dose is based on BSA:
600 mg (BSA greater than 1.50 m2),
500 mg (BSA 1.11–1.50 m2)
400 mg (BSA 0.91–1.10 m2).

10. • The response rates in infantile fibrosarcoma is 96%
• 87% of responding tumor remain responding at 1 year
• Median time to response is 1.8 mths

11. AIIMS tumor
board decision
? Amputation
? larotrectinib

12. Started on Larotrectinib w.e.f 17.02.2022

13. A B
C D
★
Pre
larotrectinib
Post 2 months of
larotrectinib

14. Newer therapies
• Infantile fibrosarcoma – The ultimate success story
• Pazopanib and other VEGF inhibitors (sorafenib/ propranolol)
• Tazemetostat – epithelioid sarcoma
• Anlotinib in synovial sarcoma
• ALK inhibitors – IMFT
• Hemangioendotheliomas – KFHE, Pediatric EHE
• Gamma secretase inhibitor/ sorafenib – fibromatosis
• Immunotherapy- Potentially active – type of soft tissue tumors

15. `
Rastogi S, Sankhala KK and Chawla SP. Recent Advances in Advanced Sarcoma Therapy: Medical Oncologist’s Perspective
. SM J Orthop. 2016; 2(3): 1040.

16. Propanolol in vascular tumors
Pasquier et al. 2016

17. Post propanolol vbl and mtx

18. Infantile solitary fibrous tumor
Permission taken from parents

19. Kaposiform hemangioendothelioma
Pre propranolol and
predniosolone
Post propranolol and
predniosolone-
complete response
Rastogi S. et al. Clinical Sarcoma Research 2020

20. Newer therapies
• Infantile fibrosarcoma – The ultimate success story
• Pazopanib and other VEGF inhibitors
• Tazemetostat – epithelioid sarcoma
• Anlotinib in synovial sarcoma
• ALK inhibitors – IMFT
• MEK inhibitor – NF1 with MPNST
• Gamma secretase inhibitor/ sorafenib – fibromatosis
• Immunotherapy- Potentially active – type of soft tissue tumors

21. Epithelioid sarcoma
• Extremely rare subtype
• Incidence ranges from .02-.05 per 100,000 population
• Data from developing countries is sparse due to various reasons.
• Propensity for lymph node involvement and local recurrences
Noujaim et al. Front. Oncol., 17 August 2015
Assi et al. Personalized medicine 2020

22. WHO classification
Classic type Epitheloid sarcoma Proximal Epitheloid sarcoma
Age group Young adults Middle age patients
Site Finger, hands and wrist Perineum, pelvis and genitourinary
tract
Pathologic characteristics Central Necrotizing component Lacks granulomatous component
but has typical rhabdoid
component.
Prognosis Less aggressive course Apparently more aggressive

23. • Pathology is characterized by deficiency of Integrase Interactor 1
(INI1) (nuclear)
• INI1 loss leads to unopposed constitutive activation of EZH2

24. Basket trial comprising of
multiple cohorts:
• Malignant Rhabdoid tumor
of Ovary
• Synovial Sarcoma
• Epithelioid
MPNST/Extraskeletal
mesenchymal
chondrosarcoma/myoepith
elial carcinoma/PR
chordoma
• Renal medullary carcinoma
• Epithelioid Sarcoma

25. Tazemetostat
• First oral in class inhibitor of EZH2
• Phase 2 open label basket study
• Primary end point – investigator objective response rate
• N=62
• 9/62 patients had response rate
• Median PFS 5.5 months and OS 19.0 months
Gounder et al. Lancet Oncol 2020.

26. Gounder et al. Lancet oncology 2020

27. Response rates to other therapies (n=20, AIIMS
Data (under publication)
• Gemcitabine / Docetaxel (in all lines)
• Given to 4 patients (only 1 partial response)
• Pazopanib ( in all lines)
• N=5
• RR 1/5=20%
• Tazemetostat
• N=5
• 1 partial response / 1 SD/2 PDs (1 response pending)
• Pembrolizumab - 2 patients (PDL1 10% and 0% respectively)
• Progressive disease, No Response

28. Post tazemetostat after 2 months
Rastogi S et al. FSOA 2021

29. 2nd patient pediatric patient
• Misdiagnosed initially in outside centre as myoepithelioma soft tissue
near scapula.
• After multiple surgeries and metastatic disease came to us
• Started on doxorubicin single agent- PD
• Syp Tazemetostat was started on compassionate basis (Courtesy
Epizyme)

30. Pre and post tazemetostat (progressive
disease)

31. Newer therapies
• Infantile fibrosarcoma – The ultimate success story
• Pazopanib and other VEGF inhibitors
• Tazemetostat – epithelioid sarcoma
• Anlotinib in synovial sarcoma
• ALK inhibitors – IMFT
• MEK inhibitor – NF1 with MPNST
• Gamma secretase inhibitor/ sorafenib – fibromatosis
• Immunotherapy- Potentially active – type of soft tissue tumors

32. Jan 2021
Maximum intensity projection(A) and trans-axial CT(B) and fused PET/CT(C)
shows multiple variable sized lung subpleural and parenchymal nodules
with some showing necrotic changes in bilateral lungs with largest
measuring 3.3x3.5cm along with associated mild atelectasis changes noted
in left lung lower lobe with mediastinal lymph nodes .
A B
C
20 year girl with
metastatic synovial
sarcoma post
ifosfamide /
doxorubicin
Gemcitabine/ docetaxel

33. March 2021
PARTIAL RESPONSE ON high dose IFOSFOMIDE
Multiple subpleural and parenchymal nodules shows decrease in
size and number with largest parenchymal lung nodule measuring –
3.1x2.5 cm
B
C
A

34. • Now surgery ? SBRT ? When
• After discussion with family – started on pazopanib 600mg per day

35. JUN 2021
A
GOOD PARTIAL RESPONSE ON PAZOPANIB
Multiple subpleural and parenchymal nodules shows decrease in
size and number with largest parenchymal lung nodule measuring
– 1.8x1.9 cm
C
B

36. Nov 2021
PROGRESSIVE DISEASE ON PAZOPANIB
Appearance of multiple new pleural based and parenchymal nodules with
increase in size of the previously noted nodules-largest measuring
A B
C

37. • Next line??

38. FEB 2021
ON ANLOTINIB-PARTIAL RESPONSE
Decrease in size ,uptake and number of most of the parenchymal and subpleural lesions
in bilateral lungs noted with increase in associated necrotic component and largest lesion
measuring 1.0x2.5cm.

39. Anlotinib

40. APROMISS trial – Anlotinib in synovial sarcoma
• Phase 3 trial with 2:1 randomization to dacarbazine (52 :27)
• Primary end point – Progression free interval
• PFS was 2.89 months (95% CI: 2.73 – 6.87) for AL3818 and 1.64
(95% CI: 1.45 – 2.70) for D.
PFR at 4 months 6 months 12 months
Anlotinib 48% 42% 26.9%
Dacarbazine 14% 11% 3.7%
Brian Van Tine ASCO 2021 (abstract)

41. Newer therapies
• Infantile fibrosarcoma – The ultimate success story
• Pazopanib and other VEGF inhibitors
• Tazemetostat – epithelioid sarcoma
• Anlotinib in synovial sarcoma
• ALK inhibitors – IMFT
• Gamma secretase inhibitor/ sorafenib – fibromatosis
• Immunotherapy- Potentially active – type of soft tissue tumors

42. • Total of 20 patients
• ALK positive n=12
• ALK negative n=8
Schoffski et al. EJC 2021

43. Schoffski et al EJC 2021

45. Patient 1 (infantile IMFT)
Rastogi S. et al. Ecancer medicine 2021
Pre ceritinib
Post ceritinib

46. ALK break apart FISH positive

47. Newer therapies
• Infantile fibrosarcoma – The ultimate success story
• Pazopanib and other VEGF inhibitors
• Tazemetostat – epithelioid sarcoma
• Anlotinib in synovial sarcoma
• ALK inhibitors – IMFT
• MEK inhibitor – NF1 with MPNST
• Gamma secretase inhibitor/ sorafenib – fibromatosis
• Immunotherapy- Potentially active – type of soft tissue tumors

50. 26.07.2022
16.04.2022
24.05.2022
Tramatenib-
Partial
Response
Pazopanib –
progressive
disease
16 year old girl
with NF1 and
MPNST
Post IA
Post
pazopanib
partial
response and
subsequent
progressive
disease

51. Newer therapies
• Infantile fibrosarcoma – The ultimate success story
• Pazopanib and other VEGF inhibitors
• Tazemetostat – epithelioid sarcoma
• Anlotinib in synovial sarcoma
• ALK inhibitors – IMFT
• MEK inhibitor – NF1 with MPNST
• Gamma secretase inhibitor/ sorafenib – fibromatosis
• Immunotherapy- Potentially active – type of soft tissue tumors

52. Desmoid tumor

53. • Double blind phase 3 trial
• n =87
•Randomized to sorafenib (400mg per day or matching
placebo)
Gounder et al. NEJM 2018

54. 2 year PFR- 81% vs 36%

55. Sorafenib for advanced desmoid tumors
• Objective response rates were 33% vs 20% (sorafenib arm vs placebo
arm)
• In the patients who had response – Median time to response was 9.6
months

56. Pretreatment Posttreatment
3 months of sorafenib

57. Sorafenib
• 8 year old Child was put on Observation till July 2018.
• Child received Sorafenib between November 2018 to March 2020.
T2/STIR image showing a large lobulated and
heterogenously hyperintense tumor involving the
anterior and lateral compartment of thigh.
14.5(SI)x5(AP)x 3.8(TR) cm in size
Overlying skin and soft tissue is intact
Neurovascular bundle is intact
Underlying bone is intact with no signs of erosion
and there is no extension into joint space

58. Stable disease on Sorafenib
October2019 March 2020

59. Progressive disease on Sorafenib
The original lesion was similar in size but there is a
significant interval increase in one of the non
fibrous soft tissue lesion consistent with
progressive disease
The child was diagnosed to have progressive
disease and was started on Pazopanib

60. “Cross-talk” between b-Catenin/Wnt and Notch
Signaling
Bui and Kummar, Oncotarget, 2017, Vol. 8, (No. 53)
GSI
Confidential |

61. Pre and post Gamma secretase inhibitor

62. Newer therapies
• Infantile fibrosarcoma – The ultimate success story
• Pazopanib and other VEGF inhibitors
• Tazemetostat – epithelioid sarcoma
• Anlotinib in synovial sarcoma
• ALK inhibitors – IMFT
• MEK inhibitor – NF1 with MPNST
• Gamma secretase inhibitor/ sorafenib – fibromatosis
• Immunotherapy- Potentially active – type of soft tissue tumors

63. Immunotherapy in Soft tissue sarcomas and
LMS
• Sarc 028 study – 7 out of 40 patients had objective response rate
(UPS, LPS, SS)1
• In SARC 028 no patient with leiomyosarcoma had any response (n=10)
• ASPS – Immunotherapy sensitive – RR 42% 2
1.Tawbi et al. SARC 028 Lancet 2017
2.CTOS 2018

64. Case of ASPS on nivolumab since Sept 2019
Journal of adolescent and young adult oncology. 2020
PDL1 =0%
22 year girl with
metastatic /
progressive ASPS

65. Baseline
After 22cycles of
immunotherapy
After 6 cycles of
immunotherapy
ASPS
Baseline
ASPS
Post 6 cycles
nivolumab
ASPS
Post 50 cycles
nivolumab

66. Newer therapies
• Infantile fibrosarcoma – The ultimate success story
• Pazopanib and other VEGF inhibitors
• Tazemetostat – epithelioid sarcoma
• Anlotinib in synovial sarcoma
• ALK inhibitors – IMFT
• MEK inhibitor – NF1 with MPNST
• Gamma secretase inhibitor/ sorafenib – fibromatosis
• Immunotherapy- Potentially active – type of soft tissue tumors