Anastasia Zherlitsyna — timeline

UNIVERSITÄTSmedizin uct | University Center for Tumor Diseases MAINZ Head: Prof. Dr. medical Thomas Kindler Dr. med. Marius Fried uct-tumorboards@unimedizin-mainz.de Mainz, March 9, 2023

Tumor Board Personalized Oncology

Date: 06.03.2023

Patient: Zherlitsyna, Anastasia *25.04.1976

Diagnosis: Leiomyosarcoma of the uterus, T2NxM1 (HEP, PER, omentum majus; failed ovary),

Question: Clinical relevance of the molecular findings

Conference participants

Molecular Oncology: Desuki, Fried, Hafez

III. Medical Clinic: -

Pathology: Wagner

Molecular pathology: Hartmann

Pediatrics: -

Bioinformatics: Ritzel

Virology: Tomicic-Christmann

Human genetics: Schweiger, Pieh

Gynecology: Schmidt

DNPM coordination: Bremer

Documentation: Kuncke, Ozdemir

External: Grundheber (MVZ Brüderkrankenhaus Trier)

Teleconference: none

Findings

KIT c.1668_1676delGTGGAAGGT/ p.Q556_V559delinsH 42.49

TPMT c.719A>G/p.Y240C 39.83

TPMT c.460G>A/p.A154T 49.93

PPM1D c.1080G>C/p.Q360H -

Comment: BRCA1/2, CHEK2,PALB2 WT

Gene Translocation

MTAT-CDKN2B-AS1_004

KIF5B-MET

BRD3-NUTM1

Conference resolution

Using OncoMine, CleanPlex Hereditary Cancer Panel, changes were detected with the following therapeutic recommendations:

MOLECULAR EVIDENCE LEVEL

• 1st therapeutic approach

MET-Inhibitor m2A

• KIF5B-MET is the result of a fusion of KIF5B and MET and results in constitutive MET Kinase Activity and transformation ability in culture (PMID: 29284707, PMID: 30015159).

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• In a clinical case study, treatment with Crizotinib resulted in a response with 74% tumor size reduction and clinical benefit for more than 8 months in a patient with NSCLC and KIF5B-MET fusion (PMID: 29284707).

• In a clinical case study, treatment with capmatinib in an NSCLC patient with KIF5B-MET resulted in a 9-month response (PMID: 36033470).

• In a clinical case study, treatment with cabozantinib in a pediatric patient with RBPMS-MET fusion and PDGFRB overexpression of infantile fibrosarcoma-like tumor resulted in clinical and radiological disease-free survival of at least 9 months (PMID: 33028644).

• MET inhibitors showed good efficacy in MET-KIF5B fusion in other tumor types.

MOLECULAR EVIDENCE LEVEL

• 2nd therapeutic approach

Multikinase Inhibitor m2A

• KIT Q556 V559delinsH results in the deletion of 4 amino acids in the juxtamembrane domain (exon 11) of the Kit protein combined with the insertion of a histidine (H) at the same spot (PMID: 16226710). Q556_V559delinsH has not been characterized, however, similar Kit exon 11 deletions are activated (PMID: 9438854, PMID: 15365079) and are therefore predicted to lead to an enhancement of Kit protein function

• lamtinib/dasatinib/nilotinib/ripretinib is approved in melanoma with KIT mutations.

• Imatinib/Sunitinib is included in the guidelines for patients with GIST with sensitizing mutations such as KIT exon 11 mutations as adjuvant therapy for patients with localized disease and as first-line therapy for patients with locally advanced, unresectable, or metastatic disease (PMID: 34560242; ESMO. org).

• In a clinical case study, treatment with Imatinib resulted in SD lasting at least 3 years in a patient with extraskeletal myxoid chondrosarcoma carrying KIT W557G (PMID: 34446510).

• In a phase II study, treatment with Nilotinib resulted in an ORR of 26.2% (11/42) in melanoma patients with KIT mutations, including 11 patients with PR, an mDOR of 7.1 months, and an OS of 18 months (PMID: 28327988).

• In KIT mutations, sunitinib and imatinib showed good efficacy in GIST and sarcoma.

The combination of a molecularly targeted therapy with other systemic or local therapy modalities is at the discretion of the treating physician and is not ruled out by the Tumor Board recommendation.

• Human Genetics Counseling

• Not required

Epicrisis:

There is a clinical rationale for the use of MET inhibitors when MET-KIF5B fusion is detected in other tumor types. In addition, Imatinib and Sunitinib show good efficacy in GIST and sarcoma with KIT mutation.

Legend

• Findings that support the therapeutic approach

• Findings that do not support the therapeutic approach

• Reference that supports the therapeutic approach

• Reference that does not support the therapeutic approach

• Range of courses currently available in Germany

• Study offer, currently not available in Germany but in other European countries

• Course offering, currently not available in Europe

CR: complete response, PR: partial response, DCR: disease control rate, ORR: objective response rate, gof: gain of function, lof: loss of function, VAF: variant allele frequency, TCN: total copy number, OS: overall survival, PFS: progression free survival

Evidence level

• m1A In the same tumor entity, the predictive value of the biomarker or clinical efficacy was demonstrated in a biomarker-stratified cohort of an adequately powered prospective study or meta-analysis.

• m1B In the same tumor entity, the predictive value of the biomarker or clinical efficacy was demonstrated in a retrospective cohort or case-control study.

• m2A In another tumor entity, the predictive value of the biomarker or clinical efficacy was demonstrated in a biomarker-stratified cohort of an adequately powered prospective study or meta-analysis.

• m2B In another tumor entity, the predictive value of the biomarker or clinical efficacy was demonstrated in a retrospective cohort or case-control study.

• m2C Irrespective of the tumor entity, clinical efficacy has been demonstrated in one or more case reports in the presence of the biomarker.

• m3 Preclinical data (in vitro/in vivo models, functional studies) show an association of the biomarker with the efficacy of the medication, which is supported by a scientific rationale.

• m4 A scientific, biological rationale suggests an association of the biomarker with the efficacy of the medication, which is not yet supported by (pre-)clinical data.

• R1 Evidence for therapy resistance from clinical trials in the same entity

• R2 Evidence for therapy resistance from clinical studies in different entities or from in-vitro investigations

• Prefix u: Unclear evidence with contradictory study results, the evidence is given that is clinically most likely (comparison of the quality of the studies: prospective phase III, ...)