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. 2020:4:79-90.
doi: 10.1200/po.19.00287. Epub 2020 Feb 14.

Response and mechanisms of resistance to larotrectinib and selitrectinib in metastatic undifferentiated sarcoma harboring oncogenic fusion of NTRK1

Matthew L Hemming  1   2 , Michael J Nathenson  2 , Jia-Ren Lin  3   4 , Shaolin Mei  3   4 , Ziming Du  3   5 , Karan Malik  2 , Adrian Marino-Enriquez  5 , Jyothi P Jagannathan  6 , Peter K Sorger  3   4   7 , Monica Bertagnolli  8 , Ewa Sicinska  9 , George D Demetri  2   4 , Sandro Santagata  3   4   5
Affiliations

Response and mechanisms of resistance to larotrectinib and selitrectinib in metastatic undifferentiated sarcoma harboring oncogenic fusion of NTRK1

Matthew L Hemming et al. JCO Precis Oncol. 2020.
No abstract available

Keywords: Drug Resistance; KRAS; NTRK translocation; Sarcoma; TRK inhibitor.

PubMed Disclaimer

Conflict of interest statement

Peter K. Sorger

Leadership: RareCyte, Merrimack, Applied BioMath

Stock and Other Ownership Interests: RareCyte, Merrimack Pharma, Applied BioMath, Glencoe Software

Honoraria: Novartis

Research Funding: Merck (Inst)

Monica Bertagnolli

Research Funding: AbbVie (Inst), Agenus (Inst), Astellas Pharma (Inst), AstraZeneca (Inst), Breast Cancer Research Foundation (Inst), Bristol-Myers Squibb (Inst), Celgene (Inst), Complion (Inst), Exelixis (Inst), Genentech (Inst), GHI Pharma (Inst), Gilead Sciences (Inst), GlaxoSmithKline (Inst), Incyte (Inst), Jazz Pharmaceuticals (Inst), Leidos (Inst), Eli Lilly (Inst), Matrex (Inst), Mayo Clinic (Inst), MGH (Inst), Millennium Pharmaceuticals (Inst), Novartis (Inst), Patient-Centered Outcomes Research Institute (PCORI) (Inst), Pfizer (Inst), Robert Wood Johnson Foundation (Inst), Sagerock Advisors (Inst), Taiho Pharmaceutical (Inst), Bayer Health (Inst), Eisai (Inst), Leidos (Inst), Lexicon (Inst), Merck (Inst), Pharmacyclics (Inst), Takeda (Inst), Tesaro (Inst), Baxalta (Inst), Sanofi (Inst), Teva (Inst), Janssen (Inst), Merck (Inst)

Uncompensated Relationships: Leap Therapeutics, Syntimmune, Syntalogic

Open Payments Link: https://openpaymentsdata.cms.gov/physician/114497/summary

George D. Demetri

Leadership: Blueprint Medicines, Merrimack

Stock and Other Ownership Interests: Blueprint Medicines, G1 Therapeutics, Bessor Pharma, Caris Life Sciences, Champions Oncology, Merrimack, Erasca

Consulting or Advisory Role: Bayer, Pfizer, Novartis, EMD Serono, Sanofi, Janssen Oncology, PharmaMar, Daiichi Sankyo, Blueprint Medicines, WIRB-Copernicus Group, ZIOPHARM Oncology, Polaris, G1 Therapeutics, Caris Life Sciences, Adaptimmune, Ignyta, Genentech, Loxo, Mirati Therapeutics, M.J. Hennessey/OncLive, Medscape, ICON Clinical Research

Research Funding: AbbVie (Inst), Janssen Oncology (Inst), Bayer (Inst), Novartis (Inst), Pfizer (Inst), Ignyta (Inst), Genentech (Inst), Loxo (Inst), AbbVie (Inst), Epizyme (Inst), Adaptimmune (Inst), GlaxoSmithKline (Inst)

Patents, Royalties, Other Intellectual Property: Patent on use of imatinib for GI stromal tumor, receive minor royalty payment from Dana-Farber after license between Dana-Farber and Novartis.

Sandro Santagata

Consulting or Advisory Role: RareCyte

Patents, Royalties, Other Intellectual Property: US9696313B2 (HSF1 as a marker in tumor prognosis and treatment), US20150241436A1 (Hsf1 and hsf1 cancer signature set genes and uses relating thereto), US20170037480A1 (Hsf1 in tumor stroma), US20170037480A1 (Hsf1 in tumor stroma), US20180306796A1 (Methods and compositions relating to proteasome inhibitor resistance), Combination Treatments of Hsp90 Inhibitors for Enhancing Tumor Immunogenicity and Methods of Use Thereof (application pending), Targeted Manipulation of the Proteasome Subunit Expression Levels as a Method for Curing Cancer (application pending).

No other potential conflicts of interest were reported.

Figures

FIG 1.
FIG 1.
Treatment timeline and assessments. (A) Timeline of diagnosis and therapeutic interventions. Surgeries are numbered sequentially, and boxed lettering indicates the time of computed tomography (CT) and positron emission tomography (PET)-CT imaging. (B-E) Contrast-enhanced CT scans (top panels) and PET-CT images (bottom panels) from patient staging scans as indicated on the timeline. (F) Plasma levels over time of selitrectinib at the indicated dose levels. Data from each dosing point are derived from cycle 1, day 1 pharmacokinetic studies. Dashed lines indicating the 90% inhibitory concentration (IC90) of wild-type (WT) and G595R-mutant TRKA are shown. BID, twice a day; ctDNA, circulating tumor DNA; POD, progression of disease; S, surgery.
FIG 2.
FIG 2.
Expression profiling of selitrectinib-sensitive and -resistant samples. (A) Plot of mapped RNA-seq reads at the NTRK1 locus for an ETV6-NTRK3 tumor and TPM3-NTRK1 tumors from surgery (S) 3 and S5. (B) Heatmap of RNA-seq data demonstrating expression of NTRK genes and fusion partners. (C and D) Hallmark gene sets for KRAS signaling up and inflammatory response comparing S3 and S5. (E) Butterfly plot of all Reactome, KEGG, and Hallmark gene sets (n = 910) comparing S3 and S5 tumors. Immune and inflammatory gene sets are outlined in green. (F) CIBERSORT analysis of S3 and S5 tumors showing relative leukocyte abundance. Cell types with nonzero leukocyte fraction are shown. (G) Heatmap showing relative expression of select immune-related genes. FDR, false discovery rate; NES, normalized enrichment score.
FIG 3.
FIG 3.
Multiplexed imaging of the immune microenvironment in serial tumor resections. (A) Tissue-based cyclic immunofluorescence images from surgery (S) 2, S3, and S5 samples demonstrating staining for tropomyosin receptor kinase (TRK), CD45, and CD68, with lower panels representing magnified images of the upper panels. (B) Immune cell counts, with digital images from the indicated single or multiplexed antibodies processed as previously described. Cell counts were calculated frame by frame and are represented as box plots, with the median indicated in red. (C) Global distribution of cells staining highest for TRK (contour map) and CD68+ cells (heatmap, with red indicating higher cell density) in S3 and S5. (D and E) Histograms representing the number of CD68+ or CD8a+ cells neighboring TRKhigh cells. Cumulative probabilities in each imaged frame are shown as a box plot (inset). (F) Representative staining of programmed cell death 1 (PD-1) and programmed death ligand 1 (PD-L1) in samples S3 and S5, respectively. (G) Proximity probability of cells staining positive for PD-1 and PD-L1, with histogram representing the number of PD-L1–positive cells neighboring PD-1–positive cells. Cumulative probabilities in each imaged frame are shown as a box plot (inset). A two-sample t test was used to compare groups, with P values indicated; the frame numbers in each sample are 33 (S2), 127 (S3), and 168 (S5).
FIG A1.
FIG A1.
Expression profiling of NTRK translocated models. (A) Plot of mapped RNA-seq reads at the NTRK1 locus for an ETV6-NTRK3 tumor and TPM3-NTRK1 tumors from surgery (S) 3, S3 patient-derived xenograft (PDX), S3 cell line, S5, and S5 PDX. (B and C) Hallmark gene set for KRAS signaling up and inflammatory response comparing S3 and S5 PDX grown in athymic, T-cell–deficient mice. FDR, false discovery rate; NES, normalized enrichment score.
FIG A2.
FIG A2.
Hedgehog pathway gene expression. (A) Expression of genes in the KEGG Hedgehog signaling pathway gene set. (B) Heatmap of RNA-seq data showing expression of select genes essential to Hedgehog cellular signaling. PDX, patient-derived xenograft; S, surgery.
FIG A3.
FIG A3.
Colocalization of CD8a+ and TRKhigh cells. Global distribution of cells staining highest for tropomyosin receptor kinase (TRK; contour map) and CD8a+ cells (heatmap, with red indicating higher cell density) in surgery (S) 3 and S5.
See this image and copyright information in PMC

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