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Basket trial of TRK inhibitors demonstrates efficacy in TRK fusion-positive cancers

Journal of Hematology & Oncology201811:78

https://doi.org/10.1186/s13045-018-0622-4

  • Received: 20 March 2018
  • Accepted: 29 May 2018
  • Published:

Abstract

Unlike many conventional cancers with preferential patterns of oncogenic genetic alterations, TRK fusions resulting from NTRK1/2/3 genetic alterations drive oncogenic transformations in more than 20 different malignancies over diverse tissue/cell lineages, in both children and adults. A recent “basket” study of larotrectinib, a TRK inhibitor, has demonstrated significant efficacy in TRK fusion-positive tumors of all types from infants to the elderly. Here, we discuss the larotrectinib study and perspectives and challenges in developing “tumor-agnostic” targeted therapies in rare tumors.

Background

Traditionally, cancers are classified and treated based on their pathologic classification and tissue of origin. Advances in sequencing technology and large-scale cancer genomics effort (e.g., the International Cancer Genome Consortium and The Cancer Genome Atlas (TCGA) have identified many targetable driver genetic alterations across different tumor types and have shifted the cancer sub-classification based on driver genetic alterations. For example, lung adenocarcinomas are further sub-classified by KRAS and EGFR mutations and ALK and ROS1 translocation. Most “driver” genetic alterations are preferentially found in certain cell/tissue lineages. For example, the BRAFV600 mutation occurs at high frequencies in specific tumor types, e.g., melanoma, thyroid cancer, hairy cell leukemia, Langerhans cell histiocytosis, and colorectal cancer, and at significantly lower frequencies in other tissue lineages. The responses to BRAFV600-targeted therapies are not uniform, with some cancer types (e.g., colorectal cancer) exhibit tissue lineage-specific primary resistance [13], underlining the importance of the tissue lineage-specific cellular context.

TRK fusions are rare but drive oncogenesis in diverse tissue lineages

The NTRK1, NTRK2, and NTRK3 genes, encoding the tropomyosin receptor kinases (TRK), TRKA, TRKB, and TRKC, respectively, are receptor tyrosine kinases that are normally expressed in the nervous system [4]. Physiologically, TRK receptor tyrosine kinases are activated by binding of mature neurotrophins, which mediate neuronal survival and synaptic plasticity in the central nervous system [4]. NTRK genetic alterations (e.g., translocations) resulting in TRK fusion proteins can lead to ligand-independent activation of TRK kinases and drive oncogenic transformation [57]. To date, TRK fusions are found in more than 20 different tumor types. With the exception of several rare tumor types (e.g., secretory breast carcinoma, mammary analog secretory carcinoma, congenital fibrosarcomas, and congenital mesoblastic nephroma), the majority of the TRK fusions occur in low frequencies in a variety of common cancers over a diverse tissue/cell lineages (e.g., lung adenocarcinoma, sarcoma, acute myeloid leukemia, colorectal cancer) [6, 7] (Table 1). The rarity of TRK fusions and the heterogeneity of tumor types present incredible challenges to clinically evaluate TRK inhibitors. Diagnostically, because of large introns, these fusions are difficult to detect using multiplex targeted exome capture panels (e.g., FoundationOne®, MSK-IMPACT™).
Table 1

Rare TRK fusions in diverse tumor types

Tumor type

NTRK1/2/3 involved (frequency)

Detection methods

Ph-like acute lymphoblastic leukemia

NTRK3 (1/154)

RNA-seq, whole-genome seq, whole-exome seq [18]

Appendiceal adenocarcinoma

NTRK (unspecified) (2/97)

MALDI-TOF mass spectroscopy genotyping (Sequenom), targeted NGS (MSK-IMPACT) [19]

Astrocytoma

NTRK2 (3/96)

RNA-seq, whole-genome seq [20]

Breast invasive carcinoma

NTRK3 (1/1072)

RNA-seq (TCGA) [21]

Intrahepatic cholangiocarcinoma

NTRK1 (1/28)

Targeted NGS [22]

Colon adenocarcinoma

NTRK1 (8/1559)

IHC, RT-PCR [23]

NTRK1 (1/66)

IHC, RT-PCR [24]

NTRK3 (2/286)

RNA-seq (TCGA) [21]

GIST

NTRK3 (1/186)

Targeted NGS (Foundation Medicine) [25]

NTRK3 (1/31)

RNA-seq, FISH, RT-PCR [26]

Glioblastoma

NTRK1 (1/157)

RNA-seq (TCGA) [21]

NTRK1 (2/185)

RNA-seq (TCGA and other) [27]

NTRK1 (3/115)

Targeted NGS [28]

Brain low-grade glioma

NTRK2 (2/461)

RNA-seq (TCGA) [21]

Pediatric DIPG and non-brainstem high-grade glioma

NTRK1 (3/127)

RNA-seq, whole-genome seq [29]

NTRK2 (3/127)

RNA-seq, whole-genome seq [29]

NTRK3 (2/127)

RNA-seq, whole-genome seq [29]

Head and neck squamous cell carcinoma

NTRK2 (1/411)

RNA-seq (TCGA) [21]

NTRK3 (1/411)

RNA-seq (TCGA) [21]

Congenital mesoblastic nephroma

NTRK3 (5/6)

RT-PCR, FISH [30]

NTRK3 (10/15)

RT-PCR [31]

NTRK3 (13/19)

FISH [32]

Infantile (congenital) fibrosarcoma

NTRK3 (10/11)

RT-PCR, IHC [33]

NTRK3 (5/5)

RT-PCR, FISH [30]

Lung adenocarcinoma

NTRK1 (3/91)

Targeted NGS (Foundation Medicine), FISH [34]

NTRK2 (1/513)

RNA-seq (TCGA) [21]

Breast secretory carcinoma

NTRK3 (12/13)

RT-PCR, FISH [35]

NTRK3 (9/9)

FISH, targeted NGS [36]

Mammary analogue secretory carcinoma (MASC) of salivary glands

NTRK3 (13/14)

RT-PCR, FISH [37]

NTRK3 (15/15)

FISH [38]

NTRK3 (5/6)

FISH, targeted NGS [36]

NTRK3 (16/20)

RT-PCR, FISH [39]

Melanoma (skin cutaneous)

NTRK3 (1/374)

RNA-seq (TCGA) [21]

Spitz tumors and spitzoid melanoma

NTRK1(23/140)

Targeted NGS(Foundation Medicine), FISH, IHC [40]

Sarcoma (NOS)

NTRK1 (1/103)

RNA-seq (TCGA) [21]

Uterine sarcoma

NTRK1 (3/97)

RNA-seq, FISH, IHC, targeted NGS [41]

NTRK3 (1/97)

RNA-seq, FISH, IHC, targeted NGS [41]

Thyroid carcinoma

NTRK1 (5/498)

RNA-seq (TCGA) [21]

NTRK3 (7/498)

RNA-seq (TCGA) [21]

Papillary thyroid carcinoma

NTRK1 (15/119)

RT-PCR [42]

NTRK1 (2/38)

Southern [43]

NTRK1(pediatric) (1/27)

Targeted NGS [44]

NTRK3(radiation-associated) (2/26)

RNA-seq [45]

NTRK3(radiation-associated) (9/62)

RNA-seq [46]

NTRK3(sporadic) (3/151)

RNA-seq [46]

NTRK3(pediatric) (6/27)

Targeted NGS [44]

TRK inhibitor larotrectinib demonstrates efficacy in a basket trial

Recently, Drilon and colleagues reported a phase I/II clinical trial to evaluate the safety and efficacy of larotrectinib, a highly selective small-molecule inhibitor of all three TRK proteins, using a novel “basket” trial design that enrolled patients based on NTRK genetic alterations regardless of age or tumor types [8]. A total of 55 patients (ages 4 months–76 years old) with 16 different tumor histologies were treated on three protocols, and the results were pooled. The investigators found that larotrectinib was generally well-tolerated with < 5% treatment-related grade 3 or 4 adverse events. The overall RECIST response rate was 75% (95% confidence interval, 61–85) by independent review and 80% (95% confidence interval, 67–90) by investigator assessment. At 1 year, 71% of patients are with ongoing responses and 55% of patients remain progression-free. The median duration of response and progression-free survival has not been reached after 8.3 and 9.9 months of median follow-up, respectively. Importantly, responses were observed in nearly all tumor types and age groups. Three of the six patients who did not response to larotrectinib (primary resistance) had undetectable TRK proteins by immunohistochemistry (IHC) despite molecularly identified TRK fusion at a screening in local laboratories. In the ten patients who progressed after an initial response for at least 6 months, nine had identifiable secondary resistant mutations in NTRK1 or NTRK3, including substitutions in the solvent front position (NTRK1 G595R or NTRK3 G623R), gatekeeper mutation (NRTK1 F589 L), and the xDFG position NTRK1 G667S or NTRK3 G696A). The acquired resistance mechanisms have been described for other oncogenic kinase-targeted therapies [911]. The next generation of TRK inhibitors is in development to overcome the acquired resistance in TRK [7, 12] (see Table 2).
Table 2

TRK inhibitors currently in clinical development

Drug name

Targets

Development stage

Clinical trial identifier

Company

LOXO-101 (larotrectinib)

NTRK1/2/3

Phase II

NCT02122913

NCT02637687

NCT02576431

NCT03213704

Loxo Oncology

LOXO-195

NTRK1/2/3 (resistant)

Phase I/II

NCT03215511

Loxo Oncology

RXDX-101 (entrectinib)

NTRK1/2/3, ALK, ROS1

Phase I/II,

Phase II,

Phase I/Ib

NCT02097810

NCT02568267

NCT02650401

Ignyta

TPX-0005 (ropotrectinib)

NTRK1/2/3, ALK, ROS1 (resistant), JAK2, SRC, DDR1, FAK

Phase I/II

NCT03093116

TP Therapeutics

LY2801653 (merestinib)

NTRK1/2/3, MET, MST1R, FLT3, AXL, MERTK, TEK, ROS1, DDR1/2, MKNK1/2

Phase II

NCT02920996

Eli Lilly and Company

DS-6051b

NTRK1/2/3, ROS1

Phase I

NCT02675491

NCT02279433

Daiichi Sankyo

PLX7486

NTRK1/2/3, CSF1R

Phase I

NCT01804530

Plexxikon/Daiichi Sankyo

MGCD516 (sitravatinib)

NTRK1/2/3, MET, KIT, PDGFRA, KDR, DDR2, RET, CBL

Phase I/Ib

NCT02219711

Mirati Therapeutics

Future perspectives

The study by Drillon et al. [8] comes on the heels of several basket trials, including the AKT inhibitor AZD5363 in AKT1 E17K-mutant tumors [13], the PD1 inhibitor pembrolizumab in mismatch repair deficient tumors [14], and the pan-HER kinase inhibitor neratinib in HER2- and HER3-mutant tumors [15], with variable clinical success. This current study provides a compelling case for tumor-agnostic, molecular-driven “basket” approaches for clinical investigations of rare driver mutations across diverse tumor types. It paves a clinical pathway to effective therapeutics for patients with rare tumors and rare driver mutations. In addition to larotrectinib, there is a variety of TRK inhibitors currently in clinical development (Table 1), including next-generation TRK inhibitors that can overcome acquired resistance (e.g., LOXO-195, TPX-0005).

Despite the early clinical success with new generations of TRK inhibitors and novel trial design, the challenges remain for real-time identification of rare TRK fusions. What would be the ideal diagnostics methodology? DNA-based next-generation sequencing (NGS) assays have relatively high false-negative and false-positive rate and do not identify novel fusions. RNA-based NGS assays (e.g., Archer Dx) can detect novel fusions and has reasonable sensitivity. However, both DNA- and RNA-based NGS assays can be costly and effort intensive. Alternatively, IHC of TRK is a sensitive and efficient method for identification of TRK expression [16, 17]. Nevertheless, it would not readily discriminate TRK fusion arising through genetic alterations where TRK inhibitors can be highly effective from full-length TRK expression in tumors inherited through development where the functional significance of TRK expression and clinically impact is unknown. TRK IHC can also be associated with false positives in certain tissue and tumor types. Furthermore, unlike NGS-based assays, IHC cannot be easily multiplexed into a panel without added cost and effort. While TRK IHC can be easily justified for high-prevalence tumors (e.g., congenital fibrosarcoma or secretory breast carcinoma), its role in low-prevalence common tumors such as colorectal cancer becomes more debatable. Importantly, it is unclear which diagnostic modality, NGS of NTRK alterations or IHC of TRK expression, is more predictive of response to TRK inhibitors. In the NEJM by Drilon et al., three out of the six non-responders to larotrectinib did not have centrally confirmed TRK expression by pan-TRK IHC, despite the detection of NTRK rearrangement by NGS in the local laboratory [8]. This observation suggests that TRK expression by IHC may be necessary for response. Currently, Pan-TRK IHC and Illumina NGS (RNA and DNA assays in one design) are both being developed as companion diagnostics to larotrectinib and other TRK inhibitors.

With a shifting paradigm of identifying genetic alterations in a tumor-agnostic manner, the development of a single assay that can identify multiple types of actionable genetic alterations would be paramount. In the meantime, TRK IHC would be a reasonable initial diagnostics for rare tumors where TRK fusions are frequent, and possibly common tumors where driver mutations are absent.

Declarations

Funding

This work was supported by grants from the NIH/NCI (R01CA193837, YC; R01CA208100, YC; P50CA092629, YC; U54CA224079, YC; P50CA140146, PC; DP2 CA174499, PC; R01CA228216, PC), FDA/OPD (R01FD005731, PC), US DOD (W81XWH-10-1-0197, PC), Prostate Cancer Foundation (YC), and Bloomberg Family Foundation (NTAP Collins Scholar, PC).

Availability of data and materials

All supporting data and materials have been included within the article.

Authors’ contributions

Both authors wrote, revised, and approved the final manuscript.

Ethics approval and consent to participate

Not applicable.

Competing interests

Both authors declare that they have no competing interests.

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Authors’ Affiliations

(1)
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
(2)
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, USA
(3)
Department of Medicine, Weill Cornell Medical College, New York, USA

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Copyright

© The Author(s). 2018

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