Annals of Oncology 30 (Supplement 8): viii23–viii30, 2019

doi:10.1093/annonc/mdz282

REVIEW

TRK inhibitors in TRK fusion-positive cancers

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A. Drilon1,2
1
Memorial Sloan Kettering Cancer Center, New York; 2Weill Cornell Medical College, New York, USA

Correspondence to: Dr. Alexander Drilon, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, Thoracic Oncology Service,
300 E 66th St. BAIC 1253, New York, NY 10022, USA. Tel: þ646-888-4206; E-mail: [email protected]

TRK fusions are oncogenic drivers of various adult and paediatric cancers. The first-generation TRK inhibitors, larotrectinib and
entrectinib, were granted landmark, tumour-agnostic regulatory approvals for the treatment of these cancers in 2018 and 2019,
respectively. Brisk and durable responses are achieved with these drugs in patients, including those with locally advanced or
metastatic disease. In addition, intracranial activity has been observed with both agents in TRK fusion-positive solid tumours
with brain metastases and primary brain tumours. While resistance to first-generation TRK inhibition can eventually occur, next-
generation agents such as selitrectinib (BAY 2731954, LOXO-195) and repotrectinib were designed to address on-target
resistance, which is mediated by emergent kinase domain mutations, such as those that result in substitutions at solvent front
or gatekeeper residues. These next-generation drugs are currently available in the clinic and proof-of-concept responses have
been reported. This underscores the utility of sequential TRK inhibitor use in select patients, a paradigm that parallels the use of
targeted therapies in other oncogenic driver-positive cancers, such as ALK fusion-positive lung cancers. While TRK inhibitors
have a favourable overall safety profile, select on-target adverse events, including weight gain, dizziness/ataxia and
paraesthesias, are occasionally observed and should be monitored in the clinic. These side-effects are likely consequences of the
inhibition of the TRK pathway that is involved in the development and maintenance of the nervous system.
Key words: TRK, tropomyosin receptor kinase, NTRK gene fusions, TRK fusion cancer

Introduction presence of targetable genomic alterations across multiple tu-

Cancer can be driven by a wide variety of clinically actionable mour types [2]. Consequently, select drug development pro-
alterations. The late 1990s and 2000s were marked by landmark grammes migrated away from histology-specific patient selection
regulatory approvals of targeted therapies that exploit these to biomarker-driven, tumour-agnostic enrichment. This gave
dependencies. These included the US Food and Drug birth to the basket trial strategy under which patients were
Administration (FDA) approval of trastuzumab for HER2- accrued to a trial of a matched therapeutic regardless of histology
positive breast cancers in 1998, imatinib for Philadelphia as long as their cancers harboured the appropriate genomic sig-
chromosome-positive chronic myelogenous leukaemias in 2001, nature [3]. Elucidation of the activity of pembrolizumab in
and gefitinib for EGFR-mutant lung cancers in 2009 [1]. These tumours of any type with high levels of microsatellite instability
sparked the subsequent approval of a growing list of matched (MSI-high) marked the first major success in this area [4]. This
therapeutics for activating alterations involving EGFR, BRAF, culminated in the US FDA approval of pembrolizumab for this
ALK and ROS1 by a wider umbrella of one or more additional indication in 2017.
regulatory agencies in Europe, Asia and/or Latin America. While The same year pembrolizumab was approved for MSI-high
these approvals have undoubtedly reshaped the therapeutic land- cancers of any type, the first-generation TRK inhibitors
scape for patients with a wide array of cancers, the respective larotrectinib and entrectinib were granted breakthrough desig-
drug development programmes largely focussed on establishing nation by the US FDA for the treatment of TRK fusion-positive
the activity of these agents within a single tumour type. cancers of any histology. Shortly thereafter, in 2018,
An increase in the adoption of more comprehensive, clinical- larotrectinib received accelerated approval by the FDA for the
grade sequencing platforms later promoted a recognition of the treatment of TRK fusion-positive cancers of any type and any

C The Author(s) 2019. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
V
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in
any medium, provided the original work is properly cited.
Review Annals of Oncology
Table 1. TRK inhibitors

Larotrectinib Entrectinib Selitrectinib Repotrectinib

Generation
First
Second
Inhibits
TRKA/B/C
ROS1

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ALK
Resistance
Inhibits most NTRK mutations

The features of four TRK tyrosine kinase inhibitors (larotrectinib, entrectinib, selitrectinib and repotrectinib) are summarised by tyrosine kinase inhibitor gen-
eration, major kinase targets and activity against resistance.

age.* This was followed in 2019 by the approval of entrectinib nintedanib and ponatinib [12, 13]) compared with larotrectinib
for TRK fusion-positive cancers in Japan and the US. or entrectinib. Furthermore, while the preclinical activity of some
Remarkably, the activity of next-generation TRK inhibitors, of these drugs against TRK fusion-containing models has been
such as selitrectinib (BAY 2731954, LOXO-195) and repotrecti- described, their clinical activity has not been as well characterised
nib, is already being explored in ongoing clinical trials. as that of larotrectinib and entrectinib.

Drug development programmes

First-generation TRK inhibitors The two major drug development programmes for larotrectinib
and entrectinib share several features. The regulatory data sets
Preclinical activity for both agents included patients with TRK fusion-positive can-
Larotrectinib and entrectinib are first-generation TRK tyrosine cers who were treated on several clinical trials. For larotrectinib,
kinase inhibitors with potent activity against wild-type TRKA, the three trials that contributed patients were an adult phase I
TRKB and TRKC (Table 1). In enzymatic assays, larotrectinib trial, a paediatric phase I/II trial (SCOUT) and an adult/adoles-
and entrectinib have IC50 values of 5–11 nM and 1–5 nM, respect- cent phase II basket trial (NAVIGATE), all of which enrolled
ively, for TRKA/B/C [5, 6]. However, the drugs differ in their ac- patients with advanced solid tumours [5]. For entrectinib,
tivity against other kinases. Larotrectinib is a selective inhibitor the four contributory trials were an adult phase I trial
of TRKA/B/C. It has greater than 100-fold selectivity against (ALKA-372-001, Italy), a separate adult phase I trial
229 other kinases and greater than 1000-fold selectivity against (STARTRK-1, global), a phase II basket trial (STARTRK-2),
80 non-kinase targets [7]. By contrast, entrectinib is a multikinase which enrolled patients with solid tumours harbouring an
inhibitor. In addition to TRKA/B/C, it inhibits ROS1 (enzymatic NTRK1/2/3, ROS1 or ALK gene fusion, and a phase I/Ib paedi-
IC50 of 0.2 nM) and ALK (enzymatic IC50 of 1.6 nM) [8, 9]. atric trial (STARTRK-NG) [8, 14].
Larotrectinib and entrectinib are active against in vitro and The activity of these agents was analysed in both data sets in ag-
in vivo models harbouring TRK fusions [9–11]. Larotrectinib ef- gregate, with the primary enrichment factor being the presence of
fectively inhibits the growth of cell lines or xenografts containing an NTRK gene fusion regardless of cancer type [5, 8]. A wide var-
TPM3-NTRK1, MPRIP-NTRK1, TRIM24-NTRK2 or ETV6-NTRK3. iety of tumour types were treated with either agent. These
This is associated with downstream inhibition of the RAF-MEK- included the four histologies enriched for the presence of an
ERK or PI3K-AKT pathways [11]. Similarly, entrectinib inhibits NTRK gene fusion (mammary analogue secretory carcinoma, se-
the growth of cell lines or xenografts containing LMNA-NTRK1 cretory breast carcinoma, infantile fibrosarcoma and congenital
or EVT6-NTRK3, with the consequent inhibition of downstream mesoblastic nephroma), and several other malignancies includ-
pathway signalling [9]. ing lung, gastrointestinal, breast and thyroid cancers, melanoma
Other multikinase agents have varying degrees of activity and soft tissue sarcoma. Objective response was the primary end
against TRKA/B/C. These include cabozantinib, crizotinib, ninte- point of both programmes [5, 8].
danib and ponatinib, which have regulatory approval for other
indications, and the investigational agents altiratinib, foretinib,
lestaurtinib, merestinib, MGCD516, PLX7486, DS-6051b and
Clinical activity
TSR-011 [12]. It is important to note that several of these drugs In 2018, the antitumour activity of larotrectinib in the first
are less potent against TRK (IC50s of 50 to >200 nM for 55 adult and paediatric patients consecutively enrolled into one

*Note added in proof: The European Medicines Agency granted marketing authorisation for larotrectinib on 23 September 2019 as monotherapy for the treatment of adult and
paediatric patients with solid tumours that display a neurotrophic tyrosine receptor kinase (NTRK) gene fusion, and who have disease that is locally advanced, metastatic or
where surgical resection is likely to result in severe morbidity, and who have no satisfactory treatment options.

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Annals of Oncology Review
Table 2. TRK inhibitor activity lung cancer (19%), mammary analogue secretory carcinoma
(13%) and breast cancer (11%). The majority of fusions involved
Larotrectinib Entrectinib NTRK1 (41%) or NTRK3 (57%). The ORR was 57% (95% CI
(n 5 122) (n 5 54) 43% to 71%; n ¼ 54 evaluable; Table 2) [17]. Response occurred
regardless of tumour type. Response did not differ between
ORR (95% CI) 81% (72% to 88%) 58% (43% to 71%) fusions involving NTRK1 or NTRK3. The median duration of re-
CR 17% – sponse was 10.4 months [17]. The median PFS and OS were 11.2
PR 63% –
and 20.9 months, respectively [17].
Median DoR, months Not reached 10.4
The activity of entrectinib in paediatric patients on the
Median PFS, months Not reached 11.2
STARTRK-NG trial was thereafter presented [14]. Seven patients

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Median OS, months Not reached 20.9
with TRK fusion-positive cancers were treated. These cancers
The clinical activity of the first-generation TRK inhibitors, larotrectinib and were high-grade gliomas (n ¼ 3), a central nervous system (CNS)
entrectinib, is summarised. Data for the breakdown of CRs/PRs with embryonal tumour (n ¼ 1), melanoma (n ¼ 1) and infantile
entrectinib not available. fibrosarcomas (n ¼ 2). Most fusions involved NTRK3 (n ¼ 4). All
CI, confidence interval; CR, complete response; DoR, duration of re- six patients with measurable disease had an objective response to
sponse; ORR, objective response rate; OS, overall survival; PFS, progres- therapy with >50% target tumour shrinkage; disease control was
sion-free survival; PR, partial response. durable with the longest duration of ongoing benefit lasting close
to 15 months.
Based on data from this drug development programme,
entrectinib was granted Breakthrough Designation by the US
FDA for the treatment of TRK fusion-positive cancers in May of
of the three larotrectinib trials was published [5]. The objective 2017. This was followed in June of 2019 by the approval of
response rate (ORR) was 75% [95% confidence interval (CI) 61% entrectinib in Japan by the Ministry of Health, Labour and
to 85%, independent review]. In the 15 paediatric patients with Welfare, and in August of 2019 by the US FDA for the treatment
evaluable disease in this series, the ORR was 93% (95% CI 68% to of adult and paediatric patients (age 12 years and above, US
100%) [15]. This initial data set has since been expanded [16]. FDA) with advanced or recurrent TRK fusion-positive cancers.
A total of 122 adult and paediatric patients (including the These were likewise landmark events, particularly the Japanese
55 patients above) with TRK fusion-positive cancers have since approval that represented the first tumour-agnostic approval of
been treated with larotrectinib. Age ranged from 1 month to a targeted therapy for a specific genomic signature in Asia.
80 years. The most common histologies were salivary gland can-
cer (16%), infantile fibrosarcoma (15%), thyroid cancer (15%)
and lung cancer (9%). Most fusions involved NTRK1 (45%) or Intracranial activity
NTRK3 (53%) and were detected by local molecular profiling [5]. NTRK gene fusions are identified in primary brain tumours and
In this updated data set, the ORR was 81% (95% CI 72% to extracranial solid tumours with a proclivity for brain metastases
88%; n ¼ 109 evaluable; Table 2). Response occurred regardless of (e.g. lung cancers) [12]. The activity of TRK inhibitors in the
tumour type, age, NTRK gene or upstream partner type. Complete CNS is thus highly relevant. Fortunately, intracranial disease con-
and partial responses were observed in 17% and 63% of patients, trol has been achieved with both entrectinib and larotrectinib in
respectively. The median duration of response was not reached. patients with TRK fusion-positive primary brain tumours and
The median time to response was 1.8 months (approximately brain metastases [14, 18–21].
when the first follow-up imaging assessment was carried out). The The adult entrectinib data set was unique in that a higher pro-
median progression-free survival (PFS) and overall survival (OS) portion of patients (22%; n ¼ 12/54) had baseline CNS metasta-
have yet to be reported for the larger integrated set [16]; neither ses relative to the larotrectinib data set [17]. The intracranial
had been reached at the earlier data cut in the first 55 patients [5]. ORR with entrectinib was 55% (95% CI 23% to 83%). Complete
Data from this drug development programme resulted in the and partial intracranial responses were each observed in 27%
approval of larotrectinib by the US FDA for the treatment of TRK (n ¼ 3) of patients. The median intracranial duration of response
fusion-positive cancers regardless of tumour type or age in was not reached. The median intracranial PFS was 14.3 months.
November of 2018. This label includes a provision for the treat- In paediatric patients, all three TRK fusion-positive high-grade
ment of cancers that are locally advanced based on the experience paediatric gliomas had durable responses to entrectinib on the
with neoadjuvant therapy in this programme. The most illustra- STARTRK-NG trial [14].
tive cases involved infants with infantile fibrosarcomas who In the larotrectinib programme, only 5% of adult and paediat-
would have required limb amputations to treat their cancer. ric patients with TRK fusion-positive solid tumours (n ¼ 6/122)
Larotrectinib use resulted in substantial disease regression had baseline CNS metastases [20]. Among these patients
(complete pathological response) that allowed limb-sparing sur- (two thyroid cancers, four non-small-cell lung cancers), the ORR
gery, underscoring the utility of this therapy in earlier stage dis- was 60% (n ¼ 3/5 evaluable). Intracranial disease regression was
ease [15]. achieved in all three patients with measurable CNS disease; intra-
A total of 54 patients with TRK fusion-positive cancers were cranial disease control was achieved in patients with evaluable
treated with entrectinib [17]. Notably, this initial data set only but non-measurable CNS disease [20, 21]. Eighteen patients with
included adult patients with a median age of 58 years (range 21– TRK fusion-positive primary CNS tumours were treated with lar-
83 years). The most common histologies were sarcoma (24%), otrectinib. The ORR was 36% (n ¼ 5/14 evaluable; two complete

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Review Annals of Oncology
responses and three partial responses) and no primary disease response to therapy in a patient with a TRK fusion-positive can-
progression was observed. The median PFS was 11 months [20]. cer with MET amplification-driven resistance to a first-
generation TRK inhibitor [27].

TRK inhibitor resistance

On-target resistance
Next-generation TRK inhibitors

TRK fusion-positive cancers can develop resistance to TRK in- Preclinical activity
hibition despite continued reliance on TRK fusion signalling

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Next-generation TRK inhibitors were specifically designed to ad-
[12]. These on-target resistance mechanisms take the form of
dress on-target resistance mutations while maintaining potency
NTRK kinase domain mutations. Interestingly, these mutations
against wild-type TRKA/B/C (Table 1). The two major agents
are paralogous to resistance mutations that have been identified
that are currently in development are selitrectinib and repotrecti-
after progression on ALK tyrosine kinase inhibitor therapy in
nib. Due to their small size, these low molecular weight macro-
ALK fusion-positive lung cancers, and ROS1 tyrosine kinase in-
cycles are able to engage the ATP-binding pocket while avoiding
hibitor therapy in ROS1 fusion-positive lung cancers [22, 23].
the steric penalties of kinase domain substitutions [25, 28].
These kinase domain mutations result in amino acid substitu-
Both drugs have increased activity against wild-type TRKA/B/C
tions that involve three major regions: the solvent front, the
compared with the first-generation TRK inhibitors. For solvent
gatekeeper residue or the xDFG motif. Mutations in the NTRK
front substitutions, the IC50s of selitrectinib and repotrectinib in
kinase domain cause resistance to TRK inhibitors by sterically
enzymatic assays are 2.0–2.3 nM and 2.7–4.5 nM, respectively.
interfering with binding of the inhibitor, altering the kinase
For gatekeeper substitutions, the IC50s of selitrectinib and repo-
domain conformation or altering ATP-binding affinity [24, 25].
trectinib are 2.0–2.3 nM and <0.2 nM, respectively. For xDFG
Solvent front substitutions include TRKAG595R, TRKBG639R and
substitutions, the IC50s of selitrectinib and repotrectinib are 2.0–
TRKCG623R [12] that are paralogous to ALKG1202R and
2.3 nM and 9.2 nM, respectively. This activity is echoed in select
ROS1G2032R. Gatekeeper substitutions include TRKAF589L,
in vitro and in vivo models, particularly for those that contain
TRKBF633L and TRKCF617L that are paralogous to ALKL1196M and
solvent front and gatekeeper substitutions [25, 28, 29].
ROS1L2026M [26]. xDFG substitutions include TRKAG667C,
TRKBG709C and TRKCG696A that are paralogous to ALKG1269
substitutions. Clinical activity
Several of these mutations have been identified in patients with
TRK fusion-positive cancers that have progressed on entrectinib The clinical activity of selitrectinib (NCT03215511) and repo-
[10, 24] or larotrectinib [20], indicating that these represent a trectinib (NCT03093116) are currently being explored in separ-
shared liability for the first-generation TRK inhibitors. The ma- ate phase I/II trials. In addition, patients have been treated with
jority of these clinically identified kinase domain mutations un- selitrectinib [25] under expanded access/compassionate use pro-
surprisingly involve NTRK1 or NTRK3, given that few patients tocols (NCT03206931). The largest data set reported thus far has
with NTRK2 gene fusions have been treated with a TRK inhibitor been the experience with selitrectinib [30].
[5, 17]. The true frequency of on-target resistance in TRK fusion- In total, 31 patients with TRK fusion-positive cancers received
positive cancers has yet to be determined. However, the identifi- selitrectinib [30]. All patients were treated with a prior TRK in-
cation of these alterations in multiple patients implies that these hibitor (larotrectinib, entrectinib or PLX7486) with a median
events are unlikely to be rare. duration of prior tyrosine kinase inhibitor therapy of 11 months
(range 2–30 months). The most common histologies were sar-
coma (16%), gastrointestinal stromal tumour (13%) and pancre-
Off-target resistance atic adenocarcinoma, mammary analogue secretory and breast
Similar to ALK and ROS1 fusion-positive lung cancers [26], TRK carcinoma (10% each). In patients with TRK kinase domain
fusion-positive cancers can develop off-target resistance to tyro- mutations (the majority of which involved the solvent front), the
sine kinase inhibitor therapy. These mechanisms take the form of ORR was 45% (n ¼ 9/20). None of the three patients with identi-
genomic alterations involving other receptor tyrosine kinases or fied bypass mechanisms of resistance responded to therapy. In
downstream pathway mediators. Specifically, MET amplification, addition, none of the five patients with unknown mechanisms of
BRAFV600E mutation or hotspot mutations involving KRAS have resistance (excluding one additional patient with prior TRK in-
been shown to emerge in tumour and/or plasma samples from hibitor intolerance) responded to therapy.
patients with TRK fusion-positive cancers that have progressed Similarly, repotrectinib has been shown to re-establish disease
on a TRK inhibitor [27]. These alterations were likewise identi- control after the development of kinase domain-mediated
fied in preclinical models of TRK inhibitor resistance. IGF1R acti- acquired resistance to a first-generation TRK inhibitor [28].
vation is also thought to play a potential role in mediating A confirmed partial response was achieved in a patient with TRK
resistance [13]. The relative frequency of off-target resistance has fusion-positive mammary analogue secretory carcinoma and
yet to be determined. TRKAG623E-mediated resistance to entrectinib [28]. In addition,
Combination therapy has been shown to re-establish disease disease regression was observed in a patient with a TRK fusion-
control in the face of off-target resistance. For example, the com- positive cholangiocarcinoma with TRKAG595R- and TRKAF589L-
bination of a TRK and MET inhibitor achieved a confirmed mediated resistance to larotrectinib [29].

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On-target resistance
Repotrectinib
Selitrectinib
Solvent front G595R G639R G623R
Gatekeeper F589L F633L F617L 2nd generation TRK Inhibitor
xDFG G667C G709C G696A
Other A608D
Entrectinib
Larotrectinib
Resistance
For oligo/solitary site progression,

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1st generation TRK Inhibitor consider local therapy and
continued TKI use.
Off-target resistance

Potential mechanisms identified

• KRAS mutation
Standard of care
• MET amplification
or clinical trial when available
• BRAF mutation
• IGF1R activation

Figure 1. Sequential therapy. Durable responses to first-generation TRK inhibitors can be achieved in TRK fusion-positive cancers. In patients
with advanced disease, when solitary site progression or oligoprogression occurs, local therapy such as radiation or surgery should be con-
sidered. The use of local therapy and continued treatment beyond progression has been shown to prolong disease control with TRK inhibi-
tor therapy. At the onset of resistance, tumours can acquire either on-target or off-target resistance mechanisms. In the face of widespread
disease progression, a second-generation TRK inhibitor trial could be considered for tumours that harbour on-target resistance, as evidence
by the acquisition of solvent front, gatekeeper or xDFG TRKA/B/C substitutions. If a cancer has developed clear off-target resistance, disease-
specific standard of care therapies could be considered if a clinical trial that meaningfully addresses these resistance mechanisms is not avail-
able. TKI, tyrosine kinase inhibitor.

This clinical activity highlights an evolving strategy for the inhibitor with a well-characterised safety profile that incidentally
treatment of TRK fusion-positive cancers (Figure 1). Next- has minimal activity against TRK (Figure 2). A notable side-effect
generation TRK inhibitors can salvage resistance to a first- unrelated to TRK inhibition that has been observed in the entrec-
generation TRK inhibitor in select cases, a paradigm similar to tinib data set was elevated creatinine. Importantly, this rise in cre-
that observed for ALK or ROS1 fusion-positive lung cancers [26]. atinine is thought to be secondary to MATE1 transporter
The responses noted thus far have been in patients whose cancers inhibition by the drug and may not be a true reflection of renal
clearly harbour on-target mechanisms of resistance [30], encour- insufficiency [14].
aging repeat molecular profiling of tumour and/or plasma in The frequency of dose reduction and treatment discontinuation
order to identify these alterations at the onset of resistance. arguably represent the best integrated metrics for overall tolerabil-
ity (Figure 3) [16, 17]. For comparison, the frequency of dose re-
duction with entrectinib [17], larotrectinib [16] and crizotinib
TRK inhibitor safety [32] was 27%, 9% and 21%, respectively. The frequency of treat-
ment discontinuation was consistently lower with both entrecti-
Overall safety profile nib (4%) and larotrectinib (<1%) than with crizotinib (13%).

The safety of TRK inhibition has been best characterised for the
first-generation agents larotrectinib and entrectinib. Each drug
On-target adverse events
has been given to more than 200 patients (207 for larotrectinib Occasional on-target adverse events can occur secondary to TRK
and 355 for entrectinib). These safety data sets include patients inhibition in normal tissues [12]. These include dizziness, paraes-
who were treated with these drugs regardless of molecular profile thesia, weight gain and cognitive changes (Figure 2) [5, 8], pre-
or cancer type. dicted by the role that the TRK signalling pathway plays in nervous
Both agents had favourable overall toxicity profiles [16, 17]. system development and maintenance [33]. Most of these adverse
Compared with other tyrosine kinase inhibitors, the frequency of events are grade 1 or 2 in nature [5, 8], highlighting that while loss
treatment-emergent adverse events (only reported thus far for or inhibition of TRKA/B/C can have substantial consequences dur-
larotrectinib) was low. For example, the most common ing embryonic development, the post-embryonic consequences of
treatment-emergent adverse event for larotrectinib (fatigue) was TRK inhibition can be relatively mild in comparison [12].
observed in 36% of patients. The frequency of drug-related ad- Dizziness occurs in approximately 16% to 25% of patients
verse events (reported for both larotrectinib and entrectinib) was treated with larotrectinib or entrectinib [5, 8]. Based on early
also low [16, 17]. data in a small subset of patients, the frequency of dizziness/
By way of illustration, the frequencies of treatment-related ataxia/gait disturbance rises with next-generation TRK inhibition
nausea, diarrhoea and transaminitis were lower with entrectinib and has been described as a dose-limiting toxicity of selitrectinib
[17] or larotrectinib [16] than with crizotinib [31], a multikinase [30]. While clinical trials of first-generation TRK inhibitors have

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Figure 2. Safety profile. The frequency of select treatment-related adverse events with entrectinib and larotrectinib is shown. To benchmark
the relative frequency of these toxicities, crizotinib was chosen for comparison as the drug has a well-known safety profile (and incidentally
has minimal anti-TRK activity). These adverse events (present in 10% or more of patients) are grouped from left to right by the following cate-
gories: general (fatigue), gastrointestinal (nausea, constipation, diarrhoea) and laboratory abnormalities (increased alanine aminotransferase,
anaemia, increased creatinine). The right-hand panel highlights adverse events that are predicted or presumed to be on-target neurologic
consequences of TRK inhibition, recognising the importance of this pathway in neuronal development and maintenance.

Figure 3. Dose modification. The rates of dose reduction and treatment discontinuation are shown for entrectinib and larotrectinib. To
benchmark the relative frequency of these dose modifications, crizotinib was chosen for comparison as the drug has a well-known safety
profile and incidentally has minimal anti-TRK activity.

described this event as ‘dizziness’ for several patients, this side-ef- are identified in paediatric patients with congenital insensitivity to
fect can be attributed to decreased proprioception and cerebellar pain and anhidrosis [39]. Despite this, all paraesthesias reported
dysfunction. Ntrk2-knockout and Ntrk3-null mice lack dorsal have been grade 1 or 2 in severity (with no grade 3 or greater events
root ganglia neurons [34, 35], and decreased levels of a TRK re- [Common Terminology Criteria for Adverse Events [40]]) [17].
ceptor ligand (BDNF) have been associated with cerebellar neu- Weight gain has also been observed. This occurs as TRKB is
ron pathology [36]. The description of ‘ataxia’ with next- involved in the regulation of appetite [35] and impaired TRKB
generation TRK inhibition supports this hypothesis [30], and the activity causes hyperphagia, obesity and hyperdipsia in mice and/
more pronounced nature of this side-effect may be related to the or humans [41, 42]. In adults, the frequency of weight gain is
more potent inhibition of wild-type TRK with these drugs (com- 19% (treatment related) with entrectinib [17] and has not been
pared with first-generation TRK inhibitors). reported as occurring in 15% or more of patients (treatment
Paraesthesias occur in a subset of patients (19% with entrecti- emergent) with larotrectinib [16]. Preliminary data show that
nib) [37]. Ntrk1-null mice suffer from severe sensory and sympa- the frequency might be higher in the paediatric population
thetic neuropathies [38] and loss-of-function NTRK1 mutations (28% [treatment related] with entrectinib in STARTK-NG

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Annals of Oncology Review
where weight gain was the most common reason for dose reduc- Disclosure
tion [and may have been associated with skeletal events such
AD discloses honoraria/advisory board participation for Ignyta/
as fracture] [14] and 18% [treatment emergent] with larotrecti-
Genentech/Roche, Loxo/Bayer/Lilly, Takeda/Ariad/Millenium,
nib [43]).
TP Therapeutics, AstraZeneca, Pfizer, Blueprint Medicines,
A dose-limiting toxicity of grade 3 cognitive disturbance was
Helsinn, Beigene, BergenBio, Hengrui Therapeutics, Exelixis,
described with entrectinib in a patient treated at a dose above the
Tyra Biosciences, Verastem and MORE Health; associated re-
recommended phase II dose of the drug [8]. This is consistent with
search funding paid to the institution from Pfizer, Exelixis,
the fact that the TRKB pathway plays a role in modulating memory
GlaxoSmithKline, Teva, Taiho and PharmaMar; research for
and mood [44]. Cognitive changes have otherwise not been identi-
Foundation Medicine; royalties from Wolters Kluwer; expenses
fied as a frequent side-effect at the recommended phase II doses of

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from Merck and Puma; CME honoraria from Medscape,
larotrectinib (100 mg twice daily) or entrectinib (600 mg daily).
OncLive, PeerVoice, Physicians Education Resources, Targeted
Dysgeusia or a distortion in the sense of taste has been
Oncology and Research to Practice.
observed. This symptom can be caused by a variety of patholo-
gies, among which neurological damage is a differential. While
this is listed as a potential on-target adverse event in a select series
[14], it is yet unclear that the TRK pathway plays a strong neuro- References
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Volume 30 | Supplement 8 | November 2019 doi:10.1093/annonc/mdz282 | viii29

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