Tyrosine Kinase Inhibitor Therapy For Advanced Gastrointestinal Stromal Tumors

11/24/21, 4:19 AM Tyrosine kinase inhibitor therapy for advanced gastrointestinal stromal tumors - UpToDate
Author: Jeffrey Morgan, MD

Section Editors: Kenneth K Tanabe, MD, Robert Maki, MD, PhD
Deputy Editor: Sonali Shah, MD
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Oct 2021. | This topic last updated: Nov 09, 2021.
What's New
Avapritinib for treatment-refractory gastrointestinal stromal tumors with

PDGFRA exon 18 D842V mutations (October 2021)
For patients with advanced gastrointestinal stromal tumor (GIST), novel agents are be…
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INTRODUCTION
Stromal or mesenchymal neoplasms affecting the gastrointestinal (GI) tract have undergone a
striking evolution in how they are perceived and classified over the last 30 years. A significant
breakthrough occurred with the identification of near-universal expression of the CD117
antigen by these tumors (now called gastrointestinal stromal tumors [GISTs]). The other group
of spindle cell neoplasms arising in the GI tract (which are analogous to soft tissue tumors
throughout the rest of the body and include lipomas, schwannomas, hemangiomas, usual
leiomyomas and the malignant counterpart, leiomyosarcomas) is typically CD117-negative [1].
The CD117 molecule is part of the KIT (c-kit) receptor, a membrane tyrosine kinase that is a
product of the KIT protooncogene. In 80 percent of cases, KIT overexpression is the result of an
activating mutation in the KIT protooncogene. Although the majority of GISTs are KIT positive,
some KIT negative GISTs have activating mutations in a related tyrosine kinase receptor,
platelet-derived growth factor receptor alpha (PDGFRA). The current view is that the
overwhelming majority of GI tract mesenchymal tumors fall into the GIST category; they are
identifiable by KIT immunoreactivity or the presence of activating mutations in KIT or PDGFRA.
(See "Clinical presentation, diagnosis, and prognosis of gastrointestinal stromal tumors",
section on 'Pathogenesis'.)
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Prior to the year 2000, there was no known effective therapy for unresectable or metastatic
GISTs. It has long been appreciated that GI tract sarcomas have lower response rates to
chemotherapy than other sites of soft tissue sarcomas, indicating a higher rate of primary
resistance to chemotherapy in these tumors [2-4].
Treatment of GISTs was revolutionized by the finding that mutational activation of KIT or
PDGFRA stimulated growth of these cancer cells. This led to effective systemic therapies in the
form of small molecule inhibitors of the receptor tyrosine kinases. Imatinib (Gleevec), the
prototype drug, was originally approved for the treatment of chronic myeloid leukemia (CML),
a disorder in which an aberrant tyrosine kinase results from molecular rearrangement. (See
"Initial treatment of chronic myeloid leukemia in chronic phase".)
It subsequently became evident that molecularly targeted therapy with imatinib induced
dramatic, rapid, and sustained clinical benefit in GISTs as well. These agents block signaling via
KIT or PDGFRA by binding to the ATP-binding pocket required for phosphorylation and
activation of the receptor. Other tyrosine kinase inhibitors (TKIs) have been identified that
block several tyrosine kinase targets, including KIT (referred to as multitargeted TKIs). Some
data suggest an anti-GIST immune response is associated with good clinical outcomes in
patients with GIST on imatinib [5].
Here we will discuss TKI therapy for patients with advanced/metastatic GISTs. Molecular
classification, clinical presentation, diagnosis, management of localized GISTS, the role of
surgery in patients with metastatic disease, and the use of preoperative as well as adjuvant
imatinib are addressed in separate topic reviews. (See "Clinical presentation, diagnosis, and
prognosis of gastrointestinal stromal tumors" and "Local treatment for gastrointestinal
stromal tumors, leiomyomas, and leiomyosarcomas of the gastrointestinal tract" and
"Adjuvant and neoadjuvant imatinib for gastrointestinal stromal tumors".)
INITIAL APPROACH BASED ON MUTATION STATUS
Imatinib for KIT and most PDGFRA mutant GIST — Imatinib is used as initial therapy for
patients with KIT and most platelet-derived growth factor receptor alpha (PDGFRA) mutant
GIST, although GISTs associated with PDGFRA D842V are an exception ( algorithm 1). (See
'Avapritinib for PDGFRA D842V mutant tumors' below.)
An assessment of tumor mutational status using DNA sequencing techniques is advised

during the initial evaluation of patients with advanced or metastatic disease because clinical
responses to imatinib (and other TKIs) correlate with tumor genotype. For most patients,
systemic treatment with imatinib can be initiated empirically while awaiting confirmation of
tumor mutational status. Treatment may be subsequently modified once tumor mutational
status becomes available. However, for those with histologies suggestive of imatinib
resistance (eg, succinate dehydrogenase [SDH] deficiency or neurofibromatosis 1 [NF1]-
related disease), referral to a tertiary care center for clinical trials is warranted, rather than
empiric imatinib. (See "Clinical presentation, diagnosis, and prognosis of gastrointestinal
stromal tumors", section on 'Diagnosis' and 'SDH-deficient tumors and those associated with
NF1' below.)
Efficacy — Since the initial report of a patient with rapidly progressive GIST who exhibited a
dramatic and sustained response within one month of starting imatinib [6], many studies have
confirmed the utility of this agent in advanced disease ( table 1) [7-11]:
● In a phase II study, for example, 147 patients received either 400 or 600 mg of imatinib
daily; 54 percent had radiographic responses documented within six months, with no
significant difference between the two doses [8]. Positron emission tomography (PET)
scanning proved to be a sensitive and reliable response indicator, with markedly
diminished uptake, compared with baseline studies, seen in responders as early as 24
hours after the first dose of imatinib. (See 'Assessing response to therapy' below.)
Adverse events were common but generally mild. These included grade 1 or 2 nausea or
diarrhea in approximately one-half, fluid retention (predominantly periorbital) in three-
fourths, muscle cramps and fatigue (40 and 35 percent, respectively), and
gastrointestinal (GI) or intra-abdominal hemorrhage in 5 percent. (See 'Side effects and
their management' below.)
A sizeable subset of patients in this trial survived long-term on first-line imatinib. In a

preliminary report of long-term follow-up of a cohort of 56 patients who continued to
take imatinib beyond three years, 26 (18 percent of the initial cohort) remained on
continuous imatinib since study entry at a median follow-up of 9.4 years [12]. The overall
likelihood of remaining progression-free at nine years or beyond was dependent on
tumor size at initial diagnosis and ranged from 29 percent in those with an initial tumor
bulk of <39.1 mm2 to 3 percent in those with an initial tumor bulk >262.6 mm2. The
corresponding rates of overall survival were 58 and 23 percent, respectively.
A similar fraction of patients with metastatic disease who achieved long-term disease
control was reported in an analysis derived from the SWOG phase III S0033 trial, which
studied two different dose levels of imatinib (see 'Impact of dose' below). In a preliminary
report presented at the 2014 American Society of Clinical Oncology (ASCO) annual
meeting, 180 of the 695 eligible patients (26 percent) survived eight years or longer, and
the estimated 10-year survival rate was 22 percent [13]. Among the 137 long-term
survivors, imatinib was the sole therapy administered continuously to 49 percent, while
39 percent received subsequent systemic agents including sunitinib and sorafenib.
● Following the introduction of imatinib, the median survival of patients with advanced
GIST increased from an average of 18 to 57 months in the trial with the longest follow-up
to date [14].
● Despite the high efficacy of imatinib in most patients with metastatic/inoperable GISTs,
complete responses are rare overall (less than 10 percent), and most patients who
initially respond eventually acquire resistance via additional mutations in KIT, discussed
below. The median time to progression is approximately two to three years [8,10,15,16],
although it is longer in some series [17]. A subset of patients with metastatic GIST
experiences durable responses and long-term survival with imatinib treatment [18].
Factors influencing the duration of disease control are not well understood [16]. (See
'Subsequent management of imatinib-refractory disease' below.)
Assessing response to therapy — The optimal method for establishing response to tyrosine

kinase inhibitors (TKIs) such as imatinib is evolving.
Positron emission tomography scanning — PET scans appear to identify a greater

number of responses and at an earlier time than computed tomography (CT) scans [19-23].
With functional imaging such as PET, responses can be observed within 24 hours of starting
therapy, although this has little practical impact on the typical patient with metastatic GIST. In
addition to detecting primary imatinib resistance, PET can aid in the detection of secondary
resistance, as does detection of the "nodule within a tumor" as a sign of drug resistance. (See
'RECIST versus Choi criteria' below.)
If employed, a rigorous standardized approach to patient preparation and study technique is

needed for reproducible results, as emphasized by consensus guidelines on use of
fluorodeoxyglucose (FDG)-PET for response assessment [24-26].
The added benefit for dual modality PET/CT imaging in most cases with advanced GIST is
unclear, and PET scans are rarely used to assess the response to therapy in patients with
advanced disease, unless in the context of a clinical trial. Newly proposed CT criteria using
either no growth in tumor size or a combination of tumor density and size criteria have shown
a close correlation with the predictive value results of FDG-PET, and serial CT or MRI scanning
at three- to six-month intervals is more often recommended during therapy. (See 'Cross-
sectional imaging' below and 'RECIST versus Choi criteria' below.)
One clinical scenario where baseline and follow-up PET scan might prove useful is for a patient
with a borderline resectable GIST or a potentially resectable tumor that requires extensive
organ disruption who is being treated with initial imatinib [22,27]. In these situations, early
assessment of treatment response might provide an opportunity to shift to an alternative
therapy (eg, resection or sunitinib) if imatinib is ineffective. (See "Adjuvant and neoadjuvant
imatinib for gastrointestinal stromal tumors".)
An important point is that patient symptoms also improve rapidly in the setting of response,
decreasing to some degree the need to obtain imaging shortly after starting neoadjuvant
imatinib.
Cross-sectional imaging — Conventional CT scans with intravenous contrast

enhancement are a good standard of care for radiographic assessment of most patients with
metastatic GIST. Contrast-enhanced magnetic resonance imaging (MRI) also provides similar
information to that obtained with contrast-enhanced CT scans.
Certain finer points are worth keeping in mind based on the experience with metastatic GIST
patients since the introduction of imatinib. For example, GISTs will infrequently increase in size
during early treatment as a consequence of intratumoral hemorrhage or myxoid
degeneration. A decrease in tumor density as seen on CT (the corollary of decreased FDG
uptake on PET, see above) is an important early clinical marker of antitumor activity [28,29], as
is decreased contrast uptake on standard CT or MRI scans. Once tumors become hypodense
(cystic), the size of the lesions may decrease slowly and eventually stabilize.
Late responses are often seen in patients who initially have stable disease, and survival in
those with stable disease parallels that of patients with an objective response [14,30]. The
median time to achieve an objective response is four months, while maximal response may
take six months or even longer [10].
As a result of these issues, response to imatinib is frequently defined as absence of

progression at the time of the first formal disease re-evaluation (typically two to three months
after starting therapy) [31]. Clear-cut evidence of progression at this time point is considered
initial (primary) resistance, while progression or relapse after a period of stable or responding
disease is referred to as late (secondary) resistance. Initial resistance was seen in 12 percent of
934 patients in a randomized European trial exploring two different doses of imatinib
(discussed below) and was more likely in patients with lung but not liver metastases (41
percent) [15]. The management of patients with imatinib-refractory disease is discussed below.
(See 'Subsequent management of imatinib-refractory disease' below.)
For patients receiving imatinib for advanced disease, the optimal interscan interval is not
established. In keeping with guidelines from the National Comprehensive Cancer Network
(NCCN) [27], we perform history and physical examination, and repeat cross-sectional imaging
of the abdomen and pelvis every three to six months. For patients who have low-volume or no
residual detectable metastatic disease who continue to have an excellent response to imatinib,
we transition to every six months imaging after three years, and then to annual imaging after
six or more years.
RECIST versus Choi criteria — As noted above, radiographic response to TKIs is often
indicated by an early decrease in tumor density, followed by slow tumor regression. This
pattern of response is not well suited to the use of standard Response Evaluation Criteria In
Solid Tumors (RECIST), which is based upon tumor measurements ( table 2) [32,33].
Likewise, disease progression in patients with GIST may also fail to be captured by standard
RECIST. Tumor progression may manifest as new or enlarging tumor masses, as partial to
complete filling-in of a previously hypodense lesion, or as a hyperdense "nodule-within-a-
mass" pattern [34]. The importance of identifying this latter situation is that successful
ablation of such resistant clones has been reported, with continued imatinib sensitivity of
areas of disease that remain [35].
An alternative set of response evaluation criteria has been proposed, the so-called Choi
criteria [36,37]. Investigators at MD Anderson initially showed that a 10 percent decrease in
unidimensional tumor size or a 15 percent decrease in tumor density on contrast-enhanced CT
scans (as reflected by differences in x-ray attenuation between a given material and water,
expressed in Hounsfield units) correlates well with PET scan findings and is a better predictor
of response to therapy (as judged by time to tumor progression) than standard RECIST [36].
These investigators compared the Choi criteria with standard (version 1.0 ( table 2)) RECIST
in 98 patients (40 in a training set and 58 a test set) receiving imatinib for advanced GIST who
had CT scans eight weeks after starting therapy [37]. The test set had 28 (48 percent) good
responders by RECIST, compared with 49 (84 percent) good responders by Choi criteria. Even
when the 98 patients were analyzed together, the response group by RECIST did not correlate
significantly with either disease-specific survival or time to tumor progression, whereas the
Choi response group did correlate with both endpoints. The authors concluded that tumor
response for GIST should preferentially be categorized by the Choi rather than the RECIST.
Impact of dose — At least two randomized trials have failed to show improved overall
survival for higher imatinib doses (800 mg daily) versus standard dosing of imatinib (400 mg
daily) [10,11]. In both trials, patients with disease progression in the standard-dose arm were
allowed to cross over to high-dose therapy. The European trial demonstrated a modestly but
significantly higher progression-free survival (PFS) with the 800 mg dose with median 25-
month follow-up, which was no longer evident with longer follow-up (median 40 months), and
which did not lead to a significant improvement in overall survival [10]. The American trial
showed no advantage for higher dose therapy in terms of either PFS or overall survival [11].
Both trials indicated more side effects from higher-dose therapy.
A meta-analysis of both trials came to the following conclusions [38]:
● At a median follow-up of 45 months, compared with standard-dose imatinib, a modest

PFS advantage was seen with higher dose imatinib (hazard ratio [HR] for progression
0.89, 95% CI 0.79-1.0), but overall survival and best response (51 versus 54 percent) were
similar.
● The presence of a KIT exon 9 mutation was the only significant predictive factor for
benefit from higher doses. Among the patients with an exon 9 mutation, compared with
standard-dose imatinib, higher dose imatinib was associated with improved PFS (HR 0.58,
95% CI 0.38-0.91) and overall response rates (47 versus 21 percent), but not overall
survival. In the absence of such mutations, no difference in these outcomes was
observed between the treatment arms.
Pharmacokinetic variability — Another possible explanation for the failure to

demonstrate benefit from higher imatinib doses in both trials is interpatient variability in
pharmacokinetic exposure [39,40]:
● In a study of 73 patients who were randomly assigned to 400 or 600 mg of imatinib daily
for advanced GIST, there was a 10-fold variance in trough levels with either dose (from
414 to 4182 ng/mL) [39]. Clinical outcomes were correlated with trough levels at steady
state. Trough values below 1100 ng/mL were associated with a significantly shorter time
to tumor progression and a lower rate of clinical benefit as compared with higher trough
levels.
● Others have shown a significant correlation between low imatinib trough levels and prior
major gastrectomy, higher creatinine clearance, and high serum albumin levels [40].
Pharmacokinetic variability may also contribute to acquired drug resistance [41]. In a small
population-based pharmacokinetic study in patients with GIST, imatinib clearance increased
after long-term treatment (>1 year), which reduced systemic exposure by 42 percent
compared with the start of treatment [42]. These findings were confirmed in a subsequent
prospective population pharmacokinetic study of 50 patents with GIST being treated with
imatinib [43]. After 90 days of treatment, there was a significant decrease in imatinib exposure
of 29 percent compared with baseline. However, there appeared to be no statistically
significant effect of pharmacokinetic variability on PFS in the subset of patients treated with
imatinib for advanced incurable disease.
It is not yet clear whether increased imatinib clearance is a significant factor in the
amelioration of imatinib toxicity that occurs with time and/or has any impact on disease
control; further work is required to ascertain the clinical implications of these observations.
Influence of mutations on response to therapy — An assessment of mutation status is

advised for patients with metastatic disease because clinical responses to imatinib (and other
TKIs) correlate with tumor genotype, which in turn impacts prognosis and treatment (
algorithm 1). (See 'KIT mutations' below and 'PDGFRA mutations' below.)
Approximately 10 percent of patients with GIST have primary resistance to imatinib, defined as
progression within the first six months of treatment. Many of these resistant tumors lack
mutations in KIT or PDGFRA, or they harbor a PDGFRA D842V mutation. While we generally do
not offer initial therapy with imatinib to these patients, the one notable exception is those with
advanced spindle cell tumors of the GI tract. Imatinib may be effective in patients with these
tumors, which appear histologically compatible with a diagnosis of GIST, even if they are
immunohistochemically KIT negative, and these patients may be offered a trial of imatinib.
(see "Clinical presentation, diagnosis, and prognosis of gastrointestinal stromal tumors",
section on 'Other risk factors')
The general approach to patients with a D842V mutation or a succinate dehydrogenase (SDH)-
deficient GIST is discussed below. (See 'Avapritinib for PDGFRA D842V mutant tumors' below
and 'SDH-deficient tumors and those associated with NF1' below.)
KIT mutations — Imatinib is approved in the United States for the treatment of all KIT-
expressing metastatic GISTs, regardless of mutation status. However, in our view and that of
others [44], assessment of mutation status is advised for most patients being treated for
metastatic disease, given the predictive and prognostic information that is provided [45].
Specific mutations in KIT (exon 11 versus exon 9) correlate with clinical response to imatinib (
algorithm 1).
For patients with a KIT exon 9 mutation, consensus-based guidelines from the NCCN suggest
initiating therapy for unresectable or metastatic disease with a higher dose of imatinib (800
mg daily) [27]. Similarly, the European Society for Medical Oncology (ESMO) recommends
mutation testing for all patients and considers this higher dose of imatinib to be a standard
treatment for patients with a KIT exon 9 mutation [44]. Although KIT exon 9 mutations are
associated with an increased response rate to higher dose imatinib, overall survival is not
improved. (See 'Impact of dose' above.)
In the United States, for patients where the KIT mutational status is unknown, one treatment
approach is to start with imatinib 400 mg daily and increase the dose to 800 mg daily if there
is no response. Initiation of second-line sunitinib is a reasonable alternative. Whether
outcomes are better with early institution of sunitinib following progression on imatinib 400
mg daily is not known. (See 'Sunitinib' below.)
Data are as follows [46-50]:
● In one study of 127 patients with GISTs receiving imatinib, activating mutations in KIT
and PDGFRA were found in approximately 88 and 5 percent, respectively [46]. All KIT
mutant isoforms were associated with a response to imatinib, while only a subset of
PDGFRA mutants was imatinib sensitive. (See 'PDGFRA mutations' below.)
Among the patients with KIT mutations, those with an exon 11 mutation had a
substantially greater likelihood of a partial response compared with patients with either
an exon 9 mutation or no detectable mutation in either KIT or PDGFRA (84 versus 48 and 0
percent, respectively), and they had a longer time to treatment failure as well.
● Data from two randomized trials (one from the United States Intergroup and another
from the European Organisation for the Research and Treatment of Cancer [EORTC]),
along with a meta-analysis of these two trials, suggest that higher daily doses of imatinib
may preferentially benefit those with exon 9 mutations [38,49,51]. Data from the
individual trials are discussed below, and data from the meta-analysis are reviewed
above. (See 'Impact of dose' above.)
In the United States Intergroup trial comparing two doses of imatinib in 324 patients,
patients whose tumors expressed an exon 11 mutant isoform were more likely to have
an objective response to imatinib compared with those with an exon 9 isoform or those
who had no kinase mutations (72 versus 44 and 45 percent, respectively) [49]. Patients
with an exon 11 mutation also had a significantly longer time to disease progression (25
versus 17 and 13 months, respectively) and median overall survival (median 60 versus 38
and 49 months, respectively).
In the EORTC trial of 58 patients whose tumors expressed an exon 9 mutant KIT protein,
an initial daily imatinib dose of 800 mg resulted in a significantly superior PFS (HR for
progression 0.39) compared with 400 mg/day [51]. In contrast, the time to progression
was not affected by the initial dose in patients with an exon 11 KIT mutation or wild-type
KIT. There were no corresponding differences in overall survival between low-dose and
high-dose initial therapy in patients with exon 9 mutations [51].
PDGFRA mutations — Platelet-derived growth factor receptor alpha (PDGFRA) mutations

in exons 12, 14, and 18 occur in approximately 10 to 20 percent of patients with GIST, with a
higher frequency among tumors that are KIT negative [48]. However, not all PDGFRA activating
mutations demonstrate the same biologic response to imatinib. In particular, the D842V
mutation in exon 18 confers relative primary resistance to imatinib ( algorithm 1) [52-54].
By contrast, other PDGFRA mutations appear to render GIST tumors sensitive to imatinib
[46,48,55,56]. As an example, in one observational study of approximately 60 patients with
PDGFRA mutant GIST, the response rate to imatinib was 0 percent among those with a D842V
substitution versus 39 percent for those with non-D842V PDGFRA mutations [52].
Further details and available treatment options for patients with advanced and metastatic
GISTs that harbor the PDGFRA D842V mutation are discussed separately. (See "Clinical
presentation, diagnosis, and prognosis of gastrointestinal stromal tumors", section on
'PDGFRA mutations' and 'Avapritinib for PDGFRA D842V mutant tumors' below.)
Duration of therapy — The optimal duration of imatinib therapy for responding patients

with advanced/metastatic disease was addressed in a French trial that randomly assigned
patients with advanced GIST and no disease progression after one year of imatinib to
continuous treatment or interruption until disease progression [57]. The study was stopped
prematurely after only 58 patients had been randomized when it became evident that the risk
of progression was significantly higher if therapy was interrupted, even in completely
responding patients. In the initial report of the 32 patients who interrupted therapy, 26
progressed and needed retreatment, compared with only 8 of 26 in the continuous therapy
arm (81 versus 31 percent). The corresponding median progression-free survival durations
were 18 versus 6 months. There were no significant differences between the groups with
respect to survival, incidence of imatinib resistance, or quality of life. Drug reintroduction
achieved tumor control in 24 of 26 of the patients whose therapy was interrupted.
The study was subsequently amended to allow randomization after three or five years of
therapy. In the final subset of 71 patients who remained free of progression after one (n = 32),
three (n = 25), or five (n = 14) years of therapy and who were randomized to discontinue
therapy, 51 patients had restarted imatinib upon documentation of progressive disease [58].
While 18 progressed only within known lesions, 33 (65 percent) had new lesions, with
concurrent progression in the known lesions in 17. Only eight (42 percent) of the patients who
had been in complete remission at randomization and 12 (52 percent) of the patients who had
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been in partial remission at randomization achieved a new complete or partial response,

respectively, after reintroduction of imatinib.
Thus, interruption of imatinib results in rapid progression in most patients with advanced
GIST, and it cannot be recommended unless there is significant toxicity or an intervening
complication, such as the need to treat another diagnosis (eg, another cancer), in the same
patient. Continuous therapy until disease progression (or lifelong if disease does not progress)
is advised.
Side effects and their management — Imatinib is generally well tolerated; most side effects
are less than grade 2, and the majority of patients can continue treatment without
interruption. In general, the side effect profile tends to improve with prolonged therapy [59].
(See "Initial treatment of chronic myeloid leukemia in chronic phase", section on 'Imatinib' and
"Initial treatment of chronic myeloid leukemia in chronic phase", section on 'Managing
toxicity'.)
Minimal data have been published on managing the side effects of imatinib [45]. The most
common side effects reported in GIST patients receiving imatinib are fluid retention, diarrhea,
nausea, fatigue, muscle cramps, abdominal pain, and rash. These and other potentially more
severe but less common side effects and proposed management strategies are summarized
below.
● Fluid retention – Fluid retention with peripheral edema, and occasionally pleural
effusion and ascites may be more common in older patients and in those with cardiac
disease. Periorbital edema is more common and often does not respond to diuretics, but
may improve with dietary salt restriction. It tends to be most prominent in the morning
and decreases in intensity if the patient is upright during the day. (See "Ocular side
effects of systemically administered chemotherapy", section on 'Imatinib'.)
In patients treated with imatinib in National Cancer Institute (NCI)-sponsored trials, the
rate of grade 3/4 edema considered likely related to imatinib was 1.3 percent.
● Muscle cramps – Muscle cramps are perhaps the most bothersome long-term symptom
associated with imatinib, most commonly affecting calves, feet, and hands. There is no
definitive treatment, although anecdotally some patients have obtained benefit from
treatment with calcium or magnesium supplements, or the use of quinine.
● Nausea, vomiting, dyspepsia – Nausea and vomiting are generally not a problem when
the drug is taken with food, which does not diminish absorption. Dyspepsia and GI upset
may also be lessened by taking the drug with meals. Symptomatic treatment with
antacids or proton pump inhibitors may be needed.
● Abdominal discomfort and diarrhea – Flatulence and mild abdominal discomfort are
common. Diarrhea is usually grade 1 to 2 but is occasionally more severe. Loose stools
can usually be managed with loperamide or atropine sulfate/diphenoxylate
hydrochloride.
● Rash – Skin rash is usually maculopapular and mild. It often resolves with continued
treatment. Severe cases may respond to a short course of high-dose glucocorticoids [60].
Some patients who flare on redosing may benefit from desensitization, starting with
doses as low as 25 mg daily, using cetirizine as premedication. (See "Cutaneous adverse
events of molecularly targeted therapy and other biologic agents used for cancer
therapy", section on 'Maculopapular eruption'.)
● Hematologic toxicity – Mild anemia is common with chronic use or higher doses [61].
Treatment with erythropoietin may benefit the occasional patient with more severe
anemia. Macrocytosis, with elevation of the mean corpuscular volume, is observed
frequently; the mechanism is unknown.
Neutropenia is rare. Patients may safely continue the drug as long as the absolute
neutrophil count is ≥1000 cells/microL. Withholding the drug usually leads to resolution
of neutropenia, often within days. Reinitiation of the same drug dose is often
accomplished without reoccurrence; dose reduction may be needed if the patient
continues to experience significant neutropenia.
● Hypophosphatemia – Hypophosphatemia is reported, especially with higher doses

[62,63]. Routine monitoring of phosphate levels has been suggested by the
manufacturer [64].
● Gynecomastia – Gynecomastia was reported in 7 of 38 men receiving imatinib for

chronic myeloid leukemia (CML) and associated with reduced levels of free testosterone.
Gynecomastia is not yet reported in men receiving imatinib for GIST.
● Lung and liver toxicity – Lung toxicity and elevation of liver function tests (LFTs) have
only occasionally been reported. Fatal hepatotoxicity was noted in a patient in blast crisis
who was taking large doses of acetaminophen concurrently, and it is recommended that
acetaminophen use be avoided, if possible. At least some data suggest that concomitant
administration of imatinib and corticosteroids may permit continued imatinib treatment
in patients who develop LFT abnormalities [65].
● Cardiac toxicity – The issue of cardiac toxicity is unresolved. In 2006, there was a report
of severe heart failure developing in 10 individuals receiving imatinib, although the
disease for which treatment was being given was not specified [66]. Subsequent
experience suggests that among patients receiving imatinib for CML, there is a risk for
heart failure, but the risk is fairly low and probably limited to those with pre-existing
heart disease. (See "Initial treatment of chronic myeloid leukemia in chronic phase",
section on 'Imatinib'.)
Whether imatinib causes cardiac toxicity in patients treated for GIST is unclear; the
following information on this issue is available:
• A report from the EORTC study of imatinib 400 versus 800 mg noted no excess of
clinical cardiac events in the study population who were treated for a median of 24
months [67]. (See 'Impact of dose' above.)
• A retrospective review of the MD Anderson experience of 219 patients enrolled in

clinical trials of imatinib for GIST over a six-year period identified potential cardiac
adverse events in 18 (8 percent) [68]. The adverse events included dyspnea, chest
pain, edema, pleural effusion, ascites, cardiac ischemia and arrhythmia. Thirteen had
risk factors for coronary artery disease or established heart disease. None of the
patients had evidence of pulmonary vascular congestion on chest radiography. Of the
eight patients who underwent echocardiography or radionuclide ventriculography,
only one had a left ventricular ejection fraction <50 percent. All patients were able to
continue imatinib with dose adjustment and toxicity-specific management.
• In the landmark phase III placebo-controlled adjuvant imatinib trial, there was no
excess of cardiotoxicity in the group that received one year of postoperative imatinib.
(See "Adjuvant and neoadjuvant imatinib for gastrointestinal stromal tumors", section
on 'Phase III trials'.)
Until further information becomes available, the following actions would be prudent:
• As part of the informed consent process, patients taking imatinib should be notified
that heart failure may be a rare but potentially serious adverse event.
• Patients currently taking imatinib should be monitored for signs and symptoms of left
ventricular systolic dysfunction.
• Heart failure should be considered in the differential diagnosis of any patient

experiencing peripheral edema while receiving this agent.
● GI bleeding – Patients with large bulky tumors have a 5 percent risk of tumor
hemorrhage not associated with thrombocytopenia. These patients should be closely
monitored for a drop in hemoglobin in the first four to eight weeks of therapy [45]. If the
hemoglobin level acutely decreases ≥2 g/dL, imatinib should be temporarily withheld
until blood counts have stabilized, with transfusion if needed. Emergent surgical
intervention may be needed if bleeding does not resolve. However, emergency surgery is
uncommonly needed. It was required in three of 232 patients in one report (1.3 percent)
[69].
If life-threatening side effects, such as GI bleeding, develop that cannot be managed with
maximal supportive care, a switch to sunitinib should be considered. (See 'Subsequent
management of imatinib-refractory disease' below.)
● Ocular toxicity – In addition to periorbital edema, imatinib is associated with epiphora

(excess tearing), spontaneous conjunctival/subconjunctival hemorrhage, and rare
instances of retinal hemorrhage and optic neuritis. (See "Ocular side effects of
systemically administered chemotherapy", section on 'Imatinib'.)
Exceptions
Avapritinib for PDGFRA D842V mutant tumors — For patients with symptomatic and/or
rapidly progressive disease harboring a platelet-derived growth factor receptor alpha
(PDGFRA) exon 18 D842V mutation, we recommend avapritinib over either imatinib or
observation in the setting of initial therapy. These tumors often demonstrate primary
resistance to imatinib, whereas the response rate with avapritinib is high (approximately 90
percent) ( algorithm 1).
For those with the PDGFRA D842V mutation who exhibit asymptomatic and/or indolent
disease, a period of observation is preferable to immediate therapy with avapritinib in order to
avoid treatment-related toxicities, such as potential cognitive impairment. In these patients,
avapritinib may be initiated at the onset of symptomatic and/or rapidly progressive disease.
Ripretinib, another agent targeting the PDGFRA D842V mutation, is approved for patients who
have progressed on multiple TKIs. (See 'Ripretinib' below.)
This is in contrast to the approach for patients with GISTs harboring a PDGFRA exon 18
mutation other than D842V. Although avapritinib is active for such patients, other agents
(including imatinib, sunitinib, and regorafenib) also are effective, and avapritinib is typically
reserved for use after progression on these therapies ( algorithm 1). (See 'PDGFRA
mutations' above and 'Management of disease refractory to imatinib, sunitinib, and
regorafenib' below.)
Avapritinib is administered at 300 mg daily until disease progression, intolerance, or

unacceptable toxicity occurs. Avapritinib is associated with central nervous system toxicities,
including cognitive impairment; mood, speech, or sleep disorders; dizziness; hallucinations;
and intracranial hemorrhage. Patients must be closely monitored for these central nervous
system toxicities, with appropriate dose reductions or permanent discontinuation of
avapritinib as clinically indicated [70]. Of note, it has been our experience that some cognitive
impairment from avapritinib may persist despite dose modification or discontinuation of
treatment, and further follow-up is needed to determine the duration and potential reversal of
symptoms. (See "Neurologic complications of cancer treatment with molecularly targeted and
biologic agents", section on 'Dasatinib, imatinib, and avapritinib'.)
Avapritinib is also teratogenic; therefore, females of reproductive potential or males with

female partners of reproductive potential should use effective contraception while on therapy
as well as for six weeks after the final dose is administered.
The efficacy of avapritinib was evaluated in a single-arm, open-label, phase I clinical trial
(NAVIGATOR) [71,72]. In this study, a cohort of 56 patients with GIST containing the PDGFRA
exon 18 D842V mutation received avapritinib at 300 or 400 mg daily. Patients with a D842V
mutation were not required to have received prior systemic therapy. After a median follow-up
of approximately 28 months, overall responses for those with the D842V mutation were seen
in 51 patients (91 percent), including seven complete responders (13 percent) and 44 partial
responders (79 percent). One-year progression-free and three-year overall survival rates were
83 and 61 percent, respectively.
Grade ≥3 toxicities included anemia (28 percent), hyperbilirubinemia (9 percent), fatigue (9

percent), abdominal pain (6 percent), diarrhea (5 percent), cognitive impairment (5 percent),
edema (2 percent), and pleural effusion (2 percent) [73].
Based on these phase I results, the US Food and Drug Administration (FDA) granted approval
to avapritinib for patients with unresectable or metastatic GISTs with a PDGFRA exon 18
mutation [73]. Further randomized trials comparing avapritinib with other standard therapies
are needed to confirm these results.
Limited data suggest that dasatinib and the investigational agent crenolanib (a TKI with
specificity for PDGFRA, platelet-derived growth factor beta [PDGFRB], and fms-like tyrosine
kinase 3 [FLT3]) may also be active against tumors with a PDGFRA D842V mutation [74-76].
These results require further investigation. (See 'Investigational therapies' below.)
SDH-deficient tumors and those associated with NF1 — Many tumors that lack mutations
in KIT and PDGFRA (so-called wild-type tumors) are deficient in expression of one or more
subunits of the genes that encode the proteins that form the succinate dehydrogenase (SDH)
protein complex. SDH-deficient tumors have a high rate of primary resistance to various TKIs
but a comparatively indolent course [77,78]. The best way to treat these patients is not
established. Although they are refractory to imatinib, they may have some responsiveness to
sunitinib or regorafenib. Referral to an expert center is preferred. These patients are also good
candidates for clinical trials ( algorithm 1). (See 'Sunitinib' below and 'Regorafenib' below.)
As an example, in one report of 95 patients with KIT/PDGFRA wild-type GIST (84 of which were
SDH deficient), only 1 of 49 patients treated with imatinib had a partial response, and there
were only four objective responses to sunitinib (one complete, three partial) [77]. Of the 63
patients with SDH mutant GIST followed for a median of six (range 1 to 44) years, only three
had died (from 8 to 24 years after initial diagnosis); in contrast, 3 of 11 (27 percent) patients
with SDH-competent wild-type GIST had died of progressive disease with a median follow-up
of eight years (range 2 to 17). (See "Clinical presentation, diagnosis, and prognosis of
gastrointestinal stromal tumors", section on 'KIT/PDGFRA wild-type GISTs'.)
Patients with neurofibromatosis type 1 (NF1), an inherited cancer predisposition syndrome

that is caused by a mutation in the NF1 gene that encodes neurofibromin, have an increased
risk of GIST. GISTs that arise in these patients may be KIT expressing, but they lack mutations
in KIT and PDGFRA. These tumors rarely respond to imatinib [79]. (See "Clinical presentation,
diagnosis, and prognosis of gastrointestinal stromal tumors", section on 'Pathogenesis'.)
ROLE OF SURGERY
The role of surgery in patients with metastatic disease is addressed elsewhere. (See "Local
treatment for gastrointestinal stromal tumors, leiomyomas, and leiomyosarcomas of the
gastrointestinal tract", section on 'Role of surgery in patients with metastatic disease'.)
SUBSEQUENT MANAGEMENT OF IMATINIB-REFRACTORY DISEASE
Dose escalation is an option for patients with primary as well as secondary (late) resistance to
standard doses of imatinib. Patients who are intolerant of imatinib are better served by
switching to an alternative tyrosine kinase inhibitor (TKI), sunitinib.
Dose escalation of imatinib — Dose escalation may be considered in patients started on

imatinib 400 mg daily who, after careful review of radiologic studies, are judged to have clear
evidence of disease progression. The efficacy of this approach was shown in follow-up reports
from both the American and European randomized dose-finding studies described above
[11,80] (see 'Impact of dose' above):
● In the European study described above [10], 247 of the 473 patients randomly assigned
to low-dose therapy progressed, and 133 were crossed over to higher dose therapy (400
mg twice daily) [80]. There were three confirmed partial responses, and 36 patients had
prolonged periods of stable disease. Anemia and fatigue increased on the higher dose,
but 18 percent were still alive and progression-free at one year.
● Similar results were noted in the American trial [11]. Of the 164 patients progressing on
low-dose therapy, 133 crossed over to 800 mg daily. Following crossover, 31 percent of
assessable patients (n = 117) achieved either an objective response (n = 3) or stable
disease (n = 33). The median durations of progression-free survival (PFS) and overall
survival after crossover were 5 and 19 months, respectively.
Increasing the dose is unlikely to benefit patients who progress rapidly (within two months)
after starting therapy.
Alternative therapies — Emerging data suggest that selection of clones with secondary KIT
mutations that cluster in the ATP-binding pocket and the activation loop of the kinase domain
is the most common mechanism of secondary imatinib resistance [81-87]. Possible methods of
overcoming imatinib resistance include resection of metastases to remove resistant clones,
the use of more-powerful selective TKIs, multitargeted inhibitors, or combination therapies
utilizing selective inhibitors of the tyrosine kinase receptor itself coupled with selective
inhibitors of downstream pathways. In vitro studies suggest that the choice of TKI for imatinib-
refractory GIST might depend, at least in part, on the specific mutation responsible for the
acquisition of resistance [87,88]. However, these data require validation in human subjects
before they can be applied to clinical practice.
Metastasectomy — Surgical resection may be considered in selected patients. In general,

resection appears to benefit responding patients (ie, those who have a partial response, stable
disease, or focal progression while receiving imatinib, and possibly those with isolated sites of
progression) but has little to offer those who experience generalized or multifocal disease
progression. The goal of metastasectomy is to halt disease progression by eliminating
resistant clones. The appropriate timing of surgical intervention is not established. This
subject is discussed in detail separately. (See "Local treatment for gastrointestinal stromal
tumors, leiomyomas, and leiomyosarcomas of the gastrointestinal tract", section on 'Role of
surgery in patients with metastatic disease'.)
Sunitinib
Efficacy — The multitargeted TKI sunitinib is active in imatinib-refractory or intolerant

patients [89-95]. An international phase III trial of sunitinib versus placebo in 312 patients with
refractory disease definitively established the role of sunitinib in this setting [92]. Patients
demonstrating progression (by Response Evaluation Criteria In Solid Tumors [RECIST] version
1.0) while on placebo crossed over to the active treatment arm. In the latest update, at a
median follow-up of 42 months, despite a low objective response rate in the sunitinib group (7
percent partial response), median time to tumor progression, the primary endpoint, was
fourfold higher as compared with the placebo group (27 versus 6 weeks) [94]. Although
survival was significantly better with sunitinib in the initial report [92], over time, as expected,
overall survival converged (median 73 versus 65 weeks) [94]. The median number of weeks on
treatment was 22.
As with imatinib, the clinical activity of sunitinib is significantly influenced by the specific
mutation type [91,96]. This was shown in a phase I/II trial performed in 97 patients with
metastatic, imatinib-refractory or intolerant GISTs [91]. Clinical benefit (partial response or
stable disease for longer than six months) was significantly higher for those with a primary KIT
9 exon (58 percent) or wild-type KIT/platelet-derived growth factor receptor alpha (PDGFRA)
mutation (56 percent) than for those with a KIT exon 11 mutation (34 percent). The same
pattern was seen for progression-free and overall survival. Following progression on imatinib,
patients with KIT exon 9 mutation or a PDGFRA mutation had a median time to progression of
19 months, while for those with exon 11 mutations, it was only five months. There was also a
correlation between secondary mutations and response to sunitinib. Both progression-free
and overall survival were significantly longer for patients with secondary KIT exon 13 or 14
mutations than for those with exon 17 or 18 mutations (7.8 versus 2.3 months).
As with imatinib, PET scans can permit an earlier assessment of response than conventional
CT scans [90,97] but are rarely used outside of the context of a clinical trial, except in patients
who cannot tolerate intravenous contrast or magnetic resonance imaging (MRI) as other
means of evaluating metastatic GISTs radiologically. (See 'Assessing response to therapy'
above.)
Sunitinib is approved in the United States for the treatment of imatinib-refractory or intolerant
advanced GISTs. The approved dose is 50 mg daily for four of every six weeks. However,
continuous daily dosing (37.5 mg daily) appears similarly safe and effective [98].
Resistance to sunitinib shares similar pathogenetic mechanisms to those identified in imatinib

failure, with acquisition of secondary mutations after an extended initial response to the drug
[99].
Side effects and management — Sunitinib can cause fatigue, nausea, vomiting,

anemia, neutropenia, diarrhea, abdominal pain, mucositis, anorexia, hypothyroidism, and
discoloration of skin and hair. Other less common toxicities include bleeding, fever,
hypertension, hand-foot skin reaction, myelosuppression, proteinuria and other forms of renal
toxicity, elevation in serum amylase and lipase, and reduced left ventricular ejection
fraction/clinical heart failure. Most sunitinib-related toxicities can be managed
symptomatically or with temporary withdrawal or dose reduction. In severe cases, the drug
may need to be discontinued.
The following represents a brief synopsis of the most common toxicities seen with sunitinib:
● Renal toxicity – Small molecule TKIs that target the vascular endothelial growth factor
receptors (VEGFR) are associated with proteinuria, which is rarely nephrotic range (>3.5
g/24 hours) and, even more rarely, associated with the nephrotic syndrome.
Hypertension frequently accompanies proteinuria. The factors associated with both the
occurrence and the severity of proteinuria in patients treated with sunitinib are
incompletely characterized.
There are no published guidelines for managing albuminuria during sunitinib treatment;
however, good clinical practice dictates obtaining a baseline urinalysis with periodic
assessment of proteinuria. Treatment interruption is appropriate management for
patients who develop moderate to severe proteinuria (≥3 g/24 hours). (See "Toxicity of
molecularly targeted antiangiogenic agents: Non-cardiovascular effects", section on
'Proteinuria/nephrotic syndrome'.)
● Hematologic toxicity – Sunitinib may cause myelosuppression. Sunitinib should be held

if the absolute neutrophil count is ≤1000 cells/mm3. Recurrent episodes of grade 3 or 4
neutropenia or thrombocytopenia should prompt dose reduction to 37.5 or 25 mg daily
[45]. Anemia, if acute, should prompt interruption of sunitinib and a search for a source
of bleeding or evidence for hemolysis. (See "Toxicity of molecularly targeted
antiangiogenic agents: Non-cardiovascular effects", section on 'Myelosuppression'.)
Rarely, sunitinib has been associated with a thrombotic microangiopathy (TMA), which
may include a thrombotic thrombocytopenic purpura (TTP) or hemolytic uremic
syndrome (HUS)-type picture with microangiopathic hemolysis and renal failure.
Hypertension is present in most cases. Withdrawal of sunitinib is crucial because this
toxicity is potentially life-threatening. Other aspects of management are presented
separately. (See "Drug-induced thrombotic microangiopathy (DITMA)", section on
'Management'.)
● Hypothyroidism – Hypothyroidism is a frequent complication of prolonged sunitinib

therapy. In one series, 15 of 42 euthyroid patients with intact thyroid glands (36 percent)
became hypothyroid (as defined as a persistently elevated level of thyroid stimulating
hormone [TSH]) while receiving sunitinib for advanced GIST [100]. The risk increased with
longer duration of therapy (18, 29, and 90 percent in patients treated for 36, 52, and 96
weeks, respectively). The mean time to development of hypothyroidism was 50 weeks.
Because of the high prevalence of hypothyroidism, regular surveillance of TSH levels is
warranted during sunitinib therapy. We and others [101] suggest that thyroid function be
evaluated at baseline and monitored at monthly intervals. (See "Toxicity of molecularly
targeted antiangiogenic agents: Non-cardiovascular effects", section on 'Thyroid
dysfunction' and "Diagnosis of and screening for hypothyroidism in nonpregnant adults"
and "Treatment of primary hypothyroidism in adults".)
Another potential mechanism for hypothyroidism that should be considered in patients

being treated with antiangiogenic TKIs for advanced GIST is consumptive
hypothyroidism due to excessive degradation of thyroid hormone. However, this appears
to be caused by overexpression of the thyroid hormone inactivating enzyme type 3
iodothyronine deiodinase (D3) within large GISTs and is not a drug-related adverse
effect. This subject is discussed in detail elsewhere. (See "Disorders that cause
hypothyroidism", section on 'Consumptive hypothyroidism' and "Clinical presentation,
diagnosis, and prognosis of gastrointestinal stromal tumors", section on 'Clinical
presentation'.)
● Hypertension and cardiac toxicity – Patients should be closely monitored for

hypertension and evidence of cardiac dysfunction while receiving sunitinib. (See "Toxicity
of molecularly targeted antiangiogenic agents: Cardiovascular effects", section on
'Hypertension' and "Toxicity of molecularly targeted antiangiogenic agents:
Cardiovascular effects", section on 'Left ventricular dysfunction and myocardial
ischemia'.)
The frequency of these events in patients treated with sunitinib for GIST can be
illustrated by the following:
• In a study of 75 patients treated with sunitinib for imatinib-resistant GISTs, 47 percent

developed hypertension (defined as a blood pressure >150/100 mmHg) during
therapy [102]. In addition, 10 of 36 patients (28 percent) who were serially assessed
had a ≥10 percent decline in left ventricular ejection fraction (LVEF) during therapy,
and clinical heart failure developed in six (8 percent). Heart failure and decreased LVEF
generally resolved with medical management and withdrawal of sunitinib.
• Somewhat lower rates of treatment-related hypertension (20 percent, any grade),

decreased ejection fraction (8 percent), and left ventricular dysfunction (2 percent)
were reported in the longitudinal report of the phase III trial of sunitinib versus
placebo discussed above [94].
● Gastrointestinal (GI) bleeding and/or bowel perforation – Patients who are treated
with sunitinib for advanced GIST can develop GI bleeding or a bowel perforation. In one
series, emergency surgery for hemorrhage, tumor perforation, or abscess was required
in 4 of 43 patients during second-line therapy with sunitinib [69]. (See "Toxicity of
'Bleeding' and "Toxicity of molecularly targeted antiangiogenic agents: Non-
cardiovascular effects", section on 'Intestinal perforation/fistula formation'.)
● Potential for delayed wound healing – Impaired wound healing (and reopening of
previously healed wounds) has been observed following treatment with all TKIs that
target VEGF, including sunitinib. However, at least some data support the view that
wound healing complications are not more common after extensive GIST resections in
patients on sunitinib as compared with imatinib [103]. (See "Toxicity of molecularly
targeted antiangiogenic agents: Non-cardiovascular effects", section on 'Delayed wound
healing'.)
Because of the potential for wound healing problems, many clinicians suggest
interruption of therapy for at least one week before surgery, and not reinitiating until
adequate wound healing has occurred. However, given that these tumors can progress
quite rapidly off therapy, it is our practice to continue sunitinib until three to four days
prior to surgery and to resume the drug at the first postoperative visit. (See "Toxicity of
'Delayed wound healing'.)
Regorafenib — Regorafenib is an orally active TKI that is structurally similar to sorafenib and

targets a variety of kinases including KIT, platelet-derived growth factor receptor (PDGFR), and
VEGFR. Efficacy in refractory patients was shown in a phase II trial of 34 patients who
developed resistance to both imatinib and sorafenib, in which four patients had a partial
response and 22 had stable disease for 16 weeks or longer; the median PFS was 10 months
[104].
Efficacy was confirmed in a later phase III trial in which 199 patients who were refractory to or
intolerant of sunitinib were randomly assigned to best supportive care plus either regorafenib
(160 mg once daily for three of every four weeks) or placebo [105]. Regorafenib was
associated with significantly better PFS (4.8 versus 0.9 months). Although there was no
apparent survival benefit, this finding is explained by the crossover design (85 percent of
patients in the placebo group received regorafenib after progression). The most common
grade 3 adverse effects were hypertension (23 percent), hand-foot skin reaction (20 percent),
and diarrhea (5 percent). Treatment related toxicity with regorafenib is discussed in more
detail elsewhere. (See "Toxicity of molecularly targeted antiangiogenic agents: Non-
cardiovascular effects" and "Toxicity of molecularly targeted antiangiogenic agents:
Cardiovascular effects".)
In February 2013, the US Food and Drug Administration (FDA) approved regorafenib for
treatment of metastatic or unresectable GIST no longer responsive to imatinib and sunitinib.
Although the available data are limited, patients with a KIT exon 11 mutation (and succinate
dehydrogenase [SDH]-deficient GISTs) seem to derive greater benefit from regorafenib than
do those with KIT/PDGFRA wild-type non-SDH-deficient tumors [106].
MANAGEMENT OF DISEASE REFRACTORY TO IMATINIB, SUNITINIB, AND

REGORAFENIB
Ripretinib — For patients with GIST (irrespective of D842V mutation status) who have
progressed on or are intolerant of three or more tyrosine kinase inhibitors (TKIs), including
imatinib, we suggest ripretinib over other available TKIs, as this agent improved survival and
was well tolerated in a placebo-controlled randomized trial [107].
Ripretinib is administered at an initial dose of 150 mg daily until disease progression,

intolerance, or unacceptable toxicity occurs [108].
Management considerations specific to use of ripretinib are as follows:
● The use of concomitant strong and moderate CYP3A inducers ( table 3) with ripretinib
should be avoided.
If the concomitant use of moderate CYP3A inducers cannot be avoided, the ripretinib
dose should be increased to 150 mg twice daily during the co-administration period, with
monitoring for efficacy and toxicity. Ripretinib can be resumed at 150 mg daily two weeks
after the moderate CYP3A inducer is stopped [109]. (See "Drugs and the liver:
Metabolism and mechanisms of injury".)
● We obtain a baseline echocardiogram or MUGA scan prior to initiation of therapy and as

clinically indicated afterwards; ripretinib should be discontinued in those who develop
grade ≥3 left ventricular diastolic dysfunction on treatment. (See "Toxicity of molecularly
targeted antiangiogenic agents: Cardiovascular effects", section on 'Ripretinib' and
"Cardiotoxicity of cancer chemotherapy agents other than anthracyclines, HER2-targeted
agents, and fluoropyrimidines", section on 'Ripretinib'.)
● Patients should receive regular dermatologic evaluation, as ripretinib is associated with

the development of primary cutaneous malignancies (such as squamous cell carcinoma
and melanoma), alopecia, and hand-foot skin reaction syndrome. (See "Hand-foot skin
reaction induced by multitargeted tyrosine kinase inhibitors".)
● Patients of reproductive potential and their partners should use effective contraception
during therapy and for at least one week after treatment completion.
● Ripretinib should be held for at least one week prior to elective surgeries and at least two
weeks after major surgery to reduce the risk of wound healing complications.
● The approach to monitoring and managing hypertension in patients treated with

ripretinib is similar to that used with antiangiogenic agents and is discussed separately.
(See "Toxicity of molecularly targeted antiangiogenic agents: Cardiovascular effects",
section on 'Hypertension'.)
Ripretinib, a "switch control" inhibitor, targets multiple molecular alterations present in GIST,
including several KIT mutations (exon 9, 11, 13, 14, 17, and 18), by stabilizing the KIT molecule
into an inactive form. Ripretinib also targets PDGFRA mutations in exon 18, including the
D842V resistance mutation, and the D816V secondary resistance mutation in exon 17, which is
also present in most patients with systemic mastocytosis. (See "Advanced systemic
mastocytosis: Management and prognosis".)
In a phase III trial (INVICTUS), 129 patients with advanced GIST either refractory to or
intolerant of imatinib, sunitinib, and regorafenib were randomly assigned to ripretinib or
placebo [107]. Ripretinib improved both median overall survival (15 versus 6 months, hazard
ratio [HR] 0.36, 95% CI 0.20-0.62) and progression-free survival (PFS) (six versus one month;
six-month PFS 51 versus 3 percent, 95% CI 0.09-0.25) relative to placebo. Objective response
rates were also higher for ripretinib compared with placebo (9 versus 0 percent). Ripretinib
was well tolerated, as the number of patients who discontinued or interrupted treatment due
to adverse events was similar between ripretinib and placebo. Grade ≥3 treatment-related
toxicities included anemia (9 percent), abdominal pain (7 percent), hypertension (7 percent),
and decreased ejection fraction (3 percent). The most common side effect was alopecia (52
percent), which is unique to ripretinib relative to other TKIs used for GIST.
Based on these data, ripretinib is approved by the US Food and Drug Administration (FDA) for
patients with advanced GIST who have received three or more TKIs, including imatinib [109].
Alternative tyrosine kinase inhibitors — For patients who are ineligible for or intolerant of
ripretinib, alternative options include nilotinib, sorafenib, or pazopanib. Avapritinib is an
option for those with the PDGFRA D842V mutation who have progressed on imatinib and
sunitinib.
Limited data are available on the efficacy of these alternative TKIs to ripretinib for imatinib-
and sunitinib-refractory GISTs [75,110-120]. These agents have not been directly compared,
and none are specifically approved for refractory disease. The choice between these agents is
based on prior therapy, tumor mutational status, pharmacokinetics, tolerance, as well as
patient and clinician preference. Patients previously treated with imatinib, sunitinib, and
regorafenib are more likely to progress and have less durable treatment responses when
these alternative agents are used beyond third-line therapy. Therefore, their use is best
considered a "holding strategy," and clinical trial enrollment is encouraged, where available.
Nilotinib — For frail patients who poorly tolerated imatinib, sunitinib, or regorafenib therapy,
nilotinib may be better tolerated and, consequently, more likely to be administered at
therapeutic doses. Although limited, the available data suggest that nilotinib is not an
effective agent in patients whose tumors have a KIT exon 9 mutation [121].
Nilotinib is a more potent second-generation TKI that targets KIT and PDGF receptors; it is not
more efficacious than imatinib as first-line therapy [121], although efficacy in imatinib-
refractory cases has been shown in several reports [114,115,122]. Benefit in patients refractory
to both imatinib and sunitinib is less certain [116,117,120]. In a phase III trial, 248 patients
with advanced GIST following prior imatinib and sunitinib failure were randomly assigned to
nilotinib (400 mg twice daily) or best supportive care with or without imatinib or sunitinib
[120]. Compared with best supportive care, nilotinib improved PFS based on local investigator
assessment (median 119 versus 70 days) but not when it was based on blinded central
radiology review (median 109 versus 111 days).
As has been shown with imatinib, prior gastrectomy may result in markedly lower
bioavailability of a variety of other TKIs such as nilotinib [123]. (See 'Pharmacokinetic
variability' above.)
Sorafenib — For those with poor tolerance of regorafenib alone, sorafenib may be helpful,
given the similarity of both agents. The half-life of sorafenib is shorter than that of
regorafenib, enabling more rapid resolution of toxicity and facilitating titration to the patient's
own maximally tolerated dose. However, for those with disease progression on regorafenib,
sorafenib is unlikely to be helpful.
The efficacy of sorafenib (a TKI that inhibits KIT, vascular endothelial growth factor receptor
[VEGFR], and platelet-derived growth factor receptor beta [PDGFRB]) was addressed in a
multicenter phase II trial involving patients with either imatinib (n = 6) or imatinib and
sunitinib-refractory (n = 32) GIST [111]. In preliminary results, the disease control rate was 68
percent, and median progression-free survival (PFS) was 5.2 months. The most common grade
3 toxicities were hand-foot syndrome (45 percent) and hypertension (21 percent).
Pazopanib — For those with KIT wild-type GIST, pazopanib may be helpful, as it is a potent
inhibitor of vascular endothelial growth factor (VEGF) signaling.
Pazopanib has activity in patients with imatinib and sunitinib-refractory disease [118,119]. The
efficacy of pazopanib, compared with best supportive care (BSC) alone, was addressed in a
small randomized phase II PAZOGIST trial conducted in 81 patients who were refractory to
imatinib and sunitinib [119]. Compared with BSC alone, pazopanib improved PFS (median 3.4
versus 2.3 months, HR 0.59, 95% CI 0.37-0.96). Although there were no objective responses, 84
percent had stable disease (compared with 70 percent with BSC only). However, toxicity rates
were high; among the 76 patients who eventually were treated with pazopanib (which
included 36 who crossed over from the BSC group), 72 percent experienced grade ≥3 adverse
events, including serious adverse events (eg, pulmonary embolism in 9 percent).
Avapritinib — Avapritinib is an option for those patients with a PDGFRA D842V mutation who
have progressed on imatinib and sunitinib. In this subset of patients, avapritinib improved PFS
and objective response rates (ORR) compared with regorafenib in a phase III trial [124]. For
other patients with a PDGFRA exon 18 mutation other than D842V, we reserve the use of
avapritinib for those with disease that has progressed on all three agents (imatinib, sunitinib,
and regorafenib). For all other patients with such treatment-refractory disease lacking a
PDGFRA exon 18 mutation, including D842V, we do not suggest the use of avapritinib because
it confers no additional clinical benefit compared with regorafenib and is associated with
central nervous system toxicity.
In an open-label phase III trial (VOYAGER), 476 patients with unresectable or metastatic GIST
previously treated with imatinib and one or two additional TKIs were randomly assigned to
either avapritinib or regorafenib [124]. A majority of patients (95 percent) also previously
received sunitinib, but none received regorafenib or more than three different TKIs. In the
entire study population, compared with regorafenib, avapritinib improved ORR (17 versus 7
percent) but had similar PFS (median 4.2 versus 5.6 months, HR 1.25, 95% CI 0.99-1.57),
disease control rates (42 versus 46 percent), and overall survival (OS) at one year (68 versus 67
percent). Among the 13 patients with PDGFRA D842V-mutant tumors, avapritinib improved PFS
over regorafenib (median not reached versus 4.5 months) and ORR (43 versus 0 percent). In
contrast, for patients without a PDGFRA D842V mutation, regorafenib improved PFS compared
with avapritinib (median 3.9 versus 5.6 months, HR 1.34, 95% CI 1.06 to 1.69). The rates of
grade ≥3 treatment-related toxicity were similar between the two treatment arms (55 versus
58 percent).
The efficacy of avapritinib as initial therapy in those with the PDGFRA D842V mutation is
discussed above. (See 'Avapritinib for PDGFRA D842V mutant tumors' above.)
Other agents
● Ponatinib – Ponatinib is an oral TKI with potent preclinical activity against primary KIT
exon 11 mutations and clinically important secondary resistance mutations, including A
loop mutations that are resistant to imatinib and sunitinib [125]. In a phase II study of
ponatinib after failure of standard approved TKIs, among patients with a primary KIT
exon 11 mutation, 11 of 22 (50 percent) had stable disease or better at 16 weeks [126].
For patients with a primary KIT exon 9 mutation, 3 of 11 (27 percent) had stable disease
or better at 16 weeks. This was a heavily pretreated patient group; 74 percent had four or
more prior regimens.
Patients considered for ponatinib should be carefully selected because of the risk of
serious arterial thrombotic events that accumulate over time, as has been seen in
patients with chronic myelogenous leukemia treated with ponatinib [127]. These findings
led to more restrictive eligibility criteria and a black box warning from the FDA. (See
"Toxicity of molecularly targeted antiangiogenic agents: Cardiovascular effects", section
on 'VEGFR tyrosine kinase inhibitors'.)
● Dasatinib – Dasatinib is an active agent as well in this setting [75,110,128]. In a phase II

study of dasatinib (70 mg orally twice daily) in 50 patients with advanced GIST who were
refractory to imatinib, 80 percent of whom were also refractory to sunitinib, 12 had a
partial response by Choi criteria, and this was sustained for at least eight weeks in five
[75]. Among patients with a mutation in KIT exon 11, median PFS and overall survival
were 2.7 and 19.6 months, respectively; median PFS for those with a mutation in PDGFRA
exon 18 was 22 months, and median overall survival was not reached. It should be noted,
however, that the Choi criteria have not been validated in patients treated with any TKI
beyond imatinib, and none of the above phase II trials of any TKI other than imatinib
have been evaluated using Choi criteria. (See 'RECIST versus Choi criteria' above.)
Imatinib or sunitinib rechallenge — For patients who are refractory to multiple TKIs

(including imatinib, sunitinib, and regorafenib) imatinib or sunitinib rechallenge is a preferred
strategy over discontinuing a TKI altogether, even in the face of worsening disease burden. It
is hypothesized that retreatment with imatinib or sunitinib provides inhibition of the bulk of
disease clones that retain sensitivity to either drug; however, the relatively short duration of
benefit suggests that TKI-resistant clones continue to progress during treatment. Data that
support a modest benefit for imatinib or sunitinib retreatment are as follows:
● A Korean trial randomly assigned 81 patients with advanced GIST following failure of all
available TKIs to imatinib rechallenge (400 mg once daily) or placebo [129]. Median PFS
was significantly greater for those patients who received imatinib (1.8 versus 0.9
months), and the disease control rate at 12 weeks was 32 percent (versus 5 percent in
the placebo group). With 93 percent of the placebo patients crossing over to active
treatment, median overall survival was similar in both groups (8.2 versus 7.5 months in
the imatinib and placebo groups, respectively).
● An Italian retrospective of 82 patients with advanced GIST previously treated with

imatinib, sunitinib, or regorafenib included 74 who were retreated with imatinib (dose
400 mg daily) and eight who were retreated with sunitinib (dose individualized according
to clinician choice) [130]. In preliminary results available in abstract form, the median
time to progression in retreated patients was 5.4 months, and overall survival was 10.4
months. A correlation between mutational status and response rate, time to progression,
or overall survival was not found.
Investigational therapies — Patients with advanced disease that has progressed on

standard therapies may be candidates for clinical trials. For patients who harbor imatinib-
resistant mutations, there are ongoing trials testing immunotherapy, TKIs [131], and
combination therapies that exploit resistance pathways [132]. Such patients should be
referred to centers of excellence specializing in the treatment of GIST.
ROLE OF RADIATION THERAPY
For patients with progressive symptomatic soft tissue metastases despite treatment with
multiple TKIs, radiation therapy (RT) is a reasonable option, although response rates are
limited for this approach.
Given the limited duration of benefit for second-line treatment with a TKI (approximately five
to six months), most patients with advanced GIST will eventually require palliative care.
Current treatment guidelines do not address radiotherapy as a therapeutic option or consider
it only for palliation of the rare patient with painful bone metastases [44,133]. GIST has been
historically considered radiotherapy resistant or minimally responsive [134-137], although
selected patients may benefit [138-140]. A prospective study of 25 patients progressing at
intra-abdominal soft tissue or liver sites during or after TKI therapy demonstrated a low
objective response rate to radiotherapy (only two [8 percent] achieved a partial remission), but
20 (80 percent) had stable target lesion size for three or more months (median duration of
stabilization 16 months), and this was fourfold longer than the median time to GIST
progression at any site.
SOCIETY GUIDELINE LINKS
Links to society and government-sponsored guidelines from selected countries and regions
around the world are provided separately. (See "Society guideline links: Gastrointestinal
stromal tumors".)
INFORMATION FOR PATIENTS
UpToDate offers two types of patient education materials, "The Basics" and "Beyond the
Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th
grade reading level, and they answer the four or five key questions a patient might have about
a given condition. These articles are best for patients who want a general overview and who
prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer,
more sophisticated, and more detailed. These articles are written at the 10th to 12th grade
reading level and are best for patients who want in-depth information and are comfortable
with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to
print or e-mail these topics to your patients. (You can also locate patient education articles on
a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
● Basics topics (see "Patient education: Soft tissue sarcoma (The Basics)")
SUMMARY AND RECOMMENDATIONS
● The majority of mesenchymal neoplasms affecting the gastrointestinal (GI) tract are
gastrointestinal stromal tumors (GISTs). Approximately 95 percent of these tumors
overexpress KIT (which can be identified by immunohistochemical staining), and 85
percent have mutations in the KIT protooncogene that leads to constitutive activation of
KIT, a receptor tyrosine kinase. A subset of GISTs that lack KIT mutations has activating
mutations in a related receptor tyrosine kinase, platelet-derived growth factor receptor
alpha (PDGFRA). (See 'Introduction' above.)
● An assessment of mutation status in individual GISTs is advised for most patients being
treated for metastatic disease because of the prognostic and predictive information that
can be derived from such an assessment. (See 'Influence of mutations on response to
therapy' above.)
● For patients with advanced unresectable GIST, we recommend an orally active tyrosine
kinase inhibitor (TKI) as initial therapy ( algorithm 1) (Grade 1A).
• For patients with KIT exon 11 mutations, initial treatment is with imatinib, typically at
400 mg daily. However, for those with KIT exon 9 mutations, we suggest imatinib at
800 mg daily rather than 400 mg daily (Grade 2C). (See 'KIT mutations' above.)
• For patients with a PDGFRA exon 18 D842V mutation and symptomatic and/or rapidly
progressive disease, we suggest initial treatment with avapritinib rather than other
TKIs or observation (Grade 2C). However, for those with asymptomatic and/or
indolent disease, a period of observation is preferable to immediate therapy with
avapritinib to avoid treatment-related toxicities, such as potential cognitive
impairment. Although avapritinib has not been directly compared with other TKIs,
these tumors often demonstrate primary resistance to imatinib. (See 'Avapritinib for
PDGFRA D842V mutant tumors' above.)
• For patients with a PDGFRA mutation other than D842V, we suggest initial treatment
with imatinib rather than other agents, given the recognized imatinib sensitivity of
this subtype of GIST. (See 'PDGFRA mutations' above.)
• For patients with succinate dehydrogenase (SDH)-deficient tumors, we refer patients

for clinical trials, as these tumors are minimally responsive to imatinib and other
agents. For those who are ineligible or who decline such trials, we offer sunitinib or
regorafenib, as these agents have some limited efficacy in this setting. (See 'SDH-
deficient tumors and those associated with NF1' above.)
● The optimal means of response assessment in patients receiving TKIs is unclear.

Radiographic response is often indicated by an early decrease in tumor density on
contrast-enhanced computed tomography (CT) scan, followed by slow tumor regression.
This pattern of response is not well suited to the use of standard response criteria.
Because of this, TKIs should be continued indefinitely in the absence of overt
radiographic progression (Grade 1B). (See 'Assessing response to therapy' above and
'Duration of therapy' above.)
Although positron emission tomography (PET) scans appear to identify a greater number
of responses and at an earlier time than CT, PET is not routinely indicated for response
assessment. (See 'Positron emission tomography scanning' above.)
However, one clinical scenario where baseline and follow-up PET scan might prove useful
is for a patient with borderline resectable GIST or a potentially resectable tumor that
requires extensive organ disruption who is being treated with initial imatinib. Early
assessment of treatment response provides the opportunity to shift to an alternative
therapy (eg, resection or sunitinib) if imatinib is ineffective. (See "Adjuvant and
neoadjuvant imatinib for gastrointestinal stromal tumors", section on 'Neoadjuvant
therapy'.)
● The role of surgery in patients with locally unresectable, nonmetastatic GISTs and in
those with potentially resectable metastatic disease who respond to imatinib is evolving.
This approach has little to offer patients with extensive disease progression while
receiving imatinib. (See "Local treatment for gastrointestinal stromal tumors,
leiomyomas, and leiomyosarcomas of the gastrointestinal tract", section on 'Role of
surgery in patients with metastatic disease'.)
● Imatinib does not appear to benefit non-GIST GI mesenchymal tumors, which are treated
similarly to other advanced soft tissue sarcomas. (See "Surgical treatment and other
localized therapy for metastatic soft tissue sarcoma".)
● For patients who are intolerant of imatinib or who become refractory to treatment, we
recommend a trial of the multitargeted TKI sunitinib (Grade 1B). Thyroid function should
be evaluated at baseline and monitored at frequent intervals during therapy. (See
'Subsequent management of imatinib-refractory disease' above.)
An alternative approach, increasing the dose of imatinib to 800 mg daily, may be useful
in patients who have clearly progressive disease while receiving 400 mg daily doses and
who are tolerating the drug reasonably well. However, this approach is unlikely to benefit
patients who have primary resistance to treatment (eg, within two months) after starting
therapy. (See 'Dose escalation of imatinib' above.)
● For patients with imatinib- and sunitinib-refractory GIST, we recommend regorafenib

rather than another TKI (Grade 1B). (See 'Regorafenib' above.)
● For patients with GIST (irrespective of PDGFRA D842V mutation status) refractory to or
intolerant of imatinib, sunitinib, and regorafenib, we suggest the use of ripretinib over
other available TKIs (Grade 2C). (See 'Management of disease refractory to imatinib,
sunitinib, and regorafenib' above and 'Ripretinib' above.)
• For those who are ineligible for or intolerant of ripretinib, options include nilotinib,
pazopanib, sorafenib, or rechallenge with either imatinib or sunitinib. Avapritinib is an
option for patients with the PDGFRA D842V mutation who have progressed on
imatinib and sunitinib. (See 'Alternative tyrosine kinase inhibitors' above and 'Imatinib
or sunitinib rechallenge' above.)
● For patients with progressive symptomatic soft tissue metastases despite treatment with
multiple TKIs, radiation therapy is a reasonable option. (See 'Role of radiation therapy'
above.)
ACKNOWLEDGMENT
The UpToDate editorial staff acknowledges George Demetri, MD, who contributed to an earlier
version of this topic review.
Use of UpToDate is subject to the Subscription and License Agreement.
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Tyrosine Kinase Inhibitor Therapy For Advanced Gastrointestinal Stromal Tumors

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11/24/21, 4:19 AM Tyrosine kinase inhibitor therapy for advanced gastrointestinal stromal tumors - UpToDate

Author: Jeffrey Morgan, MD

Avapritinib for treatment-refractory gastrointestinal stromal tumors with

INITIAL APPROACH BASED ON MUTATION STATUS

An assessment of tumor mutational status using DNA sequencing techniques is advised

A sizeable subset of patients in this trial survived long-term on first-line imatinib. In a

Assessing response to therapy — The optimal method for establishing response to tyrosine

Positron emission tomography scanning — PET scans appear to identify a greater

If employed, a rigorous standardized approach to patient preparation and study technique is

Cross-sectional imaging — Conventional CT scans with intravenous contrast

As a result of these issues, response to imatinib is frequently defined as absence of

A meta-analysis of both trials came to the following conclusions [38]:

● At a median follow-up of 45 months, compared with standard-dose imatinib, a modest

Pharmacokinetic variability — Another possible explanation for the failure to

Influence of mutations on response to therapy — An assessment of mutation status is

Data are as follows [46-50]:

PDGFRA mutations — Platelet-derived growth factor receptor alpha (PDGFRA) mutations

Duration of therapy — The optimal duration of imatinib therapy for responding patients

been in partial remission at randomization achieved a new complete or partial response,

● Hypophosphatemia – Hypophosphatemia is reported, especially with higher doses

● Gynecomastia – Gynecomastia was reported in 7 of 38 men receiving imatinib for

• A retrospective review of the MD Anderson experience of 219 patients enrolled in

• Heart failure should be considered in the differential diagnosis of any patient

● Ocular toxicity – In addition to periorbital edema, imatinib is associated with epiphora

Avapritinib is administered at 300 mg daily until disease progression, intolerance, or

Avapritinib is also teratogenic; therefore, females of reproductive potential or males with

Grade ≥3 toxicities included anemia (28 percent), hyperbilirubinemia (9 percent), fatigue (9

Patients with neurofibromatosis type 1 (NF1), an inherited cancer predisposition syndrome

SUBSEQUENT MANAGEMENT OF IMATINIB-REFRACTORY DISEASE

Dose escalation of imatinib — Dose escalation may be considered in patients started on

Metastasectomy — Surgical resection may be considered in selected patients. In general,

Efficacy — The multitargeted TKI sunitinib is active in imatinib-refractory or intolerant

Resistance to sunitinib shares similar pathogenetic mechanisms to those identified in imatinib

Side effects and management — Sunitinib can cause fatigue, nausea, vomiting,

● Hematologic toxicity – Sunitinib may cause myelosuppression. Sunitinib should be held

● Hypothyroidism – Hypothyroidism is a frequent complication of prolonged sunitinib

Another potential mechanism for hypothyroidism that should be considered in patients

● Hypertension and cardiac toxicity – Patients should be closely monitored for

• In a study of 75 patients treated with sunitinib for imatinib-resistant GISTs, 47 percent

• Somewhat lower rates of treatment-related hypertension (20 percent, any grade),

Regorafenib — Regorafenib is an orally active TKI that is structurally similar to sorafenib and

MANAGEMENT OF DISEASE REFRACTORY TO IMATINIB, SUNITINIB, AND

Ripretinib is administered at an initial dose of 150 mg daily until disease progression,

Management considerations specific to use of ripretinib are as follows:

● We obtain a baseline echocardiogram or MUGA scan prior to initiation of therapy and as

● Patients should receive regular dermatologic evaluation, as ripretinib is associated with

● The approach to monitoring and managing hypertension in patients treated with

● Dasatinib – Dasatinib is an active agent as well in this setting [75,110,128]. In a phase II

Imatinib or sunitinib rechallenge — For patients who are refractory to multiple TKIs

● An Italian retrospective of 82 patients with advanced GIST previously treated with

Investigational therapies — Patients with advanced disease that has progressed on

ROLE OF RADIATION THERAPY

limited for this approach.

SOCIETY GUIDELINE LINKS

INFORMATION FOR PATIENTS

SUMMARY AND RECOMMENDATIONS

• For patients with succinate dehydrogenase (SDH)-deficient tumors, we refer patients

● The optimal means of response assessment in patients receiving TKIs is unclear.

● For patients with imatinib- and sunitinib-refractory GIST, we recommend regorafenib

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Oncol Clin North Am 1995; 9:765.

11; 29:609s. Abstract available online at: http://www.asco.org/ASCOv2/Meetings/Abstract

31. Le Cesne A, Van Glabbeke M, Verweij J, et al. Absence of progression as assessed by