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Impact of Concomitant Administration of Gastric Acid–Suppressive Agents and Pazopanib on Outcomes in Soft-Tissue Sarcoma Patients Treated within the EORTC 62043/62072 Trials

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Purpose: Pazopanib is active in soft-tissue sarcoma (STS). Because pazopanib absorption is pH-dependent, coadministration with gastric acid-suppressive (GAS) agents such as proton pump inhibitors could affect exposure of pazopanib, and thereby its therapeutic effects. Patients and methods: The EORTC 62043 and 62072 were single-arm phase II and placebo-controlled phase III studies, respectively, of pazopanib in advanced STS. We first compared the outcome of patients treated with pazopanib with or without GAS agents for ≥80% of treatment duration, and subsequently using various thresholds. The impact of concomitant GAS therapy was assessed on progression-free survival (PFS) and overall survival (OS) using multivariate Cox models, exploring and comparing also the potential effect on placebo-treated patients. Results: Of 333 eligible patients, 59 (17.7%) received concomitant GAS therapy for >80% of pazopanib treatment duration. Median PFS was shorter in GAS therapy users versus nonusers: 2.8 vs. 4.6 months, respectively [HR, 1.49; 95% confidence interval (CI), 1.11-1.99; P = 0.01]. Concomitant administration of GAS therapy was also associated with a shorter median OS: 8.0 vs. 12.6 months (HR, 1.81; 95% CI, 1.31-2.49; P < 0.01). The longer the overlapping use of GAS agents and pazopanib, the worse the outcome with pazopanib. These effects were not observed in placebo-treated patients (HR, 0.82; 95% CI, 0.51-1.34; P = 0.43 for PFS and HR, 0.84; 95% CI, 0.48-1.48; P = 0.54 for OS). Conclusions: Coadministration of long-term GAS therapy with pazopanib was associated with significantly shortened PFS and OS. Withdrawal of GAS agents must be considered whenever possible. Therapeutic drug monitoring of pazopanib plasma concentrations may be helpful for patients on pazopanib and GAS therapy.
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Clinical Trials: Targeted Therapy
Impact of Concomitant Administration of Gastric
AcidSuppressive Agents and Pazopanib on
Outcomes in Soft-Tissue Sarcoma Patients
Treated within the EORTC 62043/62072 Trials
Olivier Mir
1
, Nathan Touati
2
, Michela Lia
2
, Saskia Liti
ere
2
, Axel Le Cesne
1
, Stefan Sleijfer
3
,
Jean-Yves Blay
4
, Michael Leahy
5
, Robin Young
6
, Ron H.J. Mathijssen
3
, Nielka P. Van Erp
7
,
Hans Gelderblom
8
, Winette T. Van der Graaf
7,9
, and Alessandro Gronchi
10
Abstract
Purpose: Pazopanib is active in soft-tissue sarcoma (STS).
Because pazopanib absorption is pH-dependent, coadminis-
tration with gastric acidsuppressive (GAS) agents such as
proton pump inhibitors could affect exposure of pazopanib,
and thereby its therapeutic effects.
Experimental Design: The EORTC 62043 and 62072 were
single-arm phase II and placebo-controlled phase III studies,
respectively, of pazopanib in advanced STS. We rst compared
the outcome of patients treated with pazopanib with or
without GAS agents for 80% of treatment duration, and
subsequently using various thresholds. The impact of con-
comitant GAS therapy was assessed on progression-free sur-
vival (PFS) and overall survival (OS) using multivariate Cox
models, exploring and comparing also the potential effect on
placebo-treated patients.
Results: Of 333 eligible patients, 59 (17.7%) received
concomitant GAS therapy for >80% of pazopanib treatme nt
duration. Median PFS was shorter in GAS therapy users
versus nonusers: 2.8 vs. 4.6 months, respectively [HR, 1.49;
95% condence interval (CI), 1.111.99; P¼0.01]. Con-
comitant administration of GAS therapy was also associat-
ed with a shorter median OS: 8.0 vs. 12.6 months (HR,
1.81; 95% CI, 1.312.49; P<0.01). The longer the over-
lapping use of GAS agents and pazopanib, the worse the
outcome with pazopanib. These effects were not observed
in placebo-treated patients (HR, 0.82; 95% CI, 0.511.34;
P¼0.43 for PFS and HR, 0.84; 95% CI, 0.481.48; P¼0.54
for OS).
Conclusions: Coadministration of long-term GAS therapy
with pazopanib was associated with signicantly shortened
PFS and OS. Withdrawal of GAS agents must be considered
whenever possible. Therapeutic drug monitoring of pazopa-
nib plasma concentrations may be helpful for patients on
pazopanib and GAS therapy.
Introduction
Although gastric acidsuppressive (GAS) agents such as proton
pump inhibitors (PPIs) or histamine H2-receptor blockers
(H2Bs) are used in 20% to 50% of patients undergoing cancer
treatment (1), the importance of gastric acidmediated drugdrug
interactions might be underestimated by medical oncologists and
prescribing physicians.
Because of the oral administration route of various molecular
targeted therapies, including multityrosine kinase inhibitors
(TKIs), drugdrug interactions concerning gastrointestinal
absorption have become apparent (2). Indeed, many TKIs show
pH-dependent solubility in the physiologically relevant pH range,
and their solubility might be decreased by the coadministration of
GAS agents, which increase gastric pH (3). Such drugdrug
interactions could reduce the systemic exposure of TKIs, resulting
in subtherapeutic exposure levels, and lead to loss of therapeutic
benet (2, 4).
Pazopanib is an orally administered, potent TKI targeting the
vascular endothelial growth factor receptors (VEGFR)-1, -2, and
-3, platelet-derived growth factor receptors (PDGFR)-aand -b,
and KIT. It is approved for the treatment of patients with advanced
nonadipocytic soft-tissue sarcoma (STS) who have received prior
chemotherapy for metastatic disease, based on the combined
results of the EORTC 62072 (PALETTE) phase III and 62043
phase II trials (5, 6).
The absorption of pazopanib is pH-dependent, and pazopanib
is practically insoluble (<0.1 mg/mL) at pH >4 (2). In a post-
marketing drugdrug interactions' study investigating the effect of
increased gastric pH on the pharmacokinetics of pazopanib,
pazopanib 800 mg OD was given as monotherapy for 7 days
followed by pazopanib 800 mg OD in combination with the PPI
esomeprazol 40 mg OD for 5 consecutive days. The combined use
1
Gustave Roussy, Sarcoma Group, Villejuif, France.
2
European Organization for
Research and Treatment of Cancer, Brussels, Belgium.
3
Erasmus MC Cancer
Institute, Rotterdam, the Netherlands.
4
L
eon B
erard Cancer Center, Lyon,
France.
5
The Christie NHS Foundation Trust, Manchester, United Kingdom.
6
Weston Park Hospital, Shefeld, United Kingdom.
7
Radboud University Medical
Centre, Nijmegen, the Netherlands.
8
Leiden University Medical Center, Leiden,
the Netherlands.
9
The Institute of Cancer Research and the Royal Marsden NHS
Foundation Trust, London, United Kingdom.
10
Fondazione IRCCS Istituto
Nazionale dei Tumori, Milano, Italy.
Note: Supplementary data for this article are available at Clinical Cancer
Research Online (http://clincancerres.aacrjournals.org/).
Corresponding Author: Olivier Mir, Gustave Roussy Cancer Campus, Sarcoma
Group, 114, rue Edouard Vaillant, 94800 Villejuif, France. Phone: 33142114316;
Fax: 33142115238; E-mail: olivier.mir@gustaveroussy.fr
doi: 10.1158/1078-0432.CCR-18-2748
2019 American Association for Cancer Research.
Clinical
Cancer
Research
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of pazopanib and esomeprazol resulted in a decrease in the
average maximum pazopanib plasma concentration and the
average area under the concentration time curve 24 hours after
dose by 42% and 40%, respectively (7).
Retrospective data suggest that low plasma concentrations of
pazopanib (through steady-state concentration <20.5 mg/mL) are
associated with poor outcomes in renal-cell carcinoma (8). This
was recently conrmed for renal cell cancer in terms of progres-
sion-free survival (PFS), and a similar trend was observed in STS
patients (9). This means that a threshold for pazopanib activity
likely exists for both tumor types.
Based on this literature, we conducted a retrospective review of
the EORTC 62043 and 62072 databases, in order to investigate the
association between the use of GAS therapy and clinical outcomes
in patients with STS treated with pazopanib.
Patients and Methods
Study design
The present analysis combined the data from the completed
trials EORTC phase II 62043 and phase III 62072 (5, 6). Both
studies were conducted in accordance with the Declaration of
Helsinki, after approval by Institutional Review Boards, and
written consent was obtained from all the subjects.
A per protocol approach was adopted using the following
patient inclusion criteria: (i) patients eligible in their respective
trial, (ii) patients who did not have liposarcoma, due to their
ineligibility for the phase III study based on the phase II
results, (iii) patients who started their allocated pazopanib
treatment.
Objectives and endpoints
The main objective of the current analysis was to assess the
potential presence of an association between the use of GAS
agents during pazopanib administration and clinical outcomes.
Primary and secondary endpoints were PFS and overall
survival (OS), and were calculated from the date of registration/
randomization to the rst documentation of progression/death
and the date of death, respectively. Patients alive at the time of
clinical cutoff were censored at the date of last follow-up.
GAS therapy embraced both PPI and histamine H2 blocking
medications for which the considered drugs are listed in
Supplementary Table S1. The percentage of the pazopanib
administration period during which there was an overlapping
administration of GAS therapy was used to classify patients
between users and nonusers of GAS agents. Based on prepa-
ratory investigations, a threshold of 80% was selected upfront
to differentiate between these patient groups. Exploratory
analyses were performed to investigate the impact of this
threshold choice on the estimated models.
An additional objective was to examine whether coadminis-
tration of GAS therapy had an attenuating effect on pazopanib-
specic toxicities such as hypertension, skin toxicities (alopecia,
hypopigmentation, skin rash), or thyroid dysfunction. Deni-
tions of these toxicities are detailed in the Supplementary Data.
Statistical analysis
HRswith their associated 95% condence intervals (CIs)
were estimated from a multivariate Cox regression model adjust-
ing for performance status (0 vs. 1), gender (male vs. female),
tumor grade (low vs. intermediate vs. high), and age at random-
ization (50 vs. >50 years). The related 2-sided log-rank test
Pvalue and KaplanMeier curves were displayed. In order to
evaluate the real impact on the drugdrug interaction on the
obtained results, similar analyses were conducted on placebo-
treated patients from the phase III study, to discriminate for a false
effect of GAS therapy on pazopanib treatment outcome, in
addition of multivariate sensitivity analyses adjusting for GAS
therapy administration at baseline as well. Analyses were per-
formed using SAS, version 9.4 (SAS Institute Inc.).
Results
GAS therapy administration
A total of 333 patients treated with pazopanib118 from the
62043 trial and 215 from the 62072 trialwere eligible for this
study. Median follow-up from registration/randomization was
27.6 months (interquartile range, 22.935.4). Among them, 117
(35.1%) received GAS therapy at least once during their pazopa-
nib treatment administration period and 59 (17.7%) of them
concomitantly for >80% of the pazopanib duration (Table 1).
Nineteen (5.7%) patients were already receiving GAS therapy at
the time of registration. Patients' baseline characteristics are
depicted in Supplementary Table S2.
Effect of concomitant use of pazopanib and GAS agents
Two patients were excluded from multivariate analyses due
to missing tumor grade status. As shown in Table 2, the
concomitant administration of GAS therapy and pazopanib
(>80% threshold) had a signicant detrimental effect on PFS
(HR, 1.49; 95% CI, 1.111.99; Pvalue 0.008), with a median
PFS of 2.8 months in GAS therapy users versus 4.6 months in
nonusers (Fig. 1A). Male gender and higher tumor grade were
associated with shorter PFS as well. From Fig. 2, the risk of
progression/death increased with the duration of GAS therapy
taken concomitantly with pazopanib. By adjusting for the use
of GAS therapy at baseline, the primary analysis was not
signicant at an >80% threshold, but the observed trend
remained (see Supplementary Fig. S1).
Translational Relevance
Pazopanib is approved for the treatment of advanced soft-
tissue sarcoma (STS) pretreated with doxorubicin-based
regimens, based on an increase in progression-free survival
(PFS), but not in overall survival (OS). From a pharmacologic
point of view, pazopanib absorption is pH-dependent, and
coadministration with gastric acidsuppressive (GAS) agents
(such as proton pump inhibitors) negatively affects pazopanib
plasma concentrations. Herein, we investigated whether GAS
agents could affect outcomes of patients with STS treated with
pazopanib in the EORTC phase II and III trials. We found
that coadministration of long-term GAS therapy with pazo-
panib was associated with signicantly shortened PFS and OS,
possibly due to suboptimal plasma concentrations. We con-
clude that withdrawal of GAS agents must be considered
whenever possible in patients with STS treated with pazopa-
nib. Monitoring of pazopanib plasma concentrations may be
helpful for patients on pazopanib and concomitant GAS
therapy.
Mir et al.
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Similarly, a signicant negative effect of the concomitant
administration of GAS therapy and pazopanib on OS was
observed (HR, 1.81; 95% CI, 1.312.49; Pvalue <0.001), even
with a low threshold value (see Table 2 and Figs. 1B and 2). A
longer period of overlap of GAS agents' intake along with pazo-
panib administration has a detrimental effect on OS (Fig. 2).
Sensitivity analysis on placebo-treated patients
A total of 110 patients within the placebo-treated patients of
the 62072 study were eligible for the sensitivity analyses.
Among them, 33 (30%) received GAS therapy at least once
during their pazopanib treatment administration period and 24
(21.8%) of them concomitantly for >80% of the pazopanib
duration (Table 1). Median follow-up from registration/
randomization for placebo-treated patients was 25.1 months
(interquartile range, 22.728.9). Unlike the pazopanib-treated
population, no association was observed between concomitant
administration of GAS therapy/placebo and PFS (HR, 0.82;
95% CI, 0.511.34; Pvalue 0.43 for threshold
>80%; Table 3; Figs. 1C and 2), as well as OS (HR, 0.84;
95% CI, 0.481.48; Pvalue 0.547 for threshold
>80%; Table 3; Figs. 1D and 2), ignorant of the threshold used.
Impact on pazopanib-related toxicities
No relevant differences in the frequency of pazopanib-related
toxicities were observed between patients who received or did not
receive GAS therapy concurrent with their pazopanib treatment
(threshold >80%). Summary results of these analyses are pre-
sented in Supplementary Tables S3 and S4.
Discussion
The aim of this study was to investigate the potential effect of
concomitant use of GAS therapy and pazopanib treatment on the
clinical outcome of patients with STS. For the primary analysis, we
chose upfront to consider that a patient was a concomitant GAS
therapy/pazopanib user if more than 80% of the pazopanib
treatment administration period overlapped with GAS therapy
prescriptions. This threshold included enough patients in each
group (user vs. nonuser) to estimate any possible association. Chu
and colleagues (10) chose a threshold value of 20% to determine
PPI-treated patients, whereas another study by Sun and collea-
gues (11) considered the presence of concomitant administration
when the patient received at least 1 PPI prescription together with
capecitabine. However, a higher threshold value allowed the
Table 2. Association between clinical outcomes (PFS/OS) and baseline characteristics/concomitant GAS therapy administration (multivariate Cox models) among
pazopanib-treated patients
Population
on pazopanib
Multivariate Cox
model for PFS
Multivariate Cox
model for OS
Covariates
Patients
a
(N¼331)
Observed PFS
events (O ¼320)
Observed OS
events (O ¼262)
HR
(95% CI)
Wald
Pvalue
HR
(95% CI)
Wald
Pvalue
Concomitant administration of GAS therapy/pazopanib
No 273 (82.5) 264 (82.5) 212 (80.9) 1.00 0.008 1.00 <0.001
Yes 58 (17.5) 56 (17.5) 50 (19.1) 1.49 (1.111.99) 1.81 (1.312.49)
Performance status
0 167 (50.5) 161 (50.3) 124 (47.3) 1.00 0.139 1.00 <0.001
1 164 (49.5) 159 (49.7) 138 (52.7) 1.18 (0.951.48) 1.73 (1.352.22)
Gender
Male 139 (42.0) 136 (42.5) 117 (44.7) 1.00 0.006 1.00 0.002
Female 192 (58.0) 184 (57.5) 145 (55.3) 0.73 (0.580.91) 0.68 (0.530.87)
Tumor grade
Low 28 (8.5) 23 (7.2) 16 (6.1) 1.00 <0.001 1.00 0.001
Intermediate 109 (32.9) 107 (33.4) 88 (33.6) 1.82 (1.162.88) 2.31 (1.383.89)
High 194 (58.6) 190 (59.4) 158 (60.3) 2.33 (1.493.63) 1.66 (0.972.84)
Age at randomization
50 y 133 (40.2) 126 (39.4) 103 (39.3) 1.00 0.414 1.00 0.623
>50 y 198 (59.8) 194 (60.6) 159 (60.7) 1.10 (0.871.39) 1.07 (0.821.38)
a
Two patients are excluded because of missing tumor grade.
Table 1. Description of GAS therapy received together with protocol treatment in EORTC 62043 and 62072 studies
Population on pazopanib Population on placebo
62043 (N¼118) 62072 (N¼215) Total (N¼333) Total (N¼110)
N(%) N(%) N(%) N(%)
Use of GAS therapy together with treatment
No GAS therapy 85 (72.0) 131 (60.9) 216 (64.9) 75 (68.2)
GAS therapy 33 (28.0) 84 (39.1) 117 (35.1) 35 (31.8)
PPI 31 (26.3) 63 (28.4) 93 (27.9) 26 (23.6)
H2 blocker 1 (0.8) 19 (8.8) 21 (6.3) 8 (7.3)
PPI and H2 blocker 1 (0.8) 2 (0.9) 3 (0.9) 1 (0.9)
Proportion of treatment duration with concomitant administration of GAS therapy
No concomitant administration 85 (72.0) 131 (60.9) 216 (64.9) 75 (68.2)
0% <(20% 7 (5.9) 23 (10.7) 30 (9.0) 5 (4.5)
20% <(40% 1 (0.8) 7 (3.3) 8 (2.4) 3 (2.7)
40% <(60% 3 (2.5) 3 (1.4) 6 (1.8) 2 (1.8)
60% <(80% 6 (5.1) 8 (3.7) 14 (4.2) 1 (0.9)
80%<16 (13.6) 43 (20.0) 59 (17.7) 24 (21.8)
Pazopanib and Gastric AcidSuppressive Agents
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composition of a more homogeneous group of GAS users,
making the occurrence of the expected drugdrug interaction
with pazopanib more likely and therefore its potential impact
on patient outcome. Moreover, the exploration of the impact of
different threshold values on the outcome for concomitant
administration neutralized the limitations of a single 80%
value choice.
From multivariate analyses, this coadministration of GAS ther-
apy was found to have a negative impact on PFS and OS, for which
the severity depended on the period of overlap of GAS agent
intake with pazopanib; a longer duration led to a worse prognosis.
Furthermore, these effects were not observed in the 62072 trial
placebo cohort when using the same analytic approach, which
conrmed that the detected impact on clinical outcomes was most
likely caused by the drugdrug interaction between GAS therapy
and pazopanib.
We consider that the effects of GAS therapy on the pharmaco-
kinetics of pazopanib could account for this observation. Indeed,
pazopanib has a pH-dependent absorption and is practically
insoluble (<0.1 mg/mL) at pH >4 (2). As a consequence, the
increase in gastric pH caused by GAS therapy could decrease
pazopanib solubility and absorption, leading to suboptimal
plasma concentrations (3).
Similar ndings were reported in the PAZOGIST trial, a ran-
domized phase II study of pazopanib in patients with advanced
GIST (12). In this trial, patients with a past history of gastrectomy
PFS duration
Concomitant GAS therapy/pazopanib (80% treatment administration) Concomitant GAS therapy/pazopanib (80% treatment administration)
Concomitant GAS therapy/placebo (80% treatment administration)
100
90
80
70
60
50
40
30
20
10
0
100
90
80
70
60
50
40
30
20
10
0
0 02 4 6 8 10 12 14 16 18 48
(Months)
4236302418126
265 274 220 145 105 85 52 39 30 26
57
O N Number of patients at risk: O N Number of patients at risk: Concomitant
59 39 23 15 11 8 4 3 3
213
51
274
59
220
37
137
20
98
14
53
4
22
1
8
1
4No
0Yes
100
90
80
70
60
50
40
30
20
10
0
100
90
80
70
60
50
40
30
20
10
0
0 0246810
(Months)
36302418126
86
24
86
24
29
12
15
9
7
1
4
0
O N Number of patients at risk: O N Number of patients at risk: Concomitant
67
17
86
24
57
20
37
11
23
9
11
2
5
0
No
Yes
Concomitant GAS therapy/placebo (80% treatment administration)
OS duration
PFS duration OS duration
AB
CD
Figure 1.
PFS and OS in concomitant GAS therapy/administered treatment users (blue curve) versus nonusers (red curve) at a threshold of 80%. PFS in the pazopanib-
treated population (A), OS in the pazopanib-treated population (B), PFS in the placebo-treated population (C), and OS in the placebo-treated population (D).
Pazopanib-treated population: median PFS, 2.8 months (users) vs. 4.6 months (nonusers); median OS, 8.0 months (users) vs. 12.6 months (nonusers).
Placebo-treated population: median PFS, 2.1 months (users) vs. 1.3 months (nonusers); median OS, 10.1 months (users) vs. 10.7 months (nonusers).
Mir et al.
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had signicantly lower plasma concentrations compared with
patients without gastrectomy and shorter PFS.
A possible negative clinical effect of GAS agents on treatment
outcomes has also been suggested for other oral anticancer agents
with pH-dependent absorption: erlotinib in non-small lung can-
cer, sunitinib in renal-cell carcinoma, and capecitabine in gastro-
esophageal cancer (13, 10, 14). Moreover, a recent study reported
that the concomitant administration of PPIs and capecitabine is
associated with an increased risk of recurrence in early-stage
colorectal cancer patients (11). All studies conducted on this
particular topic recommend avoiding GAS therapy concomitantly
with anticancer treatments whenever possible.
Of note, the circadian pattern of gastric pH and the time course
during which medications that increase gastric pH have their effect
suggest that timing of pazopanib administration could inuence
the pazopanib exposure (15). Therefore, if the concurrent use of a
GAS agent is medically necessary during pazopanib treatment, it is
currently recommended that the dose of pazopanib should be
taken without food, once daily in the evening, concomitantly with
the GAS agent.
As administration of GAS therapy during pazopanib treatment
reduced pazopanib efcacy, we undertook an exploratory analysis
to assess whether coadministration also had a protective effect
against pazopanib-specic toxicities such as hypertension, skin-
related toxicities, or thyroid dysfunction. In the corresponding
analyses shown in the appendix, no consistent differences in
occurrence of pazopanib-related toxicities were observed between
concomitant GAS users and nonusers. Only slight distinctions
PFS
Threshold concomitant interaction GAS therapy/treatment (%)
Threshold concomitant interaction GAS therapy/treatment (%)
100806040200
100
HR Pazopanib 95% CI Pazopanib
95% CI PlaceboHR Placebo
806040200
2.0
1.5
1.0
0.5
2.0
2.5
1.5
1.0
0.5
OS
HRHR
Figure 2.
Evolution of the HR (multivariate analysis) for
the effect of concomitant administration of
GAS therapy/treatment on PFS (top) and OS
(bottom) among pazopanib (red) and placebo
(blue) patients according to the selected
threshold value.
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were reported around skin toxicities, but this analysis was further
limited by the low overall incidence of adverse events.
As in previous research on this topic, our study has some
limitations (16). First of all, the retrospective nature of the
present study did not permit investigation of the respective
timings of administration of GAS therapy and pazopanib. In
addition, PPI dose and type of PPI were not considered in this
study. As the potential to suppress the acidity of the stomach
differs for the different PPI variants, this could be of rele-
vance (17). Also, it is unknown whether patients have always
mentioned their over-the-counter use of GAS therapy given its
widespread availability without prescription. Regarding GAS
therapy itself, subgroup analyses differentiating PPIs from H2
blocker intake concomitantly to pazopanib were conducted,
and a similar impact was observed on patient outcomes for
both agents.
As far as pazopanib plasma concentrations are concerned, it has
been argued that clinical activity was lower in patients with trough
steady-state concentrations <20.5 mg/mL (8, 9). In the context of
medically necessary GAS therapy, we suggest that therapeutic drug
monitoring could help detect patients with suboptimal plasma
exposure. Whether intrapatient pazopanib dose escalation would
improve outcomes in these patients remains unknown, although
a recent study has shown the feasibility of such an approach (18).
Furthermore, acidic beverages increase the bioavailability of
erlotinibanother TKI with pH-dependent absorption (19, 21)
but the impact in patients taking pazopanib with GAS therapy is
currently unknown. Another approach to prevent suboptimal
pazopanib exposure could be to use alternative schedules to
combine TKI and GAS. This is currently under investigation in
at least 2 clinical trials with TKIs: regorafenib and afatinib (see
www.clinicaltrials.gov: NCT02800330 and www.trialregister.nl:
NTR6652, respectively, last accessed on February 20, 2018).
One of the main challenges for this study was the approach
used to describe this particular type of drugdrug interaction
effect. To handle the potential time-dependence relation of the
drug, several methods such as landmark analyses, Cox models
with time-dependent covariates, or even landmark supermo-
dels (20) could be used. However, the relatively low number of
patients and the complexity of our data made the results not
applicable to these models. Moreover, by examining the patient
proles, no apparent link between patterns of GAS therapy
administration and the duration of pazopanib treatment was
identied, suggesting no specic trend over time. Therefore, we
preferred to preserve the assumption that the hazard functions are
proportional over time and consider the level of coadministration
as baseline information, even though this was conceptually
inaccurate. Dichotomizing patients between user and nonusers
was the most intelligible way to illustrate the drug interaction
impact. The proportion of concomitant GAS therapy/pazopanib
expressed as a continuous covariate has been investigated too,
showing a nonsignicant detrimental effect on PFS (HR, 1.04;
95% CI, 0.981.10; Pvalue 0.219 for a þ20% overlapping
augmentation).
In conclusion, in the EORTC 62043 and 62072 trials, 35% of
eligible patients took GAS agents at any time during pazopanib
treatment, and in half of these patients for over 80% of the
duration of their pazopanib treatment. Administration of long
duration GAS therapy with pazopanib was associated with
both shortened PFS and OS. Therefore, in patients with an
indication to start pazopanib, withdrawal of GAS agents must
be considered whenever possible, and patients should be
warned against taking over the counter GAS medications. If
patients have good medical reasons to stay on, or to start, GAS
medication, therapeutic drug monitoring of pazopanib plasma
concentrations could be helpful to optimally adjust the pazo-
panib dose.
Disclosure of Potential Conicts of Interest
O. Mir has ownership interests (including patents) at Amplitude Surgical and
Transgene, reports receiving speakers bureau honoraria from Eli-Lilly, Roche,
Pzer, and Servier, and is a consultant/advisory board member for Amgen,
Bayer, Bristol-Myers Squibb, Eli-Lilly, Ipsen, Lundbeck, MSD, Novartis, Pzer,
Roche, Servier, and Vifor Pharma. A. Le Cesne reports receiving speakers bureau
honoraria from Pharmamar, Pzer, Novartis and Lilly. J.-Y. Blay is a cons ultant/
advisory board member for Novartis and reports receiving commercial research
support from GlaxoSmithKline and Novartis. R.H.J. Mathijssen reports receiv-
ing speakers bureau honoraria from and reports receiving commercial research
support from Novartis. A. Gronchi is a consultant/advisory board member for
Novartis, Pzer, Bayer, Pharmamar, Lilly, and Nanobiotix, and reports receiving
commercial research support from Pharmamar. No potential conicts of
interest were disclosed by the other authors.
Table 3. Association between clinical outcomes (PFS/OS) and baseline characteristics/concomitant GAS therapy administration (multivariate Cox models) among
placebo-treated patients
Population
on placebo
Multivariate Cox
model for PFS
Multivariate Cox
model for OS
Covariates
Patients
(N¼110)
Observed PFS
events (O ¼110)
Observed OS
events (O ¼84)
HR
(95% CI)
Wald
Pvalue
HR
(95% CI)
Wald
Pvalue
Concomitant administration of GAS therapy/placebo
No 86 (78.2) 86 (78.2) 67 (79.8) 1.00 0.4302 1.00 0.547
Yes 24 (21.8) 24 (21.8) 17 (20.2) 0.82 (0.511.34) 0.84 (0.481.48)
Performance status
0 52 (47.3) 52 (47.3) 37 (44.0) 1.00 0.0784 1.00 0.056
1 58 (52.7) 58 (52.7) 47 (56.0) 1.43 (0.962.12) 1.54 (0.992.40)
Gender
Male 45 (40.9) 45 (40.9) 35 (41.7) 1.00 0.5801 1.00 0.532
Female 65 (59.1) 65 (59.1) 49 (58.3) 0.89 (0.581.35) 0.86 (0.551.36)
Tumor grade
Low 3 (2.7) 3 (2.7) 2 (2.4) 1.00 0.1481 1.00 0.238
Intermediate 26 (23.6) 26 (23.6) 18 (21.4) 2.93 (0.7711.07) 2.27 (0.549.56)
High 81 (73.6) 81 (73.6) 64 (76.2) 3.29 (0.9611.31) 1.55 (0.347.05)
Age at randomization
50 y 54 (49.1) 54 (49.1) 38 (45.2) 1.00 0.8242 1.00 0.124
>50 y 56 (50.9) 56 (50.9) 46 (54.8) 0.96 (0.651.41) 1.42 (0.912.24)
Mir et al.
Clin Cancer Res; 2019 Clinical Cancer ResearchOF6
Cancer Research.
on February 16, 2019. © 2019 American Association forclincancerres.aacrjournals.org Downloaded from
Published OnlineFirst February 14, 2019; DOI: 10.1158/1078-0432.CCR-18-2748
Authors' Contributions
Conception and design: O. Mir, N. Touati, M. Lia, S. Liti
ere, A. Le Cesne,
J.-Y. Blay, R. Young, H. Gelderblom, W.T. Van der Graaf, A. Gronchi
Development of methodology: O.Mir,N.Touati,M.Lia,S.Liti
ere,
J.-Y. Blay
Acquisition of data (provided animals, acquired and managed patients,
provided facilities, etc.): O. Mir, M. Lia, S. Liti
ere, A. Le Cesne, S. Sleijfer,
J.-Y. Blay, M. Leahy, H. Gelderblom, W.T. Van der Graaf
Analysis and interpretation of data (e.g., statistical analysis, biostatistics,
computational analysis): O. Mir, N. Touati, S. Liti
ere, A. Le Cesne, S. Sleijfer,
J.-Y. Blay, R. Young, R.H.J. Mathijssen, A. Gronchi
Writing, review, and/or revision of the manuscript: O. Mir, N. Touati, S. Liti
ere,
A. Le Cesne, S. Sleijfer, J.-Y. Blay, M. Leahy, R. Young, R.H.J. Mathijssen, N.P. Van
Erp, H. Gelderblom, W.T. Van der Graaf, A. Gronchi
Administrative, technical, or material support (i.e., reporting or organizing
data, constructing databases): O. Mir, N. Touati, S. Liti
ere
Study supervision: O. Mir, S. Liti
ere, A. Le Cesne, A. Gronchi
Acknowledgments
This study was supported by EORTC Soft Tissue and Bone Sarcoma Group,
EORTC staff, and Fonds Cancer (FOCA) from Belgium.
The costs of publication of this article were defrayed in part by the payment of
page charges. This article must therefore be hereby marked advertisement in
accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received August 22, 2018; revised November 5, 2018; accepted December 14,
2018; published rst February 14, 2019.
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Olivier Mir, Nathan Touati, Michela Lia, et al.
62043/62072 Trials
Soft-Tissue Sarcoma Patients Treated within the EORTC
Suppressive Agents and Pazopanib on Outcomes in Impact of Concomitant Administration of Gastric Acid
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... Finally, the influence of food on PK should not be underestimated for drugs such as cabozantinib and pazopanib [64]. With no explanations from previous factors, some genetic polymorphisms such as CYP3A4*22 [65], U GT1A1/9 [66][67][68] and P-gp/BCRP [44,69] might need to be explored since they can significantly decrease metabolism and/or enhance TKI bioavailability. In the case of subtherapeutic exposure, different parameters should be explored: adherence, PK DDI (CYP inducer [11], complementary and alternative medicines) and proton pump inhibitor uptake for tivozanib and pazopanib [11,66]. ...
... With no explanations from previous factors, some genetic polymorphisms such as CYP3A4*22 [65], U GT1A1/9 [66][67][68] and P-gp/BCRP [44,69] might need to be explored since they can significantly decrease metabolism and/or enhance TKI bioavailability. In the case of subtherapeutic exposure, different parameters should be explored: adherence, PK DDI (CYP inducer [11], complementary and alternative medicines) and proton pump inhibitor uptake for tivozanib and pazopanib [11,66]. ...
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... The latter effect seems theoretically favorable, but without a return in terms of clinical effectiveness. Considering the previously published data about the issue, these results are far from obvious [13][14][15][16][17][18]. ...
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Background: Pazopanib is an angiogenesis inhibitor approved for the treatment of renal cell carcinoma and soft tissue sarcoma. Post hoc analysis of a clinical trial demonstrated a relationship between pazopanib trough concentrations (Cmin) and treatment efficacy. The aim of this study was to explore the pharmacokinetics and exposure-survival relationships of pazopanib in a real-world patient cohort. Patients and methods: Renal cell cancer and soft tissue sarcoma patients who had at least one pazopanib plasma concentration available were included. Using calculated Cmin values and a threshold of > 20 mg/L, univariate and multivariate exposure-survival analyses were performed. Results: Sixty-one patients were included, of which 16.4% were underexposed (mean Cmin < 20 mg/L) using the 800 mg fixed-dosed schedule. In univariate analysis Cmin > 20 mg/L was related to longer progression free survival in renal cell cancer patients (34.1 vs. 12.5 weeks, n = 35, p = 0.027) and the overall population (25.0 vs. 8.8 weeks, n = 61, p = 0.012), but not in the sarcoma subgroup (18.7 vs. 8.8 weeks, n = 26, p = 0.142). In multivariate analysis Cmin > 20 mg/L was associated with hazard ratios of 0.25 (p = 0.021) in renal cancer, 0.12 (p = 0.011) in sarcoma and 0.38 (p = 0.017) in a pooled analysis. Conclusion: This study confirms that pazopanib Cmin > 20 mg/L relates to better progression free survival in renal cancer and points towards a similar trend in sarcoma patients. Cmin monitoring of pazopanib can help identify patients with low Cmin for whom individualized treatment at a higher dose may be appropriate.
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Tyrosine kinase inhibitors (TKIs) have rapidly become an established factor in oncology, and have been shown to be effective in a wide variety of solid and hematologic malignancies. Use of the oral administration route of TKIs offers flexibility and is convenient for the patient; however, despite these advantages, the oral route of administration also causes a highly relevant new problem. Acid-inhibitory drugs, such as proton pump inhibitors (PPIs), increase the intragastric pH, which may subsequently decrease TKI solubility, bioavailability, and treatment efficacy. Clear and practical advice on how to manage PPI use during TKI therapy is currently not available in the literature. Since PPIs are extensively used during TKI therapy, prescribers are presented with a big dilemma as to whether or not to continue the combined treatment, resulting in patients possibly being deprived of optimal therapy. When all pharmacological characteristics and data of either TKIs and PPIs are considered, practical and safe advice on how to manage this drug combination can be given.
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Purpose: Pazopanib is a tyrosine kinase inhibitor approved for the treatment of renal cell carcinoma and soft tissue sarcoma. Retrospective analyses have shown that an increased median PFS and tumor shrinkage appears in patients with higher plasma trough levels (Cmin). Therefore, patients with low Cmin might benefit from pharmacokinetically-guided individualized dosing. Experimental design: We conducted a prospective multicenter trial in 30 patients with advanced solid tumors. Pazopanib Cmin was measured weekly by LC-MS/MS. At week 3, 5 and 7 the pazopanib dose was increased if the measured Cmin was <20 mg/L and toxicity was < grade 3. Results: In total, 17 patients had at least one Cmin <20 mg/L at week 3, 5 and 7. Of these, 10 were successfully treated with a pharmacokinetically-guided dose escalation, leading to daily dosages ranging from 1000 to 1800 mg daily. Cmin in these patients increased significantly from 13.2 (38.0%) mg/L (mean (CV%)) to 22.9 mg/L (44.9%). Thirteen patients had all Cmin levels {greater than or equal to}20 mg/L. Of these, nine patients with a high Cmin of 51.3 mg/L (45.1%) experienced {greater than or equal to} grade 3 toxicity and subsequently required a dose reduction to 600 or 400 mg daily, yet in these patients Cmin remained above the threshold at 28.2 mg/L (25.3%). Conclusions: A pharmacokinetically-guided individualized dosing algorithm was successfully applied and evaluated. The dosing algorithm led to patients being treated at dosages ranging from 400 to 1800 mg daily. Further studies are needed to show a benefit of individualized dosing on clinical outcomes such as progression free survival.
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Background: Pazopanib, an oral angiogenesis inhibitor targeting vascular endothelial growth factor receptor (VEGFR)/platelet-derived growth factor receptor (PDGFR)/c-Kit, is approved in locally advanced/metastatic renal cell carcinoma (RCC). Methods: Data from trials in advanced solid tumours and advanced/metastatic RCC were used to explore the relationships between plasma pazopanib concentrations and biomarker changes, safety, and efficacy. Initially, the relationships between pharmacokinetic parameters and increased blood pressure were investigated, followed by analysis of steady-state trough concentration (Cτ) and sVEGFR2, safety, progression-free survival (PFS), response rate, and tumour shrinkage. Efficacy/safety end points were compared at Cτ decile boundaries. Results: Strong correlation between increased blood pressure and Cτ was observed (r(2)=0.91), whereas weak correlation was observed between Cτ and decline from baseline in sVEGFR2 (r(2)=0.27). Cτ threshold of >20.5 μg ml(-1) was associated with improved efficacy (PFS, P<0.004; tumour shrinkage, P<0.001), but there was no appreciable benefit in absolute PFS or tumour shrinkage from Cτ >20.5 μg ml(-1). However, the association of Cτ with certain adverse events, particularly hand-foot syndrome, was continuous over the entire Cτ range. Conclusions: The threshold concentration for efficacy overlaps with concentrations at which toxicity occurs, although some toxicities increase over the entire Cτ range. Monitoring Cτ may optimise systemic exposure to improve clinical benefit and decrease the risk of certain adverse events.
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To the Editor With interest, we read the report by Chu and colleagues¹ investigating the association of proton pump inhibitors (PPIs) with capecitabine efficacy in patients with advanced gastroesophageal cancer. This retrospective analysis revealed a significant difference in treatment efficacy in patients treated with capecitabine and oxaliplatin with and without concomitant PPI use, probably due to an increased intragastric pH and subsequent impaired capecitabine absorption.
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Importance: Capecitabine is an oral cytotoxic chemotherapeutic commonly used across cancer subtypes. As with other oral medications though, it may suffer from drug interactions that could impair its absorption. Objective: To determine if gastric acid suppressants such as proton pump inhibitors (PPIs) may impair capecitabine efficacy. Design, setting, and participants: This secondary analysis of TRIO-013, a phase III randomized trial, compares capecitabine and oxaliplatin (CapeOx) with or without lapatinib in 545 patients with ERBB2/HER2-positive metastatic gastroesophageal cancer (GEC); patients were randomized 1:1 between CapeOx with or without lapatinib. Proton pump inhibitor use was identified by medication records. Progression-free survival (PFS) and overall survival (OS) were compared between patients treated with PPIs vs patients who were not. Specific subgroups were accounted for, such as younger age (<60 years), Asian ethnicity, female sex, and disease stage (metastatic/advanced) in multivariate Cox proportional hazards modeling. The TRIO-013 trial accrued and randomized patients between June 2008 and January 2012; this analysis took place in January 2014. Interventions: Patients were divided based on PPI exposure. Main outcomes and measures: Primary study outcome was PFS and OS between patients treated with PPIs vs patients who were not. Secondary outcomes included disease response rates and toxicities. Results: Of the 545 patients with GEC (median age, 60 years; 406 men [74%]) included in the study, 229 received PPIs (42.0%) and were evenly distributed between arms. In the placebo arm, PPI-treated patients had poorer median PFS, 4.2 vs 5.7 months (hazard ratio [HR], 1.55; 95% CI, 1.29-1.81, P < .001); OS, 9.2 vs 11.3 months (HR, 1.34; 95% CI, 1.06-1.62; P = .04); and disease control rate (83% vs 72%; P = .02) vs patients not treated with PPIs. In multivariate analysis considering age, race, disease stage, and sex, PPI-treated patients had poorer PFS (HR, 1.68; 95% CI, 1.42-1.94; P < .001) and OS (HR, 1.41; 95% CI, 1.11-1.71; P = .001). In patients treated with CapeOx and lapatinib, PPIs had less effect on PFS (HR, 1.08; P = .54) and OS (HR, 1.26; P = .10); however, multivariate analysis in this group demonstrated a significant difference in OS (HR, 1.38; 95% CI, 1.06-1.66; P = .03). Conclusions and relevance: Proton pump inhibitors negatively effected capecitabine efficacy by possibly raising gastric pH levels, leading to altered dissolution and absorption. These results are consistent with previous erlotinib and sunitinib studies. Whether PPIs affected lapatinib is unclear given concurrent capecitabine. Given capecitabine's prevalence in treatment breast cancer and colon cancer, further studies are under way. Trial registration: clinicaltrials.gov Identifier: NCT00680901.
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Purpose: Erlotinib depends on stomach pH for its bioavailability. When erlotinib is taken concurrently with a proton pump inhibitor (PPI), stomach pH increases, which results in a clinically relevant decrease of erlotinib bioavailability. We hypothesized that this drug-drug interaction is reversed by taking erlotinib with the acidic beverage cola. The effects of cola on erlotinib bioavailability in patients not treated with a PPI were also studied. Patients and methods: In this randomized, cross-over, pharmacokinetic study in patients with non-small-cell lung cancer, we studied intrapatient differences in absorption (area under the plasma concentration time curve [AUC0-12h]) after a 7-day period of concomitant treatment with erlotinib, with or without esomeprazole, with either cola or water. At the 7th and 14th day, patients were hospitalized for 1 day for pharmacokinetic sampling. Results: Twenty-eight evaluable patients were included in the analysis. In patients treated with erlotinib and esomeprazole with cola, the mean AUC0-12h increased 39% (range, -12% to 136%; P = .004), whereas in patients not treated with the PPI, the mean AUC0-12h was only slightly higher (9%; range, -10% to +30%; P = .03) after erlotinib intake with cola. Conclusion: Cola intake led to a clinically relevant and statistically significant increase in the bioavailability of erlotinib during esomeprazole treatment. In patients not treated with the PPI, the effects of cola were marginal. These findings can be used to optimize the management of drug-drug interactions between PPIs and erlotinib.
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Background: Capecitabine is used to treat colorectal (CRC) cancer. TRIO-013, a study examining capecitabine/oxaliplatin ± lapatinib in metastatic gastro-esophageal cancer did not show increases in overall survival (OS) with lapatinib. An analysis showed concurrent proton pump inhibitor (PPI) usage negatively impacted recurrence-free survival (RFS). We retrospectively studied PPI effects on capecitabine efficacy in early stage CRC and how capecitabine adjustments impacted RFS. Methods: Early stage CRC patients taking monotherapy capecitabine treated from 2008 to 2012 were reviewed for demographics, medications, toxicities, and patient outcomes. Results: Of 298 identified patients, 25.8% (n = 77) received concurrent PPIs. Five-year RFS was 74% versus 83% (hazard ratio [HR], 1.89; 95% confidence interval [CI], 1.07-3.35; P = .03) in PPI versus non-PPI patients respectively. OS was 81% versus 78%, respectively (HR, 1.13; 95% CI, 0.60-2.14; P = .7). After accounting for gender, stage, age, and performance status, PPI patients tended toward decreased RFS (HR, 1.65; 95% CI, 0.93-2.94; P = .09). Capecitabine dose modifications affected outcomes. Five-year RFS was 84% in the control group, 100% in the treatment-delay group (P = .99), 67% in the dose reduction group (HR, 2.46; 95% CI, 1.23-4.93; P = .01), and 64% in the discontinuation group (HR, 2.27; 95% CI, 0.93-5.53; P = .07). Five-year OS was significantly less in the discontinuation group than control group (59% vs. 82%; HR, 3.27; 95% CI, 1.44-7.45; P = .005). Conclusions: PPIs appear to impact RFS; this may be due to PPIs preventing capecitabine tablet dissolution and absorption. Patients with dose reductions or who stopped treatment had worse outcomes than patients who continued with treatment at starting doses.
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The aim of this study was to evaluate the effect of coadministration of acid-reducing agents on the pharmacokinetic exposure of orally administered epidermal growth factor receptor inhibitor erlotinib, a drug that displays pH-dependent solubility. Two studies were conducted, the first with the proton pump inhibitor omeprazole and the second with the H2-receptor antagonist ranitidine. Twenty-four healthy male and female volunteers were enrolled in each study. Erlotinib was administered as a single oral 150 mg dose on day 1. After the washout a subsequent study period evaluated 150 mg erlotinib administered with the acid-reducing agent. Omeprazole (40 mg once daily) was given on days 11-14, concomitantly with erlotinib on day 15, and for two additional days (days 16-17). In the ranitidine study, on day 13, participants were randomized to either concomitant dosing (treatment B) or staggered administration (treatment C) of erlotinib and ranitidine and crossed over to the other treatment starting on day 27. For treatment B, ranitidine (300 mg once daily) was administered in the morning for 5 days, 2 h before erlotinib. For treatment C, ranitidine was administered as a divided dose (150 mg twice daily) for 5 days, with erlotinib given 10 h after the previous evening dose and 2 h before the next ranitidine morning dose. Plasma samples were obtained for determination of the concentrations of erlotinib and its metabolite OSI-420, following each erlotinib dose. All participants were monitored for safety and tolerability. The geometric mean ratios of AUC0-∞ and Cmax for erlotinib and AUC0-last and Cmax for OSI-420 were substantially decreased when erlotinib was dosed with omeprazole. The estimated mean ratio (90% confidence interval) for erlotinib was 0.54 (0.49-0.59) for AUC0-∞ and 0.39 (0.32-0.48) for Cmax. For OSI-420, the estimated mean ratio was 0.42 (0.37-0.48) for AUC0-last and 0.31 (0.24-0.41) for Cmax. AUC0-∞ and Cmax for erlotinib were substantially decreased by 33 and 54%, respectively, upon coadministration with ranitidine, but the decrease was only 15 and 17% when ranitidine and erlotinib were given staggered. Similar results were observed for the metabolite OSI-420. Erlotinib was generally well-tolerated alone or in combination with omeprazole or ranitidine. Erlotinib pharmacokinetic exposure was substantially reduced upon coadministration with omeprazole and ranitidine, but not when administered with a staggered dosing approach to ranitidine. Therefore, it is recommended that the concomitant use of erlotinib with proton pump inhibitors be avoided. If treatment with an H2-receptor antagonist such as ranitidine is required, erlotinib must be administered 10 h after the H2-receptor antagonist dosing and at least 2 h before the next dose of the H2-receptor antagonist.
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Background Erlotinib is a key therapy for advanced non-small cell lung cancer (NSCLC). Concurrent acid suppression (AS) therapy with tyrosine kinase inhibitors (TKIs) may reduce TKI plasma levels. Given gastroesophageal reflux disease prevalence, this retrospective analysis was undertaken to determine if co-administering erlotinib with AS affected NSCLC outcomes. Patients and Methods Advanced NSCLC patients receiving erlotinib from 2007-2012 at a large, centralized, cancer institution were retrospectively reviewed. Pertinent demographics were collected and concomitant AS treatment was defined as AS prescription dates overlapping with ≥ 20% of erlotinib treatment duration. Patients who received erlotinib for ≥ 1 week were analyzed for progression free survival (PFS) and overall survival (OS). Results Stage IIIB/IV NSCLC patients (n=544) were identified and 507 had adequate data for review. Median age was 64 years and 272 were female. Adenocarcinoma (318, 64%) and squamous (106, 21%) were predominant subtypes; 124 patients received concomitant AS. In this unselected population, median PFS and OS in AS vs. non-AS groups were 1.4 vs. 2.3 months (p<0.001) and 12.9 vs. 16.8 months (p=0.003), respectively. Factoring gender, subtype, and performance status in multivariate Cox proportional hazards ratios for PFS and OS between AS and non-AS groups were 1.83 (95% CI 1.48-2.25) and 1.37 (95% CI 1.11-1.69) respectively. Conclusion This large population-based study suggests erlotinib efficacy may be linked with gastric pH and OS could be adversely affected. This is the first study demonstrating a possible negative clinical impact of co-administering erlotinib with AS therapy. Further prospective investigation is warranted.