A randomized phase II study comparing erlotinib versus erlotinib with alternating chemotherapy in relapsed non-small-cell lung cancer patients: The NVALT-10 study

Abstract

Background:
Epidermal growth factor receptor tyrosine kinase inhibitors (TKIs) administered concurrently with chemotherapy did not improve outcome in non-small-cell lung cancer (NSCLC). However, in preclinical models and early phase noncomparative studies, pharmacodynamic separation of chemotherapy and TKIs did show a synergistic effect.

Patients and methods:
A randomized phase II study was carried out in patients with advanced NSCLC who had progressed on or following first-line chemotherapy. Erlotinib 150 mg daily (monotherapy) or erlotinib 150 mg during 15 days intercalated with four 21-day cycles docetaxel for squamous (SQ) or pemetrexed for nonsquamous (NSQ) patients was administered (combination therapy). After completion of chemotherapy, erlotinib was continued daily. Primary end point was progression-free survival (PFS).

Results:
Two hundred and thirty-one patients were randomized, 115 in the monotherapy arm and 116 in the combination arm. The adjusted hazard ratio for PFS was 0.76 [95% confidence interval (CI) 0.58-1.02; P = 0.06], for overall survival (OS) 0.67 (95% CI 0.49-0.91; P = 0.01) favoring the combination arm. This improvement was primarily observed in NSQ subgroup. Common Toxicity Criteria grade 3+ toxic effect occurred in 20% versus 56%, rash in 7% versus 15% and febrile neutropenia in 0% versus 6% in monotherapy and combination therapy, respectively.

Conclusions:
PFS was not significantly different between the arms. OS was significantly improved in the combination arm, an effect restricted to NSQ histology.

Study registration number:
NCT00835471.

Full text

Annals of Oncology 24: 2860–2865, 2013
doi:10.1093/annonc/mdt341
Published online 28 August 2013
A randomized phase II study comparing erlotinib
versus erlotinib with alternating chemotherapy
in relapsed non-small-cell lung cancer patients:
the NVALT-10 study
†
J. G. Aerts1,2*, H. Codrington3, N. A. G. Lankheet4,5, S. Burgers4, B. Biesma6,
A. -M. C. Dingemans7, A. D. Vincent8, O. Dalesio8,H.J.M.Groen
9&E.F.Smit
10,
on behalf of the NVALT Study Group
1
Department of Pulmonary Diseases, Amphia Hospital, Breda;
2
Erasmus MC Oncology Centre, Rotterdam;
3
Department of Pulmonary Diseases, HAGA Hospital,
s-Gravenhage;
4
Department of Pulmonary Diseases, National Cancer Institute Amsterdam, Amsterdam;
5
Department of Pharmacy, Slotervaart Hospital, Amsterdam;
6
Department of Pulmonary Diseases, Jeroen Bosch Hospital, s-Hertogenbosch;
7
Department of Pulmonary Diseases, Maastricht University Medical Center, Maastricht;
8
Department of Biostatistics, National Cancer Institute Amsterdam, Amsterdam;
9
Department of Pulmonary Diseases, University Medical Center Groningen, Groningen;
10
Department of Pulmonary Diseases, Vrije Universiteit VU Medical Center, Amsterdam, The Netherlands
Received 18 April 2013; revised 27 June 2013; accepted 8 July 2013
Background: Epidermal growth factor receptor tyrosine kinase inhibitors (TKIs) administered concurrently with
chemotherapy did not improve outcome in non-small-cell lung cancer (NSCLC). However, in preclinical models and early
phase noncomparative studies, pharmacodynamic separation of chemotherapy and TKIs did show a synergistic effect.
Patients and methods: A randomized phase II study was carried out in patients with advanced NSCLC who had
progressed on or following first-line chemotherapy. Erlotinib 150 mg daily (monotherapy) or erlotinib 150 mg during 15
days intercalated with four 21-day cycles docetaxel for squamous (SQ) or pemetrexed for nonsquamous (NSQ) patients
was administered (combination therapy). After completion of chemotherapy, erlotinib was continued daily. Primary end
point was progression-free survival (PFS).
Results: Two hundred and thirty-one patients were randomized, 115 in the monotherapy arm and 116 in the
combination arm. The adjusted hazard ratio for PFS was 0.76 [95% confidence interval (CI) 0.58–1.02; P= 0.06], for
overall survival (OS) 0.67 (95% CI 0.49–0.91; P= 0.01) favoring the combination arm. This improvement was primarily
observed in NSQ subgroup. Common Toxicity Criteria grade 3+ toxic effect occurred in 20% versus 56%, rash in 7%
versus 15% and febrile neutropenia in 0% versus 6% in monotherapy and combination therapy, respectively.
Conclusions: PFS was not significantly different between the arms. OS was significantly improved in the combination
arm, an effect restricted to NSQ histology.
Study Registration number: NCT00835471.
Key words: NSCLC, second line, intercalated, erlotinib
introduction
For patients with advanced non-small-cell lung cancer
(NSCLC) who fail first-line platinum-based chemotherapy,
several treatment options are available. Based on phase III
clinical trials and meta-analysis, single-agent pemetrexed or
docetaxel or the first-generation epidermal growth factor
receptor (EGFR) tyrosine kinase inhibitor (TKI) erlotinib are
recommended by national and international guidelines. One
way to improve therapeutic outcome may be to combine
different cytotoxic agents. The NVALT-7 study showed that the
carboplatin and pemetrexed combination was associated with
superior progression-free survival (PFS) compared with
treatment with single-agent pemetrexed in second-line NSCLC
patients [1]. Subsequently, the use of pemetrexed became
restricted to patients with nonsquamous (NSQ) histology.
Recently, a joint analysis of NVALT-7 and an identical Italian
trial revealed that the survival benefit of carboplatin–
pemetrexed was restricted to squamous (SQ) cell histology,
suggesting no improvement in survival of the doublet over
pemetrexed alone for other histologies [2].
†
Presented as oral presentation at ESMO 2012 in Vienna Austria.
*Correspondence to: Dr Joachim G. Aerts, Department of Pulmonary Diseases, Amphia
Hospital Breda, Molengracht 21, 4818 CK Breda, The Netherlands. Tel: +31-76-595-
3121; Fax: +31-76-595-3426; E-mail: jaerts@amphia.nl
original articles Annals of Oncology
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Another option to improve outcome may be to combine
EGFR-TKIs and cytotoxic chemotherapy. Although front-line
phase III studies testing this concept in advanced NSCLC
patients were negative [3,4], pharmacodynamic separation of
chemotherapy, and EGFR-TKIs were synergistic in preclinical
models and early exploratory studies [5–10].
Therefore, we designed a study in patients who failed
previous cytotoxic treatment to compare PFS between
erlotinib and intercalating erlotinib with pemetrexed for NSQ
cell lung cancer or docetaxel in SQ cell lung cancer. In
addition, quantitative and qualitative toxic effects of each
regimen, response rates, and overall survival (OS) were
characterized.
methods and patients
This is a randomized open-label phase II study carried out in patients
with pathologically confirmed locally advanced or metastatic NSCLC who
had progressed on or following first-line platinum-based chemotherapy.
Other inclusion criteria were at least one unidimensionally measurable
lesion meeting Response Evaluation Criteria In Solid Tumors (RECIST)
1.0, ECOG Performance Status (PS) 0–2, age ≥18 years, and adequate
bone marrow reserve and hepatic and renal function. Further details on
inclusion criteria are provided in supplementary data, available at Annals
of Oncology online.
Prior treatment with pemetrexed in NSQ or docetaxel in SQ was allowed
if the time between the end of first-line treatment and recurrence of the
disease was at least 9 weeks. All patients provided written informed consent
according to the local medical ethical committee rules.
treatment
After stratification for ECOG-PS (0–1 versus 2), response to prior treatment
(complete and partial response versus stable or progressive disease),
treatment-free interval after platinum-based therapy (<6 versus >6 months)
and histology (SQ versus NSQ), patients were centrally randomized to
receive either erlotinib monotherapy 150 mg daily or erlotinib 150 mg daily
from day 2 to day 16 every 21 days in combination with chemotherapy on
day 1. Erlotinib was administered daily at the same time each day on an
outpatient basis, at least 1 h before or 2 h after the ingestion of any food or
other medication. The patients kept a preprinted diary for monitoring their
medication usage. For the SQ docetaxel 75 mg/m
2
and for NSQ pemetrexed
500 mg/m
2
was administered for 4 cycles on a 3-weekly basis. After
completion of chemotherapy, erlotinib was continued daily until intolerable
toxic effect or progressive disease was observed.
To preclude any bias, all patients received supplemental vitamin B
12
1000 μm once every 6–9 weeks and folic acid 0.5 mg daily during the whole
study treatment.
Treatment after disease progression was at the discretion of the treating
physician.
assessments
Patients were evaluated at baseline with a complete medical history and
physical examination, routine hematology and biochemistry, and computed
tomography scans of chest and upper abdomen. Clinical evaluation, routine
hematology, and biochemistry were required every 3 weeks before each cycle
in both arms. Computed tomography of chest and upper abdomen were
repeated every two cycles of chemotherapy and every 6 weeks during
erlotinib treatment.
Objective response was determined by using RECIST (version 1.0). Toxic
effect was scored according to National Cancer Institute Common
Terminology Criteria for Adverse Events (CTC-AE) version 3.
erlotinib concentrations
In a subgroup of patients in the intermittent combination schedule, a plasma
sample for pharmacokinetics analysis was drawn on day 22 just before
chemotherapy (or alternatively at start of cycle 3 or 4). See supplementary
Data, available at Annals of Oncology online [11].
outcomes
The primary end point was PFS, defined as the time from randomization to
the first evidence of tumor progression or death, when it occurred before
disease progression. Secondary end points included OS, tumor response, and
toxic effect. OS duration was defined as the time between randomization and
death. No central review of tumor response was carried out.
statistical considerations
sample size calculation. A median PFS in NSCLC patients
treated with second-line erlotinib was assumed to be ⍰3
months [3]. To detect a decrease of the hazard of tumor
progression in the combined arm of 33% [hazard ratio
(HR) = 0.67] with the log-rank test (alpha = 0.05, two sided)
and with 80% power, a total of 230 patients needed to be
included (115 in each arm) and patients followed until a total of
190 had progressed.
statistical methods. All patients were analyzed on an intent-to-
treat principle. Log-rank tests and multivariate Cox regression
were used to compare end points. Tests were stratified by factors
used for stratification at randomization. The Efron
approximation was used to handle ties and the proportional
hazards assumption was assessed via scaled Schoenfeld
residuals. The Kaplan–Meier technique was used for survival
curves and to calculate 1-year survival estimates using the log–
log confidence interval (CI) method. A subgroup analysis was
preplanned to estimate treatment effect within the SQ and NSQ
subgroups. Toxic effect and tumor response were compared
using Fisher exact tests. Dose intensity was calculated as (dose
given/time given)/(dose planned/time planned).
The study was registered at clinical trials NCT00835471.
results
From March 2009 to December 2011, 231 patients were enrolled
on the study. At the time of analysis, the median follow-up for
all patients was 19 months (95% CI 15–26 months). A total of
178 (77%) patients had died, predominantly (n= 159) as a result
of disease progression. Four (2%) patients never started
treatment (two in each arm), one due to death, two due to
clinical progression, and one patient refusal.
patient characteristics
All patient characteristics were well balanced and summarized
in Table 1. Median time off platinum treatment was 10 weeks
(range 1–93 weeks) in the monotherapy arm and 9.8 weeks
(range 3–39 weeks) in the combination arm. Most patients in
both SQ and NSQ were treated with gemcitabine cisplatin as
first-line treatment. Fifteen percent of the patients in the
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second-line pemetrexed combination subgroup received
pemetrexed platinum treatment as first-line treatment and
median time off treatment was 7.5 months (range 3–20
months). In the monotherapy arm, this percentage was 19%. In
the docetaxel combination arm, docetaxel platinum as first-line
treatment was given to one (1%) patient 5 months before
randomization, compared with four (3%) in the monotherapy
arm median 18 months (range 12–42 months). In 60 (26%)
patients, EGFR mutation testing was carried out before
initiation of first-line therapy. Three (5%) patients were EGFR
mutation positive, and all the three were randomized to the
monotherapy arm.
PFS and OS
Median PFS was 4.9 months (95% CI 4.2–6.3 months) for
patients treated with erlotinib monotherapy and 6.1 months (95%
CI 4.7–7.9 months) for the combination arm (Figure 1, Table 2).
The adjusted log-rank test for PFS for all patients (P= 0.06;
unadjusted P= 0.11) and the adjusted Cox proportional HR
being 0.76 (95% CI 0.58–1.02) were not different between both
arms but showed a trend in favor of the combination arm.
Although the histology interaction did not reach statistical
significance (P= 0.49), the trend for an increase in PFS in the
combination arm was observed to be larger in the NSQ
subgroup (adjusted HR = 0.72; 95% CI 0.51–1.02; P= 0.06;
unadjusted P= 0.05) than in the SQ subgroup (adjusted
HR = 0.92; 95% CI 0.56–1.52; P= 0.73), Figure 1. For patients
treated with monotherapy erlotinib, PFS and OS for patients
with SQ histology compared with NSQ histology was not
statistically significantly different (PFS: HR = 1.27, 95% CI 0.82–
1.95, P= 0.42; OS: HR = 1.32, 95% CI 0.84–2.08, P= 0.28).
OS showed an improvement for the combination arm.
Median OS was 5.5 months (95% CI 4.5–8.5 months) versus 7.8
months (95% CI 6.5–10.8 months) for monotherapy versus
combination therapy, respectively (adjusted log-rank, P= 0.01;
HR = 0.67, 95% CI 0.49–0.91), Figure 1. This improvement was
restricted to NSQ patients. There was no evidence of failure of
proportional hazards for either PFS or OS.
We sought to determine whether the effect of treatment on
PFS or OS differed between patients known EGFR wild-type
and unknown EGFR status in NSQ. The interaction estimates
were nonsignificant, indicating that there is no detectable
difference between treatment effects between the two cohorts
(included in supplementary data, available at Annals of
Oncology online)
1-year survival rate for all patients was 30% (95% CI 24–27),
for monotherapy 22% (95% CI 15–32), and 38% (95% CI 30–
48) for patients allocated to combination therapy.
treatment delivery
In the erlotinib monotherapy, arm treatment was halted before
disease progression due to adverse events in 9%, death in 9%, and
patient refusal 5%. In the combination arm, treatment was
discontinued before disease progression in 10% due to patient
refusal (9% NSQ, 11% SQ), 17% due to adverse events (11% NSQ,
26% SQ), and 7% due to death. Forty-seven percent of patients in
the combination arm received the total planned treatment of four
cycles of chemotherapy. Additional data are presented in
Suplementary Data, available at Annals of Oncology online.
toxic effect
Toxic effect exceeding CTCAE grade 2 was significantly
increased in the combination arm 55% versus 19% in the
monotherapy arm (P< 0.0001; supplementary Table, available
at Annals of Oncology online). Hematological toxic effect was
observed in the combination arm only, with febrile neutropenia
in 6% of patients; 4% in the pemetrexed treated cohort and 10%
in the docetaxel treated cohort. Toxic deaths were not observed
in this study.
response to treatment
Response to treatment is presented in Table 2. Significantly
more patients in the combination arm experienced disease
control (response or stable disease) as best overall response than
in the monotherapy arm [62 (54%) versus 43 (39%), P= 0.03].
erlotinib concentrations
Samples from 25 patients (21%) were available for analysis. In
all of these patients, the concentrations were below 500 ng/ml,
the serum level required for adequate tyrosine kinase inhibition.
Table 1. Patient characteristics
Monotherapy
(N = 115)
Combination
(N= 116)
All
(N= 231)
Gender
Male 75 (65%) 73 (63%) 148 (64%)
Female 40 (35%) 43 (37%) 83 (36%)
Age (years)
Median (range) 64.0 (38–81) 62.5 (40–82) 63.0 (38–82)
PS
0 39 (34%) 49 (42%) 88 (38%)
1 67 (58%) 57 (49%) 124 (54%)
2 9 (8%) 9 (8%) 18 (8%)
3 1 (0.9%) 1 (0.4%)
Smoking
Never 7 (6%) 9 (8%) 16 (7%)
Present 35 (30%) 29 (25%) 64 (28%)
Past 63 (55%) 68 (59%) 131 (57%)
Unknown 10 (9%) 10 (9%) 20 (9%)
Histology
Adeno 50 (43%) 50 (43%) 100 (43%)
Large-cell 15 (13%) 22 (19%) 37 (16%)
Squamous-cell 40 (35%) 34 (29%) 74 (32%)
Undifferentiated 2 (2%) 2 (2%) 4 (2%)
Bronchoalveolar 1 (0.9%) 1 (0.4%)
Plavelsel 1 (0.9%) 1 (0.4%)
Other 2
a
(2%) 1
b
(1%) 3 (1%)
Unknown 5 (4%) 6 (5%) 11 (5%)
Stage
Ib 1 (0.9%) 1 (0.4%)
IIIb 28 (24%) 22 (19%) 50 (22%)
IV 86 (75%) 94 (81%) 180 (78%)
a
One adeno + neuroendocrine and one squamous + adeno carcinoma.
b
One large-cell neuroendocrine carcinoma.
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Thirteen samples had erlotinib concentrations below the lower
detection limit of 2 ng/ml. The other 12 samples had a mean
concentration of 79 ng/ml (SD 120 ng/ml).
post discontinuation therapy
Ninety-three (40%) of patients received third-line cytotoxic
therapy, 48 (42%) in the monotherapy, and 45 (39%) in the
combination arm. Most often, patients were treated with
pemetrexed (35% monotherapy, 31% combination arm).
discussion
This is the first randomized study investigating the role of
combining chemotherapy and intercalated erlotinib versus
erlotinib alone in Caucasian patients with recurrent, platinum-
pretreated NSCLC. Although a trend in favor of the combination
was observed, the primary end point PFS was not met
(HR = 0.76, P= 0.06). A preplanned subgroup analysis showed
that the trend for an increase in PFS was primarily in patients
with NSQ treated with pemetrexed–erlotinib. In these patients,
Figure 1. Kaplan–Meier curves of progression-free (PFS) [HR 0.76; 95% confidence interval (CI) 0.58–1.02; P= 0.06] and overall survival (OS) (HR 0.67; 95%
CI 0.49–0.91; P= 0.01) for all patients (A) and divided by histology (B). Squam, squamous cell histology; NonSquam, non-squamous histology; erlo, erlotinib.)
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PFS increased from 4.9 to 7.2 months (HR = 0.72, P= 0.06),
whereas the docetaxel-treated patients with SQ did not show a
difference. Significantly more patients in the combination arm
experienced disease control (response or stable disease) as best
overall response than in the monotherapy arm (P=0.03)
The drawbacks of PFS measured by the local investigator are
well recognized. The secondary end point OS was significantly
prolonged in the combination arm and this beneficial effect was
again restricted to the patients with NSQ.
PFS in the monotherapy arm was equal in both SQ and NSQ,
confirming the earlier observations. The intermittent dosing
schedule of erlotinib is designed to overcome the potential
antagonism between cytotoxic chemotherapy and EGFR TKIs.
In second-line treatment, both docetaxel and pemetrexed have
been investigated. Recently, comparative studies, although only
published in abstract form, with this intercalated dosing
schedule were found to be positive [12,13]. To the best of our
knowledge, no studies comparing docetaxel or pemetrexed and
intermitted erlotinib with single-agent erlotinib in second-line
treatment of NSCLC are available in the current literature.
The increased efficacy of combining these drugs is thought to
be mediated by a number of mechanisms not solely related to the
genetic signature of the tumor cells. In cell line experiments,
pemetrexed was found to increase EGFR phosphorylation and
reduce Akt phosphorylation (sensitizing tumor cells to erlotinib),
while erlotinib was found to reduce thymidylate synthase
expression and activity, which in turn may sensitize tumor cells to
pemetrexed [7]. Docetaxel and EGFR inhibition combinations
were found to increase the antiproliferative and cytotoxic effect of
the individual drugs in cancer cell lines and tumor models [14].
Erlotinib concentrations were below 500 ng/ml, the level
required for adequate tyrosine kinase inhibition [15]. The wash-
out period therefore appears adequate, but does not exclude an
interaction at the intracellular level.
Several drawbacks in the design of the study must be noted.
First, EGFR mutation testing was not mandatory at entry into
the study. In 26% of the total patient population, EGFR
mutation testing was carried out. Excluding the patients with
SQ-cell carcinoma, in whom EGFR mutation is seldom found,
the fraction of patients tested is 33%. Three mutation-positive
patients who were not pretreated with EGFR-TKI were entered
into the trial and randomized to the monotherapy arm. As
patients were not selected for the trial based on criteria to enrich
for EGFR mutation positivity, we hypothesize that the
prevalence of EGFR mutation in NSQ group will be comparable
with the general prevalence in the Dutch population of about
10%–15% in a NSQ population.
Second, the number of chemotherapy cycles is limited to four.
To optimize the synergistic effect, it can be hypothesized that
chemotherapy should be continued beyond four cycles. The
study reported by van Pawel et al. compared pemetrexed versus
pemetrexed and intermittent erlotinib in patients with NSQ
histology in a randomized phase II study. In their study,
pemetrexed in both arms was continued until disease
progression. Their study was positive for PFS and OS in
favor of the combination arm.
Third, at the time of study, design information concerning
maintenance treatment with pemetrexed was not available.
Therefore, patients were treated with standard first-line
chemotherapy without maintenance pemetrexed treatment.
The data of our study suggest no additional value of adding
docetaxel to erlotinib in SQ-cell carcinoma patients. What is not
resolved in this study is whether this lack in synergy is a
chemotherapy related, histology or mutation-related, or
pharmacodynamic-related phenomenon.
The toxic effect profiles support a synergistic effect of
pemetrexed and erlotinib but not for docetaxel and erlotinib. In
26% of patients on pemetrexed–erlotinib combination therapy,
a dose reduction of erlotinib was required compared with 6% of
patients in the docetaxel combination arm. However, to
substantiate any pharmacological interaction, detailed
pharmacokinetic studies should be carried out. As no dose
escalations were allowed, this increased number of dose
reductions may have influenced efficacy.
In conclusion, although this study, comparing monotherapy
with combination chemotherapy and erlotinib, in patients with
Table 2. Efficacy
All patients Squamous Non-squamous
Monotherapy Combination Monotherapy Combination Monotherapy Combination
N= 115 N= 116 N=42 N=34 N=73 N=82
BoR
PR* 8 (7%) 15 (13%) 1 (2%) 2 (6%) 7 (10%) 13 (16%)
SD 37 (32%) 47 (41%) 17 (40%) 12 (34%) 20 (27%) 35 (43%)
PD 58 (50%) 36 (31%) 19 (45%) 11 (32%) 39 (53%) 25 (30%)
NE 12 (10%) 18 (16%) 5 (12%) 9 (26%) 7 (10%) 9 (11%)
PFS (months)
Median 4.9 6.1 4.9 4.1 4.9 7.2
95% CI (4.2–6.3) (4.7–7.9) (3.8–8.0) (2.9–7.6) (3.9–7.6) (5.3–9.3)
OS (months)
Median 5.5 7.8 6.2 6.1 5.5 9.1
95% CI (4.5–8.5) (6.5–10.8) (4.5–9.8) (4.1–10.4) (4.3–9.4) (7.2–13.8)
*Confirmed.
NE details presented in supplementary Data, available at Annals of Oncology online.
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both SQ and NSQ was just negative for its primary end point
(PFS), a significant prolongation of OS was found. This
improvement appears restricted to the NSQ patients in whom
erlotinib was combined with pemetrexed. Combination therapy
intercalated chemotherapy and erlotinib should be further
investigated preferably with cytotoxic chemotherapy treatment
being continued beyond four cycles.
disclosure
JGA and AMCD have received research funding and honoraria
from Eli-Lilly and Roche. All remaining authors have declared
no conflicts of interest.
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Annals of Oncology original articles
Volume 24 | No. 11 | November 2013 doi:10.1093/annonc/mdt341 | 
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