Updates in non-small cell lung cancer - insights from the 2009 45th annual meeting of the American Society of Clinical Oncology
Journal of Hematology & Oncology
RUevpiewdates in non-small cell lung cancer - insights from the 2009 45th annual meeting of the American Society of Clinical Oncology
Hamid R Mirshahidi
Chung T Hsueh
0 Division of Medical Oncology and Hematology, Loma Linda University , Loma Linda, CA 92354 , USA
We have reviewed the pivotal presentations in non-small cell lung cancer (NSCLC) from the 2009 annual meeting of the American Society of Clinical Oncology. We have discussed the scientific data, the impact on standards of care, and ongoing clinical trials. In patients with early-stage NSCLC, there is still no data to support the superiority of either neoadjuvant or adjuvant chemotherapy. However, adjuvant cisplatin-based chemotherapy has sustained the survival benefits after median follow-up of more than 9 years. The first-line treatment with inhibitors of epidermal growth factor receptor (EGFR) could be considered for the treatment of EGFR mutated patients with metastatic disease. Several maintenance studies with cytotoxic or biological agents have also demonstrated promising outcomes. Finally, novel targeted agents such as inhibitors of histone deacetylase and multi-targeted tyrosine kinase inhibitor have shown promising activity in NSCLC treatment.
The 2009 Annual Meeting of the American Society of
Clinical Oncology (ASCO) in Florida introduced and
highlighted numerous important studies and medical
advancements. Among them, the meeting brought forth
much data from several key studies in non-small-cell lung
cancer (NSCLC). The purpose of this article is to review
several important abstracts that were presented in
different lung cancer tracts, which may influence the standards
of care in the future. With that said, such abstracts
include the Neoadjuvant or Adjuvant Chemotherapy in
patients with Operable Non-Small Cell Lung Cancer
(NATCH) trial and the updated long-term follow-up data
from JBR.10 adjuvant chemotherapy study in the early
stage disease. This article will also take into account and
review the data from trials regarding pemetrexed and
erlotinib present in patients with locally advanced disease
as the maintenance therapy. Moreover, in advanced
NSCLC, there have been new findings from studies that
assessed vorinostat efficacy and results from Southwest
Oncology Group (SWOG) S0536 evaluating four drug
combinations. Lastly, biomarker studies from the Iressa
Pan-Asia Study (IPASS) and the first-line Cetuximab in
lung cancer (FLEX) trials will be reviewed; such trials
managed to reveal predictive factors for inhibitors of
epidermal growth factor receptor (EGFR).
The data reviewed in this article were obtained from
the results presented in ASCO 2009 annual meeting.
Therefore, a possible discordance between these data and
the final results published in the papers should be
I. Chemotherapy in Early-Stage NSCLC
Neoadjuvant chemotherapy studies have shown to
improve survival outcomes for patients with stage II or
IIIA NSCLC in several randomized studies [1,2]. Data
from large randomized clinical trials and pooled analyses
have also supported the use of adjuvant platinum-based
chemotherapy in patients with completely resected stage
II or III NSCLC . A meta-analysis yielded similar
overall survival (OS) and disease-free survival (DFS) for
patients with resectable lung cancer who received either
neoadjuvant or adjuvant chemotherapy . Two
Chemotherapy with carboplatin and paclitaxel provided no
additional benefit to surgery in early-stage lung cancer
Felip et al. presented the results from NATCH study,
which was a multicenter, phase III study that randomly
assigned patients to surgery alone, neoadjuvant
chemotherapy followed by surgery or surgery followed by
adjuvant chemotherapy . This study enrolled 624 patients
with clinical early-stage (stage IA with tumor size > 2 cm,
IB, II, or T3N1) resectable NSCLC. Patients on
neoadjuvant and adjuvant chemotherapy arms received 3 cycles
of carboplatin AUC of 6 and paclitaxel 200 mg/m2 every
3 weeks. The primary end-point was 5-year DFS. After a
median follow-up of 43 months, the median DFS was not
significantly different among the three arms (28, 32, and
24 months in the surgery, neoadjuvant, and adjuvant
arms, respectively). The 5-year DFS rate was also similar
among the 3 groups and no significant difference in
median OS was observed as well. The rate of resection,
types of surgery, and post-operative mortality were
similar across treatment groups. Ninety seven percent of
patients in neoadjuvant and 66% of patient in the
adjuvant chemotherapy group received the planned 3 cycles
of chemotherapy. The exploratory analysis of these
results showed the patients with clinical stage II and
T3N1 disease derived the greatest benefit from
preoperative chemotherapy followed by surgery. The data were
likely influenced by the facts that nearly 50% of the
patients had stage I disease and cisplatin-based
chemotherapy regimen was not employed. Cancer Leukemia
Group B (CALGB) 9633 also failed to produce a
longterm overall survival benefit in patients with stage IB
disease who received adjuvant paclitaxel and carboplatin
after surgery . Three cycles of neoadjuvant carboplatin
and paclitaxel followed by surgery was also studied in
SWOG S990. In this study, more than two thirds of
patients were classified with earlier stage disease, IB or
IIA. This trial closed prematurely in 2004 after several
studies demonstrated a significant survival benefit for
adjuvant chemotherapy. These results did not quite
achieve statistical significance due to early closure, but
the study showed a strong trend toward improved
progression-free survival (PFS) and OS . Unfortunately,
NATCH could not determine the superiority of either
neoadjuvant or adjuvant chemotherapy over each other.
It is recommended to wait for the results of the ongoing
trials in Asia and Europe (ClinicalTrials.gov Identifier:
NCT00398385, NCT00321334, and NCT00389688) to
resolve this issue. The retrospective analyzing of NATCH
is undertaken to define prognostic and predictive
2- JBR 10
Dr. Vincent updated the survival data for JBR.10 with 9
years of median follow up. JBR.10 was a multicenter,
randomized controlled trial. Eligible patients included those
with completely resected stage IB (T2N0) or II (T1 - T2,
N1) NSCLC who were randomized to receive 4 cycles of
vinorelbine plus cisplatin or observation within 6 weeks
of surgery (Figure 1). Baseline characteristics were
well-balanced including RAS status. In the updated
results, the survival analysis continues to show the
benefits from chemotherapy beyond 12 years and suggestive
of cure (hazard ratio [HR} 0.78, p = 0.04). In comparison,
the updated IALT results with a median follow-up of 7.5
years showed a fading effect of adjuvant chemotherapy on
survival. The initial 14% reduction in the risk of death
reduced to 9% with adjuvant chemotherapy after 5 year
and this difference was no longer statistically significant
. The definite benefit appears to be confined to N1
disease. In stage II disease, the median OS was 6.8 years in
the chemotherapy arm versus 3.6 years in the observation
arm (HR 0.68, p = 0.01). The patients with stage IB did
not exhibit a significant benefit (HR 1.03; p = 0.87).
However, stage IB patients with tumors greater than 4 cm
gained a greater benefit, although this trend was not
statistically significant (HR 0.66; p = 0.13). Paclitaxel and
carboplatin also failed to produce a long-term overall
survival benefit in patients with stage IB disease in CALGB
9633. However, exploratory analysis demonstrated a
significant survival difference in favor of adjuvant
chemotherapy for patients who had tumors 4 cm in diameter
(HR, 0.69; CI, 0.48 to 0.99; P = .043) . The RAS
mutation status was not significant in COX analysis.
Competing risk analysis also showed observation to be associated
with significantly higher risk of death from lung cancer (p
= 0.02) with no difference in incidences of death from
other causes between arms including second malignancy
(p = 0.62).
The current recommended first-line treatment for
patients with advanced stage NCSLC is combination of a
Figure 1 JBR 10 - Study design of JBR 10 [Reference: ].
platinum-based regimen for 4 to 6 cycles. The prolonged
front-line platinum-based chemotherapy does not seem
to provide any other additional benefits . Therefore,
the current treatment guidelines have recommended
waiting until the disease has progressed to initiate second
and third-line regimens. Several studies have shown that
maintenance chemotherapy may improve PFS in patients
achieving disease control after first-line chemotherapy
. Maintenance chemotherapy is the extension of
chemotherapy duration with additional drugs given after a
set course of first-line chemotherapy in patients
achieving tumor response including stable disease. Usually
maintenance chemotherapy is continued till disease
progression or unacceptable toxicity. Three maintenance
studies were presented this year.
Dr. Belani gave a presentation on his research and data
that supported the notion that patients would greatly
benefit from pemetrexed maintenance therapy . The
study was a randomized, double-blind, multicenter, phase
III study in patients with advanced NSCLC who received
four cycles of first-line platinum-doublet chemo. It
demonstrated a significant PFS and OS benefit for
maintenance pemetrexed and best supportive care (BSC)
treatment compare to placebo and BSC (Table 1). In
addition, this study confirmed non-squamous histology was
predictive of the improved efficacy of pemetrexed
maintenance therapy. The administration of pemetrexed in the
maintenance setting was fairly well tolerated and was
devoid of any cumulative toxicity in the subgroup
analysis. The rates of grade 3 and 4 toxicities in the pemetrexed
arm were low. Taking that into consideration, the
difference in the deterioration of quality of life among
pemetrexed and placebo treatments were not reported this
Another concern of this study was that only 67% of the
placebo arm patients received second-line therapy.
Meanwhile 51% of the placebo arm patients received
third-line and 19% received fourth-line treatment. Only
19% of patients received pemetrexed in the placebo arm.
Therefore, it is possible that the survival benefits may
have been preserved if more patients on the placebo arm
had received pemetrexed. To be clear, this study does not
entirely prove that the maintenance strategy is the cause
for improved survival. However, this study has reinforced
the notion that pemetrexed is an active and effective
agent in patients with non-squamous NSCLC.
More than 80% of NSCLC overexpress EGFR .
Erlotinib is a highly potent EGFR tyrosine-kinase inhibitor
(TKI). Erlotinib has been shown to significantly improve
the OS and PFS in patients with advanced NSCLC who
failed prior platinum-based chemotherapy . In two
first-line studies (TRIBUTE and TALENT), combination
Placebo (n = 222)
PFS, progression free survival; OS, overall survival; HR, hazard ratio; Reference: 
of erlotinib and platinum-based chemotherapy did not
demonstrate improved outcome in advanced NSCLC,
compared to chemotherapy alone [15,16].
Sequential erlotinib in unresectable NSCLC (SATURN)
trial was a placebo-controlled, randomized, double-blind,
phase III study that enrolled 889 patients with advanced
NSCLC, and patients were randomized to erlotinib or
placebo if their cancer did not progress after at least four
cycles of first-line platinum-based chemotherapy .
The study met its primary endpoint demonstrating a
significantly improved PFS with erlotinib in all comers (HR
0.71; p < 0.0001), and in EGFR-positive subgroup (HR
0.69; p < 0.0001). Additionally, PFS was significantly
prolonged with erlotinib regardless of adenocarcinoma or
squamous cell carcinoma tumor type (P < 0.0001 and
Mutation of EGFR was the only marker significantly
predictive of differential erlotinib effect (P < 0.001) .
Patients exhibiting mutant EGFR tumors had a PFS of
about 45 weeks with erlotinib, and 13 weeks with placebo
(Table 2). Patients with EGFR wild type tumors had a
smaller gain in PFS. This study confirmed that erlotinib is
an active and efficacious agent in NSCLC, irrespective of
histology. However, the benefits are disproportionate in
patients with EGFR mutation.
FAST-ACT study, which was presented in 2008 ASCO
annual meeting, also tested erlotinib with
platinum/gemcitabine chemotherapy with erlotinib continuing as the
maintenance therapy . PFS was statistically better in
experimental arm (p = 0.0002), but it did not translate in
to improved OS.
Erlotinib and Bevacizumab (ATLAS)
The addition of bevacizumab to first-line carboplatin and
paclitaxel chemotherapy conferred a significant
improvement in OS, PFS, response rate (RR) in patients with
nonsquamous-cell carcinoma and a good performance status
. The combination of bevacizumab and erlotinib also
showed activity in phase II and III NSCLC trials [21,22].
Taking that into consideration, the ATLAS study was
conducted to test the hypothesis of maintenance erlotinib
in combination with Bevacizumab in patients with
advanced-stage . The patients with no progressive
disease or significant toxicity were randomized to receive
either erlotinib or placebo with Bevacizumab until
disease progression after initial therapy. The study included
patients with peripheral or extrathoracic squamous cell
carcinomas and patients with treated brain metastases.
The study met its primary endpoint by demonstrating
that patients who received Erlotinib in combination with
bevacizumab as maintenance treatment had a median
PFS of 4.76 months compared to 3.75 months in the
control arm (HR 0.72; p = 0.0012). Adverse events were
consistent with previous Bevacizumab or Erlotinib NSCLC
studies evaluating the two medicines together. However,
the combination arm experienced more adverse events
and serious adverse events, including more grade 3-5
toxicities (46.3% vs. 31.55%). The quality of life analysis was
not included in this trial. HR for PFS favored erlotinib
arm in nearly all patient subgroups regardless of their
ethnicity, sex, smoking history, tumor histology, and
initial chemotherapy. Data on OS are expected to be
announced in early 2010.
EGFR positive by FISH
EGFR negative by FISH
HR, Hazard Ratio; IHC, immunohistochemistry; FISH, Fluorescence In Situ Hybridization
First Line Therapy with Inhibitors of EGFR
Dr. O'Byrne presented the retrospective analysis of the
data from FLEX trail to identify the molecular and
clinical predictors of outcome for cetuximab in NSCLC .
In this study, 1125 patients with advanced NSCLC and
positive EGFR staining by immunohistochemistry (IHC)
were randomized to cisplatin and vinorelbine with or
without cetuximab. Patients remained on maintenance
therapy until disease progression. A statistically
significant difference in OS was found, with improvement from
10.1 months to 11.3 months (p = 0.0441). The RR was also
superior in the cetuximab group (29% vs. 36%, p = 0.012).
However, PFS was identical at 4.8 months in each group.
In a subgroup analysis, patients with squamous cell
histology retained survival benefit. Subgroup analysis of
Asian patients included in the study (n = 121) did not
show an improvement in survival with the addition of
cetuximab (median OS, 17.6 months for chemotherapy
plus cetuximab vs. 20.4 months for chemotherapy alone,
not statistically significant). However, on disease
progression, the Asian subgroup that received cetuximab also
received fewer EGFR TKIs (50% vs. 73%). The lack of this
may have had a negative effect on their outcomes .
Patient selection with positive IHC of EGFR might not
be the right selection criteria in this study. Most
cetuximab studies have not clearly shown an association
between EGFR expression and response. However, the
results from SWOG 0342 study have shown that the
amplification of EGFR gene copy number, determined by
fluorescent in situ hybridization (FISH), might predict an
improved survival for EGFR TKI therapy . Among
FISH-negative patients, median OS was 10.6 months with
chemotherapy and cetuximab compared to 10.0 months
with chemotherapy alone (HR, 0.91). In FISH-positive
patients, median OS was 11.6 months in the cetuximab
arm while it was 9.9 months in the control arm (HR,
0.85). Similarly, PFS and RR by FISH status failed to
indicate response to cetuximab therapy. KRAS mutation
status did not affect OS, PFS, or RR in either subgroup. The
KRAS and EGFR-biomarker data are congruent with
those from the smaller BMS-099 trial, in which
cetuximab was added to a taxane and carboplatin in the
firstline treatment of NSCLC .
The most important finding of the analysis was the
first-cycle rash, which might help to identify patients with
improved survival with cetuximab. The median overall
for survival was 15.0 months in patients that developed
an acnelike rash of any grade within 21 days of treatment
with cetuximab and chemotherapy in comparison to 8.8
months for those without a rash after cetuximab
treatment (HR 0.63; p < 0.001). The survival was 10.3 months
in the chemotherapy-alone arm. The median OS was 15.0
months in 290 patients with a grade 1-3 rash and 14.7
months in 120 patients with a grade 2-3 rash. It might
indicate that the development of a rash is important
predictive factor than the specific grade of the rash. The data
depicted the OS to be far more superior when cetuximab
was added to the standard first-line chemotherapy
regardless of histology or KRAS mutation and EGFR gene
copy number status. An important question to consider
is: if the first-cycle rash is a predictive clinical biomarker,
should we continue with cetuximab in patients with no
signs of rashes? Overall, the findings suggest that the
optimal selection strategy for treatment with cetuximab
remains to be defined.
SWOG 0536 was a phase II study that evaluated the
effectiveness and safety of utilizing combinations of
bevacizumab, paclitaxel, carboplatin, and cetuximab in
patients with advanced-stage NSCLC . Bevacizumab
and cetuximab were continued after 6 cycles of
chemotherapy till progression of disease. In this study, 104
patients with newly diagnosed stage IIIB or IV NSCLC
were treated. Overall, this 4-drug combination was
shown to be active with favorable efficacy. An analysis of
molecular biomarkers showed that neither KRAS nor
EGFR mutations were predictive of outcomes. In
addition, although there was a trend toward improved tumor
response and disease control rate in patients with
EGFRpositive tumors by FISH, no significant differences were
noted in PFS or OS. Further analysis of other
translational studies such as, EGFR status by FISH, cytokine and
angiogenic factor profiling, and proteomics are still
The SWOG 0536 study met its primary tolerability
endpoint. This combination may also have an additive
rather than a synergistic effect. However, the synergistic
benefit may be seen in a subset of patients. The positive
results of this trial warrant the continued investigation of
this 4-drug combination in the phase III SWOG 0819.
This study, with a planned enrollment of 1,545 patients,
will compare initial therapy (paclitaxel/carboplatin plus
bevacizumab with or without cetuximab) followed by
maintenance therapy (bevacizumab with or without
cetuximab). The primary endpoints are OS in entire
study population and PFS in EGFR FISH positive
EGFR TKIs have comparable clinical efficiency with the
best supportive care or standard chemotherapy as
second-line or third-line therapy for advanced
non-smallcell lung cancer [14,29]. They are most effective in
women, patients who have never smoked, patients with
adenocarcinoma, and patients of Asian origin . These
populations have also relatively high incidence somatic
mutations in tyrosine kinase domain of EGFR gene
including base-pair deletion at exon 19 or a point
mutation at exon 21 . The studies of first-line therapy with
these agents showed objective RR of 54.8 to 81.6% and
PFS of 9.7 to 13.3 months among patients with these
mutations [31,32]. Therefore, the IPASS study was
conducted to assess the efficacy, safety and tolerability of
gefitinib compared to carboplatin and paclitaxel as
firstline treatment in a clinically selected population of
patients from Asia .
The results of planned exploratory analysis to predict
the efficacy of treatment based on EGFR mutation, EGFR
gene copy number, and EGFR protein expression were
presented in 2009 ASCO meeting . One thousand
two hundred seventeen patients in Asia with advanced
NSCLC whose tumors were of adenocarcinoma histology
and who had either never smoked, or were former light
smokers were randomized in a 1:1 ratio to receive 250 mg
gefitinib per day till progression of disease or paclitaxel
(200 mg/m2) and carboplatin (AUC 5.0 or 6.0) every 3
weeks for up to 6 cycles. Biomarker status and incidence
of specific identified EGFR mutations were well balanced
between treatment arms. The study met its primary
objective and it showed the statistically significant
improved PFS in gefitinib subgroup, with hazard ratio of
0.74 (p < 0.001). PFS favored chemotherapy for the first 6
months than gefitinib, likely driven by EGFR mutation
statue or continuation of gefitinib as maintenance
therapy. The PFS and RR were similar in all subgroups in
EGFR mutation was the significant positive predictive
factor for PFS in patients who received gefitinib (p <
0.0001). Gefitinib improved PFS in patients with EGFR
mutation whereas it reduced PFS in patients without
EGFR mutation. The PFS in overall IPASS population and
in patients with unknown EGFR mutation who received
Gefitinb was similar. The difference in OS was not
statistically significant due to small number of events and
significant number (39%) of patients in both arms received
post-study Carbopaltin/Paclitaxel and gefitinb. However,
the trend was toward superior OS with gefitinib among
patients with EGFR mutation and with carboplatin and
paclitaxel in patients without EGFR mutation (table 3).
EGFR gene copy number was furthermore predictive
factor for PFS in patients treated with gefitinib (p =
0.0437). Gefitinib improved PFS in patients with high
EGFR copy number significantly (HR 0.66; p = 0.005).
The improvement in PFS possibly was driven by overlap
with positive mutation status. Patients with both
mutation and high copy number of EGFR showed substantially
extended PFS with Gefitinib (HR 0.48). In contrast, PFS
was significantly shorter mutation-negative patients with
high copy number of EGFR (HR 3.85). Gefitinb also
improved RR in patients with mutated EGFR, whereas,
carboplatin plus paclitaxel improved RR in
Mutationnegative patients. (Table 4).
One hundred thirty two patients were positive for
EGFR mutation, gene copy number, and protein
expression in this study. Only 31 patients were negative for
these three factors. The observed degree of overlap
among them was higher than previous gefitinib studies.
These results cannot be extrapolated directly to a North
American population, since there was high degree of
overlap among this highly specific patient population.
Therefore, never smokers, female, or Asians and patients
with adenocarcinoma should be screened for EGFR
mutation. EGFR inhibitor therapy should be considered a
standard approach for first-line therapy in patients with
EGFR mutation. Chemotherapy would be the treatment
of choice for patients with unknown EGFR status.
Vandetanib is an orally bioavailable, anilquinazoline
derivative, multi-targeted TKI targeting vascular
endothelial growth factor receptor (VEGFR)-2, EGFR,
and RET tyrosine kinases . This compound inhibits
two key pathways in tumor growth: VEGFR-dependent
tumor angiogenesis and EGFR-dependent tumor cell
proliferation and survival. Vandetanib was efficacious and
well tolerated in patients with advanced solid tumors
have demonstrated that the once-daily oral
administration of this multi-targeted agent at 300 mg daily was well
tolerated and recommended for phase II studies . The
subsequent phase II randomized trial involving patients
with recurrent NSCLC showed the addition of
vandetanib to docetaxel significantly improved PFS . The
data from three different studies with vandetanib in
NSCLC treatment was presented in Orlando. There was
no targeted selection in either of these studies.
ZODIAC was a randomized, double-blinded,
placebocontrolled phase III study evaluating the combination of
vandetanib with docetaxel in comparison to just
docetaxel in 1,391 patients with advanced NSCLC and
previously treated with one prior therapy . All tumor
histology, treated brain metastases and previous
bevacizumab exposure was permitted. The study met its
primary endpoint when it demonstrated that the addition of
vandetanib with docetaxel resulted in a statistically
significant improvement of PFS (4.0 vs. 3.2 months in all
patient populations, including females (Table 5). This
result was fairly modest, although, the PFS was
statistically significant. HR for PFS generally favored vandetanib
arm across clinical subgroups defined by sex, race,
smoking status, previous bevacizumab, disease stage,
histology, and number of affected organs. The HR for PFS also
Carboplatin + Paclitaxel
PFS, progression free survival; OS, overall survival; HR, hazard ratio; EGFR, epidermal growth factor receptor.
favored vandetanib arm regardless of baseline tumor and
blood biomarker subgroups, with few exceptions in cases
with negative EGFR gene amplification and positive
KRAS mutation. Retrospective analysis suggested
baseline serum VEGFR2 level might serve as a predictive
The improved OS was not statistically significant but it
was in favor of adding vandetanib to docetaxel (10.6 vs.
10.0 months). The HR for OS according to patients,
clinical subgroups, tumor, and blood marker subgroups was
near 1.0, with exception of EGFR gene amplification (HR
of 0.48). The final OS result will be available in the future.
The most common adverse events in the experimental
arm were rashes, diarrhea, neutropenia, and
hypertension. The vandetanib arm did not show any increase in
hemoptysis or thrombotic events. The incidence of QTc
prolongation was <2%. Unfortunately, the 3-week
improvement in PFS may not be clinically meaningful.
These data are not likely to change practice until the
results of the placebo-controlled ZEPHYR trial
(clinicaltrials.gov identifier: NCT00404924) is reported in the
first half of 2010. ZEPHYR trial is a direct comparison of
vandetanib to placebo in patients previously treated with
Carboplatin + Paclitaxel
8.9 Weeks TRIAL Treatment HR
3.2 Months 0.91 0.196 10.0
ZEAL was a randomized, double-blinded,
placebo-controlled phase III study evaluating vandetanib and
pemetrexed in comparison to just pemetrexed . The study
enrolled 534 patients previously treated with one prior
first-line therapy for advanced NSCLC. The combination
of vandetanib and pemetrexed did show a positive trend
in the prolongation of PFS compared to pemetrexed
alone (17.6 vs. 11.9 weeks). However, the addition of
vandetanib to pemetrexed did not benefit patients with
squamous cell carcinoma. The findings from ZEAL were
in agreement with ZODIAC results although the primary
endpoint did not reach statistical significance in the
ZEAL study. The large sample size in ZODIAC may
explain the significant improvement in PFS even though
the PFS was almost the same in both studies. Evaluation
of secondary endpoints in the ZODIAC and ZEAL
studies also showed that the addition of vandetanib to
chemotherapy significantly improved RR (p < 0.001). These
studies also showed that adding vandetanib to
chemotherapy resulted in a significantly longer time for the
deterioration of disease related symptoms.
ZEST was a randomized, double-blinded, phase III study
evaluating the efficacy of vandetanib 300 mg versus
erlotinib 150 mg . The study enrolled 1240 patients with
locally advanced or metastatic NSCLC after failure of at
least one line of chemotherapy. While the primary
objective of demonstrating a statistically significant
prolongation of PFS for vandetanib was not met in this study, in a
pre-planned non-inferiority analysis, vandetanib was
shown to have similar efficacy to erlotinib for PFS and
OS. The RR and symptom control were also similar for
The result of ZEST, ZEAL, and ZODIAC trials may not
justify the use of vandetanib alone or in combination with
chemotherapy in unselected patients at this time. The
benefit of adding VEGF inhibition to EGFR inhibition
remains unproven. Predictive biomarkers for
anti-angiogenesis therapy are needed to select the optimal patient
Histone Deacetylase Inhibitor
Histone deacetylases (HDAC) are a family of enzymes
that play an important role in the regulation of gene
transcription. Aberrant transcriptional activation and
repression mediated by histone acetyltransferases and HDACs
occurs in various malignancies. Increase in histone
acetylation transforms DNA to more open configuration.
Nontranscriptional effects of HDAC also increases
acetylation of nonhistone proteins such as hypoxia inducible
factor-1 alpha, heat shock protein 90, and -tubulin to
promote cell death, inhibition of angiogenesis, induction
of cellular differentiation, modulation of immune gene
Vorinostat is a small molecule that inhibits HDAC
activity. Vorinostat not only promotes the induction of
genes, but also causes the repression of several genes,
such as thymidylate synthetase and vascular endothelial
growth factor receptor. Inhibition of HDAC activity by
vorinostat also results in an increase of acetylated
nonhistone proteins, such as cytoskeletal proteins, molecular
chaperones, and nuclear import factors. Vorinostat is
already approved for treatment of cuteneous T-cell
lymphoma. Unfortunately, this agent is not active as
singleagent in treatment of NSCLC . However, it showed
synergistic effect with taxanes due to inhibition of tubulin
deacetylator HDAC and Platinum drugs by increasing
DNA fragmentation in preclinical and phase I studies
The randomized, double-blind, placebo-controlled
phase II study of carboplatin and paclitaxel with or
without vorinostat was presented . In this study no
crossover between treatment arms and no maintenance
therapy were permitted. There was no patient selection
related to the target agent. The results of this study
showed statistically significant improved tumor RR with
vorinostat (34%) compare to (12.5%) in placebo (p =
0.021), suggesting vorinostat enhanced the efficacy of
chemotherapy. The RR was improved in both squamous
and non-squamous histology. The study was not powered
to adequately determine PFS and OS, however, the trend
for both favored vorinostat (6.0 vs. 4.1 and 13.0 vs. 9.7
months, respectively.). The divergence of OS curves
occurred late, possible due to a subset of patient who did
benefit from vorinostat or failure of randomization to
adequately balance arms. Major toxicities, such as
cytopenias, fatigue, and nausea/vomiting, were more
frequent with vorinostat than placebo. Only
thrombocytopenia was statistically more common in experimental
arm. More treatment-related deaths also occurred in the
vorinostat than placebo arm (3% vs. 0%). Therefore, the
optimizing of dose and schedule of vorinostat is required
to improve the tolerability of the combination. This study
suggests that targeting different pathways other than
EGFR and angiogenesis signaling pathways may play an
important role in the treatment of NSCLC.
As the conclusion, the results from JBR.10 are reassuring
and show no long-term, non-lung cancer-related deaths
and the long-term positive results could be due to type of
chemotherapy regimen or biologic characteristic of
patients and the tumors. However, offering adjuvant
chemotherapy to stage IB patient still depends on the
individual cases. Unfortunately, NATCH did not show any
benefit of perioperative chemotherapy in addition to
There is no gold standard and consensus between
oncologists regarding maintenance therapy. Some
patients may benefit from maintenance therapy, however,
some will also be overtreated. We should also consider
many patients still enjoy a treatment holiday. Therefore,
these trials may actually indicate that exposure to more
active agents improves outcomes rather than validating
the concept of maintenance and selection of appropriate
treatment should be considered on an individual patient
In terms of biomarkers, we still do have conflicting
results except the documented importance of EFGR
mutation. The routine use of EGFR FISH or IHC testing
as well as KRAS testing for making decisions in the
firstline treatment setting cannot be recommended at this
time. Lastly, there is hope for improving outcomes in the
second-line setting given the positive data from the
ZODIAC trial. The important finding in this trial has
demonstrated the improvement of PFS and RR from
vandetanib translated into the clinically meaningful delay in
The authors declare that they have no competing interests.
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