Journal Thoracic Oncology

Abstracts Journal of Thoracic Oncology • Volume 12 Issue S1 January 2017
original adjuvant chemotherapy trials, a number of meta-analyses have
confirmed the benefit of adjuvant platinum-based chemotherapy after
surgical resection for NSCLC(9,10). In these meta-analyses, all-stage (IB-IIIA)
hazard ratios were in the range of HR=0.86, corresponding to an absolute
benefit for chemotherapy on overall survival of 4-5% at 5 years. The benefit,
however, was demonstrated to be stage dependent (albeit using older staging
criteria versions), with the benefit only reaching statistical significance for
stages II and III. While the role of adjuvant chemotherapy in stage I disease is
controversial (11), subgroup analyses in a number of trials in high-risk patients
with stage IB disease (tumours≥4cm) suggests that there may be an overall
survival advantage with adjuvant chemotherapy in this subgroup of patients,
comparable to those observed in stage II and III disease [Strauss 2008]. In 2009
the long term follow up of the IALT study (with a median follow up of 7.5 years)
was reported. Results showed a beneficial effect of adjuvant chemotherapy
on overall survival (hazard ratio [HR], 0.91; 95% CI, 0.81 to 1.02; P = .10) and on
disease-free survival (HR, 0.88; 95% CI, 0.78 to 0.98; P = .02). However, there
was a significant difference between the results of overall survival before and
after 5 years of follow-up (HR, 0.86; 95% CI, 0.76 to 0.97; P = .01 v HR, 1.45; 95%
CI, 1.02 to 2.07; P = .04) with P = .006 for interaction. Similar results were
observed for disease-free survival. The analysis of non-lung cancer deaths for
the whole period showed an HR of 1.34 (95% CI, 0.99 to 1.81; P = .06) suggesting
that those patients receiving adjuvant chemotherapy had a higher death rate
from non- lung causes after 5 years(12). However these conclusions were not
support by the findings of Butts and colleagues reporting on JBR10 with a
median follow-up was 9.3 years (range, 5.8 to 13.8). Adjuvant chemotherapy
continued to show a benefit (hazard ratio [HR], 0.78; 95% CI, 0.61 to 0.99; P =
.04). There was a trend for interaction with disease stage (P = .09; HR for stage
II, 0.68; 95% CI, 0.5 to 0.92; P = .01; stage IB, HR, 1.03; 95% CI, 0.7 to 1.52; P =
.87). Adjuvant chemotherapy resulted in significantly prolonged disease
specific survival (HR, 0.73; 95% CI, 0.55 to 0.97;P = .03). Observation was
associated with significantly higher risk of death from lung cancer (P = .02),
with no difference in rates of death from other causes or second primary
malignancies between the arms. They concluded that prolonged follow-up of
patients from the JBR.10 trial continues to show a survival benefit for
adjuvant chemotherapy(13). Recently in a post hoc analysis of ECOG 1505, a
trial of adjuvant chemotherapy +/- bevacizumab for early stage NSCLC,
Wakelee and colleagues had the opportunity to compare four different
cisplatin doublet regimens namely, cisplatin with one of vinorelbine,
docetaxel, gemcitabine or pemetrexed. Median follow-up time for each
chemotherapy doublet was: vinorelbine 54.3 months; docetaxel 60.3 months;
gemcitabine 57.0 months; and pemetrexed 40.6 months respectively. The
arms were well balanced for the major prognostic factors apart from smoking
where the rate was slightly lower in the pemetrexed arm. There was no
difference in the median number of cycles between arms. Both in the
nonsquamous and squamous subgroups there was no difference in overall
survival (nonsquamous logrank p=0.18 and squamous p=0.99) and disease free
survival (nonsquamous p=0.54 and p=0.83). The authors concluded that there
did not appear to be a difference in outcome between cisplatin doublet
regimens(14). Despite the established benefit of adjuvant chemotherapy after
curative surgery for NSCLC there is still much to be done with approximately
50 % of patients still dying from disease. Furthermore, not all patients with
early stage disease are eligible or willing to undergo chemotherapy following
complete surgical resection [Booth 2010]. As such, the long-term prognosis of
patients with NSCLC, even among those with early stage disease, remains
poor. Therefore it is imperative that we find new and better therapies to
improve upon the results of surgical resection and adjuvant chemotherapy.
.References: 1. American Cancer Society. Cancer Facts & Figures 2012. Atlanta:
American Cancer Society; 2012. 2. Jemal A, Siegel R, Ward E et al. Cancer
Statistics 2007. CA Cancer J Clin 2007; 57: 43-66. 3. L. A. Stewart, S. Burdett, J.
F. Tierney, J. Pignon on behalf of the NSCLC Collaborative Group: Surgery and
adjuvant chemotherapy (CT) compared to surgery alone in non-small cell lung
cancer (NSCLC): A meta-analysis using individual patient data (IPD) from
randomized clinical trials (RCT). Journal of Clinical Oncology, 2007 ASCO
Annual Meeting Proceedings (Post-Meeting Edition).Vol 25, No 18S (June 20
Supplement), 2007: 7552 4. Scagliotti GV, Fossati R, Torri V et al. Randomized
study of adjuvant chemotherapy for completely resected stage I, II, or IIIA
non-small-cell lung cancer. J Natl Cancer Inst 2003; 95: 1453–61. 5. Arriagada R,
Bergman B, Dunant A et al. Cisplatin-based adjuvant chemotherapy in
patients with completely resected non-small-cell lung cancer. N Eng J Med
2004; 350: 351-60. 6. Winton T, Livingston R, Johnson D et al. Vinorelbine plus
cisplatin vs observation in resected non-small-cell lung cancer. N Eng J Med
2005; 352: 2589-97. 7. Strauss GM, Herdone JE, Maddaus et al. Adjuvant
paclitaxel plus carboplatin compared with observation in stage IB non-small
cell lung cancer: CALGB 9633 with the Cancer and Leukemia Group B,
Radiation Therapy Oncology Group, and North Central Cancer Treatment
Group Study Groups. J Clin Oncol 2008; 26: 5043-51. 8. Douillard JY, Rosell R, De
Lena M et al. Adjuvant vinorelbine plus cisplatin versus observation in
patients with completely resected stage IB-IIIA non-small cell lung cancer
(Adjuvant Navelbine International Trialist Association [ANITA]): a randomized
controlled trial [published erratum appears in Lancet Oncol 2006; 7: 797].
Lancet Oncol 2006; 7: 719-27. 9. Pignon JP, Tribodet GV, Scagliotti G et al. Lung
adjuvant cisplatin evaluation: a pooled analysis by the LACE Collaborative
Group. J Clin Oncol 2008; 26: 3552-9. 10. NSCLC Meta-analyses Collaborative
Group. Adjuvant chemotherapy, with or without postoperative radiotherapy,
in operable non-small-cell lung cancer: two meta-analyses of individual
patient data. Lancet 2010; 375: 1267-77. 11. Wakelee H, Dubey S, Gandara D et
al. Optimal adjuvant therapy for non-small cell lung cancer – how to handle
stage I disease. Oncologist 2007; 12: 331-7. 12. Arriagada R, Dunant A, Pignon JP,
et al. Long-Term Results of the International Adjuvant Lung Cancer Trial
Evaluating Adjuvant Cisplatin-Based Chemotherapy in Resected Lung Cancer
JCO January 1, 2010 vol. 28no. 1 35-42 13. Butts C, Ding K, Seymour L,et al.
Randomized Phase III Trial of Vinorelbine Plus Cisplatin Compared With
Observation in Completely Resected Stage IB and II Non–Small-Cell Lung
Cancer: Updated Survival Analysis of JBR-10. Journal of Clinical Oncology,
January 1, 2010 vol. (28) 1 29-34. 14. H.A. Wakelee 1 , S.E. Dahlberg 2 , S.M. Keller
te al. E1505: Adjuvant chemotherapy +/bevacizumab for early stage NSCLC:
Outcomes based on chemotherapy subsets. ASCO Annual Meeting, 2016 Abstr
8507: E1505 Chemotherapy subsets. 15. Booth CM, Shepherd FA, Peng Y et al.
Adoption of adjuvant chemotherapy for NSCLC: a population-based outcome
study. J Clin Oncol 2010; 28: 3472-8.
Keywords: adjuvant chemotherapy, early stage non small cell lung cancer
ED08: EARLY-STAGE NSCLC: STATE-OF-THE-ART TREATMENT AND PERSPECTIVES
TUESDAY, DECEMBER 6, 2016 - 14:30-15:45
ED08.04 PERSPECTIVES OF TARGETED THERAPIES AND
IMMUNOTHERAPY IN COMPLETELY RESECTED NSCLC
Heather Wakelee
Department of Medicine, Division of Oncology, Stanford Cancer Institute/Stanford
University School of Medicine, Stanford/CA/United States of America
The use of four cycles of cisplatin-based adjuvant chemotherapy is now
the standard of care for patients with resected stage II and IIIA NSCLC and
is commonly used for patients with larger (at least 4 cm in size) stage IB
tumors. The survival benefit with adjuvant chemotherapy though is limited
with meta-analyses revealing a 4-5% absolute survival benefit at 5 years for
patients receiving adjuvant cisplatin-based chemotherapy. 1,2 Some recent
attempts to improve outcomes with the addition of other agents to cisplatin
doublets (or as longer term therapy) have been disappointing. The addition
of bevacizumab to chemotherapy in the ECOG-ACRIN E1505 adjuvant trial
failed to show a benefit in disease free survival (DFS) or overall survival
(OS). 3 The use of the MAGE-A3 vaccine in the MAGRIT trial was similarly
negative. 4 With knowledge about molecular drivers of NSCLC and targeted
treatment options in advanced disease, multiple studies are either completed
or underway to study molecularly targeted agents in earlier stages of lung
cancer, particularly with epidermal growth factor receptor (EGFR) tyrosine
kinase inhibitors (TKIs). In metastatic NSCLC the EGFR TKIs produce superior
response and progression free survival (PFS) compared with platinum doublet
chemotherapy in treatment naïve patients with tumors with activating EGFR
mutations (EGFRmut). 5,6 Similar outcomes with significant response and PFS
improvements with the anaplastic lymphoma kinase (ALK) inhibitor crizotinib
compared to chemotherapy have been reported in patients with tumors
harboring translocations of ALK. 7 Encouraging data from retrospective and
non-randomized trials looking at adjuvant EGFR TKI use led to randomized
trials. Earlier trials that did not select based on EGFRmut status were
negative, but more recent trials have been more encouraging. The phase III
RADIANT trial selected patients with resected early stage NSCLC for EGFR
expression by IHC/FISH, but not by EGFR mutation status, and randomized
them to adjuvant erlotinib or placebo. 8 The primary end point was DFS in
the full data set, with secondary analyses focused on patients with tumors
harboring del19 or L858R EGFR mutations. No differences were found in
DFS or OS based on treatment arm for the nearly 1000 patients who were
enrolled. In the EGFRmut subset (N=161) DFS did favor erlotinib (HR 0.61,
95% CI = 0.384-0.981, p = 0.0391), but this was not considered statistically
significant, as the primary endpoint of the trial was negative. The overall
survival results, while still immature, were not in favor of the erlotinib
arm, even in the EGFRmut subset. The conclusion from this study is that
adjuvant EGFR TKI therapy requires further investigation and should not be
considered a standard treatment option at this time. Multiple ongoing trials
are exploring adjuvant EGFR TKI (and adjuvant ALK TKI) therapy for resected
early stage NSCLC patients with tumors harboring the appropriate molecular
marker.(Table 1) The ongoing trials are looking not only at whether or not
an OS benefit can be obtained with adjuvant molecularly targeted therapy
but also duration of therapy and the potential to use EGFR TKIs instead of
chemotherapy in selected patients. The largest United States study is the NCI
National Clinical Trials Network (NCTN) ALCHEMIST trial. The study is open to
patients with resected early stage (IB-IIIA) NSCLC who are screened for EGFR
activating mutations and ALK translocations. Patients with tumors harboring
EGFR mutations or ALK translocations enter the appropriate sub-study
and, after completion of all planned adjuvant chemotherapy or radiation
therapy, are randomized to targeted TKI therapy or placebo for 2 years. Both
sub-studies will enroll approximately 400 patients (410 EGFR; 378 ALK) and
are powered for an OS endpoint. Patients without actionable mutations can
enroll on the ANVIL sub-study looking at adjuvant nivolumab, a PD-1 targeted
S22 Journal of Thoracic Oncology • Volume 12 Issue S1 January 2017