Nearly thirty years ago, the Epidermal Growth Factor Receptor (EGFR) was identified as a suitable target for cancer therapeutics ( 1, 2). Over the subsequent three decades, oncologists have sought to harness the observation that the proliferation of some malignant cells is dependent on activation of the EGFR and subsequent downstream propagation of signaling via the intracellular tyrosine kinase. Drugs such as tyrosine kinase inhibitors (TKIs) targeting this pathway were tested in a variety of malignancies, with occasional excellent responses seen in patients with non-small cell lung cancer (NSCLC) ( 3). A variety of different clinical (Asian, non smokers, women) (4-7) and molecular explanations (EGFR protein expression, EGFR copy number) ( 8- 10) were given for this selective benefit, prior to the realization that mutations in the kinase domain of the EGFR (EGFR-MT) were probably largely responsible for these dramatic responses ( 11- 14). Around the same time as the identification of EGFR-MT, results from the BR21 trial of erlotinib in the treatment of metastatic NSCLC that had previously progressed despite chemotherapy were published, showing a marginal progression free survival (PFS) and overall survival (OS) benefit in otherwise unselected NSCLC patients ( 15). Although the clinical significance of the PFS improvement of a few weeks was debatable, and a similar trial of gefitinib in this population was negative ( 15), OS was improved and erlotinib was approved by the FDA. Consequently, given lack of access to EGFR-MT testing, combined with concerns regarding cost and treatment delays ( 16, 17), many clinicians have chosen to use erlotinib in the unselected treatment of untested, previously treated NSCLC patients, reserving EGFR-MT testing for those who fit phenotypic stereotypes ( 18). The European EURTAC trial ( 19), published in the Lancet Oncology in January, alongside a body of evidence from East Asia gives cause for reconsideration of this strategy ( 20- 23). In EURTAC, patients with metastatic untreated NSCLC with EGFR-MTs were randomized to erlotinib (150 mg) or a cisplatin-based doublet (docetaxel or gemcitabine). Patients ineligible to receive cisplatin were treated with carboplatin, and patients receiving chemotherapy were treated with at most four cycles. Hospitals in France, Italy and Spain screened 1,227 patients for the trial, detecting 224 EGFR-MT patients (17.6%), of whom 174 patients were eligible for randomization on a 1:1 basis to either treatment arm. Impressively, the investigators were able to get results from EGFR mutation testing within 7 days from more than 40 centers involved in the trial.
At a preplanned interim analysis, the study was halted due to benefit in the erlotinib arm. The primary end point of progression free survival (PFS) was met, with an improvement in PFS of 9.7 months in patients treated with erlotinib compared to 5.2 months in the chemotherapy arm (HR=0.37, P<0.0001). Overall survival was similar between the two groups, 19.3 months in the erlotinib group, 19.5 months in the standard chemotherapy group. However cross-over was permitted between the groups, and less than half the study population had died at the time of the final analysis. The response rate of 64% in the erlotinib arm was superior to that in the standard chemotherapy arm (18%). These results are similar to those seen in the previously published studies of EGFR-TKI use in first line treatment of EGFR-MT NSCLC in Asian populations (OPTIMAL, NEJ002, WJOTG3405 and IPASS), confirming the advantages of treating patients with EGFR-MT NSCLC with an EGFR-TKI first line, regardless of ethnicity, or choice of EGFR-TKI (Table 1). Beyond chance effects, differences in response rates and PFS to both the TKI and chemotherapy in these trials may be possibly explained by differing sensitivity to the type of chemotherapy used in each of the comparator arms, and differing frequencies of specific EGFR-MTs {Rosell, 2010 #1153;Sun, 2011 #1154} between trials.
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| Table 1. Effects of an EGFR-TKI first line in patients with EGFR-MT NSCLC. |
| Trial |
EGFR-TKI |
Response Rate |
|
PFS |
|
OS |
| EGFR-TKI |
Chemo |
EGFR-TKI |
Chemo |
EGFR-TKI |
Chemo |
| EURTAC (19) |
Erlotinib |
58% |
15% |
|
9.7 |
5.2 |
|
19 |
19 |
| OPTIMAL (23) |
Erlotinib |
83% |
36% |
13.1 |
4.6 |
- |
- |
| NEJ002 (21) |
Gefitinib |
74% |
31% |
10.8 |
5.4 |
30.5 |
23.6 |
| WJTOG (22) |
Gefitinib |
62% |
31% |
9.2 |
6.3 |
- |
- |
| IPASS (20)* |
Gefitinib |
71% |
47% |
9.5 |
6.3 |
22 |
22 |
| *IPASS included both EGFR-MT and EGFR wild type patients, but only EGFR-MT results are shown here. Chemo: chemotherapy; PFS:
Progression free survival (months); OS: Overall survival (months). |
|
Notably all of these studies have failed to show a survival advantage between first line EGFR-TKI and platinum based chemotherapy, but these should not reinforce complacency regarding EGFR-MT testing. These trials provide several reasons why delaying EGFR-TKI therapy until the second
line may be suboptimal treatment of EGFR-MT NSCLC.
As detailed in Table 2, apart from the WJTOG 3,405 study,
there were higher rates of grade 3-4 adverse events in the
chemotherapy arm of each study and higher rates of treatment
discontinuation. Both OPTIMAL and IPASS have additionally
published quality of life data strongly supporting EGFR-TKI
use over chemotherapy. Even more significantly, between 5-39%
of patients receiving first line chemotherapy never received
second line EGFR-TKI therapy, denying them access to a
highly efficacious and tolerable therapy. Conversely, patients
who are EGFR wild type do much better receiving first line
chemotherapy, rather than an EGFR-TKI ( 20, 24).
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| Table 2. Adverse events of an EGFR-TKI first line in patients with EGFR-MT NSCLC. |
| TRIAL |
Grade 3/4 adverse events |
|
Treatment discontinuation |
Not treated with EGFR-TKI post chemotherapy |
| EGFR-TKI |
Chemo |
EGFR-TKI |
Chemo |
| EURTAC (19) |
45% |
67% |
|
13% |
23% |
24% |
| OPTIMAL (23) |
17% |
65% |
1% |
6% |
- |
| WJTOG (22) |
- |
- |
16% |
12.5% |
- |
| NEJ002 (21) |
41% |
71.7% |
- |
- |
5% |
| IPASS (20)* |
29% |
61% |
6.9% |
13.6% |
39% |
| *IPASS included both EGFR-MT and EGFR wild type patients, but only EGFR-MT results are shown here. Chemo: chemotherapy; PFS:
Progression free survival (months); OS: Overall survival (months). |
|
Of course there are barriers to obtaining suitable tissue from
patients with metastatic NSCLC, and barriers to processing
EGFR-MT testing within an acceptable time frame. Although
in the EURTAC study testing was performed within 7 days, this
may not be feasible within the community, forcing clinicians to
choose chemotherapy rather than wait for test results. Possible
ways to improve this are to perform reflex testing for actionable
molecular abnormalities such as EGFR-MT and ALK on
metastatic NSCLC specimens and improve specimen release
and tracking procedures if such testing is not performed locally,
given the significant change in treatment this would allow by
rapidly producing test results ( 16, 17, 25). Additionally, both
resected and radically treated IIIA/B disease could also be
reflex tested, allowing the use of results upon relapse. It is an
historical aberration that current pathology reports detail
immunohistochemical staining patterns for these metastatic
biopsies, but not EGFR-MT and ALK status unless requested.
Only by striving to improve the time taken for EGFR-MT
testing can clinicians implement the message from EURTAC.
The time for complacency and phenotypically guessing which
patients will benefit from EGFR-TKI therapy has passed. It is
now time for early widespread molecular testing of NSCLC
patients, and time to strive for first line treatment of EGFR-MT
NSCLC with an EGFR-TKI whenever possible. |
|
References
- Sato JD, Kawamoto T, Le AD, Mendelsohn J, Polikoff J, Sato GH. Biological
effects in vitro of monoclonal antibodies to human epidermal growth factor
receptors. Mol Biol Med 1983;1:511-29.[LinkOut]
- Kawamoto T, Sato JD, Le A, Polikoff J, Sato GH, Mendelsohn J. Growth
stimulation of A431 cells by epidermal growth factor: identification of
high-affinity receptors for epidermal growth factor by an anti-receptor monoclonal antibody. Proc Natl Acad Sci USA 1983;80:1337-41.[LinkOut]
- Baselga J, Rischin D, Ranson M, Calvert H, Raymond E, Kieback DG, et al.
Phase I safety, pharmacokinetic, and pharmacodynamic trial of ZD1839, a
selective oral epidermal growth factor receptor tyrosine kinase inhibitor, in
patients with five selected solid tumor types. J Clin Oncol 2002;20:4292-302.[LinkOut]
- Chang GC, Tsai CM, Chen KC, Yu CJ, Shih JY, Yang TY, et al. Predictive
factors of gefitinib antitumor activity in East Asian advanced non-small cell
lung cancer patients. J Thorac Oncol 2006;1:520-5.[LinkOut]
- Ho C, Murray N, Laskin J, Melosky B, Anderson H, Bebb G.Asian ethnicity
and adenocarcinoma histology continues to predict response to gefitinib in
patients treated for advanced non-small cell carcinoma of the lung in North
America. Lung Cancer 2005;49:225-31.[LinkOut]
- Kris MG, Natale RB, Herbst RS, Lynch TJ Jr, Prager D, Belani CP, et al.
Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor
tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a
randomized trial. JAMA 2003;290:2149-58.[LinkOut]
- Yang CH, Shih JY, Chen KC, Yu CJ, Yang TY, Lin CP, et al. Survival
outcome and predictors of gefitinib antitumor activity in East Asian
chemonaive patients with advanced nonsmall cell lung cancer. Cancer
2006;107:1873-82.[LinkOut]
- Cappuzzo F, Hirsch FR, Rossi E, Bartolini S, Ceresoli GL, Bemis L, et al.
Epidermal growth factor receptor gene and protein and gefitinib sensitivity
in non-small-cell lung cancer. J Natl Cancer Inst 2005;97:643-55.[LinkOut]
- Hirsch FR, Varella-Garcia M, Bunn PA Jr, Franklin WA, Dziadziuszko R,
Thatcher N, et al. Molecular predictors of outcome with gefitinib in a phase
III placebo-controlled study in advanced non-small-cell lung cancer. J Clin
Oncol 2006;24:5034-42.[LinkOut]
- Hirsch FR, Varella-Garcia M, McCoy J, West H, Xavier AC, Gumerlock P, et
al. Increased epidermal growth factor receptor gene copy number detected
by fluorescence in situ hybridization associates with increased sensitivity to
gefitinib in patients with bronchioloalveolar carcinoma subtypes: a Southwest
Oncology Group Study. J Clin Oncol 2005;23:6838-45.[LinkOut]
- Paez JG, Jänne PA, Lee JC, Tracy S, Greulich H, Gabriel S, et al. EGFR
mutations in lung cancer: correlation with clinical response to gefitinib
therapy. Science 2004;304:1497-500.[LinkOut]
- Pao W, Miller V, Zakowski M, Doherty J, Politi K, Sarkaria I, et al. EGF
receptor gene mutations are common in lung cancers from "never smokers"
and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc
Natl Acad Sci U S A 2004;101:13306-11.[LinkOut]
- Pao W, Miller VA. Epidermal growth factor receptor mutations, smallmolecule
kinase inhibitors, and non-small-cell lung cancer: current
knowledge and future directions. J Clin Oncol 2005;23:2556-68.[LinkOut]
- Sholl LM, Xiao Y, Joshi V, Yeap BY, Cioffredi LA, Jackman DM, et al.
EGFR mutation is a better predictor of response to tyrosine kinase
inhibitors in non-small cell lung carcinoma than FISH, CISH, and
immunohistochemistry. Am J Clin Pathol 2010;133:922-34.[LinkOut]
- Shepherd FA, Rodrigues Pereira J, Ciuleanu T, Tan EH, Hirsh V,
Thongprasert S, et al. Erlotinib in previously treated non-small-cell lung
cancer. N Engl J Med 2005;353:123-32.[LinkOut]
- Langer CJ. Individualized therapy for patients with non-small cell lung
cancer: Emerging trends and challenges. Crit Rev Oncol Hematol 2012.
[Epub ahead of print][LinkOut]
- Pirker R, Herth FJ, Kerr KM, Filipits M, Taron M, Gandara D, et al.
Consensus for EGFR mutation testing in non-small cell lung cancer: results
from a European workshop. J Thorac Oncol 2010;5:1706-13.[LinkOut]
- D'Angelo SP, Pietanza MC, Johnson ML, Riely GJ, Miller VA, Sima CS, et
al. Incidence of EGFR exon 19 deletions and L858R in tumor specimens
from men and cigarette smokers with lung adenocarcinomas. J Clin Oncol
2011;29:2066-70.[LinkOut]
- Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E, et al.
Erlotinib versus standard chemotherapy as first-line treatment for European
patients with advanced EGFR mutation-positive non-small-cell lung cancer
(EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet
Oncol 2012;13:239-246.[LinkOut]
- Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, et al.
Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J
Med 2009;361:947-57.[LinkOut]
- Maemondo M, Inoue A, Kobayashi K, Sugawara S, Oizumi S, Isobe H, et
al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated
EGFR. N Engl J Med 2010;362:2380-8.[LinkOut]
- Mitsudomi T, Morita S, Yatabe Y, Negoro S, Okamoto I, Tsurutani J, et al.
Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell
lung cancer harbouring mutations of the epidermal growth factor receptor
(WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol
2010;11:121-8.[LinkOut]
- Zhou C, Wu YL, Chen G, Feng J, Liu XQ, Wang C, et al. Erlotinib
versus chemotherapy as first-line treatment for patients with advanced
EGFR mutation-positive non-small-cell lung cancer (OPTIMAL,
CTONG-0802): a multicentre, open-label, randomised, phase 3 study.
Lancet Oncol 2011;12:735-42.[LinkOut]
- Gridelli C, Ciardiello F, Feld R, Butts CA, Gebbia V, Genestreti G, et al.
International multicenter randomized phase III study of first-line erlotinib
(E) followed by second-line cisplatin plus gemcitabine (CG) versus firstline
CG followed by second-line E in advanced non-small cell lung cancer
(aNSCLC): The TORCH trial. J Clin Oncol 2010;28:15s (Abstrct 7508).
- Keedy VL, Temin S, Somerfield MR, Beasley MB, Johnson DH, McShane
LM, et al. American Society of Clinical Oncology provisional clinical
opinion: epidermal growth factor receptor (EGFR) Mutation testing for
patients with advanced non-small-cell lung cancer considering first-line
EGFR tyrosine kinase inhibitor therapy. J Clin Oncol 2011;29:2121-7.[LinkOut]
Cite this article as: Weickhardt AJ, Camidge DR, Doebele RC. A time
to test, a time to treat. J Thorac Dis 2012;4(2):223-225. doi: 10.3978/
j.issn.2072-1439.2012.03.13
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