- Email: [email protected]
First-Generation Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in EGFR Mutation; Positive Non-small Cell Lung Cancer Patients
NOVEL AGENTS
IN THE
TREATMENT
OF
LUNG CANCER
First-Generation Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in EGFR Mutation Positive Non-small Cell Lung Cancer Patients Lecia V. Sequist, MD, MPH
Small molecule tyrosine kinase inhibitors of the epidermal growth factor receptor (EGFR) are important agents in the treatment of non-small cell lung cancer (NSCLC) and have enhanced activity in the subpopulation of patients with NSCLC who harbor somatic activating mutations of the EGFR gene. This review summarizes the data describing the use of EGFR tyrosine kinase inhibitors in a genotype-directed population of NSCLC patients with EGFR mutations and discusses areas that require further study. Key Words: Non-small cell lung cancer, Epidermal growth factor receptor, Genetic screening. (J Thorac Oncol. 2008;3: Suppl 2, S143–S145)
A
dvanced non-small cell lung cancer (NSCLC) is an aggressive malignancy that causes more than 165,000 deaths per year.1 Small molecule tyrosine kinase inhibitors (TKIs) targeted against the epidermal growth factor receptor (EGFR) have made a significant impact on the treatment of advanced NSCLC. For patients with advanced NSCLC who have previously received chemotherapy, the first-generation EGFR TKI agents gefitinib and erlotinib led to a response in 10 to 18%, erlotinib improves median survival by 2 months compared with placebo, and gefitinib has been shown to be noninferior to docetaxel.2– 6 Erlotinib is approved for use in NSCLC after chemotherapy in the United States and is commonly used for this indication. In 2004, somatic activating mutations in the EGFR gene were discovered.7–9 It has now been well documented that these transforming mutations, which increase EGFR signaling and cause a dependency on EGFR via a process known as “oncogene addiction,” are associated with a several-fold increase in response rates to EGFR TKIs and possibly increased survival after treatment.10,11 Furthermore, there are clinical characteristics that predict an increased chance of harboring a mutation, namely, adenocarcinoma histology, history of never Massachusetts General Hospital Cancer Center, Boston, Massachusetts. Disclosure: The authors declare no conflict of interest. Address for correspondence: Lecia V. Sequist, MD, MPH, Massachusetts General Hospital Cancer Center, 32 Fruit Street, Suite Yawkey 7B, Boston, MA 02114. E-mail: [email protected] Copyright © 2008 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/08/0306-0143
smoking, female sex, and East Asian ethnicity.2– 4,12 This scenario, an identifiable molecular marker that predicts a marked differential response to a given therapy, is an ideal one for testing the promise of genotype-directed therapy. The genotype-directed strategy aims to abandon the traditional clinical oncology approach of treating all patients with the same histologic diagnosis under the same treatment algorithm in favor of a more specific molecular analysis at the time of diagnosis that has the power to elucidate optimal therapies for each individual based on their own tumor biology.
GENOTYPE-DIRECTED THERAPY IN THE FIRST-LINE METASTATIC SETTING First-line therapy for advanced NSCLC is the clinical setting in which EGFR genotype-directed therapy has been most frequently tested to prove that the principle of the approach is valid. Four studies have been published or presented in abstract form that examine either gefitinib or erlotinib in previously untreated patients with advanced NSCLC known to harbor EGFR mutations, as summarized in Table 1.13–16 There are many notable differences in the design and results of these four studies. Three of the studies use gefitinib, whereas the Spanish study tested erlotinib. Two of the studies were performed in Japan, which has a higher baseline incidence of mutations than the European or North American population. The US study was able to make up for this handicap by incorporating clinical prescreening into their patient selection algorithm (patients had to have at least one clinical criteria associated with mutations before undergoing molecular testing), resulting in the highest screen-positive rate of the four studies. Two of the studies (those by Asahina et al.14 and Sequist et al.16) were prospective trials that asked patients to sign informed consent for study participation before molecular screening; the other two protocol designs used pathology-based screening for EGFR mutations with subsequent approach of the corresponding patients to solicit consent for upfront EGFR TKI therapy. As would be expected, the prospective consent method resulted in a higher proportion of treatment for the mutation-positive patients. Although the two Japanese studies and the Spanish study all considered only the most common EGFR mutations (deletions in exon 19 and the exon 21 point mutation L858R) as being indications for first-line EGFR TKIs, the US study accepted patients with any identified somatic mutation in the
Journal of Thoracic Oncology • Vol. 3, No. 6, Supplement 2, June 2008
S143
Journal of Thoracic Oncology • Vol. 3, No. 6, Supplement 2, June 2008
Sequist
TABLE 1. Prospective Clinical Trials Using EGFR TKIs as First-Line Therapy in Advanced NSCLC Patients with EGFR Mutations Author
Country
Drug
Enrollment
No. Screened
No. (%) Positive
No. (%) Treated
Mutations
RR, % (95% CI)
Median F/U (mo)
Median PFS (mo)
Median OS (mo)
Inoue et al. Asahina et al. Pas-Arez et al. Sequist et al.
Japan Japan Spain United States
Gefitinib Gefitinib Erlotinib Gefitinib
Pathology Prospective Pathology Prospective
75 82 428 98
25 (33) 20 (24) 67 (19) 34 (35)
16 (64) 16 (80) 43 (64) 31 (91)
Classic Classic Classic Any
75 (54–96) 75 (48–93) 82 (66–92) 55 (33–70)
7.6 12.7 7.0 12.3
9.7 8.9 13.3 9.2
–– –– –– 17.5
Pathology enrollment implies that the investigators screened a series of pathology specimens to find mutation-positive cases and then approached the patients to consider therapy. Prospective enrollment implies that patients were consented for a clinical study that involved molecular screening, and then the mutation-positive patients underwent therapy. Classic mutations refer to EGFR exon 19 deletion mutations and the exon 21 point mutation L858R. CI, confidence interval; EGFR, epidermal growth factor receptor; F/U, follow-up; OS, overall survival; PFS, progression-free survival; RR, response rate; TKIs, tyrosine kinase inhibitors.
TK region of EGFR. The 31 patients treated with gefitinib in this study included 17 with exon 19 deletions, 9 with L858R, 2 patients with exon 20 insertion mutations, 1 patient with concurrent L858R and T790M, 1 patient with L861Q, and 1 patient with G719A. The exon 20 insertion and the T790M EGFR mutation subtypes have both been associated with resistance to EGFR TKIs, although these discoveries were made after the design and implementation of the US clinical trial.17–19 Likely as a result of the inclusion of these atypical mutations, the US study had the lowest response rate to therapy for the four trials, although this did not seem to adversely affect the observed median progression-free survival estimates. Notably, 4 of the 5 patients with atypical mutations in the US study had stable disease, lasting from 2 to 10 months. There have been reports from retrospective cohorts that patients with exon 19 deletion mutations have a longer overall survival after treatment with gefitinib or erlotinib compared with those with L858R mutations, although response rates among the mutation subtypes do not seem to be statistically different.20,21 The four prospective studies of first-line EGFR TKI therapy similarly compared response rates among these two mutation types and found no significant difference. Only 2 of the 4 trials (those by Pas-Arez et al.15 and Sequist et al.16) compared time to progression among mutation subtypes, finding no clear difference, although the Spanish group observed a trend toward more durable responses in the exon 19 deletion mutation group. None of the prospective studies had the power to look at survival differences among subgroups at the time of reporting. Finally, it is worth noting that the toxic effects observed among the 106 patients treated with first-line EGFR TKIs in these four prospective studies was favorable compared with the adverse events usually observed with standard first-line combination chemotherapy for advanced NSCLC. Two patients experienced nonfatal occurrences of interstitial lung disease, a known but rare toxic effect of EGFR TKIs.22 Roughly 20% of patients had grade 3 toxic effects, but there were no grade 4 toxic effects in any of the cohorts. In contrast, chemotherapy typically yields hematologic and gastrointestinal grade 3 to 4 toxic effects in 25 to 75% of patients.23–25 Although these results are extremely promising, the use of EGFR TKIs as first-line therapy in patients with advanced NSCLC harboring EGFR mutations has not yet been studied in a randomized controlled trial setting and therefore cannot be considered a standard approach. It is thought that EGFR mutations portend a more favorable biology and natural
S144
history of advanced NSCLC regardless of therapy, so a trial that incorporates a comparison arm is paramount in defining the relative advantages of first-line TKIs.26 –28 There are several such trials in the development or ongoing throughout the world and the results are anxiously awaited. There are also several practical and logistical obstacles to making genotype-directed therapy widely applicable. At the current time, most diagnoses of advanced NSCLC are made via fine-needle aspiration, which can pose technical challenges for molecular analyses because of limited quantity of tumor material. In addition, there is no standard accepted method of genotyping for EGFR mutations, although several methods have been proposed.29 To move toward a medical system in which genotype-directed first-line therapy is universally feasible, the field needs to embrace a paradigm shift and commit to obtaining larger core biopsy specimens at diagnosis to provide sufficient material for multiple genetic analyses. We also need to develop cheap, easy-to-use, sensitive, and standardized methods of genotyping. If we can build such a foundation, we will be able to quickly translate new scientific advances into clinical practice, such as future discoveries about molecular mechanisms of resistance to EGFR TKIs and how this might change initial therapeutic recommendations, and the development of second-generation agents that target EGFR and how to choose among the various options for an individual based on genotype analyses.
ADJUVANT THERAPY FOR NSCLC PATIENTS HARBORING EGFR MUTATIONS The next step in the development of genotype-directed decision-making algorithms for NSCLC patients harboring EGFR mutations is to study adjuvant therapy. Although surgical resection is the backbone of therapy with curative intent for early stage NSCLC, relapse rates after surgery are suboptimal, ranging from 20 to 75% for stages I to III disease.30 Adjuvant chemotherapy has been shown to provide a modest benefit by reducing recurrence rates, but there is still plenty of room for improvement.31,32 For a patient whose resected tumor specimen is known to harbor an EGFR mutation, it makes sense to ask if additional adjuvant treatment with an EGFR TKI could be effective in treating micrometastatic disease and further reducing the risk of relapse. Our center is preparing to open a multicenter clinical trial examining this approach in early-stage NSCLC. Patients
Copyright © 2008 by the International Association for the Study of Lung Cancer
Journal of Thoracic Oncology • Vol. 3, No. 6, Supplement 2, June 2008
with fully resected stage I to IIIA adenocarcinoma who also have at least one other clinical predictor for EGFR mutations (female sex, history of never smoking, East Asian ethnicity) will be screened for exon 19 deletion or L858R EGFR mutations. If positive, they will be treated with 24 months of adjuvant erlotinib therapy to start within 6 months of surgery. Adjuvant chemotherapy may precede the erlotinib at the discretion of the investigator. The primary end point of the study is 2-year disease-free survival, and we have powered the study to detect a 20% increase in this end point compared with historical data from published phase three adjuvant chemotherapy trials. We will also examine the safety and feasibility of genotype-directed therapy in the adjuvant setting.
CONCLUSIONS In summary, genotype-directed therapy is promising for first-line treatment of advanced NSCLC, but practical obstacles must be overcome before it can be widely applicable and a randomized control trial is needed. Areas that require future study include developing and testing a panel of appropriate genotype analyses to be performed at diagnosis that allow an oncologist to recommend optimal first-line treatment regimens for patients with advanced NSCLC and defining the role of EGFR TKIs in the adjuvant setting for early-stage NSCLC.
13.
14.
15.
16.
17. 18.
19.
20.
21.
REFERENCES 1. Cancer Statistics 2007. Available at: http://www.cancer.org/docroot/ STT/stt_0. asp. Accessed August 24, 2007. 2. Fukuoka M, Yano S, Giaccone G, et al. Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer (The IDEAL 1 Trial) [corrected]. J Clin Oncol 2003;21:2237–2246. 3. Kris MG, Natale RB, Herbst RS, 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 –2158. 4. Perez-Soler R, Chachoua A, Hammond LA, et al. Determinants of tumor response and survival with erlotinib in patients with non-small-cell lung cancer. J Clin Oncol 2004;22:3238 –3247. 5. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 2005;353: 123–132. 6. Douillard JY, Kim ES, Hirsh V, et al. Phase III, randomized, open-label, parallel-group study of oral gefitinib (IRESSA) versus intravenous docetaxel in patients with locally advanced or metastatic non small cell lung cancer who have previously received platinum-based chemotherapy (INTEREST). Eur J Cancer 2007;5(6 Suppl):2. 7. Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of nonsmall-cell lung cancer to gefitinib. N Engl J Med 2004;350:2129 –2139. 8. Paez JG, Janne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004;304: 1497–1500. 9. Pao W, Miller V, Zakowski M, 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 USA 2004;101:13306 –13311. 10. Sequist LV, Bell DW, Lynch TJ, Haber DA. Molecular predictors of response to epidermal growth factor receptor antagonists in non-smallcell lung cancer. J Clin Oncol 2007;25:587–595. 11. Sharma SV, Bell DW, Settleman J, Haber DA. Epidermal growth factor receptor mutations in lung cancer. Nat Rev Cancer 2007;7:169 –181. 12. Pham D, Kris MG, Riely GJ, et al. Use of cigarette-smoking history to estimate the likelihood of mutations in epidermal growth factor receptor
22.
23.
24.
25.
26.
27.
28.
29.
30. 31.
32.
EGFR Inhibitors in EGFR-Mutant Lung Cancer
gene exons 19 and 21 in lung adenocarcinomas. J Clin Oncol 2006;24: 1700 –1704. Inoue A, Suzuki T, Fukuhara T, et al. Prospective phase II study of gefitinib for chemotherapy-naive patients with advanced non-small-cell lung cancer with epidermal growth factor receptor gene mutations. J Clin Oncol 2006;24:3340 –3346. Asahina H, Yamazaki K, Kinoshita I, et al. A phase II trial of gefitinib as first-line therapy for advanced non-small cell lung cancer with epidermal growth factor receptor mutations. Br J Cancer 2006;95:998 –1004. Pas-Ares L, Sanchez JM, Garcia-Velasco A, et al. prospective phase II trial of erlotinib in advanced non-small cell lung cancer (NSCLC) patients(p) with mutations in the tyrosine kinase (TK) domain of the epidermal growth factor receptor (EGFR). Paper presented at: American Society of Clinical Oncology meeting; Atlanta, GA; 2006. Sequist LV, Martins RG, Spigel D, et al. First-line gefitinib in patients with advanced non-small-cell lung cancer harboring somatic EGFR mutations. J Clin Oncol 2008. In press. Greulich H, Chen TH, Feng W, et al. Oncogenic transformation by inhibitor-sensitive and resistant EGFR mutants. PLoS Med 2005;2:e313. Kobayashi S, Boggon TJ, Dayaram T, et al. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med 2005;352:786 –792. Pao W, Miller VA, Politi KA, et al. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med 2005;2:e73. Riely GJ, Pao W, Pham D, et al. Clinical course of patients with non-small cell lung cancer and epidermal growth factor receptor exon 19 and exon 21 mutations treated with gefitinib or erlotinib. Clin Cancer Res 2006;12(3 Pt 1):839 – 844. Jackman DM, Yeap BY, Sequist LV, et al. Exon 19 deletion mutations of epidermal growth factor receptor are associated with prolonged survival in non-small cell lung cancer patients treated with gefitinib or erlotinib. Clin Cancer Res 2006;12:3908 –3914. Yoneda KY, Hardin KA, Gandara DR, Shelton DK. Interstitial lung disease associated with epidermal growth factor receptor tyrosine kinase inhibitor therapy in non-small-cell lung carcinoma. Clin Lung Cancer 2006;8(Suppl 1):S31–S35. Schiller JH, Harrington D, Belani CP, et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 2002;346:92–98. Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 2006;355: 2542–2550. Fossella F, Pereira JR, von Pawel J, et al. Randomized, multinational, phase III study of docetaxel plus platinum combinations versus vinorelbine plus cisplatin for advanced non-small-cell lung cancer: the TAX 326 study group. J Clin Oncol 2003;21:3016 –3024. Eberhard DA, Johnson BE, Amler LC, et al. Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non-small-cell lung cancer treated with chemotherapy alone and in combination with erlotinib. J Clin Oncol 2005;23:5900 –5909. Shepherd FA, Tsao MS. Unraveling the mystery of prognostic and predictive factors in epidermal growth factor receptor therapy. J Clin Oncol 2006;24:1219 –1220; author reply 1220 –1211. Hotta K, Kiura K, Toyooka S, et al. Clinical significance of epidermal growth factor receptor gene mutations on treatment outcome after first-line cytotoxic chemotherapy in Japanese patients with non-small cell lung cancer. J Thorac Oncol 2007;2:632– 637. Pao W, Ladanyi M. Epidermal growth factor receptor mutation testing in lung cancer: searching for the ideal method. Clin Cancer Res 2007;13: 4954 – 4955. Spira A, Ettinger DS. Multidisciplinary management of lung cancer. N Engl J Med 2004;350:379 –392. Arriagada R, Bergman B, Dunant A, et al. Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med 2004;350:351–360. Winton T, Livingston R, Johnson D, et al. Vinorelbine plus cisplatin vs. observation in resected non-small-cell lung cancer. N Engl J Med 2005;352:2589 –2597.
Copyright © 2008 by the International Association for the Study of Lung Cancer
S145
IN THE
TREATMENT
OF
LUNG CANCER
First-Generation Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in EGFR Mutation Positive Non-small Cell Lung Cancer Patients Lecia V. Sequist, MD, MPH
Small molecule tyrosine kinase inhibitors of the epidermal growth factor receptor (EGFR) are important agents in the treatment of non-small cell lung cancer (NSCLC) and have enhanced activity in the subpopulation of patients with NSCLC who harbor somatic activating mutations of the EGFR gene. This review summarizes the data describing the use of EGFR tyrosine kinase inhibitors in a genotype-directed population of NSCLC patients with EGFR mutations and discusses areas that require further study. Key Words: Non-small cell lung cancer, Epidermal growth factor receptor, Genetic screening. (J Thorac Oncol. 2008;3: Suppl 2, S143–S145)
A
dvanced non-small cell lung cancer (NSCLC) is an aggressive malignancy that causes more than 165,000 deaths per year.1 Small molecule tyrosine kinase inhibitors (TKIs) targeted against the epidermal growth factor receptor (EGFR) have made a significant impact on the treatment of advanced NSCLC. For patients with advanced NSCLC who have previously received chemotherapy, the first-generation EGFR TKI agents gefitinib and erlotinib led to a response in 10 to 18%, erlotinib improves median survival by 2 months compared with placebo, and gefitinib has been shown to be noninferior to docetaxel.2– 6 Erlotinib is approved for use in NSCLC after chemotherapy in the United States and is commonly used for this indication. In 2004, somatic activating mutations in the EGFR gene were discovered.7–9 It has now been well documented that these transforming mutations, which increase EGFR signaling and cause a dependency on EGFR via a process known as “oncogene addiction,” are associated with a several-fold increase in response rates to EGFR TKIs and possibly increased survival after treatment.10,11 Furthermore, there are clinical characteristics that predict an increased chance of harboring a mutation, namely, adenocarcinoma histology, history of never Massachusetts General Hospital Cancer Center, Boston, Massachusetts. Disclosure: The authors declare no conflict of interest. Address for correspondence: Lecia V. Sequist, MD, MPH, Massachusetts General Hospital Cancer Center, 32 Fruit Street, Suite Yawkey 7B, Boston, MA 02114. E-mail: [email protected] Copyright © 2008 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/08/0306-0143
smoking, female sex, and East Asian ethnicity.2– 4,12 This scenario, an identifiable molecular marker that predicts a marked differential response to a given therapy, is an ideal one for testing the promise of genotype-directed therapy. The genotype-directed strategy aims to abandon the traditional clinical oncology approach of treating all patients with the same histologic diagnosis under the same treatment algorithm in favor of a more specific molecular analysis at the time of diagnosis that has the power to elucidate optimal therapies for each individual based on their own tumor biology.
GENOTYPE-DIRECTED THERAPY IN THE FIRST-LINE METASTATIC SETTING First-line therapy for advanced NSCLC is the clinical setting in which EGFR genotype-directed therapy has been most frequently tested to prove that the principle of the approach is valid. Four studies have been published or presented in abstract form that examine either gefitinib or erlotinib in previously untreated patients with advanced NSCLC known to harbor EGFR mutations, as summarized in Table 1.13–16 There are many notable differences in the design and results of these four studies. Three of the studies use gefitinib, whereas the Spanish study tested erlotinib. Two of the studies were performed in Japan, which has a higher baseline incidence of mutations than the European or North American population. The US study was able to make up for this handicap by incorporating clinical prescreening into their patient selection algorithm (patients had to have at least one clinical criteria associated with mutations before undergoing molecular testing), resulting in the highest screen-positive rate of the four studies. Two of the studies (those by Asahina et al.14 and Sequist et al.16) were prospective trials that asked patients to sign informed consent for study participation before molecular screening; the other two protocol designs used pathology-based screening for EGFR mutations with subsequent approach of the corresponding patients to solicit consent for upfront EGFR TKI therapy. As would be expected, the prospective consent method resulted in a higher proportion of treatment for the mutation-positive patients. Although the two Japanese studies and the Spanish study all considered only the most common EGFR mutations (deletions in exon 19 and the exon 21 point mutation L858R) as being indications for first-line EGFR TKIs, the US study accepted patients with any identified somatic mutation in the
Journal of Thoracic Oncology • Vol. 3, No. 6, Supplement 2, June 2008
S143
Journal of Thoracic Oncology • Vol. 3, No. 6, Supplement 2, June 2008
Sequist
TABLE 1. Prospective Clinical Trials Using EGFR TKIs as First-Line Therapy in Advanced NSCLC Patients with EGFR Mutations Author
Country
Drug
Enrollment
No. Screened
No. (%) Positive
No. (%) Treated
Mutations
RR, % (95% CI)
Median F/U (mo)
Median PFS (mo)
Median OS (mo)
Inoue et al. Asahina et al. Pas-Arez et al. Sequist et al.
Japan Japan Spain United States
Gefitinib Gefitinib Erlotinib Gefitinib
Pathology Prospective Pathology Prospective
75 82 428 98
25 (33) 20 (24) 67 (19) 34 (35)
16 (64) 16 (80) 43 (64) 31 (91)
Classic Classic Classic Any
75 (54–96) 75 (48–93) 82 (66–92) 55 (33–70)
7.6 12.7 7.0 12.3
9.7 8.9 13.3 9.2
–– –– –– 17.5
Pathology enrollment implies that the investigators screened a series of pathology specimens to find mutation-positive cases and then approached the patients to consider therapy. Prospective enrollment implies that patients were consented for a clinical study that involved molecular screening, and then the mutation-positive patients underwent therapy. Classic mutations refer to EGFR exon 19 deletion mutations and the exon 21 point mutation L858R. CI, confidence interval; EGFR, epidermal growth factor receptor; F/U, follow-up; OS, overall survival; PFS, progression-free survival; RR, response rate; TKIs, tyrosine kinase inhibitors.
TK region of EGFR. The 31 patients treated with gefitinib in this study included 17 with exon 19 deletions, 9 with L858R, 2 patients with exon 20 insertion mutations, 1 patient with concurrent L858R and T790M, 1 patient with L861Q, and 1 patient with G719A. The exon 20 insertion and the T790M EGFR mutation subtypes have both been associated with resistance to EGFR TKIs, although these discoveries were made after the design and implementation of the US clinical trial.17–19 Likely as a result of the inclusion of these atypical mutations, the US study had the lowest response rate to therapy for the four trials, although this did not seem to adversely affect the observed median progression-free survival estimates. Notably, 4 of the 5 patients with atypical mutations in the US study had stable disease, lasting from 2 to 10 months. There have been reports from retrospective cohorts that patients with exon 19 deletion mutations have a longer overall survival after treatment with gefitinib or erlotinib compared with those with L858R mutations, although response rates among the mutation subtypes do not seem to be statistically different.20,21 The four prospective studies of first-line EGFR TKI therapy similarly compared response rates among these two mutation types and found no significant difference. Only 2 of the 4 trials (those by Pas-Arez et al.15 and Sequist et al.16) compared time to progression among mutation subtypes, finding no clear difference, although the Spanish group observed a trend toward more durable responses in the exon 19 deletion mutation group. None of the prospective studies had the power to look at survival differences among subgroups at the time of reporting. Finally, it is worth noting that the toxic effects observed among the 106 patients treated with first-line EGFR TKIs in these four prospective studies was favorable compared with the adverse events usually observed with standard first-line combination chemotherapy for advanced NSCLC. Two patients experienced nonfatal occurrences of interstitial lung disease, a known but rare toxic effect of EGFR TKIs.22 Roughly 20% of patients had grade 3 toxic effects, but there were no grade 4 toxic effects in any of the cohorts. In contrast, chemotherapy typically yields hematologic and gastrointestinal grade 3 to 4 toxic effects in 25 to 75% of patients.23–25 Although these results are extremely promising, the use of EGFR TKIs as first-line therapy in patients with advanced NSCLC harboring EGFR mutations has not yet been studied in a randomized controlled trial setting and therefore cannot be considered a standard approach. It is thought that EGFR mutations portend a more favorable biology and natural
S144
history of advanced NSCLC regardless of therapy, so a trial that incorporates a comparison arm is paramount in defining the relative advantages of first-line TKIs.26 –28 There are several such trials in the development or ongoing throughout the world and the results are anxiously awaited. There are also several practical and logistical obstacles to making genotype-directed therapy widely applicable. At the current time, most diagnoses of advanced NSCLC are made via fine-needle aspiration, which can pose technical challenges for molecular analyses because of limited quantity of tumor material. In addition, there is no standard accepted method of genotyping for EGFR mutations, although several methods have been proposed.29 To move toward a medical system in which genotype-directed first-line therapy is universally feasible, the field needs to embrace a paradigm shift and commit to obtaining larger core biopsy specimens at diagnosis to provide sufficient material for multiple genetic analyses. We also need to develop cheap, easy-to-use, sensitive, and standardized methods of genotyping. If we can build such a foundation, we will be able to quickly translate new scientific advances into clinical practice, such as future discoveries about molecular mechanisms of resistance to EGFR TKIs and how this might change initial therapeutic recommendations, and the development of second-generation agents that target EGFR and how to choose among the various options for an individual based on genotype analyses.
ADJUVANT THERAPY FOR NSCLC PATIENTS HARBORING EGFR MUTATIONS The next step in the development of genotype-directed decision-making algorithms for NSCLC patients harboring EGFR mutations is to study adjuvant therapy. Although surgical resection is the backbone of therapy with curative intent for early stage NSCLC, relapse rates after surgery are suboptimal, ranging from 20 to 75% for stages I to III disease.30 Adjuvant chemotherapy has been shown to provide a modest benefit by reducing recurrence rates, but there is still plenty of room for improvement.31,32 For a patient whose resected tumor specimen is known to harbor an EGFR mutation, it makes sense to ask if additional adjuvant treatment with an EGFR TKI could be effective in treating micrometastatic disease and further reducing the risk of relapse. Our center is preparing to open a multicenter clinical trial examining this approach in early-stage NSCLC. Patients
Copyright © 2008 by the International Association for the Study of Lung Cancer
Journal of Thoracic Oncology • Vol. 3, No. 6, Supplement 2, June 2008
with fully resected stage I to IIIA adenocarcinoma who also have at least one other clinical predictor for EGFR mutations (female sex, history of never smoking, East Asian ethnicity) will be screened for exon 19 deletion or L858R EGFR mutations. If positive, they will be treated with 24 months of adjuvant erlotinib therapy to start within 6 months of surgery. Adjuvant chemotherapy may precede the erlotinib at the discretion of the investigator. The primary end point of the study is 2-year disease-free survival, and we have powered the study to detect a 20% increase in this end point compared with historical data from published phase three adjuvant chemotherapy trials. We will also examine the safety and feasibility of genotype-directed therapy in the adjuvant setting.
CONCLUSIONS In summary, genotype-directed therapy is promising for first-line treatment of advanced NSCLC, but practical obstacles must be overcome before it can be widely applicable and a randomized control trial is needed. Areas that require future study include developing and testing a panel of appropriate genotype analyses to be performed at diagnosis that allow an oncologist to recommend optimal first-line treatment regimens for patients with advanced NSCLC and defining the role of EGFR TKIs in the adjuvant setting for early-stage NSCLC.
13.
14.
15.
16.
17. 18.
19.
20.
21.
REFERENCES 1. Cancer Statistics 2007. Available at: http://www.cancer.org/docroot/ STT/stt_0. asp. Accessed August 24, 2007. 2. Fukuoka M, Yano S, Giaccone G, et al. Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer (The IDEAL 1 Trial) [corrected]. J Clin Oncol 2003;21:2237–2246. 3. Kris MG, Natale RB, Herbst RS, 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 –2158. 4. Perez-Soler R, Chachoua A, Hammond LA, et al. Determinants of tumor response and survival with erlotinib in patients with non-small-cell lung cancer. J Clin Oncol 2004;22:3238 –3247. 5. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 2005;353: 123–132. 6. Douillard JY, Kim ES, Hirsh V, et al. Phase III, randomized, open-label, parallel-group study of oral gefitinib (IRESSA) versus intravenous docetaxel in patients with locally advanced or metastatic non small cell lung cancer who have previously received platinum-based chemotherapy (INTEREST). Eur J Cancer 2007;5(6 Suppl):2. 7. Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of nonsmall-cell lung cancer to gefitinib. N Engl J Med 2004;350:2129 –2139. 8. Paez JG, Janne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004;304: 1497–1500. 9. Pao W, Miller V, Zakowski M, 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 USA 2004;101:13306 –13311. 10. Sequist LV, Bell DW, Lynch TJ, Haber DA. Molecular predictors of response to epidermal growth factor receptor antagonists in non-smallcell lung cancer. J Clin Oncol 2007;25:587–595. 11. Sharma SV, Bell DW, Settleman J, Haber DA. Epidermal growth factor receptor mutations in lung cancer. Nat Rev Cancer 2007;7:169 –181. 12. Pham D, Kris MG, Riely GJ, et al. Use of cigarette-smoking history to estimate the likelihood of mutations in epidermal growth factor receptor
22.
23.
24.
25.
26.
27.
28.
29.
30. 31.
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EGFR Inhibitors in EGFR-Mutant Lung Cancer
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