Commentary (Dziadziuszko/Hirsch): EGFR Inhibitors in Lung Cancer
Commentary (Dziadziuszko/Hirsch): EGFR Inhibitors in Lung Cancer
Inhibitors targeting the family of epidermal growth factor receptors (EGFRs) are novel antitumor compounds investigated in many cancer types, including non-small-cell lung cancer (NSCLC). In this special lung cancer issue of ONCOLOGY, Drs. Buter and Giaccone provide us with an updated review of clinical research on two classes of these agents in NSCLC: small-molecule tyrosine kinase inhibitors (TKIs) and monoclonal antibodies. The former class includes gefitinib (Iressa) and erlotinib (Tarceva), two orally available quinazoline derivatives targeting the tyrosine kinase domain of EGFR. The latter includes cetuximab (Erbitux), a chimeric monoclonal antibody directed against EGFR. The authors extensively discuss single-agent and combination activities of these drugs in NSCLC. The challenges of selecting patients to receive these agents and information about novel multitarget compounds in the pipelines of the pharmaceutical industry are also addressed. Putting this excellent review into perspective, we would like to discuss the issues of patient selection for treatment with EGFR TKIs and prospects on the future incorporation of these compounds into the first-line treatment of NSCLC. Selecting NSCLC Patients for Treatment With EGFR TKIs
Data from the prospective clinical studies of gefitinib and erlotinib as well as from expanded access protocols with these agents indicate that about 10% of the patients in Western populations and about 20% of the patients from the Far East experience objective responses; an additional 20% to 30% of patients benefit from disease stabilization and symptomatic improvement.[1-4] Clinical factors associated with increased response rate (never-smoking history, female gender, Asian ethnicity, and adenocarcinoma histology) constitute relatively small subgroups and can guide clinicians to use EGFR TKIs. However, clinical trials have shown that these factors are not sufficient for patient selection because a much larger percentage of patients could benefit from these drugs in terms of improved survival.[3,4] During the past 2 years, a number of studies have identified potential predictive biomarkers for response and survival benefit with EGFR TKIs, with EGFR gene copy number assessment by fluorescence in situ hybridization (FISH), EGFR mutations, and EGFR immunohistochemistry (IHC) being the closest to clinical application for patient selection. Data on EGFR FISH analysis in NSCLC are very consistent across three published studies.[5-7] The frequency of high EGFR gene copy number or amplification is approximately 30% to 45%; response rates vary between 20% and 36% and impressive hazard ratios of approximately 0.5 favoring treatment with EGFR TKIs in FISH-positive NSCLC patients are reported in chemotherapy-pretreated populations.[5-7] Results of the FISH analysis of 370 tumor samples from ISEL, a phase III clinical trial described in detail by Drs. Buter and Giaccone, were presented at the AACR-NCI-EORTC meeting in November 2005 and confirmed the above data. EGFR FISH-positive patients constituted 31% of the study group and had a prolonged survival if treated with gefitinib as compared to placebo (median survival of 8.3 vs 4.5 months, corresponding to a hazard ratio of 0.61). FISH-negative patients did not benefit from gefitinib (hazard ratio of 1.14). The success of EGFR FISH in predicting gefitinib or erlotinib sensitivity in NSCLC is remarkably similar to the well-established predictive value of HER2 FISH for the treatment benefit from trastuzumab (Herceptin), an anti-HER2 monoclonal antibody used in the management of breast cancer. Activating mutations in the tyrosine kinase domain of EGFR represents a breakthrough discovery in the biology of lung cancer. These abnormalities were reported to correlate with long-lasting responses to EGFR TKIs in numerous studies and were also linked to survival benefit in a retrospective series of patients, particularly from Asia.[10-13] However, in a placebo-controlled clinical trial of erlotinib in the second- or thirdline treatment of NSCLC (the BR21 study), the hazard ratios indicating survival benefit in the subsets of EGFR-mutant and wild-type patients were almost identical, suggesting that EGFR mutations are not useful in selecting patients for treatment with EGFR TKIs. Several findings could explain the discrepancy between results from retrospective reports and the above prospective study: EGFR mutations occur in approximately 30% of patients of Asian descent as compared to 10% of Western populations,[ 14] not all patients with EGFR mutations respond to EGFR TKIs, and EGFR mutations poorly predict disease stabilizations. In addition to that, two recent biomarker reports from the phase III INTACT and TRIBUTE studies indicated that EGFR mutations carry positive prognostic significance.[15,16] There is also very little knowledge about the association of the subtypes of EGFR mutations with clinical outcome and sensitivity to EGFR inhibitors. Data on EGFR immunohistochemistry as a biomarker for treatment benefit are even more conflicting. Two early studies of patients from the IDEAL and INTACT gefitinib studies indicated no response or survival benefit in patients with EGFR IHCpositive tumors.[17,18] Contrary to these findings, studies from Cappuzzo et al and Tsao et al have shown that survival benefit is confined to the population of patients with positive EGFR immunostaining.[5,7] In the biomarker analysis of the ISEL trial, positive EGFR IHC was not significantly predictive of a treatment effect for survival. These differences may be due to different methodologies of EGFR IHC assessment (including antibodies, scoring criteria, and selection of the optimal cut point for positivity) and different populations among the studies. It is also possible that the negative result of IHC in combination with other biomarkers, such as EGFR copy number by FISH, will be used to help us ascertain which patients will not obtain any clinical benefit from EGFR TKIs. Chemotherapy- pretreated patients with negative EGFR IHC and negative FISH have a response rate of 2%, disease control of 19%, and a time to progression of 2 months, similar to patients offered best supportive care. Concomitant treatment with chemotherapy and EGFR TKIs failed to improve survival in all four large randomized clinical studies in the firstline setting.[20-23] The evidence against concomitant treatment with EGFR TKIs and chemotherapy also comes from in vitro studies, demonstrating chemoresistance in EGFRsensitive cell lines. The sequential treatment may offer a clinical advantage in NSCLC, similar to what has been observed for many years in chemotherapy and hormonal therapy of breast cancer in both advanced and adjuvant settings.[25,26] Future Prospects of EGFR TKIs in the Management of NSCLC
The response rates of single-agent EGFR TKIs in advanced unselected NSCLC in Western populations are lower than the response rates to standard first-line chemotherapy regimens, ie, approximately 10% vs 30%. However, given the relatively long duration of response to the former agents (approximately 6 to 9 months, comparing favorably to response duration after chemotherapy[1,2]) and much better tolerance, it is appealing to use EGFR TKIs in the first-line treatment of NSCLC. This is even more compelling in Asian patients, with response rates to EGFR TKIs in the range of 20% in unselected patients.[ 1] Future clinical trials of EGFR TKIs need to explore the role of these agents in first-line treatment; it remains to be established whether patients who fail EGFR TKIs in this setting may be successfully treated with standard chemotherapy. The issue of proper patient selection is of critical importance for future studies in this field. Assays of EGFR gene copy number by FISH, alone or in combination with other biomarkers (eg, positive EGFR IHC), are currently being explored as selection criteria for first-line treatment of NSCLC in US and European prospective phase II clinical studies. Mutations of EGFR are also being validated for this purpose. Populations of patients from the Far East might benefit more from EGFR mutation selection than non-Asian patients, because EGFR mutations are more prevalent; survival benefit has been confirmed in several retrospective reports,[10- 12] although prospective studies are clearly needed to confirm these findings. FISH data are not yet available in these populations. Other important strategies to be investigated in properly selected subsets of patients include consolidation with EGFR TKIs after chemotherapy and adjuvant postsurgical treatment. Several other research plans are also being explored and could positively affect the role of EGFR TKI treatment in the first-line setting of advanced NSCLC. This includes modulation of gefitinib sensitivity by histone deacetylase inhibitors and concomitant treatment with EGFR TKIs and cytotoxic agents using pulsed administration of the former drugs between chemotherapy cycles.
Dr. Hirsch has participated in advisory board meetings for AstraZeneca, Lilly Oncology, Bristol-Myers Squibb, and Ligand Pharmaceuticals.
1. 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). J Clin Oncol 21:2237-2246, 2003.
2. 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 290:2149-2158, 2003.
3. Shepherd FA, Rodrigues PJ, Ciuleanu T, et al: Erlotinib in previously treated non-smallcell lung cancer. N Engl J Med 353:123-132, 2005.
4. Thatcher N, Chang A, Parikh P, et al: Gefitinib plus best supportive care in previously treated patients with refractory advanced nonsmall- cell lung cancer: Results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet 366:1527-1537, 2005.
5. Cappuzzo F, Hirsch FR, Rossi E, et al: Epidermal growth factor receptor gene and protein and gefitinib sensitivity in non-small-cell lung cancer. J Natl Cancer Inst 97:643-655, 2005.
6. Hirsch FR, Varella-Garcia M, McCoy J, 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 23:6838-6845, 2005.
7. Tsao MS, Sakurada A, Cutz JC, et al: Erlotinib in lung cancer—Molecular and clinical predictors of outcome. N Engl J Med 353:133-144, 2005.
8. Hirsch FR, Varella-Garcia M, Bunn PA, el al: Molecular analysis of EGFR gene copy number, EGFR expression and Akt activation status in advanced non-small-cell lung cancer (NSCLC) treated with gefitinib or placebo (ISEL trial) (abstract A268). Proceedings of AACR-NCI-EORTC International Conference, Molecular Targets and Cancer Therapeutics. Philadelphia, November 14-18, 2005.
9. Janne PA, Engelman JA, Johnson BE: Epidermal growth factor receptor mutations in non-small-cell lung cancer: Implications for treatment and tumor biology. J Clin Oncol 23:3227-3234, 2005.
10. Han SW, Kim TY, Hwang PG, et al: Predictive and prognostic impact of epidermal growth factor receptor mutation in non-smallcell lung cancer patients treated with gefitinib. J Clin Oncol 23:2493-2501, 2005.
11. Mitsudomi T, Kosaka T, Endoh H, et al: Mutations of the epidermal growth factor receptor gene predict prolonged survival after gefitinib treatment in patients with non-smallcell lung cancer with postoperative recurrence. J Clin Oncol 23:2513-2520, 2005.
12. Takano T, Ohe Y, Sakamoto H, et al: Epidermal growth factor receptor gene mutations and increased copy numbers predict gefitinib sensitivity in patients with recurrent non-small-cell lung cancer. J Clin Oncol 23:6829-6837, 2005.
13. Taron M, Ichinose Y, Rosell R, et al: Activating mutations in the tyrosine kinase domain of the epidermal growth factor receptor are associated with improved survival in gefitinibtreated chemorefractory lung adenocarcinomas. Clin Cancer Res 11:5878-5885, 2005.
14. Shigematsu H, Lin L, Takahashi T, et al: Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers. J Natl Cancer Inst 97:339-346, 2005.
15. Bell DW, Lynch TJ, Haserlat SM, et al: Epidermal growth factor receptor mutations and gene amplification in non-small-cell lung cancer: Molecular analysis of the IDEAL/INTACT gefitinib trials. J Clin Oncol 23:8081- 8092, 2005.
16. 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 23:5900-5909, 2005.
17. Bailey LR, Kris MG, Wolf M, et al: Tumor EGFR membrane staining is not clinically relevant for predicting response in patients receiving gefitinib (Iressa, ZD1939) monotherapy for pretreated advanced non-small-cell lung cancer: IDEAL1 and 2 (abstract LB-170). Proc Am Assoc Cancer Res 44:1362, 2003.
18. Bailey LR, Janas M, Schmidt K, et al: Evaluation of epidermal growth factor receptor as a predictive marker in patients with nonsmall- cell lung cancer (NSCLC) receiving firstline gefitinib combined with platinum based chemotherapy (abstract 7013). J Clin Oncol 22(suppl 14S), 2004.
19. Hirsch FR, McCoy J, Cappuzzo F, et al: FISH and immunohistochemistry can be used to select NSCLC patients, who will not benefit from gefitinib treatment. Lung Cancer 49(suppl 2):S38, 2005.
20. Giaccone G, Herbst RS, Manegold C, et al: Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: A phase III trial—INTACT 1. J Clin Oncol 22:777-784, 2004.
21. Herbst RS, Giaccone G, Schiller JH, et al: Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: A phase III trial—INTACT 2. J Clin Oncol 22:785-794, 2004.
22. Herbst RS, Prager D, Hermann R, et al: TRIBUTE: A phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced nonsmall- cell lung cancer. J Clin Oncol 23:5892- 5899, 2005.
23. Gatzemeier U, Pluzanska A, Szczesna A, et al: Results of a phase III trial of erlotinib (OSI-774) combined with cisplatin and gemcitabine (GC) chemotherapy in advanced non-small cell lung cancer (NSCLC) (abstract 7010). J Clin Oncol 22(suppl 14S):619s, 2004.
24. Sordella R, Bell DW, Haber DA, et al: Gefitinib-sensitizing EGFR mutations in lung cancer activate anti-apoptotic pathways. Science 305:1163-1167, 2004.
25. Albain KS, Green SJ, Ravdin PM, et al: Adjuvant chemohormonal therapy for primary breast cancer should be sequential instead of concurrent: Initial results from Intergroup trial 0100 (SWOG-8814) (abstract 143). Proc Am Soc Clin Oncol 21:37a, 2002.
26. Pfeiffer P, Rose C, Ejlertsen B, et al: Concurrent tamoxifen (TAM)+ cyclophosphamide, epirubicin, and fluorouracil (CEF) versus TAM + delayed CEF after six months of endocrine therapy in metastatic breast cancer—A randomized trial from the Danish Breast Cancer Cooperative Group (DBCCG). Acta Oncol 35(suppl 5):57, 1996.
27. Witta SE, Helfrich B, Chan D, et al: Overcoming resistance to EGFR inhibitors in NSCLC cell lines by sequential treatment with histone deacetylase inhibitors (abstract 7083). J Clin Oncol 23(16S):641s, 2005.
28. Davies AM, Lara PN, Lau DH, et al: Intermittent erlotinib in combination with docetaxel (DOC): Phase I schedules designed to achieve pharmacodynamic separation (abstract 7038). J Clin Oncol 23(16S):630s, 2005.