- Email: [email protected]
Targeted therapies for stage III non-small cell lung cancer: integration in the combined modality setting
Lung Cancer (2003) 41, S115 /S121
www.elsevier.com/locate/lungcan
Targeted therapies for stage III non-small cell lung cancer: integration in the combined modality setting Everett E. Vokesa,*, Hak Choyb a
Section of Hematology/Oncology, University of Chicago Medical Center, University of Chicago, 5841 S. Maryland Avenue, MC 2115, Chicago, IL 60637-1470, USA b Vanderbilt University Medical Center, Nashville, TN, USA
KEYWORDS Stage III; Non-small cell lung cancer; Preclinical models
Summary Combined modality therapy represents current standard therapy for locoregionally advanced non-small cell lung cancer. In particular, concomitant chemoradiotherapy has emerged as the preferred approach. At the same time, efforts to increase locoregional and systemic antitumor activity are necessary to further improve long-term survival rates for these patients. In recent years, multiple cellular targets have emerged in the development of novel antitumor therapies. Several of these are of high relevance in the carcinogenesis of lung cancer including the epidermal growth factor receptor (EGFR), the ras signaling pathway, tumor angiogenesis, and cyclooxygenase-2 (COX-2) expression. Novel agents directed against these targets are currently under development with promising early results in non-small cell lung cancer when administered as single agents or in combination with chemotherapy in stage IV or recurrent disease. Similarly their use with concurrent radiation therapy is supported by preclinical models. Selected early clinical trials utilizing these agents in combination with radiotherapy or chemoradiotherapy are discussed. – 2003 Elsevier Science Ireland Ltd and American Society of Clinical Oncology. Published by Elsevier Science Ireland Ltd. All rights reserved.
1. Introduction Combined modality therapy has emerged as standard therapy for stage III unresectable NSCLC in recent years. Two models of clinical investiga-
Presented in part at the IASLC/ASCO First International Conference for Targeted Therapies for Lung Cancer, Marbella, Spain, 14 /19 January 2003. *Corresponding author. Tel.: /1-773-834-3093; fax: /1-773702-3002. E-mail address: [email protected] (E.E. Vokes).
tions were initially pursued. Among these were induction chemotherapy and concurrent chemoradiotherapy [1,2]. Induction chemotherapy was the first model to show enhanced survival times in randomized clinical trials when added to standard radiation therapy. Several studies demonstrated a 3 /4 months increase in median survival times of approximately 14 versus 10 months. Pattern of failure analysis demonstrated the increased survival to be due to increased systemic control with no impact on locoregional control [3 /5]. In parallel, studies were investigating the role of concomitant chemoradiotherapy. At least one trial
0169-5002/03/$ - see front matter – 2003 Elsevier Science Ireland Ltd and American Society of Clinical Oncology. Published by Elsevier Science Ireland Ltd. All rights reserved. doi:10.1016/S0169-5002(03)00155-7
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succeeded in demonstrating a statistically significant increase in median survival times (MST) when adding concurrent chemotherapy [2,6,7]. Better locoregional control following concurrent chemoradiotherapy was demonstrated. Thus, two competing treatment strategies had been shown to be superior to radiotherapy alone though different in their toxicity and tumor control patterns. This allowed to directly compare the two competing strategies, or alternatively, attempt to combine them into one treatment program. A comparative trial strategy was pursued by several groups. Initially, Japanese investigators compared the use of sequential chemotherapy (with the MVP regimen of mitomycin C, vinblastine and cisplatin) versus the concomitant administration of MVP and radiotherapy. MST were 16 versus 13 months favoring the concomitant approach [8]. A second trial by the Radiation Therapy Oncology Group (RTOG) showed similar results for a regimen of cisplatin and vinblastine (a third treatment arm utilizing twice daily radiation fractions was not superior to induction chemotherapy) [9]. More recently additional studies have been presented at International meetings that are compatible with the Japanese and RTOG data [10,11]. Based on these observations, it has been concluded by many that concomitant chemoradiotherapy represents current standard therapy that should function as control arm on most randomized trials. Since toxicity spectra and patterns of failure differ between sequential and concomitant approaches, it has also been investigated whether they should be used in sequence, i.e. adding either induction or consolidation chemotherapy to concurrent chemoradiotherapy (Fig. 1). The Cancer and Leukemia Group B has conducted several trials investigating induction chemotherapy and concomitant chemoradiotherapy. There was no benefit when adding weekly low doses of concomitant
Fig. 1 Therapy approaches for stage III unresectable NSCLC.
E.E. Vokes, H. Choy
carboplatin to radiotherapy after induction chemotherapy [12]. Subsequently, CALGB 9431 showed that it was feasible to add the novel agents of the last decade to cisplatin and radiotherapy in the setting of induction chemotherapy followed by concurrent chemoradiotherapy [13]. Vinorelbine, gemcitabine and paclitaxel could all be safely administered in this randomized phase II study. The MST of 17 months for all patients was higher that that achieved in previous CALGB trials but compatible with published data from the large trials investigating concomitant chemoradiotherapy. Thus, it was decided to conduct a randomized trial investigating the role of induction chemotherapy in the context of concomitant chemoradiotherapy. CALGB 39801 was designed to treat approximately 350 patients with either sequential and concomitant chemoradiotherapy or concomitant chemoradiotherapy alone (see Fig. 2). Accrual to this trial was completed in May 2002 but no analysis of this trial is available to date. In the Southwest Oncology Group (SWOG) concomitant chemoradiotherapy with cisplatin and etoposide has represented standard therapy [14,15]. Recently, promising phase II data were presented from a trial of this concomitant regimen followed by three cycles of docetaxel as consolidation chemotherapy [16]. These data suggested that consolidation chemotherapy might have a major role in stage III disease. Here too, a definitive phase III trial evaluating concomitant chemoradiotherapy with or without consolidation chemotherapy has been initiated by the Hoosier Oncology Group (HOG).
2. The integration of targeted therapies Targeted therapies of interest in stage III disease will ideally have single agent activity that is
Fig. 2 CALGB 39801.
Targeted therapies for stage III NSCLC
mechanistically understood and predictable for individual patients. In addition, it should at least be additive to chemotherapy and/or radiotherapy with acceptable toxicities. The experience with these targeted agents in stage IV disease suggests that preclinical models need to be validated with plausible clinical data and that preclinical additivity or synergy may not necessarily translate into a clinically measurable benefit. Recent advances in molecular biology have identified a number of molecular targets that may be responsible for resistance of cancer cells to radiation or other cytotoxic agents, and as such may serve as targets for augmentation of radiation or chemotherapy response. Among these determinants are the epidermal growth factor receptor (EGFR), cyclooxygenase-2 (COX-2) enzyme, rassignaling pathway, angiogenic molecules, and various other molecules that regulate different steps in their signal transduction pathways [17,18]. Among these agents, focus to date has been on the clinical development of the EGFR pathway inhibitors. In preclinical studies they have been shown to be synergistic with the taxanes and with radiation, at least in some models, and have been shown to have a modest single agent response rate when tested in populations of patients with recurrent NSCLC [19 /21]. In CALGB 30106 (principal investigator Neal Ready) genitifib (ZD-1839), an orally administered tyrosine kinase inhibitor of the EGFR is being added to carboplatin/paclitaxel induction chemotherapy followed by concomitant chemoradiotherapy as in the experimental arm of CALGB 39801 in stratum 2, and to induction chemotherapy followed by single modality radiotherapy in stratum 1 (see Figs. 3 and 4). For stratum 1, it is hypothesized that the addition of genitifib as a single agent to radiotherapy will result in more tolerable toxicities than those associated with traditional concomitant chemoradiotherapy, and thus, might define a feasible
Fig. 3
CALGB 30106 Stratum-1.
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Fig. 4
CALGB 30106 Stratum-2.
approach to the treatment of patients with a performance status of 2 or pretreatment weight loss exceeding 5%. Patients with performance status of 1 or 2 are treated on stratum 2 with induction chemotherapy followed by concomitant chemoradiotherapy and genitifib added to each treatment component. Here it is hoped that the genitifib will add to the antitumor activity of the induction and concomitant portions (although the recent results of the INTACT trials suggest that the addition of genitifib to induction chemotherapy is unlikely to result in increased activity). The dose of genitifib is fixed at 250 mg/day since studies in patients with advanced lung cancer have failed to show a benefit from further dose escalation of the drug. Another trial is currently investigating the addition of the EGFR tyrosine kinase inhibitor tarceva (OSI-774) to chemoradiotherapy in stage III NSCLC. This NCI supported study (PI: Dr Ann Mauer) conducted by the University of Chicago phase II network is designed as a ‘‘ping-pong’’ phase I trial where the agent is added in increasing doses to alternating cohorts of patients receiving either the CALGB or the SWOG chemoradiotherapy regimens. The treatment design is shown in Figs. 5 and 6.
Fig. 5
Protocol 5411 Arm A (SWOG).
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E.E. Vokes, H. Choy
Fig. 6 Protocol 5411 Arm B CALGB.
Fig. 7 Definition of dose-limiting toxicity.
Dose-limiting toxicity is defined as outlined in Fig. 7. COX-2, another potential molecular target, relates to prostaglandins (PGs). PGs are metabolites of arachidonic acid that induce diverse biologic activities including vasoconstriction, vasodilatation, stimulation or inhibition of platelet aggregation, and immunomodulation (primarily immunosuppression). They are also implicated in the promotion of development and growth of malignant tumors, as well as in the response of tumor and normal tissues to cytotoxic agents, including radiation [22 /24]. Two cyclooxygenase enzymes, COX-1 and COX-2, mediate production of PGs. While COX-1 is constitutively expressed and ubiquitous with physiological roles in maintaining homeostasis, such as the integrity of gastric mucosa, normal platelet function, and regulation of renal blood flow, COX-2 is nonphysiological but induced by diverse inflammatory stimuli, mitogens, and carcinogens. Increasing evidence shows that COX-2 expression is up-regulated in many human tumors, including colon, pancreatic, prostate, gastric and head and neck cancers, where it is associated with more aggressive tumor behavior
and poor patient prognosis. COX-2 is implicated as causative factor in colorectal tumorigenesis [24]. This selective or preferential expression of COX2 in tumors makes this enzyme a potential target for cancer therapy. Selective inhibitors of COX-2 have recently been developed for use as antiinflammatory and analgesic agents, but the availability of these inhibitors provided a critical tool for evaluating the role of COX-2 in cancer. There is preclinical evidence that these agents are more potent than standard non-steroidal anti-inflammatory drugs (NSAIDs) (which inhibit both COX-1 and COX-2 enzymes) at inhibiting colon carcinogenesis and at slowing the growth of established tumors [24]. Also, selective COX-2 inhibitors are reported to enhance tumor response to chemotherapeutic drugs or radiation [23 /25]. The mechanisms of the enhancement seem to be multiple, including increases in intrinsic cell radiosensitivity and inhibition of tumor neoangiogenesis. The action correlates with a reduction in PG production in tumors. The use of selective inhibitors of COX-2 is unlikely to be limited by normal tissue toxicity because inhibition of this enzyme does not affect production of PGs by normal tissues.
3. Clinical trials with celecoxib and radiotherapy Radiation enhancing effects of COX-2 inhibitors provide impetus for conducting clinical trials evaluating combined-modality therapy, including selective COX-2 inhibitors and radiation. As discussed previously, combined modality therapy may enhance the therapeutic index for radiotherapy and additional combinations may be beneficial. Celecoxib has direct antitumor effects in preclinical studies. Combining it with radiation may produce complementary effects by enhancing response to radiation. Six NSCLC clinical trials evaluating combined-modality therapy with celecoxib have been initiated. The RTOG is conducting two of these trials. One is a phase II postoperative adjuvant study of 2 years of celecoxib (400 mg bid) and radiation (50.4 Gy) in completely resected stage I/ II NSCLC patients. The second is a phase I/II trial in intermediate-prognosis locally advanced NSCLC (stages IIB, IIIA and IIIB). Patients are treated with fractionated radiation (66 Gy) and twice-daily celecoxib for up to 2 years. In both studies, objectives include assessing the tolerability of celecoxib at 400 mg twice daily, evaluating the role of biomarkers as predictors of celecoxib
Targeted therapies for stage III NSCLC
activity, and determining whether celecoxib improves response and survival. Additional NSCLC clinical trials are evaluating regimens combining celecoxib, standard chemotherapy, and radiotherapy. At the Vanderbilt Cancer Center (VCC), patients with previously untreated stage III NSCLC are being accrued for a phase II trial. Patients are treated with celecoxib plus a standard regimen of paclitaxel, carboplatin, and radiation. Preliminary results suggest that changes in circulating levels of VEGF may be a marker of response to celecoxib. A second phase II study at VCC is evaluating celecoxib combined with radiation and taxane chemotherapy in recurrent NSCLC (treated with at least 1 prior chemotherapy regimen). Two partial responses and three disease stabilizations have been observed in 13 evaluable patients; none of these patients had responded to previous therapy. In this study, COX-2 was overexpressed in 75% of the tumors. A third VCC study is accruing stage I/II patients with inoperable NSCLC. In this phase II study, patients will be treated with radiation (62.5 Gy) and celecoxib will be administered daily until disease progression. A phase I study at the University of Texas M.D. Anderson Cancer Center (MDACC) is evaluating radiotherapy and celecoxib (twice daily at doses of up to 400 mg) in medically inoperable NSCLC. Patients include those with locally advanced disease and poor performance status, stage I/II disease and comorbidities that preclude surgery, and stage IIIA/ B disease previously treated with platinum-based induction therapy. Patients are divided into three groups. Each group is treated with a different radiotherapy regimen and celecoxib, with dose escalation to 800 mg/day. Results in 28 patients enrolled to date indicate that celecoxib has not significantly increased radiation-induced toxicity in normal tissues.
4. Proteasome inhibitors The proteasome is critically involved in cell cycle regulation and represents an important component of protein degradation in the cell. It serves as a central conduit for cellular regulatory signals and has evolved as a target for novel therapeutics. PS341 is a potent and selective small molecule inhibitor of the proteasome [26]. Preclinical studies have demonstrated antitumor activity and clinical trials are currently ongoing. Proteasome inhibitors also target the NF Kappa B signaling pathway, induce apoptosis and are antiangiogenic. Activation of the NF Kappa B pathway is an important feature of human malignancies and can
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stimulate cell proliferation and/or interfere with the efficacy of antitumor agents. Preclinical trials have shown that PS-341 can increase the cytotoxicity of chemotherapy or radiation. Phase I trials have been completed and phase II trials are currently in progress. In lung cancer, two phase I studies investigating this agent with docetaxel or gemcitabine and carboplatin are ongoing. An NCIsponsored study with radiation therapy at the Mayo Clinic is currently also in planning.
5. Farnesyltransferase inhibitors Farnesyltransferase inhibitors (FTIs) are a class of agents currently under intensive clinical investigation in lung cancer, other solid tumors and hematological malignancies. The primary target is thought to be inhibition of the ras signaling pathway and subsequent inhibition of cell growth. Preclinical data have shown that FTIs can reverse radiation resistance as well as increase the activity of chemotherapy [27,28]. A single agent phase II trial of a FTI in non-small cell lung cancer showed no objective responses [29]. However, the median survival in this group of previously untreated patients was 8 months and similar to trials of traditional cytotoxic therapies. Additional investigations administering an FTI with chemotherapy are currently in progress. Radiation sensitization with FTIs has been described in tumor cells expressing activated H-ras, but not in cells expressing wild type ras [27,28,30]. Enhanced radiation cytotoxicity in the presence of any FTI was also observed in a murine xenograft model. Hahn et al. have recently reported on a phase I trial administering the FTI L-778123 in combination with radiotherapy in non-small cell lung and head and neck cancers [30]. No clear increase in radiotherapy-associated toxicities was demonstrated suggesting that FTI related radiation sensitization might be clinically achieved without concurrent increased radiation related toxicity. To date, no phase II studies investigating an FTI with concurrent radiotherapy or chemoradiotherapy have been published.
6. Antiangiogenic agents Several antiangiogenic agents are currently in clinical development. These agents may add intrinsic antitumor activity by preventing the formation of new blood vessels. They may also increase the antitumor activity of cytotoxic agents and increase the cytotoxicity of radiation [31,32].
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The major focus of antiangiogenic investigations in NSCLC has been in stage IV disease where a randomized phase II trial suggested therapeutic benefit from the addition of the antibody to vascular epithelial growth factor (anti-VEGF, Bevacizumab) to standard doublet chemotherapy [33]. This observation is currently being pursued further in a randomized phase III setting. Another trial is being pursued in stage III NSCLC in a trial by the Eastern Cooperative Oncology Group (ECOG). Here patients receive concomitant chemotherapy or radiotherapy with carboplatin, paclitaxel and standard radiotherapy and are randomized to also receive thalidomide as an antiangiogenic agent. The administration of thalidomide with concomitant chemoradiotherapy had previously been shown to be feasible in a small pilot trial [34] Accrual to this study is currently in progress.
7. Outlook The combination of chemotherapy and radiation has become a common strategic practice in the therapy of locoregionally advanced non-small cell lung cancer, with recent emphasis on the concurrent delivery of both modalities. Improvements in treatment outcome both in terms of local control and patient survival have been achieved with traditional chemotherapeutic agents such as cisplatin and taxanes. Nonetheless, cures rates remain low, and combined treatments are frequently associated with increased normal tissue toxicity. Thus, there is considerable room for improvement of the combined treatment strategies. However, selection of the most effective drug or the optimal treatment approach remains as a significant challenge. Significant progress has been made in our understanding of the basic mechanisms of radiation injury as well as the injury inflicted by chemotherapeutic agents and cellular processing of these injuries in both normal and malignant cells. Recent advances in molecular biology have exposed many potential targets for augmentation of radioresponse or chemoresponse including EGFR, COX-2, angiogenic molecules and various components of the signal transduction pathways that these molecules initiate. It has become possible to intervene actively in some molecular pathways in order to improve the therapeutic ratio and the incorporation of molecular targeting strategies into chemoradiotherapy is becoming increasingly used for therapeutic intervention in many types of human cancer.
E.E. Vokes, H. Choy
References [1] Ginsberg R, Vokes EE, Rosenzweig K. Non-small cell lung cancer. In: DeVita JV, Hellman S, Rosenberg SA, editors. Cancer */principles and practice of oncology, 6th ed. Philadelphia, PA: J.B. Lippincott, 2001:925 /82. [2] Gordon GS, Vokes EE. Chemoradiation for locally advanced, unresectable NSCLC. New standard of care, emerging strategies. Oncology (Huntingt) 1999;13:1075 /88 (discussion 1088, 1091 /4). [3] Dillman RO, Seagren SL, Propert KJ, et al. A randomized trial of induction chemotherapy plus high-dose radiation versus radiation alone in stage III non-small-cell lung cancer [see comments]. New Engl J Med 1990;323:940 /5. [4] Le Chevalier T, Arriagada R, Quoix E, et al. Radiotherapy alone versus combined chemotherapy and radiotherapy in nonresectable non-small-cell lung cancer: first analysis of a randomized trial in 353 patients [see comments]. J Natl Cancer Inst 1991;83:417 /23. [5] Sause W, Kolesar P, Taylor SI, et al. Final results of phase III trial in regionally advanced unresectable non-small cell lung cancer: Radiation Therapy Oncology Group, Eastern Cooperative Oncology Group, and Southwest Oncology Group. Chest 2000;117:358 /64. [6] Schaake-Koning C, van den Bogaert W, Dalesio O, et al. Effects of concomitant cisplatin and radiotherapy on inoperable non-small-cell lung cancer [see comments]. New Engl J Med 1992;326:524 /30. [7] Jeremic B, Shibamoto Y, Acimovic L, et al. Randomized trial of hyperfractionated radiation therapy with or without concurrent chemotherapy for stage III non-small-cell lung cancer. J Clin Oncol 1995;13:452 /8. [8] Furuse K, Fukuoka M, Kawahara M, et al. Phase III study of concurrent versus sequential thoracic radiotherapy in combination with mitomycin, vindesine, and cisplatin in unresectable stage III non-small-cell lung cancer. J Clin Oncol 1999;17:2692 /9. [9] Curran W, Scott C, Langer C. Phase III comparison of sequential versus concurrent chemoradiation for patients with unresected stage III non-small cell lung cancer: report of Radiation Therapy Oncology Group 9410, 9th World Conference on Lung Cancer. Lung Cancer 2000;29:93. [10] Zemanova M, Petruzelka L, Zemanova M, et al. Concurrent versus sequential radiochemotherapy with vinorelbine plus cisplatin (v /p) in locally advanced non-small cell lung cancer: a randomized phase II study. Proc Am Soc Clin Oncol 2002;21:290a (Abstract 1159). [11] Pierre F, Maurice P, Gilles R, et al. A randomized phase III trial of sequential chemo-radiotherapy versus concurrent chemoradiotherapy in locally advanced non-small cell lung cancer (NSCLC) (GLOT-GFPC NPC 95-01 study). Proc Am Soc Clin Oncol 2001;20:312a (Abstract 1246). [12] Clamon G, Herndon J, Cooper R, et al. Radiosensitization with carboplatin for patients with unresectable stage III non-small-cell lung cancer: a phase III trial of the Cancer and Leukemia Group B and the Eastern Cooperative Oncology Group. J Clin Oncol 1999;17:4 /11. [13] Vokes EE, Herndon JE, II, Crawford J, et al. Randomized phase II study of cisplatin with gemcitabine or paclitaxel or vinorelbine as induction chemotherapy followed by concomitant chemoradiotherapy for stage IIIB non-small-cell lung cancer: cancer and leukemia group B study 9431. J Clin Oncol 2002;20:4191 /8. [14] Albain KS, Rusch VW, Crowley JJ, et al. Concurrent cisplatin/etoposide plus chest radiotherapy followed by surgery for stages IIIA (N2) and IIIB non-small-cell lung
Targeted therapies for stage III NSCLC
[15]
[16]
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cancer: mature results of Southwest Oncology Group phase II study 8805. J Clin Oncol 2001;13:1880 /92. Albain KS, Crowley JJ, Turrisi AT, III, et al. Concurrent cisplatin, etoposide, and chest radiotherapy in pathologic stage IIIB non-small-cell lung cancer: a Southwest Oncology Group phase II study, SWOG 9019. J Clin Oncol 2002;20:3454 /60. Gaspar L, Gandara D, Chansky K, et al. Consolidation docetaxel following concurrent chemoradiotherapy in pathologic stage IIIb non-small cell lung cancer (NSCLC) (SWOG 9504): patterns of failure and updated survival. Proc Am Soc Clin Oncol 2001;20:315a (Abstract 1255). Mason KA, Komaki R, Cox JD, et al. Biology-based combined-modality radiotherapy: workshop report. Int J Radiat Oncol Biol Phys 2001;50:1079 /89. Pyo H, Choy H, Amorino GP, et al. A selective cyclooxygenase-2 inhibitor, NS-398, enhances the effect of radiation in vitro and in vivo preferentially on the cells that express cyclooxygenase-2. Clin Cancer Res 2001;7:2998 / 3005. Harari PM, Huang SM. Modulation of molecular targets to enhance radiation. Clin Cancer Res 2000;6:323 /5. Bianco C, Tortora G, Bianco R, et al. Enhancement of antitumor activity of ionizing radiation by combined treatment with the selective epidermal growth factor receptortyrosine kinase inhibitor ZD1839 (Iressa). Clin Cancer Res 2002;8:3520 /8. Kris M, Natale RB, Herbst RS, et al. A phase II trial of ZD 1839 (‘Iressa’) in advanced non-small cell lung cancer (NSCLC) patients who had failed platinum- and docetaxelbased regimens (IDEAL 2). Proc Am Soc Clin Oncol 2002;21:292a (Abstract 1166). Milas L, Hanson WR. Eicosanoids and radiation. Eur J Cancer 1995;31A:1580 /5. Milas L. Cyclooxygenase-2 (COX-2) enzyme inhibitors as potential enhancers of tumor radioresponse. Semin Radiat Oncol 2001;11:290 /9.
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S121 [24] Koki AT, Leahy KM, Masferrer JL. Potential utility of COX-2 inhibitors in chemoprevention and chemotherapy. Expert Opin Invest Drugs 1999;8:1623 /38. [25] Milas L, Kishi K, Hunter N, et al. Enhancement of tumor response to gamma-radiation by an inhibitor of cyclooxygenase-2 enzyme. J Natl Cancer Inst 1999;91:1501 /4. [26] Adams J. Development of the proteasome inhibitor PS-341. Oncologist 2002;7:9 /16. [27] Bernhard EJ, McKenna WG, Hamilton AD, et al. Inhibiting ras prenylation increases the radiosensitivity of human tumor cell lines with activating mutations of ras oncogenes. Cancer Res 1998;58:1754 /61. [28] Cohen-Jonathan E, Muschel RJ, Gillies McKenna W, et al. Farnesyltransferase inhibitors potentiate the antitumor effect of radiation on a human tumor xenograft expressing activated HRAS. Radiat Res 2000;154:125 /32. [29] Adjei A, Mauer A, Marks R, et al. A phase II study of the farnesyltransferase inhibitor R115777 in patients with advanced non-small cell lung cancer. Proc Am Soc Clin Oncol 2002;21:290a (Abstract 1156). [30] Hahn SM, Bernhard EJ, Regine W, et al. A phase I trial of the farnesyltransferase inhibitor L-778,123 and radiotherapy for locally advanced lung and head and neck cancer. Clin Cancer Res 2002;8:1065 /72. [31] Mauceri HJ, Hanna NN, Beckett MA, et al. Combined effects of angiostatin and ionizing radiation in antitumour therapy. Nature 1998;394:287 /91. [32] Lee CG, Heijn M, di Tomaso E, et al. Anti-vascular endothelial growth factor treatment augments tumor radiation response under normoxic or hypoxic conditions. Cancer Res 2000;60:5565 /70. [33] Johnson D, DeVore R, Kabbinavar F, et al. Carboplatin (C)/ paclitaxel (T)/RhuMab-VEGF (AV) may prolong survival in advanced non-squamous lung cancer. Proc Am Soc Clin Oncol 2001;20:315a (Abstract 1256). [34] Merchant J, Kim K, Mehta M, et al. Pilot and safety trial of carboplatin, paclitaxel, and thalidomide in advanced nonsmall-cell lung cancer. Clin Lung Cancer 2000;2:48 /52.
www.elsevier.com/locate/lungcan
Targeted therapies for stage III non-small cell lung cancer: integration in the combined modality setting Everett E. Vokesa,*, Hak Choyb a
Section of Hematology/Oncology, University of Chicago Medical Center, University of Chicago, 5841 S. Maryland Avenue, MC 2115, Chicago, IL 60637-1470, USA b Vanderbilt University Medical Center, Nashville, TN, USA
KEYWORDS Stage III; Non-small cell lung cancer; Preclinical models
Summary Combined modality therapy represents current standard therapy for locoregionally advanced non-small cell lung cancer. In particular, concomitant chemoradiotherapy has emerged as the preferred approach. At the same time, efforts to increase locoregional and systemic antitumor activity are necessary to further improve long-term survival rates for these patients. In recent years, multiple cellular targets have emerged in the development of novel antitumor therapies. Several of these are of high relevance in the carcinogenesis of lung cancer including the epidermal growth factor receptor (EGFR), the ras signaling pathway, tumor angiogenesis, and cyclooxygenase-2 (COX-2) expression. Novel agents directed against these targets are currently under development with promising early results in non-small cell lung cancer when administered as single agents or in combination with chemotherapy in stage IV or recurrent disease. Similarly their use with concurrent radiation therapy is supported by preclinical models. Selected early clinical trials utilizing these agents in combination with radiotherapy or chemoradiotherapy are discussed. – 2003 Elsevier Science Ireland Ltd and American Society of Clinical Oncology. Published by Elsevier Science Ireland Ltd. All rights reserved.
1. Introduction Combined modality therapy has emerged as standard therapy for stage III unresectable NSCLC in recent years. Two models of clinical investiga-
Presented in part at the IASLC/ASCO First International Conference for Targeted Therapies for Lung Cancer, Marbella, Spain, 14 /19 January 2003. *Corresponding author. Tel.: /1-773-834-3093; fax: /1-773702-3002. E-mail address: [email protected] (E.E. Vokes).
tions were initially pursued. Among these were induction chemotherapy and concurrent chemoradiotherapy [1,2]. Induction chemotherapy was the first model to show enhanced survival times in randomized clinical trials when added to standard radiation therapy. Several studies demonstrated a 3 /4 months increase in median survival times of approximately 14 versus 10 months. Pattern of failure analysis demonstrated the increased survival to be due to increased systemic control with no impact on locoregional control [3 /5]. In parallel, studies were investigating the role of concomitant chemoradiotherapy. At least one trial
0169-5002/03/$ - see front matter – 2003 Elsevier Science Ireland Ltd and American Society of Clinical Oncology. Published by Elsevier Science Ireland Ltd. All rights reserved. doi:10.1016/S0169-5002(03)00155-7
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succeeded in demonstrating a statistically significant increase in median survival times (MST) when adding concurrent chemotherapy [2,6,7]. Better locoregional control following concurrent chemoradiotherapy was demonstrated. Thus, two competing treatment strategies had been shown to be superior to radiotherapy alone though different in their toxicity and tumor control patterns. This allowed to directly compare the two competing strategies, or alternatively, attempt to combine them into one treatment program. A comparative trial strategy was pursued by several groups. Initially, Japanese investigators compared the use of sequential chemotherapy (with the MVP regimen of mitomycin C, vinblastine and cisplatin) versus the concomitant administration of MVP and radiotherapy. MST were 16 versus 13 months favoring the concomitant approach [8]. A second trial by the Radiation Therapy Oncology Group (RTOG) showed similar results for a regimen of cisplatin and vinblastine (a third treatment arm utilizing twice daily radiation fractions was not superior to induction chemotherapy) [9]. More recently additional studies have been presented at International meetings that are compatible with the Japanese and RTOG data [10,11]. Based on these observations, it has been concluded by many that concomitant chemoradiotherapy represents current standard therapy that should function as control arm on most randomized trials. Since toxicity spectra and patterns of failure differ between sequential and concomitant approaches, it has also been investigated whether they should be used in sequence, i.e. adding either induction or consolidation chemotherapy to concurrent chemoradiotherapy (Fig. 1). The Cancer and Leukemia Group B has conducted several trials investigating induction chemotherapy and concomitant chemoradiotherapy. There was no benefit when adding weekly low doses of concomitant
Fig. 1 Therapy approaches for stage III unresectable NSCLC.
E.E. Vokes, H. Choy
carboplatin to radiotherapy after induction chemotherapy [12]. Subsequently, CALGB 9431 showed that it was feasible to add the novel agents of the last decade to cisplatin and radiotherapy in the setting of induction chemotherapy followed by concurrent chemoradiotherapy [13]. Vinorelbine, gemcitabine and paclitaxel could all be safely administered in this randomized phase II study. The MST of 17 months for all patients was higher that that achieved in previous CALGB trials but compatible with published data from the large trials investigating concomitant chemoradiotherapy. Thus, it was decided to conduct a randomized trial investigating the role of induction chemotherapy in the context of concomitant chemoradiotherapy. CALGB 39801 was designed to treat approximately 350 patients with either sequential and concomitant chemoradiotherapy or concomitant chemoradiotherapy alone (see Fig. 2). Accrual to this trial was completed in May 2002 but no analysis of this trial is available to date. In the Southwest Oncology Group (SWOG) concomitant chemoradiotherapy with cisplatin and etoposide has represented standard therapy [14,15]. Recently, promising phase II data were presented from a trial of this concomitant regimen followed by three cycles of docetaxel as consolidation chemotherapy [16]. These data suggested that consolidation chemotherapy might have a major role in stage III disease. Here too, a definitive phase III trial evaluating concomitant chemoradiotherapy with or without consolidation chemotherapy has been initiated by the Hoosier Oncology Group (HOG).
2. The integration of targeted therapies Targeted therapies of interest in stage III disease will ideally have single agent activity that is
Fig. 2 CALGB 39801.
Targeted therapies for stage III NSCLC
mechanistically understood and predictable for individual patients. In addition, it should at least be additive to chemotherapy and/or radiotherapy with acceptable toxicities. The experience with these targeted agents in stage IV disease suggests that preclinical models need to be validated with plausible clinical data and that preclinical additivity or synergy may not necessarily translate into a clinically measurable benefit. Recent advances in molecular biology have identified a number of molecular targets that may be responsible for resistance of cancer cells to radiation or other cytotoxic agents, and as such may serve as targets for augmentation of radiation or chemotherapy response. Among these determinants are the epidermal growth factor receptor (EGFR), cyclooxygenase-2 (COX-2) enzyme, rassignaling pathway, angiogenic molecules, and various other molecules that regulate different steps in their signal transduction pathways [17,18]. Among these agents, focus to date has been on the clinical development of the EGFR pathway inhibitors. In preclinical studies they have been shown to be synergistic with the taxanes and with radiation, at least in some models, and have been shown to have a modest single agent response rate when tested in populations of patients with recurrent NSCLC [19 /21]. In CALGB 30106 (principal investigator Neal Ready) genitifib (ZD-1839), an orally administered tyrosine kinase inhibitor of the EGFR is being added to carboplatin/paclitaxel induction chemotherapy followed by concomitant chemoradiotherapy as in the experimental arm of CALGB 39801 in stratum 2, and to induction chemotherapy followed by single modality radiotherapy in stratum 1 (see Figs. 3 and 4). For stratum 1, it is hypothesized that the addition of genitifib as a single agent to radiotherapy will result in more tolerable toxicities than those associated with traditional concomitant chemoradiotherapy, and thus, might define a feasible
Fig. 3
CALGB 30106 Stratum-1.
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Fig. 4
CALGB 30106 Stratum-2.
approach to the treatment of patients with a performance status of 2 or pretreatment weight loss exceeding 5%. Patients with performance status of 1 or 2 are treated on stratum 2 with induction chemotherapy followed by concomitant chemoradiotherapy and genitifib added to each treatment component. Here it is hoped that the genitifib will add to the antitumor activity of the induction and concomitant portions (although the recent results of the INTACT trials suggest that the addition of genitifib to induction chemotherapy is unlikely to result in increased activity). The dose of genitifib is fixed at 250 mg/day since studies in patients with advanced lung cancer have failed to show a benefit from further dose escalation of the drug. Another trial is currently investigating the addition of the EGFR tyrosine kinase inhibitor tarceva (OSI-774) to chemoradiotherapy in stage III NSCLC. This NCI supported study (PI: Dr Ann Mauer) conducted by the University of Chicago phase II network is designed as a ‘‘ping-pong’’ phase I trial where the agent is added in increasing doses to alternating cohorts of patients receiving either the CALGB or the SWOG chemoradiotherapy regimens. The treatment design is shown in Figs. 5 and 6.
Fig. 5
Protocol 5411 Arm A (SWOG).
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Fig. 6 Protocol 5411 Arm B CALGB.
Fig. 7 Definition of dose-limiting toxicity.
Dose-limiting toxicity is defined as outlined in Fig. 7. COX-2, another potential molecular target, relates to prostaglandins (PGs). PGs are metabolites of arachidonic acid that induce diverse biologic activities including vasoconstriction, vasodilatation, stimulation or inhibition of platelet aggregation, and immunomodulation (primarily immunosuppression). They are also implicated in the promotion of development and growth of malignant tumors, as well as in the response of tumor and normal tissues to cytotoxic agents, including radiation [22 /24]. Two cyclooxygenase enzymes, COX-1 and COX-2, mediate production of PGs. While COX-1 is constitutively expressed and ubiquitous with physiological roles in maintaining homeostasis, such as the integrity of gastric mucosa, normal platelet function, and regulation of renal blood flow, COX-2 is nonphysiological but induced by diverse inflammatory stimuli, mitogens, and carcinogens. Increasing evidence shows that COX-2 expression is up-regulated in many human tumors, including colon, pancreatic, prostate, gastric and head and neck cancers, where it is associated with more aggressive tumor behavior
and poor patient prognosis. COX-2 is implicated as causative factor in colorectal tumorigenesis [24]. This selective or preferential expression of COX2 in tumors makes this enzyme a potential target for cancer therapy. Selective inhibitors of COX-2 have recently been developed for use as antiinflammatory and analgesic agents, but the availability of these inhibitors provided a critical tool for evaluating the role of COX-2 in cancer. There is preclinical evidence that these agents are more potent than standard non-steroidal anti-inflammatory drugs (NSAIDs) (which inhibit both COX-1 and COX-2 enzymes) at inhibiting colon carcinogenesis and at slowing the growth of established tumors [24]. Also, selective COX-2 inhibitors are reported to enhance tumor response to chemotherapeutic drugs or radiation [23 /25]. The mechanisms of the enhancement seem to be multiple, including increases in intrinsic cell radiosensitivity and inhibition of tumor neoangiogenesis. The action correlates with a reduction in PG production in tumors. The use of selective inhibitors of COX-2 is unlikely to be limited by normal tissue toxicity because inhibition of this enzyme does not affect production of PGs by normal tissues.
3. Clinical trials with celecoxib and radiotherapy Radiation enhancing effects of COX-2 inhibitors provide impetus for conducting clinical trials evaluating combined-modality therapy, including selective COX-2 inhibitors and radiation. As discussed previously, combined modality therapy may enhance the therapeutic index for radiotherapy and additional combinations may be beneficial. Celecoxib has direct antitumor effects in preclinical studies. Combining it with radiation may produce complementary effects by enhancing response to radiation. Six NSCLC clinical trials evaluating combined-modality therapy with celecoxib have been initiated. The RTOG is conducting two of these trials. One is a phase II postoperative adjuvant study of 2 years of celecoxib (400 mg bid) and radiation (50.4 Gy) in completely resected stage I/ II NSCLC patients. The second is a phase I/II trial in intermediate-prognosis locally advanced NSCLC (stages IIB, IIIA and IIIB). Patients are treated with fractionated radiation (66 Gy) and twice-daily celecoxib for up to 2 years. In both studies, objectives include assessing the tolerability of celecoxib at 400 mg twice daily, evaluating the role of biomarkers as predictors of celecoxib
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activity, and determining whether celecoxib improves response and survival. Additional NSCLC clinical trials are evaluating regimens combining celecoxib, standard chemotherapy, and radiotherapy. At the Vanderbilt Cancer Center (VCC), patients with previously untreated stage III NSCLC are being accrued for a phase II trial. Patients are treated with celecoxib plus a standard regimen of paclitaxel, carboplatin, and radiation. Preliminary results suggest that changes in circulating levels of VEGF may be a marker of response to celecoxib. A second phase II study at VCC is evaluating celecoxib combined with radiation and taxane chemotherapy in recurrent NSCLC (treated with at least 1 prior chemotherapy regimen). Two partial responses and three disease stabilizations have been observed in 13 evaluable patients; none of these patients had responded to previous therapy. In this study, COX-2 was overexpressed in 75% of the tumors. A third VCC study is accruing stage I/II patients with inoperable NSCLC. In this phase II study, patients will be treated with radiation (62.5 Gy) and celecoxib will be administered daily until disease progression. A phase I study at the University of Texas M.D. Anderson Cancer Center (MDACC) is evaluating radiotherapy and celecoxib (twice daily at doses of up to 400 mg) in medically inoperable NSCLC. Patients include those with locally advanced disease and poor performance status, stage I/II disease and comorbidities that preclude surgery, and stage IIIA/ B disease previously treated with platinum-based induction therapy. Patients are divided into three groups. Each group is treated with a different radiotherapy regimen and celecoxib, with dose escalation to 800 mg/day. Results in 28 patients enrolled to date indicate that celecoxib has not significantly increased radiation-induced toxicity in normal tissues.
4. Proteasome inhibitors The proteasome is critically involved in cell cycle regulation and represents an important component of protein degradation in the cell. It serves as a central conduit for cellular regulatory signals and has evolved as a target for novel therapeutics. PS341 is a potent and selective small molecule inhibitor of the proteasome [26]. Preclinical studies have demonstrated antitumor activity and clinical trials are currently ongoing. Proteasome inhibitors also target the NF Kappa B signaling pathway, induce apoptosis and are antiangiogenic. Activation of the NF Kappa B pathway is an important feature of human malignancies and can
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stimulate cell proliferation and/or interfere with the efficacy of antitumor agents. Preclinical trials have shown that PS-341 can increase the cytotoxicity of chemotherapy or radiation. Phase I trials have been completed and phase II trials are currently in progress. In lung cancer, two phase I studies investigating this agent with docetaxel or gemcitabine and carboplatin are ongoing. An NCIsponsored study with radiation therapy at the Mayo Clinic is currently also in planning.
5. Farnesyltransferase inhibitors Farnesyltransferase inhibitors (FTIs) are a class of agents currently under intensive clinical investigation in lung cancer, other solid tumors and hematological malignancies. The primary target is thought to be inhibition of the ras signaling pathway and subsequent inhibition of cell growth. Preclinical data have shown that FTIs can reverse radiation resistance as well as increase the activity of chemotherapy [27,28]. A single agent phase II trial of a FTI in non-small cell lung cancer showed no objective responses [29]. However, the median survival in this group of previously untreated patients was 8 months and similar to trials of traditional cytotoxic therapies. Additional investigations administering an FTI with chemotherapy are currently in progress. Radiation sensitization with FTIs has been described in tumor cells expressing activated H-ras, but not in cells expressing wild type ras [27,28,30]. Enhanced radiation cytotoxicity in the presence of any FTI was also observed in a murine xenograft model. Hahn et al. have recently reported on a phase I trial administering the FTI L-778123 in combination with radiotherapy in non-small cell lung and head and neck cancers [30]. No clear increase in radiotherapy-associated toxicities was demonstrated suggesting that FTI related radiation sensitization might be clinically achieved without concurrent increased radiation related toxicity. To date, no phase II studies investigating an FTI with concurrent radiotherapy or chemoradiotherapy have been published.
6. Antiangiogenic agents Several antiangiogenic agents are currently in clinical development. These agents may add intrinsic antitumor activity by preventing the formation of new blood vessels. They may also increase the antitumor activity of cytotoxic agents and increase the cytotoxicity of radiation [31,32].
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The major focus of antiangiogenic investigations in NSCLC has been in stage IV disease where a randomized phase II trial suggested therapeutic benefit from the addition of the antibody to vascular epithelial growth factor (anti-VEGF, Bevacizumab) to standard doublet chemotherapy [33]. This observation is currently being pursued further in a randomized phase III setting. Another trial is being pursued in stage III NSCLC in a trial by the Eastern Cooperative Oncology Group (ECOG). Here patients receive concomitant chemotherapy or radiotherapy with carboplatin, paclitaxel and standard radiotherapy and are randomized to also receive thalidomide as an antiangiogenic agent. The administration of thalidomide with concomitant chemoradiotherapy had previously been shown to be feasible in a small pilot trial [34] Accrual to this study is currently in progress.
7. Outlook The combination of chemotherapy and radiation has become a common strategic practice in the therapy of locoregionally advanced non-small cell lung cancer, with recent emphasis on the concurrent delivery of both modalities. Improvements in treatment outcome both in terms of local control and patient survival have been achieved with traditional chemotherapeutic agents such as cisplatin and taxanes. Nonetheless, cures rates remain low, and combined treatments are frequently associated with increased normal tissue toxicity. Thus, there is considerable room for improvement of the combined treatment strategies. However, selection of the most effective drug or the optimal treatment approach remains as a significant challenge. Significant progress has been made in our understanding of the basic mechanisms of radiation injury as well as the injury inflicted by chemotherapeutic agents and cellular processing of these injuries in both normal and malignant cells. Recent advances in molecular biology have exposed many potential targets for augmentation of radioresponse or chemoresponse including EGFR, COX-2, angiogenic molecules and various components of the signal transduction pathways that these molecules initiate. It has become possible to intervene actively in some molecular pathways in order to improve the therapeutic ratio and the incorporation of molecular targeting strategies into chemoradiotherapy is becoming increasingly used for therapeutic intervention in many types of human cancer.
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