How Today s Developments in the Treatment of Non-Small Cell Lung Cancer Will Change Tomorrow s Standards of Care

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1 How Today s Developments in the Treatment of Non-Small Cell Lung Cancer Will Change Tomorrow s Standards of Care Mark G. Kris Memorial Sloan-Kettering Cancer Center, New York, New York, USA Key Words. NSCLC EGFR Adjuvant Neoadjuvant Docetaxel Gefitinib Bevacizumab Erlotinib Learning Objectives After completing this course, the reader will be able to: 1. Discuss the current status of adjuvant therapy in NSCLC. 2. Articulate the developing rate of targeted agents in the treatment of NSCLC. 3. Describe how tumor molecular biology may impact response to novel treatment. CME Access and take the CME test online and receive 1 hour of AMA PRA category 1 credit at CME.TheOncologist.com Abstract Cisplatin (Platinol ; Bristol-Myers Squibb, Princeton, NJ, and carboplatin (Paraplatin ; Bristol-Myers Squibb), together with newer chemotherapies, such as docetaxel (Taxotere ; Aventis Pharmaceuticals Inc., Bridgewater, NJ, aventispharma-us.com), paclitaxel (Taxol ; Bristol- Myers Squibb), vinorelbine (Navelbine ; GlaxoSmith- Kline, Philadelphia, pemetrexed (Alimta ; Eli Lilly and Company, Indianapolis, and gemcitabine (Gemzar ; Eli Lilly and Company), have improved treatment outcomes in both advanced non-small cell lung cancer (NSCLC) and in the adjuvant/neoadjuvant setting. Newer systemic treatments for NSCLC, used in advanced stage IV management, are beginning to be studied in earlier stages of the disease, when treatment is better tolerated and potentially curative. Hopefully, newer agents with proven efficacies in advanced disease will enhance curability. Following the successful addition of bevacizumab (Avastin ; Genentech, Inc., South San Francisco, CA, to carboplatin/paclitaxel in advanced disease, bevacizumab is now being incorporated into adjuvant and neoadjuvant trials. Trials in stage IB IIIA patients will study neoadjuvant docetaxel/cisplatin/bevacizumab. The discovery that patients with exon 19 and 21 mutations in the epidermal growth factor receptor gene EGFR have around an 80% response rate to gefitinib (Iressa ; AstraZeneca Pharmaceuticals, Wilmington, DE, and that this response confers survival benefit indicates its potential utility for mutation-positive patients with advanced- and earlierstage disease. Clinical characteristics, such as never smoking status and adenocarcinoma, and especially bronchioloalveolar carcinoma histological features, can also identify individuals likely to respond to EGFR tyrosine kinase inhibitors. Studies of neoadjuvant erlotinib (Tarceva ; OSI Pharmaceuticals, Inc., Melville, NY, in operable NSCLC are planned. One such study includes cisplatin and docetaxel. Effective development of active agents and disease management based on molecular profiling of lung tumors will change tomorrow s standard of care. The Oncologist 2005;10(suppl 2):23 29 Correspondence: Mark G. Kris, M.D., Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021, USA. Telephone: ; Fax: Received September 5, 2005; accepted for publication September 5, AlphaMed Press /2005/$12.00/0 The Oncologist 2005;10(suppl 2):

2 24 Developments in Treating NSCLC Introduction Table 1. Non-small cell lung cancer chemotherapy: In both advanced disease and in the adjuvant setting, progress is being made in non-small cell lung cancer (NSCLC) rate survival survival Response 1-year 2-year treatment. Newer agents added to our treatment armamentarium over the past 2 3 decades include the taxanes docetaxel (Taxotere ; Aventis Pharmaceuticals Inc., Bridgewater, NJ, and paclitaxel (Taxol ; Bristol-Myers Squibb, Princeton, NJ, the vinca alkaloid vinorelbine No chemotherapy Active single agent Active two-drug combination 0% 15% 25% 10% 20% 35% 0% 10% 20% (Navelbine ; GlaxoSmithKline, Philadelphia, Active three-drug gsk.com), and the nucleoside analogue gemcitabine (Gemzar combination 35% 35% 20% ; Eli Lilly and Company, Indianapolis, com). One-year survival rates in patients with advanced NSCLC have increased from around 10% without chemotherapy, to 20% with an active single agent, and to 35% with and after the 1995 meta-analysis. Table 2. Non-small cell lung cancer adjuvant trials including the combination of two active drugs (Table 1) [1 8]. Trial Survival In the adjuvant setting, a meta-analysis published 10 No. of 5 year years ago (involving 1,396 patients in eight trials) suggested patients (%) HR 95% CI p value the benefit of cisplatin (Platinol ; Bristol-Myers Squibb)- based chemotherapy [1]. There was clear evidence of better survival among patients having surgery plus cisplatin-based chemotherapy when compared with patients having surgery alone. At 5 years, the survival rates were 45% and 40%, respectively, an absolute difference of 5% and a very substantial increase in the proportion of patients alive. At 5 years, the extent of benefit surpassed that seen by Bonadonna et al. [9] using adjuvant cyclophosphamide/methotrexate/5-fluorouracil Meta-analysis [1] Italian Study [10] International [11] Canadian trial [12] U.S. study [13] 1,394 1,209 1, yr < (CMF) in breast cancer. Since 1995, four trials of adjuvant chemotherapy in NSCLC (from Italy, Canada, and the U.S., plus an international Abbreviations: 5 year (%), absolute increase in overall survival at 5 years for patients receiving adjuvant therapy (4-year survival date for U.S. study); CI, confidence interval; HR, hazard ratio. trial) have continued to suggest benefits in outcome (Table 2) [10 13]. Although some patients had stage I and II disease, the majority had stage III disease (mediastinal spread or spread to locoregional nodes). These studies are consistent with each other and with the degree of benefit suggested by the 1995 meta-analysis. The overall hazard ratio is around 0.87; and there is evidence that these trials (unlike the data from the meta-analysis) are changing clinical practice. These data provide the basis for combined modality therapy with the agents introduced in the 1990s [14 17]. At the Memorial Sloan-Kettering Cancer Center (MSKCC), it is now routine for patients with completely resected stage IB IIIA NSCLC to be referred for adjuvant treatment. Bevacizumab to Enhance Curability In the National Cancer Institute sponsored Eastern Cooperative Oncology Group (ECOG) 4599 phase III study, 878 stage IIIB/IV patients with no prior therapy were randomized to receive either carboplatin (Paraplatin ; Bristol- Myers Squibb)/paclitaxel chemotherapy alone or chemotherapy plus bevacizumab (Avastin ; Genentech, Inc., South San Francisco, CA, at a dose of 15 mg/kg. An interim analysis of that study showed that the median survival in the arm containing bevacizumab was 12.5 months, while the median survival in control patients given carboplatin/paclitaxel alone was 10.2 months [18]. That study changed our standard of care for stage IIIB and IV patients and challenged us to extend the benefits of this regimen into the adjuvant and neoadjuvant settings. Neoadjuvant studies offer vital opportunities for in vivo sensitivity testing, providing ample time to permit molecular profiling that can facilitate both cure and research. The Bevacizumab and Chemotherapy for Operable NSCLC (BEACON) trial, recently opened at MSKCC, involves stage IB IIIA patients with resectable NSCLC. It makes a distinction between nonsquamous, noncentral tumors on the one hand and tumors that are either squamous or large and central and on the other. Patients with nonsquamous peripheral tumors receive two cycles of docetaxel (75 mg/m 2 ) plus cisplatin (75 mg/m 2 ) plus

3 Kris 25 bevacizumab (15 mg/kg) every 3 weeks. Those with squamous or central tumors have the same chemotherapy but no bevacizumab (Fig. 1). Patients with a 10% or greater reduction in tumor by World Health Organization (WHO) criteria receive a further two cycles. The remainder are removed from the study. Patients who continue in the trial undergo surgical resection 4 weeks after the last cycle of chemotherapy. Bevacizumab is not administered with the final cycle of chemotherapy. Postoperatively, patients receive maintenance bevacizumab (15 mg/kg every 3 weeks) for 1 year. In early bevacizumab trials, patients with squamous tumors tended to have the greatest benefit from treatment but were also at greatest risk of hemoptysis. The hemoptysis does not appear to be an adverse effect affecting clotting mechanisms but rather a result of bevacizumab-induced disintegration of tumor. Following surgical removal of the primary lesions, patients with squamous tumors may be able to benefit from use of the a vascular endothelial growth factor antibody to attack microscopic residual disease remaining after surgery and neoadjuvant chemotherapy. Targeting the Epidermal Growth Factor Receptor Gene EGFR Between 1997 and 2002, 140 patients at MSKCC received single-agent gefitinib (Iressa ; AstraZeneca Pharmaceuticals, Wilmington, DE, [19]. There were partial responses in 21 patients (15%). Univariate analysis showed that the probability of a response was greater in never-smokers than in smokers (36% versus 8%; p <.001), greater in patients with adenocarcinoma than in those with other histologies (21% versus 0%; p <.001), and greater in bronchioloalveolar than in other adenocarcinomas (37% versus 15%; p <.001). A multivariate analysis showed highly significant differences between never smokers and others (p =.005) and between those with bronchioloalveolar carcinoma (BAC) and those with other adenocarcinomas (p =.007). Exon 19 Deletion and Exon 21 Point Mutations in EGFR The discovery that patients responsive to gefitinib have mutations in the ATP-binding site of the EGFR tyrosine kinase domain has opened up exciting possibilities. Several researchers have now studied gefitinib specifically in NSCLC patients with EGFR mutations. In a total of 86 such patients reported in the literature at this time (Table 3), 73 had a partial or complete response, giving the extraordinarily high response rate of 85% (ranging between 76% and 92% among the eight studies) [20 27]. As response has been shown to confer survival benefit, this is a major advance for the 10,000 or so U.S. patients with the mutation (and the thousands in Japan, Korea, and Taiwan). Han et al. [27] in Korea compared the survival of gefitinib-treated patients with wild-type EGFR with that of patients with mutated EGFR. Patients with EGFR mutations had a median survival time of 31 months, compared with 7 months for patients with wild-type EGFR (p <.001). KRAS Mutations For evolutionary reasons, EGFR and KRAS mutations tend to be mutually exclusive. Pao et al. [22] have produced evidence that KRAS mutations confer primary resistance to both gefitinib and erlotinib (Tarceva ; OSI Pharmaceuticals, Inc., Melville, NY, In our series, 17 Table 3. Partial responses with gefitinib in non-small cell lung cancer: results in patients with epidermal growth factor receptor gene (EGFR) mutations No. No. with Response Study treated PR/CR rate Figure 1. Summary of treatment schema of the Bevacizumab and Chemotherapy for Operable NSCLC trial. Abbreviations: CT, computed tomography; NSCLC, non-small cell lung cancer; POD, progression of disease; q3 weeks, every 3 weeks; WHO, World Health Organization. Lynch et al. [20] % Paez et al. [21] % Pao et al. [22] % Huang et al. [23] % Mitsudomi et al. [24] % Cortes-Funes et al. [25] % Tokumo et al. [26] % Han et al. [27] % Total % (76% 92%) Abbreviations: CR, complete response; PR, partial response.

4 26 Developments in Treating NSCLC of 22 patients with EGFR mutations were sensitive to either gefitinib or erlotinib. None of the patients with KRAS mutations were sensitive. This research has permitted us to identify some groups of patients for treatment with EGFR tyrosine kinase inhibitors. Those with an EGFR mutation but not a KRAS mutation have a high likelihood of response to either gefitinib or erlotinib. Those negative for both mutations are indeterminate. Those positive for a KRAS mutation and negative for the EGFR mutation should be considered for an alternative agent. Clinical Surrogates for EGFR Mutation Testing At present, analysis of EGFR mutations appears to be the most promising means of predicting sensitivity to EGFR tyrosine kinase inhibitors; however, clinical surrogates for the mutation have been identified. The literature suggests a strong correlation between never smoking and response to gefitinib or erlotinib (Table 4) [19, 27 32]. Of patients who have never smoked, between 18% and 63% respond to the EGFR tyrosine kinase inhibitors. In current or former smokers, the range is 4% 18%. Two huge, randomized, placebo-controlled, studies showed a clear survival advantage in never smokers treated with EGFR-inhibiting agents (Table 5) [32, 33]. In the Iressa Survival Evaluation in Lung Cancer (ISEL) trial, Table 4. Smoking history and sensitivity to epidermal growth factor receptor gene (EGFR) tyrosine kinase inhibitors Response Response rate, rate, Agent never- current/former Study (trial) smokers smokers Difference Miller et al. Gefitinib [19] (MSKCC) 36% 8% 28% Cohen et al. Gefitinib [28] (IDEAL2) 29% 5% 24% Fukuoka et al. Gefitinib [29] (Japan) 33% 9% 24% Takano et al. Gefitinib [30] (Japan) 63% 18% 45% Han et al. Gefitinib [27] (Korea) 33% 15% 18% Shepherd et al. Erlotinib [31] (BR.21) 25% 4% 21% Tamura et al. Gefitinib [32] (ISEL) 18% 5% 13% Abbreviations: BR.21, National Cancer Institute of Canada Clinical Trials Group BR.21 trial; IDEAL2, Iressa Dose Evaluation in Advanced Lung Cancer 2; ISEL, Iressa Evaluation in Lung Cancer; MSKCC, Memorial Sloan-Kettering Cancer Center. the hazard ratio for gefitinib versus placebo was 0.67, and it was 0.42 in the National Cancer Institute of Canada Clinical Trials Group BR.21 trial of erlotinib versus placebo. The incidence of EGFR mutation in NSCLC patients who never smoked ranges from 26% in Korea [27] to 68% in Japan [34], and consistently is far higher than in patients with a smoking history. The likelihood of EGFR mutation also relates to extent of smoking, at around 50% in those with 10 pack-years and less and 0% in those with more than 75 pack-years [35]. Trials adding an EGFR tyrosine kinase inhibitor to chemotherapy for nonselected patients were negative on all survival end points. However, the Tarceva Responses in Conjunction with Paclitaxel and Carboplatin (TRIBUTE) trial incorporated a prospective analysis of the effect of adding erlotinib to chemotherapy in never-smokers [36]. In that group, the median survival in patients given erlotinib plus chemotherapy was 23 months, compared with 10 months in patients receiving placebo plus chemotherapy. Based on these data, we are routinely recommending initial treatment with both erlotinib and chemotherapy to never smokers with advanced NSCLC. A Cancer and Leukemia Group B (CALGB) trial will randomize patients with a minimal smoking history (a group that represents around 20% of all cases) to erlotinib alone or erlotinib plus chemotherapy to confirm and extend the TRIBUTE observations. Patients with adenocarcinoma with BAC features (a histology found in up to one fourth of NSCLC cases) are also more likely to be sensitive to EGFR agents and again are likely to have relevant mutations [37]. A multicenter phase II trial of erlotinib in patients with BAC produced response rates of 45% in patients who had never smoked and 18% in smokers [38]. Table 5. Patients treated in placebo-controlled trials of gefitinib or erlotinib: survival improvement in patients who had never smoked Number of Hazard Trial Regimens never-smokers ratio (year) compared (% of total) (95% CI) ISEL [32] Gefitinib versus placebo (22%) ( ) BR.21 [33] Erlotinib versus placebo (20%) ( ) Abbreviations: BR.21, National Cancer Institute of Canada Clinical Trials Group BR 21 trial; CI, confidence interval; ISEL, Iressa Evaluation in Lung Cancer.

5 Kris 27 These findings have also prompted a neoadjuvant trial of erlotinib in association with docetaxel and cisplatin (Fig. 2). Proof of Principle Trial Investigators at MSKCC are now conducting a proof of principle trial to test the hypothesis that a radiographic response to gefitinib in NSCLC correlates with the presence of an EGFR mutation (Trial ). In this study, stage I or II patients with adenocarcinomas with BAC features or who have smoked fewer than 10 pack-years and have measurable lesions on a chest computed tomography (CT) scan will have a core needle biopsy for assessment of KRAS and EGFR mutation, pretreatment (Fig. 3). They then will receive gefitinib (250 mg) for at least 21 days, followed by a repeat CT scan. At surgery, tumor specimens will be banked, and EGFR and KRAS mutation status will be again assayed if no Figure 2. Study design of the Erlotinib and Chemotherapy for Operable NSCLC trial. Abbreviations: BAC, bronchioloalveolar carcinoma; CT, computed tomography; NSCLC, nonsmall cell lung cancer; po, orally; POD, progression of disease; q3 weeks, every 3 weeks; WHO, World Health Organization. mutations were detected in the initial biopsy specimen. Following the operation, patients who have had at least a minor response by standard criteria by CT (established using a standard scan but specially developed software) or who have an EGFR mutation will continue to receive gefitinib as an adjuvant treatment. Several statistical hypotheses stand to be confirmed. First, in this enriched population, it is assumed that 25% of patients will have a radiographic response to gefitinib. Secondly, the expectation is that EGFR mutations will be present in 80% of those who respond radiographically to gefitinib but in only 10% of those who do not. An example of a response following gefitinib in a patient with an exon 19 deletion in EGFR is shown in Figure 4. Conclusions Efforts should be made to find and treat all patients who can benefit from the range of current therapies. This especially includes patients in need of adjuvant therapy, and those who could be helped by specific agents, such as those with EGFR mutations, who have a good chance of responding to gefitinib or erlotinib. Clinical leads can provide guidance valuable to bench research and vice versa. It is imperative to concentrate on strategies that improve survival, with the ultimate aim of achieving cure. As data become available, agents such as gefitinib, erlotinib, or bevacizumab should be added to potentially curative adjuvant and neoadjuvant treatments. Disclosure of Potential Conflicts of Interest Dr. Kris has acted as a consultant for and has received support from Eli Lilly, Genentech, GlaxoSmithKline, and Bristol-Myers Squibb. Figure 3. Epidermal growth factor receptor gene (EGFR) mutations and gefitinib sensitivity: MSKCC proof of principle trial (Trial ). Abbreviations: BAC, bronchioloalveolar carcinoma; CT, computed tomography; NSCLC, non-small cell lung cancer; po, orally. Figure 4. Computed tomography scan response of a patient with an epidermal growth factor receptor gene (EGFR) exon 19 deletion.

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7 Kris Pham D, Kris MG, McDonough T et al. Estimation of the likelihood of epidermal growth factor receptor (EGFR) mutations based on cigarette smoking history in patients with adenocarcinoma of the lung. Presented at the 41st Annual Meeting of the American Society of Clinical Oncology, Orlando, Florida, May 14 17, 2005:7069a. 36 Miller VA, Herbst R, Prager D et al. Long survival of never smoking non-small cell lung cancer (NSCLC) patients (pts) treated with erlotinib HCl (OSI-774) and chemotherapy: sub-group analysis of TRIB- UTE. J Clin Oncol 2004;22(suppl 14):7061a. 37 Kris MG, Sandler A, Miller VA et al. EGFR and KRAS mutations in patients with bronchioloalveolar carcinoma treated with erlotinib in a phase II multicenter trial. Presented at the 41st Annual Meeting of the American Society of Clinical Oncology, Orlando, Florida, May 14 17, 2005:7029a. 38 Kris MG, Sandler A, Miller V et al. Cigarette smoking history predicts sensitivity to erlotinib: results of a phase II trial in patients with bronchioloalveolar carcinoma (BAC). J Clin Oncol 2004;22(suppl 14):7062a.