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1 This material is protected by U.S. Copyright law. Unauthorized reproduction is prohibited. For reprints contact: Regulatory Issues - FDA FDA Drug Approval Summary: Erlotinib (Tarceva ) Tablets Martin H. Cohen, John R. Johnson, Yeh-Fong Chen, Rajeshwari Sridhara, Richard Pazdur Division of Oncology Drug Products, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Rockville, Maryland, USA Key Words. Erlotinib (Tarceva ) tablets Non-small cell lung cancer Metastatic Second-line treatment Abstract On November 18, 2004, erlotinib (Tarceva ; OSI Pharmaceuticals, Inc., Melville, NY, and Genentech, Inc., South San Francisco, CA, received regular approval as monotherapy for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) after failure of at least one prior chemotherapy regimen. Survival of erlotinib-treated patients was superior to that of placebo-treated patients. The median survival duration of erlotinib-treated patients was 6.67 months, compared with 4.70 months for placebo-treated patients. Exploratory univariate analyses showed a larger survival prolongation in two subsets of patients: those who Introduction Erlotinib (Tarceva ; OSI Pharmaceuticals, Inc., Melville, NY, and Genentech, Inc., South San Francisco, CA, is a human epidermal growth factor receptor type 1/epidermal growth factor receptor (HER1/EGFR) tyrosine kinase inhibitor [1, 2]. Specificity of inhibition with regard to other tyrosine kinase receptors has not been fully characterized. Erlotinib is metabolized predominantly by hepatic cytochrome P450 CYP3A4 enzyme. Cotreatment with the potent CYP3A4 inhibitor ketoconazole (Nizoral ; Janssen Pharmaceutical Products, L.P., Titusville, NJ, com) increased the erlotinib area under the concentration time curve (AUC) by two thirds. Pre- or cotreatment never smoked and those with epidermal growth factor receptor (EGFR)-positive tumors. Patients who never smoked and were EGFR-positive had a large erlotinib survival benefit. Erlotinib was also superior to placebo for progression-free survival and a response rate of 8.9% versus 0.9%. Skin rash and diarrhea were the most common erlotinib adverse events. Severe rash occurred in 8%, and severe diarrhea occurred in 6% of erlotinibtreated patients. In the first-line treatment of NSCLC, two large, controlled, randomized trials showed no benefit from adding erlotinib to doublet, platinum-based chemotherapy. Therefore, erlotinib is not indicated for use in this setting. The Oncologist 2005;10: with the CYP3A4 inducer rifampicin (Rifadin ; Aventis Pharmaceuticals Inc., Bridgewater, NJ, increased erlotinib clearance threefold and reduced the AUC by two thirds. A phase I trial established that the maximal tolerated dose of erlotinib, on a protracted daily schedule, was 150 mg/day. The dose-limiting toxicities were diarrhea and skin rash [3]. No studies have been conducted comparing a lower daily dose of erlotinib with the 150-mg/day dose. Pharmacokinetic studies demonstrated that biologically relevant plasma drug concentrations of erlotinib were achieved and were maintained at the 150-mg/day dosage. These studies further demonstrated that erlotinib, 150 mg/day, results in a plasma AUC that is higher by one Correspondence: Martin H. Cohen, M.D., U.S. Food and Drug Administration, HFD-150, 5600 Fishers Lane, Rockville, Maryland 20857, USA. Telephone: ; Fax: ; cohenma@cder.fda.gov Received March 22, 2005; accepted for publication June 9, AlphaMed Press /2005/$12.00/0 The Oncologist 2005;10:

2 462 Tarceva for Non-Small Cell Lung Cancer order of magnitude than the plasma AUC achieved by gefitinib (Iressa ; AstraZeneca Pharmaceuticals, Wilmington, DE, a related EGFR inhibitor [1]. Patients and Methods One double-blinded, multicenter, multinational, randomized trial comparing orally administered erlotinib, 150 mg daily, with placebo for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) after failure of at least one prior chemotherapy regimen was submitted. The trial was conducted by the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG). A total of 731 patients was randomized using a 2:1 randomization schema 488 patients in the erlotinib arm and 243 patients in the placebo arm. Prerandomization stratification variables included Eastern Cooperative Oncology Group performance status score, number of prior treatment regimens, prior platinum, and best response to prior chemotherapy. EGFR status was determined for 238 of the 731 study patients (33%) who had tissue samples available prior to the study (samples obtained either at diagnosis or at relapse). A positive EGFR expression status was defined as having at least 10% of cells staining for EGFR using the DAKO EGFR pharmdx kit (DakoCytomation, Glostrup, Denmark, The primary efficacy objective was to compare overall survival between the two treatment arms. Secondary objectives were to compare the two treatment arms for progression-free survival (PFS), response rate and duration, and quality of life as measured by the European Organization for the Research and Treatment of Cancer (EORTC) quality of life questionnaires QLQ-C30 and the lung cancer module QLQ-LC13. An additional objective was to correlate the expression of tissue EGFR levels with treatment outcome. Results Demographics and disease characteristics are summarized in Table 1. The two study arms were well balanced for gender, age, race, pretreatment performance status, weight loss in the previous 6 months, smoking history, time from initial diagnosis to randomization, best response to prior therapy, number of prior drug regimens, and prior platinum therapy. There were 127 EGFR-positive patients (78 treated with erlotinib, 49 receiving placebo) and 111 EGFR-negative patients (74 treated with erlotinib, 37 receiving placebo). Survival was significantly longer in the erlotinib arm, with median overall survival times of 6.7 months and 4.7 months in the erlotinib and placebo groups, respectively (Fig. 1). The adjusted hazard ratio (HR) for death in the Table 1. Demographic and disease characteristics Erlotinib (n = 488) Placebo (n = 243) Characteristic n (%) n (%) Gender Female 173 (35) 83 (34) Male 315 (65) 160 (66) Age (years) < (61) 153 (63) (39) 90 (37) Race White 379 (78) 188 (77) Black 18 (4) 12 (5) Asian 63 (13) 28 (12) Other 28 (6) 15 (6) Eastern Cooperative Oncology Group performance status score a 0 64 (13) 34 (14) (52) 132 (54) (26) 56 (23) 3 42 (9) 21 (9) Weight loss in previous 6 months <5% 320 (66) 166 (68) 5% 10% 96 (20) 36 (15) >10% 52 (11) 29 (12) Unknown 20 (4) 12 (5) Smoking history Never smoked 104 (21) 42 (17) Current or former smoker 358 (73) 187 (77) Unknown 26 (5) 14 (6) Histological classification Adenocarcinoma 246 (50) 119 (49) Squamous 144 (30) 78 (32) Undifferentiated large cell 41 (8) 23 (9) Other 57 (11) 23 (10) Time from initial diagnosis to randomization (months) <6 63 (13) 34 (14) (32) 85 (35) > (55) 124 (51) Best response to prior therapy a Complete response/partial 196 (40) 96 (40) response Stable disease 191 (39) 96 (40) Progressive disease 101 (21) 51 (21) Number of prior regimens a (50) 121 (50) (49) 119 (49) 3 7 (1) 3 (1) Exposure to prior platinum a Yes 454 (93) 224 (92) No 34 (7) 19 (8) Epidermal growth factor receptor status Positive 78 (17) 49 (20) Negative 74 (17) 37 (15) Unmeasured 296 (66) 157 (65) a Stratification factor as documented at baseline; distribution differs slightly from values reported at time of randomization.

3 Cohen, Johnson, Chen et al. 463 erlotinib group relative to the placebo group was 0.73 (p <.001). One-year survival rates were 31.2% and 21.5% in the erlotinib and placebo groups, respectively. A series of exploratory univariate subset survival analyses was performed. These analyses could include relatively small numbers of patients and could be confounded by known and unknown prognostic differences within the subsets. Table 2 shows the HR for death for specific subsets of erlotinib-treated patients relative to placebo-treated patients and the 95% confidence interval (CI) for the HR. An HR < 1 indicates that survival was better in the erlotinib arm than in the placebo arm in that subgroup. An exploratory analysis of the effect of EGFR protein expression status on treatment survival was performed. This analysis was limited because EGFR status was known Figure 1. Kaplan-Meier survival curves in the intent-to-treat population. Table 2. Treatment comparison with respect to survival within subgroups Characteristic No. of patients Hazard ratio 95% confidence interval Erlotinib:placebo Female Male Age <65 Age 65 White Asian Performance status 0 1 Performance status 2 3 Prior weight loss <5% Prior weight loss 5% 10% Prior weight loss >10% Never smoked Current or former smoker Adenocarcinoma Squamous Other <6 months from initial diagnosis 6 12 months from initial diagnosis >12 months from initial diagnosis Best prior response complete response/partial response Best prior response stable disease Best prior response progressive disease One prior regimen 2+ prior regimens Prior platinum therapy No prior platinum Prior taxane therapy No prior taxane Stage IV at diagnosis Stage <IV at diagnosis EGFR positive EGFR negative EGFR unmeasured Abbreviation: EGFR, Epidermal growth factor receptor

4 464 Tarceva for Non-Small Cell Lung Cancer for only 238 study patients (33%). However, the survival in the EGFR-tested population was almost identical to that in the entire study population, suggesting that the tested population was representative of the entire patient population. In the EGFR-positive subset, erlotinib produced a longer survival duration than did placebo (median, 10.7 months versus 3.8 months; HR, 0.65; p =.033). No apparent erlotinib survival effect was observed in the EGFR-negative subset (erlotinib median of 5.2 months versus placebo median of 7.5 months; HR, 1.01; p =.958). However, the confidence intervals for the EGFR-positive and EGFR-negative subsets were wide and overlapped. Thus, an erlotinib survival effect in the EGFR-negative subset cannot be excluded. Postapproval clinical trials will prospectively examine the relationship between EGFR status and survival effects. A subset analysis according to smoking status showed that the erlotinib survival benefit was greater in patients who had never smoked (HR, 0.42; 95% CI, ) than in smokers (HR, 0.87; 95% CI, ). The subset of patients who had never smoked and were EGFR positive had a large erlotinib survival benefit (18 treated with erlotinib, 12 given placebo; HR, 0.27; 95% CI, ; p =.003). There were insufficient patients who were never smokers and were EGFR negative to perform an analysis. Table 3. Adverse events occurring in 10% of erlotinib-treated patients Erlotinib (n = 485) Multivariate analyses consistently confirmed a favorable erlotinib survival effect in the EGFR-positive group. The multivariate analyses failed to rule out a small erlotinib survival effect in EGFR-negative patients. PFS was significantly longer in the erlotinib arm, with a median of 9.9 weeks, versus 7.9 weeks in the placebo arm. The adjusted HR for PFS was 0.59 (95% CI, ; p <.001). A longer PFS time was demonstrated in the EGFRpositive subgroup (HR, 0.49; 95% CI, ) and the EGFR-unmeasured subgroup (HR, 0.56; 95% CI, ). Improvement in PFS was less apparent in the EGFRnegative subgroup (HR, 0.91; 95% CI, ). The objective response rate by the response evaluation criteria in solid tumors (RECIST) in the erlotinib group was 8.9% (95% CI, 6.4% 12.0%). The median duration of response was 34.3 weeks, ranging from weeks. Two responses (0.9%; 95% CI, ) were reported in the placebo group. The median duration of placebo responses was 15.9 weeks. Tumor responses were observed in all EGFR subgroups: 11.6% in the EGFR-positive subgroup, 9.5% in the EGFR-unmeasured subgroup, and 3.2% in the EGFR-negative subgroup. The sponsor s quality-of-life analysis was not found to be sufficiently robust/consistent to be included in the package insert. Placebo (n = 242) National Cancer Institute Common Toxicity Criteria grade Any grade Grade 3 Grade 4 Any grade Grade 3 Grade 4 MedDRA preferred term % % % % % % Rash 75 8 < Diarrhea 54 6 <1 18 <1 0 Anorexia <1 Fatigue Dyspnea Cough Nausea Infection Vomiting 23 2 < Stomatitis 17 < Pruritus 13 < Dry skin Conjunctivitis 12 <1 0 2 <1 0 Keratoconjunctivitis sicca Abdominal pain 11 2 <1 7 1 <1 Abbreviation: MedDRA, medical dictionary for regulatory activities.

5 Cohen, Johnson, Chen et al. 465 In addition to erlotinib trials in refractory patients, two large trials were conducted in chemotherapy-naïve, stage III and IV NSCLC patients. Two thousand two hundred fifty-one patients were randomized to receive either erlotinib, 150 mg daily, or placebo in combination with platinum-based chemotherapy regimens. The chemotherapies given in these first-line trials were gemcitabine (Gemzar ; Eli Lilly and Company, Indianapolis, lilly.com) and cisplatin (Platinol ; Bristol-Myers Squibb, Princeton, NJ, (n = 1,172) or carboplatin (Paraplatin ; Bristol-Myers Squibb) and paclitaxel (Taxol ; Bristol-Myers Squibb) (n = 1,059). There was no evidence of erlotinib benefit in tumor response rates, time to progression, or overall survival when compared with placebo-treated patients [4, 5]. Safety The most common adverse reactions in patients receiving erlotinib were diarrhea and rash (Table 3). Grade 3/4 rash and diarrhea occurred in 9% and 7% of erlotinib-treated patients, respectively. Rash and diarrhea each resulted in study discontinuation in 1% of erlotinib-treated patients. Only 6% and 1% of patients needed dose reductions for rash and diarrhea, respectively. The median time to onset of rash was 8 days, and the median time to onset of diarrhea was 12 days. Liver function test abnormalities (including elevated alanine aminotransferase [ALT], aspartate aminotransferase [AST], and bilirubin) were observed. These elevations were mainly transient or associated with liver metastases. Grade 2 (> times the upper limit of normal [ULN]) ALT elevations occurred in 4% and <1% of erlotinib- and placebo-treated patients, respectively. Grade 3 (>5 20 times the ULN) elevations were not observed in erlotinibtreated patients. Infrequent cases of gastrointestinal bleeding have been reported in clinical studies, some associated with concomitant warfarin (Coumadin ; Bristol-Myers Squibb) administration and some with concomitant nonsteroidal anti-inflammatory drug administration. National Cancer Institute Common Toxicity Criteria grade 3 conjunctivitis and keratitis have been reported infrequently in patients receiving erlotinib therapy. Corneal ulcerations may also occur. Cases of interstitial lung disease (ILD) have been observed in patients receiving erlotinib at an overall incidence of about 0.8% (patients in the placebo group had a similar incidence of ILD). Reports have included interstitial pneumonia, pneumonitis, acute respiratory distress syndrome, pulmonary fibrosis, and alveolitis. Patients often present with the acute onset of dyspnea, sometimes associated with cough or low-grade fever, often becoming severe within a short time and requiring hospitalization. Symptoms started from 5 days to >9 months (median 47 days) after initiating erlotinib therapy. Most of the cases were associated with confounding or contributing factors such as concomitant/prior chemotherapy, prior radiotherapy, preexisting parenchymal lung disease, metastatic lung disease, or pulmonary infections. In the event of pulmonary symptoms (dyspnea, cough, fever), erlotinib therapy should be interrupted and a prompt investigation of these symptoms should occur. If ILD is confirmed, erlotinib should be discontinued and the patient treated appropriately. Discussion Efforts are ongoing to identify patients and tumor types that are likely to respond favorably to treatment with erlotinib and other tyrosine kinase inhibitors. The present data suggest that erlotinib has a survival effect (HR, 0.65) for patients who are EGFR-positive, defined as having at least 10% of cells staining for EGFR using the method described above, whereas survival is not affected by erlotinib in EGFR-negative patients (HR, 1.01). Patients who never smoked had a strong erlotinib survival effect (HR, 0.42) whereas current or former smokers did not (HR, 0.87). Patients who never smoked and were EGFR-positive had the largest erlotinib survival benefit (HR, 0.27). While only 30 patients were included in this analysis, the results are included because of their dramatic nature. Other studies have not completely supported the above results. One such phase II erlotinib trial enrolled 57 patients with EGFR-expressing ( 10% of tumor cells staining positive) advanced NSCLC. There were seven partial responders and 34 patients with stable disease. Neither tumor response nor stable disease was associated with a higher percentage of cells positive for EGFR expression or more intensive EGFR staining [6]. A similar study, performed in patients receiving gefitinib treatment, also found that the degree of tumor cell membrane EGFR staining was not clinically relevant to treatment outcome [7]. More recent studies have investigated the effect of specific somatic mutations of the EGFR gene on treatment outcome. In one study of gefitinib-treated NSCLC patients, eight of nine patients whose tumors responded to treatment had documented mutations (small, in-frame deletions or amino acid substitutions) in the tyrosine kinase domain of the EGFR gene. None of the seven patients who failed to respond to gefitinib treatment had a gene mutation. All responding patients had bronchoalveolar carcinoma or adenocarcinoma. Six of the nine responding patients had never smoked and three were former smokers. Six of the nine responding patients were female [8].

6 466 Tarceva for Non-Small Cell Lung Cancer Paez et al. provide supportive evidence that EGFR mutation status may predict sensitivity to gefitinib. They demonstrated that mutations were more frequent in adenocarcinomas than in other NSCLC histologies, in females than in males, and in Japanese patients than in U.S. patients. (Japanese patients have higher gefitinib response rates than U.S. patients.) Clinical and/or symptomatic responses to gefitinib were observed in five patients with somatic EGFR kinase domain mutations, while none of the four patients without mutations had a tumor response [9]. Pao et al. studied both gefitinib- and erlotinib-treated NSCLC patients. They reported similar findings for both drugs. Seven of the 10 gefitinib-responding patients had somatic mutations, whereas none of the eight gefitinib-refractory tumors were mutation-positive. Five of the seven erlotinib-responding patients were mutation-positive whereas all 10 erlotinib-refractory patients were mutation-negative. Mutations were most commonly observed in patients with adenocarcinomas with or without bronchoalveolar carcinoma features and in never smokers [10]. Additional studies are obviously required. To date, EGFR mutational status has correlated with response rate. Whether it will correlate with survival must be determined. Further, does the observation that small numbers of responders appear to be mutation-negative suggest that there are additional, as yet undiscovered, EGFR mutations? The fact that most patients with EGFR mutations are never-smokers who are female and have adenocarcinomas or bronchoalveolar carcinomas suggests that future study References 1 Perez-Soler R. The role of erlotinib (Tarceva, OSI 774) in the treatment of non-small cell lung cancer. Clin Cancer Res 2004;10:4238s 4240s. 2 Herbst RS, Bunn PA Jr. Targeting the epidermal growth factor receptor in non-small cell lung cancer. Clin Cancer Res 2003;9: Hidalgo M, Siu LL, Nemunaitis J et al. Phase I and pharmacologic study of OSI-774, an epidermal growth factor receptor tyrosine kinase inhibitor, in patients with advanced solid malignancies. J Clin Oncol 2001;19: 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. Proc Am Soc Clin Oncol 2004;23: Herbst RS, Prager D, Hermann R et al. TRIBUTE a phase III trial of erlotinib HCl (OSI-774) combined with carboplatin and paclitaxel (CP) chemotherapy in advanced non-small cell lung cancer. Proc Am Soc Clin Oncol 2004;23:617. populations might be enriched for this patient group. The sponsor has agreed to perform two postmarketing studies in stage IIIB unresectable and stage IV NSCLC patients who have EGFR expression status determined by the method outlined above prior to randomization. Analyses of results will include an assessment of treatment effect in the subgroup with positive EGFR expression status and the subgroup with negative EGFR expression status. In one study, patients with objective responses or stable disease following four cycles of platinum-based chemotherapy will be randomized to receive either erlotinib or placebo maintenance therapy. The primary end point is PFS. In the second study, patients who experienced disease progression or unacceptable toxicity during platinum-based chemotherapy will be randomized to receive erlotinib, pemetrexed (Alimta ; Eli Lilly and Company), or docetaxel (Taxotere ; Aventis Pharmaceuticals Inc.) chemotherapy. The primary end point is overall survival. These two studies, in which 100% of patients will have known DAKO kit EGFR status, should provide useful information on the prognostic value of the determination. Acknowledgment The views expressed are the result of independent work and do not necessarily represent the views and findings of the U.S. Food and Drug Administration. Disclosure of Potential Conflicts of Interest The authors indicate no potential conflicts of interest. 6 Perez-Soler R, Chachoua A, Huberman M et al. A phase II trial of epidermal growth factor receptor kinase inhibitor OSI-774, following platinum based chemotherapy, in patients with advanced, EGFR expressing, nonsmall cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 2001;20: Bailey LR, Kris M, Wolf M et al. Tumor EGFR membrane staining is not clinically relevant for predicting response in patients receiving gefitinib (Iressa, ZD1839) monotherapy for pretreated advanced non-small cell lung cancer: IDEAL 1 and 2. Proc Am Assoc Cancer Res 2003;14:44. 8 Lynch TJ, Bell DW, Sordella R et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non small-cell lung cancer to gefitinib. N Engl J Med 2004;350: Paez JG, Janne PA, Lee JC et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004;304: 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 U S A 2004;101: