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Journal of Clinical Oncology, Vol 25, No 12 (April 20), 2007: pp. 1545-1552 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.05.1474 Phase III Study of Erlotinib in Combination With Cisplatin and Gemcitabine in Advanced Non–Small-Cell Lung Cancer: The Tarceva Lung Cancer Investigation Trial
From the Zentrum Fur Pneumologie Und Thoraxchirurgie, Krankenhaus D LVA; Pneumology, Hospital Harburg, Hamburg; Asklepios Fachkliniken Muenchen-Gauting, Onkologie, Gauting, Germany; Chemotherapy Clinic, Medical Academy of Lodz, Lodz; Mazowieckie Centrum Leczenia Chorob Pluc I Gruzlicy, Oddzial III, Otwock; Akademia Medyczna W Lublinie, Karedra I Klinika Chorob Pluc, Lublin; Oddzial Chemioterapii, Szpital Morski Im. Pck, Gdynia; Specjalistyczny Szpital Im., Oddzial Chemioterapii, Szczecin; Wielkopolskie Centrum Chorób P Address reprint requests to Ulrich Gatzemeier, MD, Department of Thoracic Oncology, Hospital Grosshansdorf, Grosshansdorf, Germany; e-mail: pneumo.onko{at}t-online.de
Purpose: Erlotinib is a potent inhibitor of the epidermal growth factor receptor tyrosine kinase, with single-agent antitumor activity. Preclinically, erlotinib enhanced the cytotoxicity of chemotherapy. This phase III, randomized, double-blind, placebo-controlled, multicenter trial evaluated the efficacy and safety of erlotinib in combination with cisplatin and gemcitabine as first-line treatment for advanced non–small-cell lung cancer (NSCLC). Patients and Methods: Patients received erlotinib (150 mg/d) or placebo, combined with up to six 21-day cycles of chemotherapy (gemcitabine 1,250 mg/m2 on days 1 and 8 and cisplatin 80 mg/m2 on day 1). The primary end point was overall survival (OS). Secondary end points included time to disease progression (TTP), response rate (RR), duration of response, and quality of life (QoL). Results: A total of 1,172 patients were enrolled. Baseline demographic and disease characteristics were well balanced. There were no differences in OS (hazard ratio, 1.06; median, 43 v 44.1 weeks for erlotinib and placebo groups, respectively), TTP, RR, or QoL between treatment arms. In a small group of patients who had never smoked, OS and progression-free survival were increased in the erlotinib group; no other subgroups were found more likely to benefit. Erlotinib with chemotherapy was generally well tolerated; incidence of adverse events was similar between arms, except for an increase in rash and diarrhea with erlotinib (generally mild). Conclusion: Erlotinib with concurrent cisplatin and gemcitabine showed no survival benefit compared with chemotherapy alone in patients with chemotherapy-naïve advanced NSCLC.
Lung cancer is a major cause of morbidity and mortality,1-4 and the majority of new cases are advanced non–small-cell lung cancer (NSCLC).5 The standard first-line treatment for advanced NSCLC is a platinum-based two-drug combination regimen.6 However, no doublet regimen has proved superior,7-10 and survival outcomes are poor (median survival, 8 to 10 months; 1-year survival rate 35% to 40%).11 Thus, new, well-tolerated treatments that can improve overall survival (OS) in NSCLC are urgently needed. The epidermal growth factor receptor (EGFR) has a pivotal role in tumorigenesis,12-14 with many human cancers overexpressing EGFR,15-17 including up to 80% of NSCLCs. Overexpression of EGFR is associated with advanced disease and poor survival.18,19 Erlotinib (Tarceva; F. Hoffmann-La Roche, Basel, Switzerland) is a highly potent, orally active EGFR tyrosine-kinase inhibitor (TKI) that has shown significant antitumor activity in preclinical studies.20-23 Evidence of antitumor activity with single-agent erlotinib came from phase I/II studies in previously treated patients. In one phase II trial in NSCLC, median OS was 8.4 months and 1-year survival was 40%.27 Erlotinib was generally well tolerated at 150 mg/d (the maximum tolerated dose).24-28 In a large phase III trial in previously treated patients with advanced NSCLC, erlotinib significantly prolonged survival versus placebo (6.7 v 4.7 months; hazard ratio [HR], 0.70; P < .001), delayed disease progression, and delayed worsening of disease-related symptoms.29,30 This is the only placebo-controlled trial to have shown prolonged survival with an EGFR inhibitor in advanced NSCLC. Cisplatin plus gemcitabine is widely used for first-line treatment of advanced NSCLC. In A549 human NSCLC xenografts, erlotinib showed additive effects with gemcitabine, and synergism with cisplatin.31 Although no phase I/II trials had evaluated the triplet regimen, it was postulated that adding erlotinib could lead to improved efficacy, without significant additional toxicity. The toxicity profile of cisplatin plus gemcitabine (involving neutropenia, thrombocytopenia, nausea, and vomiting32,33) is distinct from that of erlotinib. Here we report the results of a phase III, randomized, placebo-controlled trial (Tarceva Lung Cancer Investigation [TALENT]) of cisplatin and gemcitabine with or without erlotinib in patients with previously untreated advanced NSCLC.
Eligibility Criteria Entry criteria included histologically documented, unresectable, locally advanced, recurrent or metastatic (stage IIIb/IV) NSCLC; age  18 years; Eastern Cooperative Oncology Group performance status 0 or 1; and adequate hematologic, renal, and hepatic function. Exclusion criteria included prior chemotherapy/systemic antitumor therapy or exposure to human epidermal growth receptor–directed agents; unstable systemic disease; other malignancies within 5 years; and any significant ophthalmologic abnormalities. The study was conducted at 164 centers in 27 countries in Europe, Canada, South America, and Australasia. All patients provided written informed consent. Approval was obtained from each center's independent ethics committee. The study conformed to the principles of the Declaration of Helsinki34 and Good Clinical Practice guidelines.35
Trial Design Patients then received erlotinib 150 mg/d or placebo, in combination with a maximum total of six 21-day cycles of chemotherapy, in the absence of disease progression (Fig 1). Initially, all patients received gemcitabine 1,250 mg/m2 on days 1 and 8 and cisplatin 80 mg/m2 on day 1 of each cycle. Patients continued to receive erlotinib or placebo until unacceptable toxicity or death. On disease progression, patients could continue with study treatment (erlotinib or placebo), with or without second-line therapy or, alternatively, receive second-line therapy alone.
Assessments The primary end point was OS (time from random assignment to death, irrespective of cause). Secondary end points included time to disease progression (TTP; time from random assignment to disease progression or death, whichever was first); response rate (RR; according to Response Evaluation Criteria in Solid Tumors)36; duration of response; quality of life (QoL); EGFR expression; pharmacokinetic (PK) parameters; and safety. QoL was evaluated by the time to symptomatic progression (the time from random assignment to the first QoL assessment when symptomatic progression was identified). Symptomatic progression was defined as a worsening from baseline in the average symptom burden index by 25% on the Lung Cancer Symptom Scale. Where possible, tumor EGFR expression was assessed at baseline by immunohistochemistry (EGFR pharmDx; DakoCytomation, Carpinteria, CA). Samples were scored for membrane staining (0, 1+, 2+, 3+) according to the highest intensity seen in at least 10% of the cells. PK analysis of erlotinib, gemcitabine, and cisplatin was performed in the initial 50-patient safety cohort (study-intensive PK) and in the main phase of the trial (study-population PK). Study-intensive PK samples were collected predosing and at intervals for 24 hours postdose on days –1, 1, and 7 of cycle 1 for the analysis of erlotinib and its active metabolite, OSI-420. Gemcitabine and cisplatin were analyzed in blood samples collected pre- and postinfusion on day 1 of cycle 1. Study-population PK samples for erlotinib evaluation were taken predose from at least 400 patients on day 1 of cycles 1 to 4. The first 400 patients randomly assigned in the main phase of the trial underwent intense safety evaluation, with monitoring of adverse events (AEs), laboratory data, population PKs, and PK samples for premature discontinuations, medical resource use, and ophthalmologic examinations. For the remaining patients, safety was monitored using National Cancer Institute Common Toxicity Criteria.
Statistical Analysis
Secondary efficacy parameters were analyzed using a two-sided log-rank test (TTP and time to symptomatic progression) and a
Patients A total of 1,172 patients (586 per treatment arm) were randomly assigned between November 2001 and September 2002. The number of treated patients in each arm was 580 (erlotinib) and 579 (placebo). Baseline demographics and disease characteristics were well balanced between treatment arms (Table 1).
Efficacy OS was similar for the erlotinib and placebo arms (Fig 2). Median OS was 43 and 44.1 weeks, respectively (HR, 1.06; 95% CI, 0.90 to 1.23; P = .49). One-year survival rates were 41% and 42%, respectively. Median overall TTP was 23.7 and 24.6 weeks, respectively (HR, 0.98; 95% CI, 0.86 to 1.11; P = .74).
The proportion of patients with objective responses (complete and partial) was also similar (31.5% v 29.9% for erlotinib and placebo, respectively). More than 50% of patients in both groups had a partial response or stable disease. The duration of response was significantly greater for erlotinib than for placebo (median, 25.4 v 23.9 weeks, respectively; HR, 0.77; 95% CI, 0.60 to 1.00; P = .045; Fig 3). The median time to symptomatic progression (QoL) was similar between treatment groups (68 v 76 days; n = 1,054).
Exploratory subgroup analyses of OS, TTP, and tumor response by baseline characteristics (as shown in Table 1) showed no better or worse outcomes in any subgroup than overall. Median survival was 227 days in patients without rash, versus 323 days (grade 1 rash), 313 days (grade 2), and 387 days (grade 3; P = .0001, log-rank test) in patients with rash. Smoking history was collected retrospectively, and was available for a small number of patients. Median survival in never-smokers (n = 10) was 11.4 months with placebo, but was not reached with erlotinib (n = 8). Median progression-free survival was longer with erlotinib (7.9 months) than with placebo (5.4 months; HR, 0.195; P = .02). EGFR expression was analyzed in 376 tumor samples; the final score was available for 375 samples. The distribution of immunohistochemistry scores was similar in the placebo and erlotinib arms (0+, 30% and 33%; 1+, 9% and 9%; 2+, 19% and 20%; 3+, 32% and 40% for placebo and erlotinib arms, respectively). EGFR expression was not correlated with response or survival.
Duration of Therapy, Exposure, and PK Parameters Exposure was similar between the treatment groups, although mean and median cumulative exposures were slightly lower for erlotinib (23.2 and 18.9 g, respectively) than for placebo (26.8 and 24.9 g). The mean daily dose of erlotinib (134.7 mg/d) was slightly lower than that for placebo (145.2 mg/d). More than 50% of patients in both arms received five or six cycles of chemotherapy; there were only marginal differences in cumulative exposure. Blood samples from 12 patients in the initial safety cohort showed no difference in PK parameters between erlotinib administered alone (day –1) or with cisplatin and gemcitabine (cycle 1, day 1; Fig 4). Furthermore, erlotinib concentrations after daily dosing (cycle 1, day 7) were similar to those on days –1 and 1 of cycle 1, indicating no effect of repeated dosing with cisplatin and gemcitabine on the PK of erlotinib. PK parameters for cisplatin and gemcitabine were unaffected by coadministration of erlotinib (data not shown).
Second-Line Therapy Of the 348 patients (179 erlotinib, 169 placebo) who received additional chemotherapy (mostly second-line therapy), the most frequently prescribed treatment was docetaxel (67 erlotinib, 88 placebo); the next most used were carboplatin and vinorelbine. Median survival time (with second-line treatment censored) was 44.9 weeks (erlotinib) and 48.7 weeks (placebo; HR, 1.08), whereas median survival regardless of second-line therapy was 43 and 44.1 weeks for the erlotinib and placebo groups, respectively (HR, 1.06).
Safety and Tolerability
The combination of erlotinib, cisplatin, and gemcitabine was generally well tolerated and did not produce substantial additional toxicity. Overall, a slightly higher proportion of AEs in the erlotinib group was considered treatment related (63.3% v 56.9%). The incidence of grade 3/4 AEs for erlotinib plus chemotherapy (77%) was only marginally higher than for chemotherapy alone (72%). Similarly, only slightly greater incidence of serious AEs was seen with erlotinib plus chemotherapy (53%) than chemotherapy alone (47%), and slightly more patients withdrew from treatment because of AEs (22% v 17%), mainly due to skin disorders (5% v < 1%). Two occurrences of interstitial lung disease (ILD) were recorded in the placebo group, but were not serious. One patient receiving erlotinib died as a result of atypical primary pneumonia, which was considered remotely related to treatment, and postmortem examination revealed ILD. During the trial, 680 patients died: 343 (59%) in the erlotinib arm and 337 (58%) in the placebo arm. Most deaths were attributable to disease progression (277 and 268, respectively). A similar number of patients died as a result of an AE in each treatment arm (64 v 68, respectively). Of these AEs, almost all were considered unrelated to study medication. Nine AEs leading to death were probably related to treatment (eight erlotinib, one placebo). These were renal failure (n = 2), neutropenia/febrile neutropenia/neutropenic sepsis (n = 3), dyspnea (n = 1), cardiovascular disorder (n = 1), and myocardial infarction (n = 1; placebo).
This study examined the efficacy and safety of erlotinib combined with cisplatin and gemcitabine for first-line treatment of advanced NSCLC. Overall, the erlotinib combination did not show any survival benefit compared with chemotherapy alone; median OS was 43 weeks for erlotinib plus chemotherapy and 44.1 weeks for placebo plus chemotherapy. There were no significant differences in TTP, RR, or time to symptomatic progression (QoL) between the two groups. Similar results were reported from a phase III trial of erlotinib plus carboplatin and paclitaxel (TRIBUTE [Tarceva responses in conjunction with paclitaxel and carboplatin]), in advanced NSCLC.37 These results are also consistent with phase III trials of the EGFR TKI gefitinib combined with platinum-based chemotherapy.38,39 Most AEs seen during the study were attributable to disease progression or chemotherapy. Diarrhea and skin toxicity were the most common AEs in the erlotinib group. Erlotinib plus chemotherapy was associated with a small increase in serious AEs and treatment-related deaths. An unexpected finding was an increased incidence in renal failure with the erlotinib combination (5% v < 1%). This increase probably was due to insufficient hydration after erlotinib-related diarrhea, thus exacerbating the known renal toxicity of cisplatin.40 No increase in renal failure was observed with erlotinib plus carboplatin (a less renal-toxic drug) and paclitaxel.37 A high incidence of ILD was reported in NSCLC patients treated with gefitinib in Japan.41,42 In the current study, two of the three patients with ILD had received placebo, indicating that ILD can be related to disease progression rather than EGFR TK inhibition. The findings of the current study are in contrast with preclinical and other clinical studies with erlotinib. In mice bearing human NSCLC xenografts, coadministration of erlotinib with cisplatin or gemcitabine produced additive or synergistic antitumor activity.31 In patients with advanced pancreatic cancer, erlotinib plus gemcitabine prolonged survival significantly. This was the first trial to show an improvement in survival in pancreatic cancer by adding a second drug to gemcitabine, and led to approval of erlotinib for the treatment of pancreatic cancer in the United States.43 Furthermore, in a phase III trial (BR.21), erlotinib monotherapy significantly improved survival (42.5%) compared with placebo (6.7 v 4.7 months; HR, 0.70; P < .001) in 731 patients with previously treated, advanced NSCLC,29 leading to approval in a number of countries (including the United States and European Union) as second-/third-line monotherapy for advanced NSCLC. Conversely, the lack of benefit seen here is analogous to other findings in advanced NSCLC, in which the addition of a third cytotoxic drug provided minimal survival benefit compared with newer two-drug combinations,7,44-46 possibly due to greater toxicity with triplets. The reasons for the lack of benefit from erlotinib plus chemotherapy are unknown, but the PK results indicate that erlotinib had no effect on plasma levels of either cisplatin or gemcitabine, or vice versa. Thus, a negative PK interaction between erlotinib and chemotherapy is unlikely. An analysis of the BR.21 study indicated that smoking reduces erlotinib exposure due to induction of cytochrome P450IA enzymes.47 This may help to explain the apparent survival benefit among never-smokers in the current study, but due to the small numbers of patients involved, this is only supposition. Among never-smokers in the TRIBUTE study (n = 72), addition of erlotinib led to a more than two-fold improvement in median survival versus chemotherapy alone. TTP was also prolonged; the RR was 30% for erlotinib plus chemotherapy versus 11% for chemotherapy alone.37 There was no clear association between EGFR expression and response, corroborating previous findings with erlotinib and other EGFR TKIs in NSCLC.27,37,48,49 However, the methods used may have been insufficiently sensitive to detect this effect; chemotherapy may be another confounding factor. EGFR TK mutations seem to be associated with tumor response to another EGFR TKI, gefitinib, in NSCLC.50,51 However, there has been no prospective correlation between the presence of mutations and OS. In a small retrospective study, mutations were found in five of seven tumors from NSCLC patients sensitive to erlotinib and were found more commonly in never-smokers. None were found in nonresponding tumors.52 Tumor samples from TALENT currently are being analyzed for mutations; the results will be published separately.53 The lack of an additive effect with erlotinib and chemotherapy may relate to a mechanistic interaction. Erlotinib and gemcitabine/cisplatin have different mechanisms of action (cytostatic and cytotoxic, respectively). The antiproliferative effects of erlotinib, arising from cell-cycle arrest,22 may render tumor cells less sensitive to cytotoxic agents, as suggested by recent preclinical studies of combinations of EGFR TKIs with chemotherapy.54,55 Erlotinib also has proapoptotic effects22 that could enhance the antitumor effects of chemotherapy, and this may be more prominent in tumors with mutant EGFR than those with wild-type receptors.56 This may partly explain the benefit seen in never-smoking patients, who are more likely to have mutations. The mechanisms by which erlotinib may achieve antitumor activity when added to chemotherapy are unclear, as shown by the improvement in survival with erlotinib plus gemcitabine in pancreatic cancer. Preclinical data suggest that alternative dosing schedules, such as sequential or pulse dosing of erlotinib, may prove more effective than concurrent administration.54 In the current trial, patients treated with erlotinib for more than 150 days showed increased response duration compared with placebo, suggesting that treatment with erlotinib after chemotherapy may be beneficial; maintenance therapy with erlotinib is the subject of an ongoing investigation. As reported in a phase II NSCLC trial,27 a relationship between treatment-emergent rash and survival was observed, but the relevance is unclear. Rash is also common with other compounds targeting EGFR. In conclusion, TALENT did not demonstrate improved efficacy from addition of erlotinib to cisplatin and gemcitabine in patients with previously untreated, advanced NSCLC. Long survival times were seen in a small number of patients who had never smoked. The triplet combination was well tolerated, confirming the good tolerability of erlotinib. Alternative dosing schedules are being investigated, to integrate effectively erlotinib with chemotherapy in advanced NSCLC, and analyses to identify patients most likely to benefit from erlotinib are ongoing.
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment: Flavio De Rosa, F. Hoffmann-La Roche Ltd Leadership: Flavio De Rosa, F. Hoffmann-La Roche Ltd Consultant: Ulrich Gatzemeier, AstraZeneca, Eli Lilly & Co, Roche Stock: Flavio De Rosa, F. Hoffmann-La Roche Ltd Honoraria: Ulrich Gatzemeier, Alfacell, Biogenerix, Pierre Fabre Research Funds: Ulrich Gatzemeier, Bayer; Aleksandra Szczesna, Quintiles; Rodryg Ramlau, Roche Testimony: N/A Other: N/A
Conception and design: Flavio De Rosa Financial support: Flavio De Rosa Provision of study materials or patients: Ulrich Gatzemeier, Anna Pluzanska, Aleksandra Szczesna, Eckhard Kaukel, Jaromir Roubec, Janusz Milanowski, Hanna Karnicka-Mlodkowski, Milos Pesek, Piotr Serwatowski, Rodryg Ramlau, Terezie Janaskova, Johan Vansteenkiste, Janos Strausz, Georgy Mioseevich Manikhas, Joachim Von Pawel Collection and assembly of data: Joachim Von Pawel Final approval of manuscript: Ulrich Gatzemeier, Anna Pluzanska, Aleksandra Szczesna, Eckhard Kaukel, Jaromir Roubec, Flavio De Rosa, Janusz Milanowski, Hanna Karnicka-Mlodkowski, Milos Pesek, Piotr Serwatowski, Rodryg Ramlau, Terezie Janaskova, Johan Vansteenkiste, Janos Strausz, Georgy Mioseevich Manikhas, Joachim Von Pawel
The authors thank their collaborator, Ulrich Brennscheidt, MD, who regrettably died before finalization of this manuscript, for the invaluable contribution to the design and conduct of the study. We also thank J. Phillipson of Gardiner-Caldwell Communications for assistance in drafting the manuscript.
Supported by F. Hoffmann-La Roche Ltd. Presented in part at the 40th Annual Meeting of the American Society of Clinical Oncology, June 5-8, 2004, New Orleans, LA. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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uc i Gru
licy, Pozna
Poland; Klinika TBC a Respiracnich Onemocneni, Ostrava-Poruba, Czech Republic; F. Hoffmann-La Roche, Basel, Switzerland; Fakultni Nemocnice V Plzni, Plicni Klinika, Plzen; Vitkovicka Nemocnice Bma A.S., Plicni Oddeleni, Ostrava, Czech Republic; Department of Pulmonary Medicine, Universitair Ziekenhuis Leuven, Leuven, Belgium; 2nd Department of Pulmonary Medicine, Institute of Pulmonary Medicine Torokbalint, Torokbalint, Hungary; and the Pulmonary Department, St Petersburg City Oncological Dispensary, St Petersburg, Russian Federation
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ABSTRACT
INTRODUCTION
For disease progression, patients could continue receiving either study drug (erlotinib or placebo) in combination with second-line chemotherapy or chemotherapy alone. 
Treatment continued to data cutoff point on June 30, 2003.
2 test (objective RR), whereas Kaplan-Meier survival analysis was used to estimate medians and 95% CIs (duration of survival, TTP, and duration of response). PK data were analyzed by noncompartmental methods using WinNonLin version 4.0.1 (Scientific Consultant, Apex, NC; Pharsight Corp, Mountain View, CA). Safety analyses were performed for all patients who received at least one dose of trial medication and had at least one safety follow-up visit. 
