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© 2001 American Society for Clinical Oncology
Superior Efficacy of Letrozole Versus Tamoxifen as First-Line Therapy for Postmenopausal Women With Advanced Breast Cancer: Results of a Phase III Study of the International Letrozole Breast Cancer GroupFrom the Rigshospitalet, Copenhagen, Denmark; Petrov Research Institute of Oncology, St Petersburg, Russia; Chinese Academy of Medical Sciences, Beijing, China; Hospital Universitario de la Princesa, Madrid, Spain; Arcipedale Santa Maria Nuova, Reggio Emilia, Italy; Centre Hospitalier Général André-Boulloche, Montbéliard, France; University of Stellenbosch, Cape Town, South Africa; South Carolina Oncology Associates, Columbia, SC; Ziekenhuis Leyenburg, Den Haag, the Netherlands; University of Hamburg, Hamburg, Germany; Regional Center of Oncology, Lodz, Poland; Semmelweis University, Budapest, Hungary; General Hospital, Middelheim, Antwerp, Belgium; Kidwai Memorial Institute of Oncology, Bangalore, India; Turku University Central Hospital, Turku, Finland; St Vincent’s Hospital, Fitzroy, Victoria, Australia; Independent Consultant, Basel; Novartis Pharma AG, Milan, Italy; and Novartis Pharmaceuticals Corporation, East Hanover, NJ. Address reprint requests to Hilary A. Chaudri-Ross, DEP, Novartis Pharma AG, WSJ-27.2.023, CH-4002 Basel, Switzerland; email: hilary_anne.chaudri{at}pharma.novartis.com
PURPOSE: To compare the efficacy and tolerability of tamoxifen with that of letrozole, an oral aromatase inhibitor, with tamoxifen as first-line therapy in postmenopausal women with advanced breast cancer. PATIENTS AND METHODS: Nine hundred seven patients were randomly assigned letrozole 2.5 mg once daily (453 patients) or tamoxifen 20 mg once daily (454 patients). Patients had estrogen receptor– and/or progesterone receptor–positive tumors, or both receptors were unknown. Recurrence during adjuvant antiestrogen therapy or within the following 12 months or prior endocrine therapy for advanced disease precluded enrollment. One prior chemotherapy regimen for metastatic disease was allowed. The primary end point was time to progression (TTP). Secondary end points included overall objective response rate (ORR), its duration, rate and duration of clinical benefit, time to treatment failure (TTF), overall survival, and tolerability. RESULTS: TTP was significantly longer for letrozole than for tamoxifen (median, 41 v 26 weeks). Treatment with letrozole reduced the risk of progression by 30% (hazards ratio, 0.70; 95% confidence interval, 0.60 to 0.82, P = .0001). TTP was significantly longer for letrozole irrespective of dominant site of disease, receptor status, or prior adjuvant antiestrogen therapy. Similarly, TTF was significantly longer for letrozole (median, 40 v 25 weeks). ORR was higher for letrozole (30% v 20%; P = .0006), as was the rate of clinical benefit (49% v 38%; P = .001). Survival data are currently immature and not reported here. Both treatments were well tolerated. CONCLUSION: Letrozole was significantly superior to tamoxifen in TTP, TTF, ORR, and clinical benefit rate. Our results support its use as first-line endocrine therapy in postmenopausal women with advanced breast cancer.
INITIAL PALLIATIVE treatment for postmenopausal women with hormone-sensitive advanced breast cancer is endocrine. Such therapy is better tolerated than cytotoxic chemotherapy and is at least as effective in stopping or slowing tumor growth. Tamoxifen, the current agent of choice as first-line therapy, is at least as effective as other endocrine therapies with less toxicity.1,2 Response rates of between 30% and 45% have been reported for first-line therapy with tamoxifen as well as with other hormonal agents, such as the nonspecific aromatase inhibitor aminoglutethimide or the progestins medroxyprogesterone acetate and megestrol acetate.2-5 However, data suggest that neither progestins nor aminoglutethimide are superior to tamoxifen in efficacy or tolerability.6-8 Patients whose tumors progress after responding to tamoxifen initially can achieve a series of further responses from subsequent second-line therapy with agents such as megestrol acetate or aminoglutethimide. More selective and potent aromatase inhibitors, such as letrozole, have shown superior efficacy and tolerability to megestrol acetate and aminoglutethimide as second-line therapy of advanced breast cancer in postmenopausal women after tamoxifen has failed.9-13 Response rates for these agents used in second-line therapy range from 8% to 24%. Two studies with the selective aromatase inhibitor anastrozole versus tamoxifen were published recently.14,15 In both studies, response rates were similar. In the North American study,14 time to progression (TTP) was in favor of anastrozole, but in the larger, mainly European study, TTP was similar for both treatments. Analysis of the two studies combined16 showed comparable efficacy of anastrozole to tamoxifen, and the authors concluded that their data supported the use of anastrozole as an alternative treatment to tamoxifen in postmenopausal women with advanced breast cancer. The better efficacy and improved safety of letrozole when compared against two other endocrine treatments as second-line therapy suggested that letrozole could show at least similar activity as first-line therapy in advanced breast cancer. This hypothesis led to the study reported here.
Study Design This phase III, randomized, double-blind, double-dummy, parallel-group study was originally designed as a three-arm study, involving two monotherapy arms (letrozole or tamoxifen) and a combination arm of both treatments. After results of a pharmacokinetic study showed that adding tamoxifen to letrozole lowered letrozole blood levels by 38% on average, randomization to the combination arm was stopped.17 The study was then redesigned and rerandomized to include only the monotherapy arms ( Fig 1) and was conducted at 201 centers in 29 countries. Patients were randomly assigned once daily treatment with either letrozole (Femara; Novartis Pharma AG, Basel, Switzerland) 2.5 mg or tamoxifen (Tamofen; Leiras Oy, Turku, Finland) 20 mg using a double-dummy technique with matching placebo tablets. Patients continued treatment until progressive disease (PD) or other reason necessitated discontinuation. If after disease progression or discontinuation of treatment due to an adverse event the patient remained suitable for further endocrine therapy, she could be switched to the alternative (crossover) treatment in a double-blind fashion. Treatment was allocated according to computer-generated randomization lists that used permuted blocks of a fixed size and no stratification. Treatment compliance was monitored by tablet count at each patient visit. All patients are being monitored for overall survival.
The study was conducted in accordance with the ethical principles that originated in the Declaration of Helsinki and the Good Clinical Practice (GCP) requirements of the International Conference on Harmonisation. The appropriate local ethics review boards approved the protocol. All patients gave written informed consent before study enrollment.
Inclusion Criteria
Exclusion Criteria Adjuvant endocrine therapy other than antiestrogens, prior systemic endocrine treatment for advanced disease, systemic investigational drugs within the past 30 days, or topical investigational drugs within the past 7 days precluded enrollment onto the study. Concomitant anticancer treatments, prolonged systemic corticosteroid treatment (except for topical applications, inhaled sprays, eye drops or local injections), chronic concomitant bisphosphonate therapy for hypercalcemia, and bisphosphonate treatment for the prevention of bone metastases were not permitted during the study. Bisphosphonate treatment at the time of randomization or at the start of crossover therapy when progression in bone was documented was allowed for the treatment of bone metastases. Radiation or surgery to a sole site of disease was not permitted. However, radiation or surgery to a limited area other than a sole site of disease was allowed. Irradiated or excised lesions were then considered nonassessable and monitored only for disease progression.
Clinical and Radiologic Assessments
Primary Efficacy Assessments
Secondary Efficacy Assessments Duration of overall objective response was defined for those patients with a confirmed response (CR or PR) as the interval between the date of randomization and the earliest date of disease progression. TTR was defined for those patients with a confirmed response (CR or PR) as the interval between randomization and the earliest documentation of response. The rate of clinical benefit was defined as the proportion of patients who achieved a confirmed objective response (CR or PR) or who had stabilization or no change lasting for 24 weeks or more. Duration of clinical benefit was defined for these patients as the interval between the date of randomization and the earliest date of disease progression. TTF was defined as the interval between the date of randomization and the earliest date of disease progression, withdrawal of study treatment for any reason, withdrawal of consent, loss to follow-up, or death from any cause. The duration of the study was defined as the interval between the earliest date of randomization and the latest date of contact, irrespective of treatment.
Safety Assessments
Statistical Methodology The same sample size would also be sufficient to detect as significant an absolute difference of 10% in overall objective tumor response under similar conditions (two-sided, 5%; 80% power; 10% loss to follow-up or nonassessability of response). All patients with advanced breast cancer documented at study entry and treated at GCP-compliant centers were included in the efficacy intent-to-treat population. Safety analysis excluded patients who never received study drug and patients in GCP-noncompliant centers. Only treatment-emergent adverse events were considered in the analyses. A patient was counted once for any adverse event term, even if the event occurred multiple times. The main end point was TTP. ORR and TTF were major secondary end points, as defined in the protocol. Treatments were compared by Cox proportional hazards regression for all time-to-event variables. Median time to event was estimated by the Kaplan-Meier product-limit method. TTP was censored in the following circumstances: patient was still receiving treatment without evidence of progression, patient died of unknown cause without evidence of clinical deterioration due to breast cancer, and patient discontinued treatment for any reason without evidence of clinical deterioration due to breast cancer before discontinuation. The same censoring rules applied to the estimates of duration of objective response and duration of clinical benefit. TTF was censored for patients who continued to receive treatment without evidence of progression or clinical deterioration due to breast cancer, as well as for patients whose reasons for withdrawal of treatment were clearly documented as unrelated to either study drug or to breast cancer. Overall objective (CR+PR) tumor response rate (ORR) was analyzed by logistic regression. Supportive (prospectively planned) multivariate and stratified analyses were conducted for TTP and ORR. A similar methodology was applied as previously described, but treatment comparisons were adjusted on key baseline covariates of receptor status (at least one receptor positive v no receptor known to be positive), prior adjuvant therapy with antiestrogens (no or yes), and dominant site of disease (soft tissue, bone, or viscera). The dominant site as assessed at baseline was defined as soft tissue if only soft tissue disease was present, as bone if skeletal metastases were present (regardless of coexistent soft tissue disease) without involvement of visceral sites, and as viscera if visceral metastases were present (irrespective of soft tissue or bone involvement). Multivariate analyses (Cox proportional hazards for TTP and logistic regression for ORR) tested the influence of the baseline covariates on the treatment comparison, as well as examined the effect of each covariate in the presence of the other covariates. Stratified analyses (stratified log-rank test for TTP and stratified Mantel-Haenszel test for ORR) compared treatments one covariate at a time. More detailed analyses were also conducted for selected baseline covariates (treatments compared within each stratum of the covariate, applying Cox regression for TTP, and logistic regression for ORR).
A total of 939 postmenopausal women with advanced breast cancer were enrolled onto the study between November 1996 and early January 1999. Thirty-two patients were excluded from the intent-to-treat analysis: 23 had been allocated combination treatment; four (two letrozole, two tamoxifen) had been enrolled at a site found to be GCP-noncompliant (one patient receiving combination therapy was also enrolled at the GCP-noncompliant center); and five patients (three letrozole, two tamoxifen) did not have active, advanced breast cancer at study enrollment. An analysis of TTP, ORR, and TTF including the four patients receiving monotherapy at the GCP-noncompliant center as well as an analysis based on all randomized patients provided almost identical results, and these data are not reported here. Two patients (one letrozole, one tamoxifen) were never treated but were included in the intent-to-treat population. Of the 907 patients in the intent-to-treat population, 453 patients were allocated letrozole therapy and 454 were allocated tamoxifen. Patient baseline characteristics were well balanced in the two treatment arms (Table 1), as were relevant medical histories and concomitant medical conditions. Patients were predominantly white (86%). The Karnofsky performance status score was 80 to 100 (World Health Organization grades 0 and 1) in 92% of patients. At study entry, 93% (841 of 907) of the study population had metastatic disease; they presented with either stage IV disease at enrollment (25%: 114 letrozole, 111 tamoxifen) or with relapsing metastatic disease (68%: 308 patients in each arm). In addition, 62 patients (29 letrozole, 33 tamoxifen) had locally advanced disease and four patients (two letrozole, two tamoxifen) had stage IIA/B disease.
Soft tissue lesions were present in 63% (288 of 456) of the patients in the letrozole arm and 61% (277 of 456) in the tamoxifen arm, with soft tissue being the dominant site in a quarter of all patients. Bone metastases were present in 54% (247 of 456) and 50% (226 of 456) of patients in the letrozole and tamoxifen arms, respectively, and bone was the dominant site in around 30% of patients in each arm. The dominant site of disease was viscera in 43% of the patients in the letrozole arm and 46% of the patients in the tamoxifen arm (Table 1). Liver metastases were present in 13% (60 of 453) of the patients receiving letrozole and 12% (55 of 454) receiving tamoxifen. The percentage of study population who received chemotherapy either as adjuvant chemotherapy or for metastatic disease was low. Of those patients who received adjuvant tamoxifen, the majority (109 of 167) received the antiestrogen for at least 2 years, and the treatment-free interval between stopping the adjuvant therapy and entering the study was more than 2 years in most (126 of 167). The cutoff date for this analysis was March 2000, at which time the overall median duration of the study was approximately 18 months. At this time, 111 patients were still receiving letrozole and 67 patients were receiving tamoxifen. Of the 729 patients who discontinued treatment, 197 letrozole-treated patients and 194 tamoxifen-treated patients entered crossover.
Efficacy Results
Supportive Analyses The results of the supportive multivariate analysis of TTP, with the treatment comparison adjusted on the key baseline covariates of receptor status, prior adjuvant antiestrogen therapy, and dominant site of disease, were very similar to the results of the unadjusted analysis, with letrozole significantly decreasing the risk of progression (hazards ratio, 0.70; 95% CI, 0.60 to 0.81; P = .0001) ( Table 4). This analysis indicated that the presence of visceral metastases significantly increased the risk of progression compared with soft tissue as the dominant site. Bone as the dominant site significantly increased the risk of progression compared with soft tissue as the dominant site. Neither receptor status nor prior adjuvant therapy with antiestrogens significantly affected TTP (Table 4).
The supportive stratified analysis of TTP (for each key baseline covariate) revealed the superiority of treatment with letrozole over tamoxifen (P = .0001 for each covariate). Detailed analysis (within each stratum of the covariate) showed superiority of letrozole over tamoxifen for all strata of the baseline covariates ( Table 5). The median TTP in each stratum was very similar to the overall study results for each treatment.
The results of the supportive multivariate analysis of ORR adjusted on the same key baseline covariates as the analysis of TTP were similar to the results of the unadjusted analysis, with letrozole significantly increasing the odds of achieving CR or PR compared with tamoxifen (odds ratio, 1.80; 95% CI, 1.32 to 2.47; P = .0002) ( Table 6). This analysis indicated that the covariates that influenced overall response were similar to those that influenced TTP, with the addition of prior adjuvant antiestrogen therapy. The odds of achieving a response were significantly reduced in patients with visceral involvement or bone as the dominant site of disease compared with patients with soft tissue disease only; prior adjuvant antiestrogen therapy significantly reduced the odds of achieving a response compared with antiestrogen-naive patients; a trend was observed for higher odds of achieving an objective tumor response in receptor-positive patients compared with receptor-unknown patients (Table 6).
The supportive stratified analyses of ORR were consistent with the multivariate analyses and revealed the superior ORR of letrozole over tamoxifen on key covariates (P = .001 for each covariate). Detailed analysis of ORR showed superiority of letrozole over tamoxifen for all strata of the baseline covariates except for unknown hormone receptor status and bone as the dominant site of disease, where a clear trend toward superiority in favor of letrozole was seen ( Table 7). In general, ORR in each stratum was very similar to the overall study results. However, in patients who had been exposed to adjuvant antiestrogen therapy, ORR was dramatically lowered for tamoxifen (8%) compared with the overall study results for tamoxifen (Table 7).
Safety A total of 910 patients (455 in each treatment arm) were included in the safety analysis of the two monotherapies. Most patients experienced at least one adverse event during treatment (including worsening of tumor-related symptoms). The nature and frequency of adverse events were similar for the letrozole and tamoxifen treatment arms ( Table 8).
Adverse events suspected to be related to the study drug were reported with similar frequency (38% for letrozole and 37% for tamoxifen) and were similar in nature for both treatments. Adverse events with suspected causality reported for more than 5% of patients were hot flushes, nausea, and hair thinning (Table 8). Thromboembolic events irrespective of drug relationship were reported in 1% (six patients) of the letrozole arm and in 2% (11 patients) of the tamoxifen arm. Pulmonary embolism irrespective of study drug relationship was reported in two patients, one in each treatment arm. The frequency of discontinuation due to an adverse event, withdrawal of consent, or death was similar in both groups, with 7% overall discontinuing for these reasons. Most discontinuations for adverse events were associated with progression of disease. The nature and frequency of laboratory abnormalities were similar for the letrozole and tamoxifen arms, and no clinically meaningful trends were observed.
This is the largest single study to date conducted with an aromatase inhibitor in the first-line endocrine treatment of advanced breast cancer. The results clearly show letrozole to be more effective than the established first-line endocrine therapy, tamoxifen, in the treatment of advanced breast cancer in postmenopausal women. Letrozole was superior to tamoxifen in TTP, reducing the risk of progression by 30% (hazards ratio, 0.70; 95% CI, 0.60 to 0.82; P = .0001) compared with tamoxifen. Median TTP was prolonged by 57%, 41 weeks for letrozole and 26 weeks for tamoxifen. Letrozole was also significantly superior for the secondary end points TTF, ORR, and rate of clinical benefit, with a similar median duration of objective response and similar duration of clinical benefit. The robustness of this result is supported by the consistency of results among different subgroups within the trial. Although approximately one third of patients had tumors of unknown receptor status, the consistency of results with ER and/or PgR positivity supports the sensitivity of these patients to endocrine treatment. The safety and tolerability of the two drugs were quite similar, and there was no evidence that the greater efficacy of letrozole was associated with any increase in the number or seriousness of adverse events compared with tamoxifen. The two recently published trials with anastrozole versus tamoxifen conducted in North America14 and mainly European countries15 were designed with very similar inclusion/exclusion criteria. However, the demographics of the two studies were different, mainly in receptor status (proportion of receptor-unknown patients, 11% v 55%), prior adjuvant endocrine therapy (20% v 11% of the patients), and site of disease. The patient population of the present study appeared to resemble that of the combined study, which showed comparable efficacy of anastrozole and tamoxifen.16 Our study was analyzed by geographic area (prespecified analysis), namely Europe, North America, and rest of the world. Letrozole was significantly superior to tamoxifen in TTP in all three areas, with closely similar hazards ratios for each region (approximately 0.7).19 An important feature of the results from the letrozole study reported here, which is also supported by recently published trials,16,20,21 is the consistently lower response rate for tamoxifen of approximately 20% (despite a similar and consistently reported median TTP of approximately 6 months for tamoxifen) compared with that reported previously in the literature for a similar population.22 This divergence in tamoxifen response rates may possibly be a consequence of the stricter criteria used to confirm response in this study. Another feature of the current study that needs comment and that is of importance for the future use of letrozole is the fact that less than 20% of the patients had received adjuvant tamoxifen. This is similar to the 18% to 21% reported in the anastrozole studies.16 As more and more patients receive adjuvant tamoxifen, it is to be expected that in the future a much larger proportion of patients will relapse after adjuvant tamoxifen, thus possibly making them less responsive to tamoxifen in the advanced setting. Consequently, an agent like letrozole for use in first-line advanced breast cancer is a significant therapeutic advance. A recently completed, randomized, double-blind, multicenter study comparing the efficacy of 4 months of therapy with letrozole and tamoxifen as primary treatment in the preoperative setting confirms the superior efficacy of letrozole over tamoxifen.23 Response rate assessed by clinical palpation (primary end point) was 55% for letrozole compared with 36% for tamoxifen (P < .001). Response rates were similarly significantly in favor of letrozole when assessed by ultrasound or mammography. A study in the adjuvant setting comparing letrozole and tamoxifen is underway at the present time. Preclinical data in vitro and in vivo comparing letrozole with anastrozole and tamoxifen show that letrozole is significantly more potent in vitro and more efficacious in vivo.24-27 The effects of letrozole, anastrozole, and tamoxifen have been compared in a tumor xenograft nude mouse model described by Brodie et al. In this model, letrozole was the most efficacious agent in reducing tumor size.28-30 The preclinical data lend support to the improved efficacy of letrozole seen in the clinical setting. In conclusion, the data reported here document the superior efficacy of letrozole compared with tamoxifen and strongly support the use of letrozole in the first-line endocrine treatment of advanced breast cancer in postmenopausal women.
APPENDIX Argentina: L. Balbiani, C. Castillo, F. Coppola, R. De Angelis, L. Fein, L. Freue, C. Lopez, J. Martinez, E. Mickiewicz, E. Palazzo, H. Requejo, L. Silberman, M. Torello, R. Viroglio, and R. Wainstein. Australia: E. Abdi, R. Bell, P. Craft, D. Dalley, M. Green, D. Grimes, P. Harnett, R. Kimber, J. McKendrick, J. Stewart, and J. Trotter. Austria: M. Stierer and V. Wette. Belgium: F. Bastin, L. Dirix, L. Marcelis, and D. Vanstraelen. Canada: M. Blackstein, F. Couture, C. Germond, and S. Legault-Poisson. Chile: L. Prieto and L. Soto Diaz. Denmark: E. Andersen, J. Andersen, S. Cold, C. Gadeberg, P. Grundtvig, C. Kamby, N. Keldsen, M. Kjaer, E. Madsen, K. M/oller, P. Philip, and E. Sandberg. Egypt: M. Hamza and O. Zaki. Finland: G. Blanco and V. Kataja. France: B. Audhuy, A. Daban, T. Delozier, P. Fargeot, O. LeFloch, A. Lortholary, E. Malaurie, M. Marty, L. Mauriac, L. Mignot, F. Morvan, M. Namer, G. Netter-Pinon, P. Quetin, G. Romieu, M. Spielmann, N. Tubiana-Mathieu, and B. Weber. Germany: W. Abenhardt, M. Brandtner, R. Dengler, G. von Minckwitz, P. Reichardt, F. Opri, K. Possinger, and S. Völkl. Great Britain: S. Chan, N. Davidson, TRJ Evans, T. Iveson, R. Leonard, R. Mansel, C. Price, and J. Robertson. Greece: G. Arvantinos, V-A Georgoulias, and N. Pavlidis. Hungary: Z. Faluhelyi, M. Kispál, T. Nagykálnai, and J. Szántó. Iceland: H. Sigurdsson. India: I. Mittra and V. Raina. Israel: B. Kaufman, T. Tichler, and N. Wigler. Italy: P. Carlini, M. Cremonesi, M. D’Aprile, F. Di Costanzo, M. Fornasiero G. Francini, M. Indelli, A. Molino, G. Monti, A. Pacagnella, R. Silva, and E. Villa. Netherlands: E. Balk, J. Coenen, E. Maartense, J. Nortier, D. Richel, W. van Deijk, S. van der Vegt, F. van Nierop, and H. van Veelen. New Zealand: S. Costello. Poland: P. Koralewski. Portugal: M. Pinto. Russia: A. Garin, V. Gorbunova, and M. Litchinitser. South Africa: N. Cronje, C. Falkson, L. Goedhals, C. Jacobs, J. Jordaan, J. Raats, I. Werner, and A. Zietsman. Spain: A. Balil, R. Bastús, J. Illarramendi, and A. Llombart-Cussac. Sweden: M. Albertsson and A. Malmstr/om. United States: M. Alden, R. Asbury, C. Badolato, E. Balcueva, J. Bitran, R. Blachly, D. Blayney, T. Brotherton, R. Brown, L. Campos, R. Chapman, F. Cummings, M. Ellis, R. Fredric, J. Hainsworth, G. Harrer, S. Jubelirer, L. Kalman, J. Kroener, M. Levin, M. Lewis, J. Liebmann, R. Marsh, J. McCann, S. McCachren, J. McCracken, B. O’Connor, R. Odders, D. Osborn, K. Pendergrass, B. Pruitt, R. Rodriguez, M. Rubin, T. Shiftan, P. Silverman, S. Tchekmedyian, W. Waterfield, K. Weichert, R. Yanagihara, B. Yanes, F. Yunus, and M. Zimmer. Uruguay: C. Garbino and G. Sabini.
Supported by Novartis Pharma AG, Basel, Switzerland. We acknowledge Ajay Bhatnagar for preparing an early draft of the manuscript, as well as for his continuous support; Franzanne Vreeland, MD, for study design; Elizabeth Baguley and her team for data management; Carolyn Brady and Carol Gano for study management; Malek Belmatoug for programming; Katrina Masih for statistical analysis; and all study investigators and study monitors worldwide. In addition, we acknowledge Lakeland Clinical for technical support.
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ABSTRACT
INTRODUCTION
