Pivotal Trials of Letrozole: A New Aromatase Inhibitor

ABSTRACT: Letrozole (Femara) is a nonsteroidal aromatase inhibitor that is approximately 10,000 times as potent as aminoglutethimide in vivo. Two pivotal multinational phase III trials have compared letrozole (0.5 and 2.5 mg/d) against megestrol acetate and aminoglutethimide, respectively, in patients with locally advanced or metastatic breast cancer. The letrozole vs megestrol acetate trial showed the superiority of letrozole (2.5 mg/d) over megestrol acetate with respect to response rate, response duration, duration of overall clinical benefit (complete response plus partial response plus stable disease ³ 6 months), time to progression, and time to treatment failure. The letrozole-treated patients also showed a nonsignificant trend toward better survival. In the letrozole vs aminoglutethimide trial, letrozole (2.5 mg/d) was significantly superior in terms of duration of overall clinical benefit and survival. There were also strong trends favoring letrozole with regard to objective response rate and duration of response. Unexpectedly, both trials demonstrated a dose-response effect for 2.5 mg of letrozole over 0.5 mg in terms of response and overall survival. This finding raises the possibility that intratumoral aromatase suppression may be more relevant in breast cancer therapy than are plasma estrogen levels.[ONCOLOGY(Suppl 5):41-44, 1998]

Over the last 15 years, inhibitors of aromatase, the enzyme responsible for estrogen biosynthesis, have been found to be active agents in the treatment of breast cancer. Aminoglutethimide, the first aromatase inhibitor, was shown to be an effective, useful agent,[1] with activity at least equivalent to that of tamoxifen (Nolvadex)[2] in advanced breast cancer. Aminoglutethimide was associated with unwanted side effects, however, including somnolence (at higher doses) and rash.[3]

The next step in the clinical development of aromatase inhibitors was 4-hydroxyandrostenedione (formestane), the first steroidal compound to be structurally designed to inhibit aromatase.[4] This agent proved to be more specific than aminoglutethimide and had fewer systemic side effects, but it had poor oral availability and therefore had to be given by intravenous injection.[5]

A third generation of nonsteroidal imidazole aromatase inhibitors has now been developed; these new inhibitors are several orders more potent than aminoglutethimide. The first of the third-generation agents, fadrozole (COS 16949A), initially led the field in clinical trials. It gradually became apparent, however, that fadrozole had minor but unwanted aldosterone-suppressing effects.

Three other important imidazole-type aromatase inhibitors are now in advanced clinical trials or are registered for use in advanced breast cancer: anastrozole (Arimidex), vorozole (Rivizor), and letrozole (Femara). This paper focuses on the clinical development of letrozole, with particular emphasis on the pivotal large phase III clinical trials that led to its approval by the FDA for use in the treatment of advanced breast cancer.

Potency and Endocrine Effects

Letrozole is a nonsteroidal triazole derivative. One of the most potent aromatase inhibitors yet developed, letrozole is approximately 10,000 times as potent as aminoglutethimide in vivo, with no evidence of inhibition of other steroid pathways at doses required to inhibit estrogen.[6] In animal models, it achieves almost complete regression of estrogen-dependent, dimethylbenzanthracene-induced mammary tumors.[6]

Endocrine Effects

In a phase I study conducted at the Royal Marsden Hospital, 21 postmenopausal patients were treated with letrozole in three successive groups of seven, receiving 0.1, 0.5, and 2.5 mg/d orally, respectively. Letrozole produced a statistically significant suppression of estradiol by 74% from baseline levels and estrone by 79% (P < .0001). Suppression occurred in all three patient groups, with many patients having serum estradiol and estrone concentrations below the limit of detection of the assays (3 and 10 pM, respectively), corresponding to a maximum measurable estrogen suppression of 86%.[7] Letrozole had no significant effect on serum follicle-stimulating hormone (FSH), thyroid-stimulating hormone (TSH), cortisol, 17-hydroxyprogesterone, androstenedione, or aldosterone.

In a subsequent Royal Marsden phase I trial of letrozole specifically designed to measure aromatase inhibition in vivo (see below), 13 patients were randomly allocated to 0.5 and 2.5 mg/d.[8] Estrone and estradiol levels fell by 82% and 84.1%, respectively, at 0.5 mg/d and by 81% and 68%, respectively, at 2.5 mg/d.

In a nonrandomized comparative phase I clinical efficacy study, Demers et al[9] compared the endocrine-suppressing effects of fadrozole and letrozole using the same high-sensitivity estrogen radioimmunoassay. Letrozole appeared to be the more potent of the two drugs. Fadrozole achieved a 68% suppression of estrone and 70% suppression of estradiol at all of the doses used. Letrozole, at doses of 0.1 to 5 mg/d, suppressed both estrone and estradiol by > 95%, resulting in undetectable levels in many patients.

In Vivo Aromatase Inhibition

At the Royal Marsden, we measured in vivo aromatase inhibition by letrozole in 13 postmenopausal patients with advanced breast cancer randomized to a daily dose of 0.5 or 2.5 mg for at least 6 weeks.[8] After 6 weeks, 0.5 and 2.5 mg/d of letrozole inhibited aromatization by a mean (geometric) of 98.4% (range, 97.3% to > 99.1%) and > 98.9% (98.5% to > 99.1%), respectively. This was a greater degree of aromatase inhibition than had been achieved previously with any other inhibitor.

Phase I and II Studies

In our original phase I study,[7] 7 (33%) of 21 patients achieved an objective response and 5 had stable disease for more than 3 months. All of these patients had received at least one prior endocrine treatment.

In an American phase I trial, 23 heavily pretreated postmenopausal patients with metastatic breast cancer were given letrozole at doses ranging from 0.1 to 5 mg/d. Only two patients (10%) had partial responses, but an additional seven had stable disease.[10]

Better results were achieved in a third phase I Italian trial, in which 14 postmenopausal patients were treated with 0.5 mg/d of letrozole. One patient achieved a complete response and four patients, a partial response, for an overall objective response rate of 36%. No toxic effects relating to letrozole were seen in any patient.[11]

Pivotal Phase III Trials

Two pivotal multinational trials have compared the efficacy and tolerability of letrozole in two doses (0.5 and 2.5 mg/d) against megestrol acetate and aminoglutethimide, respectively. The data presented here come from a second extension analysis covering a 50-month trial period.

Letrozole vs Megestrol Acetate

In this double-blind, randomized trial conducted at 91 centers in 10 countries, 551 patients with locally advanced or metastatic breast cancer were randomly assigned to letrozole (2.5 mg), letrozole (0.5 mg), or megestrol acetate (160 mg) once daily.[12] To be eligible for the trial, patients had to have a tumor with positive or unknown estrogen-receptor (ER) or progestogen-receptor (PR) status and were regarded as ER- or PR-positive if any assay of primary or secondary tumor tissue was positive.

Patients also were required to have failed to respond to previous antiestrogen therapy, either by relapsing while on adjuvant therapy given for ³ 6 months or within 12 months of stopping treatment, or by progressing on first-line antiestrogen treatment for metastatic disease. Another inclusion criterion for this trial was World Health Organization (WHO) performance status £ 2. Patients with rapidly progressive disease, central nervous system (CNS) involvement, diffuse lymphangitis carcinomatosa, inflammatory breast cancer, or hepatic metastases involving more than one-third of the liver were excluded.

The primary end point of objective tumor response was analyzed by logistic regression and was presented as odds ratios with 95% confidence intervals. Duration of response, duration of clinical benefit, time to progression, time to treatment failure, and survival were estimated by Kaplan-Meier product limit methods, and treatment comparisons were made by applying the Cox proportional hazard regression model. Analyses were performed on an intent-to-treat basis.

Response Rate and Response Duration-Objective responses occurred in 24.1% of patients treated with letrozole (2.5 mg), 12.28% of those given letrozole (0.5 mg), and 16.4% of those who received megestrol acetate (160 mg). This represented a significant dose-response effect in favor of 2.5 mg of letrozole compared with 0.5 mg (P = .0014) and a significant superiority of 2.5 mg of letrozole over megestrol acetate (P = .034).

Response rates (complete responses plus partial responses plus stable disease for ³ 6 months) were 35% for letrozole (2.5 mg), 26% for letrozole (0.5 mg), and 32% for megestrol acetate. There were no significant differences among the three treatment arms.

Median duration of objective response was significantly longer in patients treated with 2.5 mg of letrozole than in those given megestrol or the 0.5-mg dose of letrozole (P = .002). Median duration of objective response was 33 months for letrozole (2.5 mg), compared with 18 months for both megestrol acetate and letrozole (0.5 mg).

Duration of Clinical Benefit and Survival-Median duration of clinical benefit (including patients who achieved an objective response, as well as those with stable disease) was significantly longer for letrozole (2.5 mg) than megestrol acetate (23 vs 14 months; P = .00061). Median duration of clinical benefit was also significantly longer for letrozole (0.5 mg) than megestrol acetate (P = .01).

Median survival was 25 months for letrozole (2.5 mg), compared with 22 months for letrozole (0.5 mg) and 22 months for megestrol acetate. This difference between the two doses of letrozole was not statistically significant (P = .15), nor was the difference between letrozole (2.5 mg) and megestrol acetate (P = .24).

Time to Treatment Progression and Treatment Failure-Median time to treatment progression was 5.6 months for letrozole (2.5 mg), 5.5 months for megestrol acetate, and 3.4 months for letrozole (0.5 mg). There was a significant difference between letrozole (2.5 mg) and megestrol acetate (P = .05). With regard to overall time to treatment progression, the difference between letrozole (0.5 mg) and megestrol acetate was not statistically significant (P = .9), whereas the difference between letrozole (2.5 mg) and letrozole (0.5 mg) was significant (P = .03).

Median time to treatment failure was longer in those treated with the 2.5-mg dose of letrozole (5.1 months) than in those given megestrol acetate (3.9 months) or 0.5 mg of letrozole (3.2 months). Letrozole (2.5 mg) was significantly superior to megestrol acetate with respect to overall time to treatment failure (P = .02). The dose-response effect in favor of letrozole (2.5 mg) compared to letrozole (0.5 mg) was also significant (P = .004). There was no significant difference between letrozole (0.5 mg) and megestrol acetate (P = .72).

Subjective Assessments, Tolerability, and Safety-A deterioration in WHO performance status occurred in fewer patients given 2.5 mg of letrozole than in those given megestrol acetate (41% vs 55%; P = .01).

The most frequent adverse experiences reported by investigators to be drug-related were: nausea (6% and 11% in the 2.5- and 0.5-mg letrozole groups vs 4% in the megestrol acetate group), headache (7% and 6% vs 5%), peripheral edema (7% and 3% vs 4%), hot flushes (5% and 5% vs 4%), fatigue (5% and 4% vs 6%), weight gain (2% and 2% vs 9%), and dyspnea (0.6% and 2% vs 6%). The percentage of patients discontinuing treatment due to poor tolerability was significantly higher with megestrol acetate (9.5%) than with 2.5 or 0.5 mg of letrozole (2.9% and 5.3%, respectively).

Summary-These data show letrozole (2.5 mg/d) to be superior to megestrol acetate (160 mg once daily) in terms of objective response rate, response duration, duration of overall clinical benefit, time to treatment failure, performance status, and tolerability. Interestingly, the data also demonstrate the 2.5-mg dose of letrozole to be superior to the 0.5-mg dose in terms of response rate, time to progression, and time to treatment failure.

A dose-response effect of letrozole on overall survival was also reported in the phase III aminoglutethimide trial described below and is therefore likely to be real. This effect is surprising and is in contrast to endocrine data on letrozole, which show that the degree of estrogen suppression and inhibition of in vivo aromatization are similar for the 2.5- and 0.5-mg doses.[8] The finding of a dose-response effect suggests that the role of intratumoral aromatase may be important in the treatment of breast cancer, with the larger dose of letrozole achieving greater inhibition.

Letrozole vs Aminoglutethimide

The phase III trial of letrozole vs aminoglutethimide is very similar in design to the trial of letrozole vs megestrol acetate. A total of 555 postmenopausal patients with advanced or metastatic breast cancer were randomly allocated to letrozole (2.5 or 0.5 mg) or aminoglutethimide (500 mg) orally with hydrocortisone or cortisone acetate supplementation. Unlike the megestrol acetate trial, the aminoglutethimide trial was not double-blinded. Patients were enrolled over a 2-year period at 86 centers in 11 countries.

The aminoglutethimide trial is less mature than the megestrol trial, and a full manuscript on the former is being submitted for publication. Preliminary results have been presented in abstract form,[13] and the results of the extension over a 45-month trial duration period are reported here.

Patient entry and eligibility criteria for the aminoglutethimide trial were similar to those used in the megestrol acetate trial, as described above. Treatment groups were well matched with respect to standard baseline characteristics, and the definitive assessment of overall tumor response and disease progression was provided by an independent treatment-blinded peer review committee.

Response Rate and Response Duration-The highest overall objective response rate was seen with 2.5 mg of letrozole (19.5%). Rates of objective response were 16.7% for letrozole (0.5 mg) and 12.4% for aminoglutethimide. None of the differences was statistically significant, but the difference between letrozole (2.5 mg) and aminoglutethimide showed a trend in favor of letrozole (P = .06); a similar trend was seen between letrozole (0.5 mg) and aminoglutethimide (P = .10).

Response duration was 24 months for letrozole (2.5 mg), as compared with 21 months for letrozole (0.5 mg) and 15 months for aminoglutethimide. This trend in favor of letrozole did not achieve statistical significance.

Duration of Clinical Benefit and Survival-Median duration of overall clinical benefit (complete response plus partial response plus stable disease for³ 6 months) was 21 months for letrozole (2.5 mg), 18 months for letrozole (0.5 mg), and 14 months for aminoglutethimide. The difference between letrozole (2.5 mg) and aminoglutethimide was statistically significant (P = .03).

Median overall survival duration was 28 months in the patients treated with 2.5 mg of letrozole. This was significantly longer than the 21-month survival duration in patients who received 0.5 mg of letrozole (P = .04) and the 20-month duration in those given aminoglutethimide (P = .002).

Treatment-Related Side Effects-Rash was reported in 11% of the patients treated with aminoglutethimide, compared with 3% and 1% of those given the 2.5- and 0.5-mg doses of letrozole, respectively. The respective figures for somnolence were 7%, 3%, and 3%. Treatment had to be discontinued due to adverse events in 5% patients receiving aminoglutethimide, compared with 3% of those receiving either dose of letrozole.

Conclusions

These trials show that letrozole (2.5 mg orally daily) is of greater clinical benefit than megestrol acetate (160 mg daily) or aminoglutethimide (250 mg orally twice daily).

In the letrozole vs megestrol acetate trial, letrozole was significantly superior in terms of response rate, response duration, duration of overall clinical benefit (complete response plus partial response plus stable disease ³ 6 months), time to progression, and time to treatment failure. There was also a trend toward improved survival in the letrozole-treated patients that was not statistically significant. In addition, letrozole was better tolerated, with a lower incidence of adverse events, including, in particular, thromboembolic complications and weight gain.

In the letrozole vs aminoglutethimide trial, letrozole (2.5 mg) was significantly superior in terms of duration of overall clinical benefit, as well as survival. There were also strong trends toward the superiority of letrozole (2.5 mg) with respect to objective response rate and duration of response, although these trends did not reach statistical significance. As would have been predicted clinically, letrozole produced a lower incidence of rash and somnolence than aminoglutethimide.

Finally, an unexpected and potentially very important finding of both these trials was a dose-response effect for 2.5 mg of letrozole over 0.5 mg in terms of response and overall survival. Previous data have shown no significant difference between these two doses with regard to plasma estrogen suppression. This raises the possibility that intratumoral aromatase suppression may be more relevant in breast cancer therapy than are plasma estrogen levels. In any case, plasma estrogen levels with an aromatase inhibitor as powerful as letrozole are at the lower limits of detection, even with the most sensitive assays. Further clinical development of aromatase inhibitors must take into account that plasma estrogen is probably not a surrogate marker for optimal response.

In summary, letrozole is clinically superior to both megestrol acetate and aminoglutethimide in the treatment of patients with advanced breast cancer who relapse during or after tamoxifen therapy.

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