Justin Lindemann

Results of the CONFIRM Phase III Trial Comparing Fulvestrant 250 mg With Fulvestrant 500 mg in Postmenopausal Women With Estrogen Receptor–Positive Advanced Breast Cancer

PURPOSE We compared fulvestrant 500 mg regimen with the approved dose of fulvestrant 250 mg per month for treatment of postmenopausal women with estrogen receptor-positive advanced breast cancer who experienced progression after prior endocrine therapy. PATIENTS AND METHODS Comparison of Faslodex in Recurrent or Metastatic Breast Cancer (CONFIRM) is a double-blind, parallel-group, multicenter, phase III study. Patients were randomly assigned to fulvestrant 500 mg (500 mg intramuscularly [IM] on day 0, then 500 mg IM on days 14 and 28 and every 28 days thereafter) or 250 mg every 28 days. Primary end point was progression-free survival (PFS). Secondary end points included objective response rate, clinical benefit rate (CBR), duration of clinical benefit (DoCB), overall survival (OS), and quality of life (QOL). RESULTS PFS was significantly longer for fulvestrant 500 mg (n = 362) than 250 mg (n = 374) (hazard ratio [HR] = 0.80; 95% CI, 0.68 to 0.94; P = .006), corresponding to a 20% reduction in risk of progression. Objective response rate was similar for fulvestrant 500 mg and 250 mg (9.1% v 10.2%, respectively). CBR was 45.6% for fulvestrant 500 mg and 39.6% for fulvestrant 250 mg. DoCB and OS were 16.6 and 25.1 months, respectively, for the 500-mg group, whereas DoCB and OS were 13.9 and 22.8 months, respectively, in the 250-mg group. Fulvestrant 500 mg was well tolerated with no dose-dependent adverse events. QOL was similar for both arms. CONCLUSION Fulvestrant 500 mg was associated with a statistically significant increase in PFS and not associated with increased toxicity, corresponding to a clinically meaningful improvement in benefit versus risk compared with fulvestrant 250 mg.

Activity of Fulvestrant 500 mg Versus Anastrozole 1 mg As First-Line Treatment for Advanced Breast Cancer: Results From the FIRST Study

PURPOSE To compare the clinical activity of the pure antiestrogen fulvestrant at 500 mg/mo (double the approved dose) with the aromatase inhibitor anastrozole as first-line endocrine therapy for advanced hormone receptor-positive breast cancer in postmenopausal women. PATIENTS AND METHODS FIRST (Fulvestrant First-Line Study Comparing Endocrine Treatments) is a phase II, randomized, open-label, multicenter study of a fulvestrant high-dose (HD) regimen (500 mg/mo plus 500 mg on day 14 of month 1) versus anastrozole (1 mg/d). The primary efficacy end point was clinical benefit rate (CBR), defined as the proportion of patients experiencing an objective response (OR) or stable disease for > or = 24 weeks. The primary analysis was performed 6 months after the last patient was randomly assigned. RESULTS CBR was similar for fulvestrant HD (n = 102) and anastrozole (n = 103), 72.5% v 67.0%, respectively (odds ratio, 1.30; 95% CI, 0.72 to 2.38; P = .386). Objective response rate (ORR) was also similar between treatments: fulvestrant HD, 36.0%; anastrozole, 35.5%. Time to progression (TTP) was significantly longer for fulvestrant versus anastrozole (median TTP not reached for fulvestrant HD v 12.5 months for anastrozole; hazard ratio, 0.63; 95% CI, 0.39 to 1.00; P = .0496). Duration of OR and CB also numerically favored fulvestrant HD. Both treatments were well tolerated, with no significant differences in the incidence of prespecified adverse events. CONCLUSION First-line fulvestrant HD was at least as effective as anastrozole for CBR and ORR and was associated with significantly longer TTP. Fulvestrant HD was generally well tolerated, with a safety profile similar to that of anastrozole.

FACT: An Open-Label Randomized Phase III Study of Fulvestrant and Anastrozole in Combination Compared With Anastrozole Alone as First-Line Therapy for Patients With Receptor-Positive Postmenopausal Breast Cancer.

PURPOSE To compare the effect of therapy with anastrozole versus a combination of fulvestrant and anastrozole in women in first relapse of endocrine-responsive breast cancer. PATIENTS AND METHODS Postmenopausal women, or premenopausal women receiving a gonadotropin-releasing hormone agonist, with estrogen receptor- and/or progesterone receptor-positive disease at first relapse after primary treatment of localized disease were open-label randomly assigned to a fulvestrant loading dose (LD) regimen followed by monthly injection plus 1 mg of anastrozole daily or to 1 mg of anastrozole daily alone. The primary end point was time to progression (TTP). RESULTS In all, 514 women were randomly assigned to fulvestrant plus anastrozole (experimental arm; n = 258) or anastrozole (standard arm; n = 256). Approximately two thirds had received adjuvant antiestrogens, but only eight individuals had received an aromatase inhibitor. Median TTP was 10.8 and 10.2 months in the experimental versus standard arm, respectively (hazard ratio [HR] = 0.99; 95% CI, 0.81 to 1.20; P = .91); median overall survival was 37.8 and 38.2 months, respectively (HR = 1.0; 95% CI, 0.76 to 1.32; P = 1.00). Incidences of prespecified adverse events (AEs) were similar. Hot flashes were more common in the experimental arm: 63 patients (24.6%) versus 35 patients (13.8%) in the standard arm (P = .0023). Death owing to AEs was reported in 11 (4.3%) and five patients (2.0%) in the experimental versus standard arm, respectively. CONCLUSION Fulvestrant (250 mg + LD regimen) in combination with anastrozole offered no clinical efficacy advantage over anastrozole monotherapy in this population of individuals with a relatively high proportion of previous adjuvant antiestrogen exposure.

AKT Inhibition in Solid Tumors With AKT1 Mutations

Purpose AKT1 E17K mutations are oncogenic and occur in many cancers at a low prevalence. We performed a multihistology basket study of AZD5363, an ATP-competitive pan-AKT kinase inhibitor, to determine the preliminary activity of AKT inhibition in AKT-mutant cancers. Patients and Methods Fifty-eight patients with advanced solid tumors were treated. The primary end point was safety; secondary end points were progression-free survival (PFS) and response according to Response Evaluation Criteria in Solid Tumors (RECIST). Tumor biopsies and plasma cell-free DNA (cfDNA) were collected in the majority of patients to identify predictive biomarkers of response. Results In patients with AKT1 E17K-mutant tumors (n = 52) and a median of five lines of prior therapy, the median PFS was 5.5 months (95% CI, 2.9 to 6.9 months), 6.6 months (95% CI, 1.5 to 8.3 months), and 4.2 months (95% CI, 2.1 to 12.8 months) in patients with estrogen receptor-positive breast, gynecologic, and other solid tumors, respectively. In an exploratory biomarker analysis, imbalance of the AKT1 E17K-mutant allele, most frequently caused by copy-neutral loss-of-heterozygosity targeting the wild-type allele, was associated with longer PFS (hazard ratio [HR], 0.41; P = .04), as was the presence of coincident PI3K pathway hotspot mutations (HR, 0.21; P = .045). Persistent declines in AKT1 E17K in cfDNA were associated with improved PFS (HR, 0.18; P = .004) and response ( P = .025). Responses were not restricted to patients with detectable AKT1 E17K in pretreatment cfDNA. The most common grade ≥ 3 adverse events were hyperglycemia (24%), diarrhea (17%), and rash (15.5%). Conclusion This study provides the first clinical data that AKT1 E17K is a therapeutic target in human cancer. The genomic context of the AKT1 E17K mutation further conditioned response to AZD5363.

First Results from FACT – An Open-Label, Randomized Phase III Study Investigating Loading Dose of Fulvestrant Combined with Anastrozole Versus Anastrozole at First Relapse in Hormone Receptor Positive Breast Cancer.

Background: Although aromatase inhibitors, including anastrozole (A) have been shown to be effective for treatment of hormone-dependent postmenopausal breast cancer, many patients with advanced disease will develop resistance. Fulvestrant (F) down regulates estrogen receptors in human breast cancer and has similar single agent activity as A and tamoxifen. Fulvestrant demonstrates a dose-response effect and the present standard dosing strategy takes 3-6 months to reach pharmokinetically sufficient drug levels. Combining A with F might counteract resistance by increasing estrogen blockade through different, yet synergistic modes of action A lowering estrogen levels and F antagonizing and down-regulating the estrogen receptor. Here, the combination of F+A vs A was investigated at first relapse in hormone receptor positive breast cancer in the phase III FACT study, by using a loading dose (LD) schedule followed by monthly injections of F, with the aim to overcome some endocrine resistance mechanisms by maximal estrogen blockade and to use F more optimally. Methods: Postmenopausal women, or premenopausal women receiving a GnRH agonist, with ER+ and/or PgR+ disease at first relapse following primary treatment of localized disease, were randomized to F LD (500 mg i.m. day 0, 250 mg day 14 and 28, then 250mg monthly thereafter) + 1 mg A daily, or 1 mg A daily alone at first relapse. The primary endpoint was time to progression (TTP). Secondary endpoints included objective response rate (ORR), clinical benefit rate (ORR + stable disease ≥24 weeks) (CBR), overall survival (OS) and tolerability. With 512 patients, approximately 380 events were required to detect a 3 month increase in TTP (5% two-sided significance level with 80% power). Results: 514 patients, 256 in A alone group and 258 in F+A group, were randomized and approximately 2/3 of the full analysis set were either endocrine-naive patients or patients with recurrence ≥12 month9s gap following completion of adjuvant endocrine therapy. The study is mature while disease progression was demonstrated in 78.1% in the A alone group and 77.5% in the F+A combination group (HR 0.99; CI 95% 0.81-1.20, p-value 0.91). Investigator assessed ORR using the RECIST criteria on patients with measurable disease was 33.6% for the A alone group (38/113), and 31.8% for the F+A combination group (41/129) (odds ratio (OR) 0.92; 95% CI 0.54-1.58), respectively. The CBR rates were 55.1% for A and 55.0% for the F+A combination, respectively. F+A is a well-tolerated combination, but with an increased incidence of hot flushes over A alone. A total of 156 patients (61.4%) in the A alone group and 155 (60.5%) in the F+A combination group reported AEs. AEs for both groups were predominantly mild or moderate in intensity, whereas AEs CTC 3 or higher occurred in 16.9% vs 16.4%. 11 deaths due to side effects were recorded in the F+A arm and 5 in the A alone arm. In the investigators69(24 Suppl):Abstract nr 23.

A Good Drug Made Better: The Fulvestrant Dose-Response Story

Sequential use of endocrine therapies remains the cornerstone of treatment for hormone receptor-positive advanced breast cancer, before the use of cytotoxic chemotherapy for unresponsive disease. Fulvestrant is an estrogen receptor (ER) antagonist approved for the treatment of postmenopausal women with ER+ advanced breast cancer after failure of prior antiestrogen therapy. Initially approved at a monthly dose of 250 mg, the recommended fulvestrant dose was revised to 500 mg (500 mg/mo plus 500 mg on day 14 of month 1) after demonstration of improved progression-free survival versus fulvestrant 250 mg. We have reviewed the dose-dependent effects of fulvestrant, both from a retrospective combined analysis of dose-dependent reduction of tumor biomarkers in the presurgical setting (3 previously reported studies: Study 18, Neoadjuvant Endocrine Therapy for Women with Estrogen-Sensitive Tumors, and Trial 57) and from a review of clinical studies for advanced breast cancer in postmenopausal women. Analysis of presurgical data revealed a consistent dose-dependent effect for fulvestrant on tumor biomarkers, with increasing fulvestrant dose resulting in greater reductions in ER, progesterone receptor, and Ki67 labeling index. The dose-dependent biological effect corresponds with the dose-dependent clinical efficacy observed in the treatment of advanced breast cancer after failure of prior antiestrogen therapy. Although it remains to be determined in a phase III trial, cross-trial comparisons suggest a dose-dependent relationship for fulvestrant as first-line treatment for advanced breast cancer. Overall, biological and clinical data demonstrate a strong dose-dependent relationship for fulvestrant, supporting the efficacy benefit seen with fulvestrant 500 mg over the 250 mg dose.

Tumors with AKT1E17K Mutations Are Rational Targets for Single Agent or Combination Therapy with AKT Inhibitors

AKT1E17K mutations occur at low frequency in a variety of solid tumors, including those of the breast and urinary bladder. Although this mutation has been shown to transform rodent cells in culture, it was found to be less oncogenic than PIK3CA mutations in breast epithelial cells. Moreover, the therapeutic potential of AKT inhibitors in human tumors with an endogenous AKT1E17K mutation is not known. Expression of exogenous copies of AKT1E17K in MCF10A breast epithelial cells increased phosphorylation of AKT and its substrates, induced colony formation in soft agar, and formation of lesions in the mammary fat pad of immunodeficient mice. These effects were inhibited by the allosteric and catalytic AKT inhibitors MK-2206 and AZD5363, respectively. Both AKT inhibitors caused highly significant growth inhibition of breast cancer explant models with AKT1E17K mutation. Furthermore, in a phase I clinical study, the catalytic Akt inhibitor AZD5363 induced partial responses in patients with breast and ovarian cancer with tumors containing AKT1E17K mutations. In MGH-U3 bladder cancer xenografts, which contain both AKT1E17K and FGFR3Y373C mutations, AZD5363 monotherapy did not significantly reduce tumor growth, but tumor regression was observed in combination with the FGFR inhibitor AZD4547. The data show that tumors with AKT1E17K mutations are rational therapeutic targets for AKT inhibitors, although combinations with other targeted agents may be required where activating oncogenic mutations of other proteins are present in the same tumor. Mol Cancer Ther; 14(11); 2441–51. ©2015 AACR.

CONFIRM: A Phase III, Randomized, Parallel-Group Trial Comparing Fulvestrant 250 mg vs Fulvestrant 500 mg in Postmenopausal Women with Estrogen Receptor-Positive Advanced Breast Cancer.

Background: Fulvestrant (Faslodex®) is an estrogen-receptor (ER) antagonist licensed for the treatment of postmenopausal women with advanced breast cancer who have progressed or recurred following prior endocrine therapy. The efficacy of fulvestrant at the approved dose (250 mg/month; F250) is well established; however, increasing the dose to 500 mg (500 mg i.m. on Day 0, then 500 mg i.m. on Days 14 and 28 and every 28 days thereafter; F500) may further improve clinical outcome. Data from the NEWEST and FIRST studies have suggested improved biological and clinical activity for F500 in the neoadjuvant and 1st-line advanced disease settings respectively. Further data are required to clarify the clinical role of F500 in ER+ advanced breast cancer.Methods: CONFIRM (COmparisoN of Faslodex In Recurrent or Metastatic breast cancer) is a randomized, double-blind, parallel-group, multicenter, Phase III study (9238IL/0064; NCT00099437) comparing F250 with F500 in postmenopausal women with ER+ advanced disease recurring or progressing after prior endocrine therapy (anti-estrogen or aromatase inhibitor). Eligible patients (pts) were randomized 1:1 to F250 or F500, and assessed for tumor progression every 12 weeks. The primary objective was to compare the efficacy of F250 and F500 in terms of time to progression (TTP). Secondary objectives included: objective response rate (ORR), clinical benefit rate (CBR; complete or partial response or stable disease lasting ≥24 weeks), duration of clinical benefit (DoCB)(all by modified RECIST criteria), overall survival and quality of life (QoL). Safety and tolerability were also assessed. Treatment with fulvestrant continued until disease progression, or discontinuation for any other reason. All patients were followed up for disease progression and survival, regardless of treatment discontinuation, unless consent was withdrawn.Results: In total, 736 women (median age 61.0yrs) were recruited between Feb 905 and Aug 907 from 128 centers in 17 countries (F500: n=362; F250: n=374). TTP was significantly longer for F500 vs F250 (HR 0.80 [95% CI: 0.68, 0.94]; p=0.006), corresponding to a 20% reduction in risk of progression. The treatment effect was consistent for all predefined subgroups analysed. ORR was similar for F500 and F250 (13.8% vs 14.6%; odds ratio 0.94 [95% CI 0.57, 1.55]; p=0.795). There was a numerical advantage in CBR for pts receiving F500 vs F250 (45.6% vs 39.6%; odds ratio 1.28 [95% CI 0.95, 1.71]; p=0.1) and in DoCB (16.6 vs 13.9 months for F500 [n=165] and F250 [n=148] respectively). There was a trend for improved overall survival for pts treated with F500 compared with F250 (HR 0.84 [95% CI: 0.69, 1.03] p=0.091). QoL (n=145) was similar for both arms. F500 was well tolerated, with a safety profile consistent with that of F250 and no evidence of dose-dependence for any AE.Discussion: The CONFIRM trial has shown a statistically significant increase in TTP for F500 compared with F250, without increase in toxicity. This translates into a clinically meaningful advantage for F500 over F250. We anticipate that the 500mg regimen will become the established dose for fulvestrant. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 25.

Development and Validation of a Gene Expression Score That Predicts Response to Fulvestrant in Breast Cancer Patients

Fulvestrant is a selective estrogen receptor antagonist. Based on the measured growth inhibition of 60 human cancer cell lines (NCI60) in the presence of fulvestrant, as well as the baseline gene expression of the 60 cell lines, a gene expression score that predicts response to fulvestrant was developed. The score is based on 414 genes, 103 of which show increased expression in sensitive cell lines, while 311 show increased expression in the non-responding cell lines. The sensitivity genes primarily sense signaling through estrogen receptor alpha, whereas the resistance genes modulate the PI3K signaling pathway. The latter genes suggest that resistance to fulvestrant can be overcome by drugs targeting the PI3K pathway. The level of this gene expression score and its correlation with fulvestrant response was measured in a panel of 20 breast cancer cell lines. The predicted sensitivity matched the measured sensitivity well (CC = −0.63, P = 0.003). The predictor was applied to tumor biopies obtained from a Phase II clinical trial. The sensitivity of each patient to treatment with fulvestrant was predicted based on the RNA profile of the biopsy taken before neoadjuvant treatment and without knowledge of the subsequent response. The prediction was then compared to clinical response to show that the responders had a significantly higher sensitivity prediction than the non-responders (P = 0.01). When clinical covariates, tumor grade and estrogen receptor H-score, were included in the prediction, the difference in predicted senstivity between responders and non-responders improved (P = 0.003). Using a pre-defined cutoff to separate patients into predicted sensitive and predicted resistant yielded a positive predictive value of 88% and a negative predictive value of 100% when compared to clinical data. We conclude that pre-screening patients with the new gene expression predictor has the potential to identify those postmenopausal women with locally advanced, estrogen-receptor-positive breast cancer most likely to respond to fulvestrant.

Differences in the Transcriptional Response to Fulvestrant and Estrogen Deprivation in ER-Positive Breast Cancer

Purpose: Endocrine therapies include aromatase inhibitors and the selective estrogen receptor (ER) downregulator fulvestrant. This study aimed to determine whether the reported efficacy of fulvestrant over anastrozole, and high- over low-dose fulvestrant, reflect distinct transcriptional responses. Experimental Design: Global gene expression profiles from ERα-positive breast carcinomas before and during presurgical treatment with fulvestrant (n = 22) or anastrozole (n = 81), and corresponding in vitro models, were compared. Transcripts responding differently to fulvestrant and estrogen deprivation were identified and integrated using Gene Ontology, pathway and network analyses to evaluate their potential significance. Results: The overall transcriptional response to fulvestrant and estrogen deprivation was correlated (r = 0.61 in presurgical studies, r = 0.87 in vitro), involving downregulation of estrogen-regulated and proliferation-associated genes. The transcriptional response to fulvestrant was of greater magnitude than estrogen deprivation (slope = 0.62 in presurgical studies, slope = 0.63 in vitro). Comparative analyses identified 28 genes and 40 Gene Ontology categories affected differentially by fulvestrant. Seventeen fulvestrant-specific genes, including CAV1/2, SNAI2, and NRP1, associated with ERα, androgen receptor (AR), and TP53, in a network regulating cell cycle, death, survival, and tumor morphology. Eighteen genes responding differently to fulvestrant specifically predicted antiproliferative response to fulvestrant, but not anastrozole. Transcriptional effects of low-dose fulvestrant correlated with high-dose treatment, but were of lower magnitude (ratio = 0.29). Conclusions: The transcriptional response to fulvestrant has much in common with estrogen deprivation, but is stronger with distinctions potentially attributable to arrest of estrogen-independent ERα activity and involvement of AR signaling. Genes responding differently to fulvestrant may have predictive utility. These data are consistent with the clinical efficacy of fulvestrant versus anastrozole and higher dosing regimens. Clin Cancer Res; 20(15); 3962–73. ©2014 AACR.