Phase II, randomized, placebo-controlled study of dovitinib in combination with fulvestrant in postmenopausal patients with HR⁺, HER2⁻ breast cancer that had progressed during or after prior endocrine therapy

We conducted a phase II, multicenter, international, randomized, double-blind, placebo-controlled trial (ClinicalTrials.gov identifier: NCT01528345) designed to evaluate the efficacy and safety of dovitinib in combination with fulvestrant in postmenopausal women with HR⁺, HER2⁻ locally advanced or metastatic breast cancer who had evidence of disease progression. Enrolled patients were randomized in a 1:1 ratio to receive dovitinib plus fulvestrant or placebo plus fulvestrant, stratified by FGF pathway amplification status (amplified vs nonamplified) and presence of visceral disease (yes vs no). All patients received fulvestrant 500 mg (intramuscular injection once every 4 weeks, with an additional dose 2 weeks after the initial dose) and dovitinib (500 mg) or placebo orally following a weekly 5 days on and 2 days off schedule until death, loss to follow-up, disease progression, or consent withdrawal.

Patients and medications were randomized using automated systems. At the time of initial screening, enrolled patients received a patient number, which was used as the primary identifier for the patient throughout the study. The interactive response technology provider generated a randomized patient list, using a validated automated system, by randomly assigning patient numbers to randomization numbers. Each randomization number was linked to a treatment arm and a medication number. Patients were randomized 1:1 to each of the study arms, with 45 FGF pathway–amplified and 30 FGF pathway–nonamplified patients planned in each arm. Medications were separately randomized by the study sponsor using a validated automated system that randomly assigned medication numbers to medication packs containing each of the study treatments. In this double-blind study, patients, investigators, study team members, and anyone involved in the conduct of the study remained blinded to the identity of the treatment from the time of randomization until database lock. The study medication and placebo had identical packaging, labeling, appearance, and administration schedules to conceal the identity of the treatments.

Eligible patients were postmenopausal women with HR⁺, HER2⁻ locally advanced or metastatic breast cancer who had evidence of disease progression. Progression was defined as at least one measurable lesion per Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1 or at least one nonmeasurable lytic or mixed bone lesion in the absence of measurable disease. Progression could have occurred  during or after prior endocrine therapy, within 12 months of the end of adjuvant endocrine therapy, or within 1 month of the end of any endocrine therapy for localized advanced or metastatic breast cancer. Eligible patients had confirmed postmenopausal status (i.e., aged ≥55 years with ≥1 year of amenorrhea, aged <55 years with ≥1 year of amenorrhea in the absence of ovarian suppression with an estradiol assay result of <20 pg/ml, or surgical menopause with bilateral oophorectomy), Eastern Cooperative Oncology Group (ECOG) performance status ≤2, and available archival or fresh tumor tissue for FGF pathway status determination in the primary tumor by the central laboratory. FGF pathway amplification was determined by a designated Clinical Laboratory Improvement Amendments–certified laboratory using a TaqMan PCR assay (Life Technologies, Carlsbad, CA, USA), as previously described [38]. Positive amplification for each FGF pathway marker tested (i.e., FGFR1, FGFR2, or FGF3) was defined as a copy number ≥6; copy number was quantified by comparison with a reference gene (human ribonuclease P RNA component H1) and calculated using CopyCaller software (version 1.1; Applied Biosystems, Foster City, CA, USA). Samples were considered to be FGF pathway–amplified if they had positive amplification of FGFR1, FGFR2, and/or FGF3. Given that the previously defined amplification cutoff of at least six copies for FGFR1 was associated with higher sensitivity to dovitinib monotherapy [38], the same cutoff was used in this combination therapy study. Exclusion criteria included HER2 overexpression (assessed by immunohistochemistry), prior therapy with fulvestrant (as a single agent or in combination with other therapies) or FGFR inhibitors, or chemotherapy or more than one line of any prior hormone therapy for locally advanced or metastatic breast cancer. An estimated 1000 patients were expected to be screened for FGF pathway amplification in order to identify and randomize a total of 150 patients stratified by FGF pathway amplification and presence of visceral disease.

Radiographic assessments (computed tomography, magnetic resonance imaging, or radiography) were performed at screening, on day 5 of weeks 8 and 16, before fulvestrant administration every 8 weeks for the remainder of study treatment, and at the end of treatment (if not assessed within 8 weeks before visit). Safety assessments were performed continually until 30 days after the last study treatment. No additional tumor assessments were required to confirm response (complete response [CR] or partial response [PR]) outside the protocol-specified 8-week tumor assessment.

Patients who did not discontinue study treatment owing to disease progression or death, or who were not lost to follow-up or did not withdraw consent, were assessed every 8 weeks for disease status, ECOG performance status, and patient-reported outcomes until the start of new anticancer therapy, disease progression, death, loss to follow-up, or consent withdrawal. Survival follow-up was performed every 3 months until death, loss to follow-up, or consent withdrawal for patients who discontinued the treatment.

The coprimary endpoints were PFS in the overall patient population regardless of FGF pathway amplification status and PFS in the subgroup of patients with FGF pathway amplification. PFS was defined as the time from date of randomization to the date of first radiologically documented, investigator-assessed disease progression per RECIST v1.1 or death due to any cause. The key secondary endpoint was ORR, defined as the percentage of patients with best overall response of CR or PR. Additional secondary endpoints included DOR, OS, safety, and pharmacokinetics of dovitinib. Safety analysis, by treatment arm, was based on the frequency of adverse events (AEs), summarized by system organ class, severity (based on the Common Terminology Criteria for Adverse Events version 4.03), type, and relationship to study treatment.

The full analysis set, which consisted of all patients who were randomized and assigned study treatment, was the primary population for the efficacy endpoint analyses. The safety set consisted of all randomized patients who received at least one dose of any compound of the study treatment (dovitinib plus fulvestrant or placebo plus fulvestrant).

The primary endpoint, PFS, was evaluated in each of the treatment arms using three sets of comparisons, following a Bayesian design: (1) all patients regardless of FGF pathway amplification status, (2) FGF pathway–amplified, and (3) FGF pathway–nonamplified (Additional file 1). Patients who did not have a PFS event at the time of analysis or who had received further antineoplastic therapy were censored at the time of the last tumor assessment. Kaplan-Meier plots were generated by treatment arm for the full population, FGF pathway–amplified subpopulation, and FGF pathway–nonamplified subpopulation. The HR of PFS in the full population was estimated using a Cox proportional hazards model stratified by FGF pathway amplification status and presence of visceral disease (yes vs no).

Efficacy of dovitinib plus fulvestrant over placebo plus fulvestrant was established if the estimated HR was <0.68 for the full population (i.e., improvement of approximately 3.0 months in median PFS) or <0.65 for the FGF pathway–amplified subpopulation (i.e., improvement of approximately 3.5 months in median PFS). Futility criteria in the FGF pathway–nonamplified subpopulation was determined if the posterior probability (HR >0.81) was >50% (i.e., improvement of <1.5 months in median PFS). The number of PFS events needed for the final analysis was calculated by assuming a 10% prevalence of FGF pathway amplification and a median PFS of 6.5 months with fulvestrant and placebo. To achieve the required number of PFS events for the final analysis (≥90 in the full population and ≥50 in the FGF pathway–amplified subgroup, whichever occurred later), a total of 150 patients had to be randomized as follows: 75 patients per treatment arm (45 FGF pathway–amplified and 30 FGF pathway–nonamplified).

Separate interim analyses were planned for patients with and without FGF pathway amplifications, owing to the faster enrollment expected for the FGF pathway–nonamplified subgroup. The first interim analyses occurred when 36 PFS events had been documented in the FGF pathway–nonamplified subgroup, and the second interim analysis occurred when ≥10 (20%) of 50 PFS events had been documented in the FGF pathway–amplified subgroup. The intent of these interim analyses was to assess the efficacy or futility of the study treatment. If the futility criteria were met (HR >0.81 in the first interim analysis; HR >0.7 in the second interim analysis), the study could be terminated early by the data monitoring committee.

The key secondary endpoint, ORR, was summarized as a percentage rate with 95% CI. OS was estimated using Kaplan-Meier analysis for each treatment arm; patients still alive at the time of analysis were censored at the last contact date.

From 15 May 2012 to 26 November 2014, a total of 97 postmenopausal patients with HR⁺, HER2⁻ locally advanced or metastatic breast cancer that had progressed during or after hormone therapy were enrolled in 36 centers. The last patient’s last visit was on 3 April 2015. All patients received fulvestrant; 47 were randomized to receive dovitinib and 50 were randomized to receive placebo (Fig. 1). Overall, 31 patients were classified as FGF pathway amplified (15 in the dovitinib arm vs 16 in the placebo arm); 725 patients were screened to enroll 31 FGF pathway–amplified patients. Although the data monitoring committee recommended continuing the study after 2 interim analyses, it subsequently recommended early termination of the study on 30 October 2014 due to lower than anticipated frequency of FGF pathway amplification and slow enrollment of patients with FGF pathway–amplified status. A total of 25 patients in each arm were classified as having visceral disease (53.2% vs 50.0% of patients in the dovitinib and placebo arms, respectively).

Baseline characteristics, including age, ECOG performance status, disease characteristics, and type and number of prior therapies were comparable between the study arms (Table 1). The median age for all patients was 63 (range 38–82) years; the median weight for all patients was 66.0 (range 38.0–135.5) kg; and the majority (57.7%) of patients had an ECOG performance status of 0. For patients with metastatic disease, the most common metastatic site was bone (77.3%), followed by lymph nodes (48.5%) and liver (39.2%). Most patients (76.3%) had been initially diagnosed ≥24 months before study start. Overall, 48.5% of patients had de novo stage IV disease, which was balanced between the dovitinib and placebo arms (48.9% vs 48.8% overall; 19.1% vs 16.0% FGF pathway–amplified; 29.8% vs 32.0% FGF pathway–nonamplified). The majority of patients relapsed at or within 12 months of the end of adjuvant treatment with any endocrine therapy (50 [51.5%] of 97 patients), and 48.5% (47 of 97) of patients progressed at or within 1 month of end of any endocrine therapy treatment for first-line treatment of metastatic disease. All patients had received prior antineoplastic therapy, including surgery (100%), hormone therapy (100%), radiotherapy (77.3%), and chemotherapy (66.0%). Approximately one-half (49.5%) of patients had received prior tamoxifen, and most patients had received prior aromatase inhibitors, including letrozole (42.3%), anastrozole (35.1%), and exemestane (17.5%). The majority (62.9%) of patients had received hormone therapy as their last prior treatment.

All patients received at least one dose of dovitinib or placebo and have discontinued study treatment (see Fig. 1). Of note, on the basis of the intention-to-treat principle, one patient with FGF pathway amplification who was misclassified as nonamplified at randomization remained in the nonamplified group in all analyses. The reasons for discontinuation in the dovitinib vs placebo arms were progressive disease (55.3% vs 80.0%), AEs (21.3% vs 2.0%), patient or guardian decision (10.6% vs 0%), termination by sponsor (8.5% vs 16.0%), death (2.1% vs 2.0%), and nonadherence to study treatment (2.1% vs 0%). The majority of patients who received dovitinib required at least one dose reduction or interruption (74.5% vs 26.0% for those who received placebo) and/or a dose change (57.4% vs 8.0% for those who received placebo); most patients required a dose interruption or delay or a dose change owing to experiencing an AE (70.2% and 53.2%, respectively) (Additional file 2: Table S1).

The most common any-grade AEs in the dovitinib arm, regardless of cause, were diarrhea (78.7%), nausea (72.3%), vomiting (57.4%), asthenia (38.8%), and headache (36.2%) (Table 3). In the placebo arm, diarrhea (32.0%), fatigue (26.0%), nausea and asthenia (22.0% each), and decreased appetite (16.0%) were the most common any-grade AEs. The most common grade 3 AEs (occurring in ≥10% of patients) in the dovitinib vs placebo arms were hypertension (21.3% vs 6.0%), diarrhea (14.9% vs 4.0%), alanine aminotransferase increase (14.9% vs 2.0%), fatigue (12.8% vs 2.0%), blood alkaline phosphatase increase (12.8% vs 0%), and γ-glutamyltransferase increase (10.6% vs 6.0%). The median (range) time to the onset of hypertension or blood pressure increase was 2.9 (0.1–28.1) weeks in the dovitinib arm and 2.7 (0.1–20.1) weeks in the placebo arm. In general, grade 4 AEs were infrequent and were comparable in the two arms, occurring in eight patients (17.0%) in the dovitinib arm and six patients (12.0%) in the placebo arm. Serious AEs suspected to be related to the study drug were reported in six patients (12.8%) in the dovitinib plus fulvestrant arm and included grade 3 pulmonary embolism, deep vein thrombosis, dehydration, esophageal varices hemorrhage, pneumonia, and varices esophageal (2.1% each), and grade 4 pulmonary embolism, ischemic cerebral infarction, and thrombocytopenia (2.1% each). In the placebo plus fulvestrant arm, two patients (4.0%) reported serious AEs suspected to be related to study drug (grade 4 hypotension [2.0%] and pancreatitis [2.0%]). The overall incidence of proteinuria and thyroid function abnormality was low in the dovitinib arm (two patients [4.3%] and one patient [2.1%], respectively; all grade 1/2 AEs) and was not reported in the placebo arm.

More patients discontinued study treatment owing to AEs in the dovitinib arm than in the placebo arm (38.3% vs 8.0%). The most frequently reported AEs (occurring in ≥3% of patients) leading to discontinuation were diarrhea (6.4% vs 0%), alanine aminotransferase increase (4.3% vs 2.0%), aspartate aminotransferase increase (4.3% vs 2.0%), and rash (4.3% vs 0%) (Additional file 2: Table S2). A total of four on-treatment deaths were reported (two deaths in each treatment arm); of the two on-treatment deaths that occurred in the dovitinib arm, one patient died as a result of breast cancer progression and one patient died because of a pulmonary embolism suspected to be related to study treatment. Overall, 14 patients (29.8%) in the dovitinib arm and 18 patients (36.0%) in the placebo arm died during the entire study period (i.e., including the time beyond the 30-day end of treatment follow-up period).