- Research article
- Open Access
Final results from IMPROVE: a randomized, controlled, open-label, two-arm, cross-over phase IV study to determine patients’ preference for everolimus in combination with exemestane or capecitabine in combination with bevacizumab in advanced HR-positive, HER2-negative breast cancer
BMC Cancer volume 20, Article number: 286 (2020)
The objective of the IMPROVE study was patients’ preference for either endocrine-based therapy or combined chemo- and anti-angiogenic therapy in advanced HR-positive/HER2-negative breast cancer.
In this randomized, cross-over phase IV study, 77 patients were recruited in 26 sites in Germany. Patients were randomized 1:1 to receive either capecitabine plus bevacizumab (Cap+Bev) as first-line therapy followed by cross-over to everolimus plus exemestane (Eve+Exe) as second-line therapy (Arm A) or the reverse sequence (Arm B). The primary endpoint was patients’ preference for either regimen, assessed by the Patient Preference Questionnaire 12 weeks after cross-over. Key secondary endpoints included progression-free survival (PFS), overall survival (OS), safety, and quality of life (QoL).
61.5% of patients preferred Cap+Bev (p = 0.1653), whereas 15.4% preferred Eve+Exe and 23.1% were indecisive. Physicians showed a similar tendency towards Cap+Bev (58.1%) as the preferred regimen versus Eve+Exe (32.3%). Median first-line PFS was longer for Cap+Bev than for Eve+Exe (11.1 months versus 3.5 months). Median second-line PFS was similar between Cap+Bev and Eve+Exe (3.6 months versus 3.7 months). Median OS was comparable between Arm A (28.8 months) and Arm B (24.7 months). 73.0% and 52.6% (first−/second-line, Cap+Bev) and 54.1% and 52.9% (first−/second-line, Eve+Exe) of patients experienced grade 3/4 TEAEs. No treatment-related deaths occurred. QoL and treatment satisfaction were not significantly different between arms or treatment lines.
Patients tended to favor Cap+Bev over Eve+Exe, which was in line with physicians’ preference. Cap+Bev showed superior first-line PFS, while QoL was similar in both arms. No new safety signals were reported.
EudraCT No: 2013–005329-22. Registered on 19 August 20
Breast cancer (BC) is the second-most common cancer worldwide. Approximately 20–30% of all patients treated with curative intent develop metastatic BC (MBC) . Depending on subtype, systemic treatment of advanced BC (locally recurrent and inoperable or MBC) offers a wide range of options including endocrine therapy, immunochemotherapy, kinase inhibitors, radiation therapy, and supportive measures. For postmenopausal patients with advanced hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR-positive/HER2-negative) BC various treatment options exist. Current international guidelines recommend endocrine therapy as the first-line treatment of choice in the vast majority of these patients. Chemotherapy may be considered as a reasonable alternative in patients for whom endocrine treatment is inappropriate including individuals presenting with acute visceral crisis and/or hormone-resistant tumors [2,3,4]. Up to now, there are limited data from clinical trials having directly compared chemotherapy and endocrine-based treatment in patients with MBC. A previous meta-analysis reported similar efficacy of both treatment strategies, however, the drugs utilized were outdated as per today’s standard of care .
Capecitabine (Cap) + bevacizumab (Avastin®, Bev) combination therapy is indicated for first-line treatment of adult patients with MBC for whom treatment with taxanes and/or anthracyclines is inappropriate [6,7,8,9]. Regarding endocrine therapy, the everolimus (Afinitor®, Eve) + exemestane (Aromasin®, Exe) combination is indicated in postmenopausal patients with advanced HR-positive, HER2-negative BC after recurrence or progression following treatment with non-steroidal aromatase inhibitors [10,11,12,13].
Assuming comparable efficacy between different therapeutic options, it is of utmost importance to identify the treatment with the least negative impact on patients’ quality of life (QoL). The IMPROVE study evaluated patients’ preference for either combined antihormonal therapy (everolimus + exemestane, Eve+Exe) or combined chemo- and anti-angiogenic therapy (capecitabine + bevacizumab, Cap+Bev) in postmenopausal patients with advanced HR-positive, HER2-negative BC and indication for first-line chemotherapy or endocrine therapy after failure of ≥1 standard non-steroidal aromatase inhibitor therapy.
Eligible patients were aged ≥18 years, postmenopausal, diagnosed with HR-positive, HER2-negative advanced BC (locally recurrent and inoperable or MBC), with indication for first-line chemotherapy or endocrine therapy after failure of ≥1 non-steroidal aromatase inhibitor therapy, no indication for treatment with taxanes and/or anthracyclines, measurable or non-measurable disease according to RECIST v1.1 , adequate bone marrow and organ function as per current Summary of Product Characteristics (SmPC) of respective study drug [8, 9, 12, 13], ECOG performance status ≤2, and fluency in German. Key exclusion criteria included prior palliative cytotoxic chemotherapy, prior treatment with mTOR (mammalian target of rapamycin)-inhibitors (prior treatment with exemestane was permitted), symptomatic visceral metastases, unstable skeletal metastases, medically uncontrolled cardiovascular diseases or diabetes mellitus, and known dihydropyrimidine dehydrogenase deficiency.
Study design and endpoints
This open-label, randomized, controlled, multicenter, two-arm, cross-over phase IV study (EudraCT No 2013–005329-22) randomly assigned patients (1:1) to receive either Cap+Bev first-line therapy during the first treatment phase (TP) followed by cross-over to Eve+Exe as second-line therapy during the second TP (Arm A) or the reverse sequence (Arm B; Fig. 1). For allocation of patients, a computer-generated randomization list was used to automatically allocate patients in the electronic Case Report Form by using an integrated randomization tool within the Electronic Data Capture system. Patients were stratified by (i) visceral metastases versus non-visceral metastases, (ii) prior (neo) adjuvant treatment (anthracycline and/or taxane; yes versus no), (iii) number of prior palliative anti-hormonal therapies (0–1 versus > 1) and (iv) disease-free interval (DFI; ≤2 years versus > 2 years) by using a permuted block randomization with block lengths of two and four. DFI was defined as the time from first R0 resection until first local relapse or occurrence of distant metastases, whichever occurred first. The block sizes were not disclosed to ensure concealment. Patients were treated in each TP until progression, intolerable toxicity, or withdrawal of consent. Each TP was separated by a washout phase (7–28 days). Dosing and administration of the study drugs are detailed in Table 1.
The primary endpoint was patients’ preference for either Cap+Bev or Eve+Exe combination therapy, assessed by questionnaire 12 weeks after cross over. Key secondary endpoints included progression-free survival (PFS), overall survival (OS), treatment satisfaction, QoL, and safety.
Patients’ treatment preference was assessed by the Patient Preference Questionnaire (PPQ) 12 weeks after cross over. Patients having discontinued therapy after < 12 weeks of treatment were asked to complete the PPQ within 2 weeks of treatment discontinuation. Patients were asked in the PPQ for their treatment preference (Cap+Bev, Eve+Exe, or no preference) and reason for their preference. Similarly, physicians were asked for their treatment preference (case-based), assessed by the Physician Preference Questionnaire. Patients were asked to complete the Treatment Satisfaction Questionnaire in week 12 of each TP. Additionally, patients were asked to complete QoL questionnaires in each TP (baseline and at week 12) including the European Organisation for Research and Treatment of Cancer (EORTC) quality of life questionnaire (QLQ)-C30 questionnaire .
Tumor assessment and adverse events
Tumor evaluation according to RECIST v1.1 was to be performed by the investigator at screening, every 12 weeks and at end of each TP, and every 6 months during follow-up (FU; ≥24 months or until death). During the FU, patients were also assessed for survival status. Any treatment-emergent adverse event (TEAE) and toxicity were to be recorded from day of first administration of study treatment until 30 days after end of treatment in each TP. TEAEs were graded by the investigator according to NCI CTCAE v4.03 .
The initial null hypothesis stated that there is no difference in patients’ preference for either regimen assuming that 80% of patients do have a preference, whereas 20% cannot decide. The study was designed to control the α error rate at 0.05 with a power of 80%. Required sample size was estimated to 192 patients assuming a drop-out rate at 35%. The assumptions for the null hypotheses were chosen according to the PISCES trial .
The intent-to-treat (ITT) population comprised all patients to whom study treatment had been assigned by randomization. The modified ITT (mITT) population was used to assess the primary endpoint and was predefined as all patients who had received both first-line and second-line therapy for ≥12 weeks per line or less for other reasons than progressive disease (PD), crossed over to second-line therapy within 12 weeks of termination of first-line therapy, and answered the preference question. Additionally, the primary endpoint was assessed in a post hoc analysis by using the per-protocol (PP) population including all patients who had received ≥1 dose of study medication in first-line and second-line therapy and answered the preference question. The safety set (SAF) included all patients who had received ≥1 dose of study medication.
To analyze the primary endpoint and to test the significance of difference in patient preference between the regimens, a Chi-square test was used to compare the actual preference against the null hypothesis of no difference in patient preference taking into account the proportion of indifferent patients. For the final analysis, the null hypothesis was adopted for the actually observed proportion of indifferent patients. By this means, the actual null hypothesis for the primary analysis was 38.45% prefer Cap+Bev, 38.45% prefer Eve+Exe, and 23.1% are indifferent about their preference. Reasons for preference were analyzed descriptively.
Difference in overall treatment satisfaction was analyzed by using an asymptotic chi-square test (satisfied versus not satisfied).
The EORTC QLQ-C30 questionnaire was analyzed descriptively. Differences in scores were evaluated by a t-test.
PFS and OS were estimated by using the Kaplan-Meier method .
The primary endpoint was further evaluated by age (< 60 years vs. ≥60 years) in the mITT, ITT and PP populations. However, further subgroup and explorative analyses pre-planned for the primary endpoint were not performed due to low number of available observations (mITT; N = 13).
This study was initially planned to enroll 192 patients. Due to emergence of new treatment options and low recruitment rate, the recruitment was stopped after 77 patients had been randomized. The study was prematurely terminated in September 2017.
Disposition of patients
Seventy-seven patients (ITT population) were recruited from October 2014 through April 2017 in 26 sites in Germany (Fig. 2); 39 patients were randomized to Arm A (Cap+Bev / Eve+Exe) and 38 patients to Arm B (Eve+Exe / Cap+Bev). In Arm A, 37 of the 39 randomized patients received the allocated first-line therapy. Of these, 17 patients crossed over to second-line therapy. In Arm B, 37 of the 38 randomized patients received the allocated first-line therapy. Of these, 19 patients crossed over to second-line therapy. Overall, 44 patients started the FU, which was planned to last ≥24 months or until death (FU completed: n = 21).
The mITT population comprised 13 patients (Arm A: N = 5; Arm B: N = 8) and the PP population 31 patients (Arm A: N = 13; Arm B: N = 18). The SAF population was used to analyze TEAEs in first-line (Arm A: N = 37; Arm B: N = 37) and second-line therapy (Arm A: N = 17; Arm B: N = 19).
Patient characteristics at baseline
All patients had HR-positive, HER2-negative BC. Baseline patient demographics, clinical characteristics, and treatment history in the randomized ITT population were balanced between study arms (Table 2).
Overall, 61.5% of patients reported Cap+Bev as their preferred regimen, though not statistically significant (mITT, p = 0.1653, Table 3). In Arm A and Arm B, 40% and 75% of patients reported Cap+Bev as their preferred therapy versus Eve+Exe (Arm A: 20.0%; Arm B: 12.5%), respectively. Overall, a similar tendency towards Cap+Bev as the preferred regimen was observed in the PP and ITT populations (Table 3). Notably, 10 of the 13 patients preferring Cap+Bev were found in Arm B.
The main reason for preference was improved QoL reported both among patients (ITT population) having preferred Cap+Bev (n = 9; 69.2%) or Eve+Exe (n = 3; 42.9%).
Patient’s preference was further evaluated by age (< 60 years vs. ≥60 years) in the mITT, ITT and PP populations. Overall, a similar pattern towards a preference for Cap+Bev over Eve+Exe was observed in both age groups in all three analytical populations (data not shown).
Overall, physicians rated in 46.2% and 30.8% of their cases Cap+Bev and Eve+Exe as their preferred regimen (mITT, Table 4), respectively. A similar pattern was observed in the PP and ITT populations (Table 4).
The majority of the patients in the ITT population in both arms were satisfied with first-line therapy (Arm A: 76.9%; Arm B: 63.2%) and second-line therapy (Arm A: 58.8%; Arm B: 57.9%). There was no major difference between arms either in first-line therapy or in second-line therapy (Table 5).
Global health status (EORTC-QLQ-C30)
Median global health score was 50.0 during the first TP across both arms both at baseline and at week 12. There was no significant difference in the mean scores of global health status between arms in either TP (ITT, Fig. 3).
Median first-line PFS was longer (p = 0.0008) in Arm A (11.1 months) than in Arm B (3.5 months, Fig. 4a). 51.3% of the patients in Arm A were censored for first-line PFS. The estimated 3-month first-line PFS rate was 79.3% (95% CI: 61.4–89.6) in Arm A and 51.4% (95% CI: 34.4–65.9) in Arm B. There was no major difference (p = 0.8345) in median second-line PFS between Arm A (3.7 months) and Arm B (3.6 months, Fig. 4b). The estimated 3-month second-line PFS rate was similar between Arm A (62.5%; 95% CI: 34.9–81.1) and Arm B (63.2%; 95% CI: 37.9–80.4).
Thirty-one patients (Arm A: n = 13; Arm B: n = 18) died during the course of the study. There was no major difference (p = 0.2088) in median OS between Arm A (28.8 months) and Arm B (24.7 months, Fig. 5).
Median duration of Cap+Bev therapy (first-line, 6.4 months; second-line, 4.0 months) was longer in both TPs as compared to Eve+Exe therapy (first-line, 3.4 months; second-line, 2.7 months).
Four fatal serious TEAEs (Arm A; n = 1; Arm B: n = 3) due to PD were reported during the course of the study; none were attributable to any study drug. 73.0% and 52.6% of the patients in Cap+Bev first-line and second-line therapy experienced TEAEs of CTCAE grade 3/4, respectively. 54.1% and 52.9% of the patients in Eve+Exe first-line and second-line therapy experienced TEAEs of CTCAE grade 3/4, respectively. Most common TEAEs of CTCAE grade 3/4 were observed in Arm A including hand-foot syndrome (18.9%) and hypertension (13.5%) during Cap+Bev first-line therapy, and pain (11.8%) and pneumonia (11.8%) during Eve+Exe second-line therapy (Table 6).
Current guidelines unequivocally indicate endocrine therapy as the preferred systemic treatment in the vast majority of patients with advanced HR-positive, HER2-negative BC [2,3,4]. However, this is in contrast to treatment reality; 43% of these patients are primarily subjected to first-line chemotherapy with > 80% receiving first-line chemotherapy when aged ≤50 years . The reason for this non-adherence remains unclear at present.
Knowing patients’ treatment preference is paramount in patient care. There is a renewed interest in implementation of a shared decision-making process between patients and healthcare, ultimately enhancing treatment quality [20, 21]. Notably, it has been proven that patients with BC (16%) value the efficacy less than the side-effects  and are willing to make trade-offs between side-effects and different regimens .
Although prematurely terminated, to our knowledge the IMPROVE study is the first randomized study having evaluated patients’ preference for either combined chemo- and anti-angiogenic therapy (Cap+Bev) or combined endocrine therapy (Eve+Exe) in postmenopausal patients with advanced HR-positive, HER2-negative BC. Furthermore, IMPROVE is the first study to date having compared the efficacy outcome of endocrine-based therapy with an anti-angiogenic-based chemotherapy approach.
In this study, patients tended to favor Cap+Bev over Eve+Exe (mITT), which was in line with physicians’ preference. The potential influence from the treating physician should be taken into account. However, the primary endpoint could not be adequately assessed due to low number of observations owing to premature termination of the study and low number of PPQs as a high number of patients did not cross over to second-line therapy. Therefore, the data are of limited interpretability and further conclusions cannot be made. Nevertheless, despite the low number of patients in the mITT population, the data provide important and valuable novel information on patient preference regarding endocrine-based therapy versus anti-angiogenic-based chemotherapy in advanced BC. A similar tendency towards Cap+Bev as patients’ and physicians’ preferred regimen was observed in the PP population. It is intriguing to also look at the ITT population; overall, patients tended to prefer Cap+Bev over Eve+Exe. The main reason for deciding for Cap+Bev was improved QoL. However, patient-reported QoL was similar in both arms bearing in mind the large variation in QoL scores across arms and TPs. Keeping in mind the small number of evaluable questionnaires in the ITT population, it was nevertheless surprising to see Cap+Bev as the preferred regimen, despite the higher percentage of first-line grade 3/4 TEAEs observed in Arm A, possibly attributable to the differences in treatment duration between regimens.
Median first-line PFS was longer in Arm A than in Arm B. The PFS of only 3.5 months in Arm B was unexpected when comparing with the BOLERO-2 trial , which reported a superior median PFS of 6.9 months/10.6 months (local/central assessment) in the Eve+Exe arm. Possible reasons for the short PFS in our study include the low number of patients in each arm, the slightly shorter DFI and more prior treatments in Arm B versus Arm A, the higher percentage of comorbidities observed in Arm B (92.1%) compared to Arm A (84.6%) and a higher percentage of patients in Arm B (68.4%) with prior adjuvant treatment with anthracycline/taxane versus Arm A (56.4%), possibly reflecting a higher risk profile at initial diagnosis in Arm B. In the BOLERO-6 trial, a median PFS of 8.4 months was reported for Eve+Exe combination therapy versus median 9.6 months for Cap monotherapy ; although not directly comparable, these results point towards the data in our study. Due to a high number of censored cases in the present study, the OS data are not further interpretable.
Although prematurely terminated, to our knowledge the IMPROVE study is the first randomized study having evaluated patients’ preference for either combined chemo- and anti-angiogenic therapy (Cap+Bev) or combined endocrine therapy (Eve+Exe) in postmenopausal patients with advanced HR-positive, HER2-negative BC. There was a tendency to favor Cap+Bev over Eve+Exe, which was in line with physicians’ preference. The efficacy of Cap+Bev proved to be superior in terms of first-line PFS. Patient-reported QoL was similar in both arms. No new safety signals were reported.
Availability of data and materials
Clinical data were documented in electronic Case Report Forms (eCRFs; iostudy office edc, iOMEDICO) and are the property of iOMEDICO. The data are not publicly available due to them containing information that could compromise patient and/or research participant privacy / consent.
Common Terminology Criteria for Adverse Events
Eastern Cooperative Oncology Group
European Organisation for Research and Treatment of Cancer
Human epidermal growth factor receptor 2
Mammalian target of rapamycin
National Cancer Institute
Patient preference questionnaire
Quality of life questionnaire
Quality of life
Response Evaluation Criteria In Solid Tumors
Summary of Product Characteristics
Treatment-emergent adverse event
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The authors thank all patients, physicians and study teams participating in this study. We would also like to thank Dr. med. Norbert Marschner (iOMEDICO), Dr. med. Jens Hasskarl (iOMEDICO), Dr. med. Kirsten Hauswald (iOMEDICO), and Dr. med. Tanja Trarbach (iOMEDICO) for support during study design, Melanie Frank (iOMEDICO) for writing the statistical analysis plan and for performing a large part of the statistical analysis, Dr. med. Leonora Houet (iOMEDICO) for support during data analysis and critical review of the manuscript, Dr. Andrea Kiemen (iOMEDICO) for support during the writing of the study protocol, and Dr. Christian Johansson (iOMEDICO) for the writing of the clinical study report and preparation of the manuscript. This project was supported financially by Novartis Pharma GmbH, Germany.
Consent to publish
This iOMEDICO-sponsored project received financial support from Novartis Pharma GmbH, Germany. Novartis had no role in the study design, data collection and analysis, interpretation of results, decision to publish, or preparation of the manuscript.
Ethics approval and consent to participate
The study protocol was approved by all relevant bodies (BfArM, Bonn, Germany). The study received positive opinions from the consulting Ethics Committee of the State Chamber of Physicians at the Federal States of Berlin, Bremen, Dessau-Roßlau, Dresden, Düsseldorf, Frankfurt a.M., Hamburg, Hannover, Mainz, München, Münster, Saarbrücken and Stuttgart as well as from the Ethics Committees at the Medical Faculty of the Universities of Bochum, Essen, Greifswald, Heidelberg, Mannheim and Würzburg, Germany. The study was conducted in accordance with Good Clinical Practice and all procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The study adheres to CONSORT guidelines. Written informed consent was obtained from all individual participants included in the study.
Thomas Decker: CONSULTANT OR ADVISORY ROLE: Novartis.
Ulrike Söling: No conflict of interest.
Antje Hahn: No conflict of interest.
Christoph Maintz: No conflict of interest.
Christian Martin Kurbacher: HONORARIA: Amgen, Eli Lilly, Mundipharma, Novartis, Pfizer, Roche, Tesaro; CONSULTANT OR ADVISORY ROLE: Amgen, Eli Lilly, Mundipharma, Novartis, Pfizer, Riemser, Roche, Tesaro; RESERACH FUNDING: Astra Zeneca, MSD Sharp & Dohme (Merck), Novartis, Pfizer, Seattle Genetics; TRAVEL, ACCOMODATIONS: Amgen, Hexal, PharmaMar, Pfizer, Tesaro.
Ursula Vehling-Kaiser: No conflict of interest.
Dagmar Sent: No conflict of interest.
Peter Klare: No conflict of interest.
Volker Hagen: HONORARIA: Amgen, BMS, Celgene, FomF, Gilead, Janssen Cilag, iOMEDICO, Pfizer, Roche; SHAREHOLDINGS: Bristol-Myers Squibb, Johnson & Johnson.
Marco Chiabudini: No conflict of interest.
Julia Falkenstein: No conflict of interest.
Martin Indorf: No conflict of interest.
Eva Runkel: No conflict of interest.
Karin Potthoff: No conflict of interest.
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Decker, T., Söling, U., Hahn, A. et al. Final results from IMPROVE: a randomized, controlled, open-label, two-arm, cross-over phase IV study to determine patients’ preference for everolimus in combination with exemestane or capecitabine in combination with bevacizumab in advanced HR-positive, HER2-negative breast cancer. BMC Cancer 20, 286 (2020). https://doi.org/10.1186/s12885-020-06747-y
- Advanced breast Cancer
- Endocrine therapy
- Combined chemo- and anti-Angiogenic therapy
- Patient preference
- Randomized, cross-over phase IV study