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Real-World Outcomes of Ribociclib and Aromatase Inhibitor Use in First Line Hormone Receptor Positive, HER2-Negative Metastatic Breast Cancer

Published:August 30, 2022DOI:https://doi.org/10.1016/j.clbc.2022.08.011

      Highlights

      • Combination ribociclib and letrozole is a new standard first-line treatment option for hormone-positive, HER2-negative metastatic breast cancer, demonstrated by MONALEESA-2 trial.
      • KARMA, an Australian registry, is the first real-world study, developed alongside a Medicine Access Program, to report first-line ribociclib and AI treatment outcomes.
      • Our study found similar rates of dose reduction (56%) and treatment discontinuation (11%) due to toxicity as compared to MONALEESA-2.
      • This real-world registry cohort had a longer median duration of treatment (24.5 vs. 20.2 months) and superior progression free survival (>36.5 vs. 25.3 months) as compared to MONALEESA-2.
      • Real world evidence continues to be valued by clinicians to see drug tolerability and efficacy replicated in populations not always captured by trial settings.

      Abstract

      Background

      International guidelines recommend combining a CDK4/6 inhibitor and endocrine therapy (ET) as first line treatment for hormone receptor (HR) positive, HER2 negative metastatic breast cancer (MBC). Results from MONALEESA-2 demonstrate superior progression free survival (PFS) and overall survival (OS) with ribociclib (CDK4/6 inhibitor) and ET compared to ET alone. Real world outcomes have yet to be reported.

      Materials and Methods

      KARMA is a non-interventional registry of Australian patients receiving first-line treatment with ribociclib and aromatase inhibitor (AI), obtained via a Medicine Access Program (MAP) for HR+, HER2- MBC. Outcomes were compared with the ribociclib/letrozole cohort in MONALEESA-2.

      Results

      Data from 160 patients at 17 sites was analysed. Median follow-up is 36.5 months. Compared to MONALEESA-2, patients were numerically younger (54.3 vs. 62 years), with higher rates of bone-only metastases (31% vs. 21%). A total of 63 of 160 (39%) patients remain on treatment. A total of 56% of patients had at least 1 dose reduction, with neutropenia (68%) and abnormal liver enzymes (17%) the most common reasons. A total of 17 of 160 (11%) discontinued treatment due to toxicity, with no treatment related deaths. Median PFS was not reached (95% CI 29.9- NR), with PFS at 12 months and 18 months being 76% and 67% respectively versus 25.3 months, 73% and 63% in MONALEESA-2.

      Conclusion

      The ribociclib and AI combination was well tolerated in this real-world setting. The KARMA registry cohort achieved a superior PFS (>36.5 months) to MONALEESA-2, potentially due to more favourable baseline disease characteristics. Less frequent assessment scheduling in this non trial setting may also contribute.

      Keywords

      Introduction

      Breast cancer is now the most common cancer diagnosed worldwide, with hormone receptor (HR+) positive, HER2 negative (HER2-) breast cancer accounting for nearly 70% of cases.
      • Cancer of the Breast (Female) – Cancer Stat Facts
      In recent years, the combination of a CDK 4/6 inhibitor and endocrine therapy (ET) has transformed the treatment landscape of HR+ HER2- metastatic breast cancer (MBC) emerging as the new "standard of care" first line treatment.
      • Gennari A
      • André F
      • Barrios C
      • et al.
      ESMO Clinical Practice Guideline for the diagnosis, staging and treatment of patients with metastatic breast cancer.
      First published in 2016, the MONALEESA-2 trial demonstrated improved median progression free survival (PFS) with ribociclib, a CDK4/6 inhibitor, plus letrozole compared to letrozole alone in a randomised population of 668 post-menopausal patients with HR+ HER2- MBC.
      • Hortobagyi GN
      • Stemmer SM
      • Burris HA
      • et al.
      Ribociclib as first-line therapy for HR-positive, advanced breast cancer [published correction appears in N Engl J Med. 2018 Dec 27;379:2582].
      More recently, the final protocol-specified analysis for MONALEESA-2 demonstrated a 12-month overall survival (OS) benefit (hazard ratio for death, 0.76; 95% CI, 0.63-0.93; 2-sided P = .008) for ribociclib and aromatase inhibitor (AI), marking the first and only CDK 4/6 inhibitor/AI combination to report an OS benefit in the first line post-menopausal HR+ HER2- MBC treatment setting.
      • Hortobagyi GN
      • Stemmer SM
      • Burris HA
      • et al.
      Overall survival with ribociclib plus letrozole in advanced breast cancer.
      Prior to ribociclib being government funded by the Australian Pharmaceutical Benefits Scheme (PBS), approximately 800 patients in Australia participated in a Novartis sponsored ribociclib compassionate medicine access program (MAP), run between May 2017 and June 2018, subsequently transitioning to PBS funded supply from July 2018. Despite the potential for valuable outcome data to be generated from patients who participate in MAPs, this data has traditionally not been collected due to many perceived challenges relating to ethics, data ownership, data security and patient privacy. However, our group has previously demonstrated the feasibility of successful data collection alongside a MAP, and that such a registry can yield valuable data on real world efficacy and safety.
      • Lok SW
      • De Boer R
      • Cordwell C
      • et al.
      Demonstrating the feasibility of collecting secondary, de-identified data on Australian patients receiving treatment as part of a Medicine Access Programme.
      To our knowledge there is limited published real-world data pertaining to treatment and outcomes for MBC patients treated with first line ribociclib and ET, with no studies describing Australian practices. Patients routinely seen in the community setting often differ in critical factors from those participating in clinical trials, including older age, presence of comorbidities, poorer performance status and living outside of the catchment of a tertiary cancer centre, all of these are often trial exclusion criteria. Thus, the external validity of clinical trial data remains uncertain with increasing importance on real-world studies to complement randomised controlled trial data. Real world data can provide information on safety and therapeutic effectiveness, better translating outcomes into routine clinical care. By establishing a registry alongside a MAP, we aimed to collect and describe the real-world patient and treatment outcomes of patients with HR+ HER2- MBC in Australia who received ribociclib in combination with an AI in the first-line setting.

      Methods

      KARMA (Kisqali Access Registry for Metastatic breast cancer in Australia) was established in August 2019 as a secondary data use, noninterventional study of Australian patients who received first line combination treatment of ribociclib obtained through the ribociclib MAP between May 2017 and June 2018, and an AI. Key eligibility criteria for the MAP mirrored that of the MONALEESA-2 study, that is, postmenopausal women with HR+, HER2- MBC who had not received prior systemic treatment in the metastatic setting.
      Clinicians from Australian hospitals who had enrolled patients in the ribociclib MAP were approached to gauge interest in study participation. De-identified patient data of enrolled patients were retrieved from medical records and entered onto an electronic REDCap case report form. Adverse events of special interest for this study included neutropenia, abnormal liver function tests and cardiac events (eg, QT prolongation). Data with regards to dose reductions and drug discontinuations with rationale for these clinician decisions were also collected. Censor date of data was December 2020, allowing for a minimum of 30 month follow up for all patients from start date of treatment with ribociclib and aromatase inhibitor. Since this was an extremely low to negligible risk study and patient identifiers are not contained within the data collected, the study utilised a waiver of patient consent. This study and its reporting have been approved by the institutional Melbourne Health Human Research Ethics Committee.
      The primary objective was to describe the real world clinical and tumour characteristics of patients with HR+ HER2- metastatic breast cancer in Australia who received ribociclib in combination with an aromatase inhibitor as part of the ribociclib MAP. The secondary objectives were to assess safety data including rates and reasons for dose interruptions and dose reductions of ribociclib, describe duration of treatment and progression free survival. Univariate and multivariate Cox analysis was performed with age ≥ 65 years, post-menopausal status, visceral metastases, de novo metastatic breast cancer, receipt of adjuvant chemotherapy, receipt of adjuvant ET and ET free interval as pre-specified variables. For relapsed patients, disease free interval was defined as time from primary cancer diagnosis to metastatic relapse, whilst ET free interval was defined as time from cessation of adjuvant ET to metastatic relapse. PFS was defined as time from commencement of line of treatment till confirmation of progressive disease. Where possible, direct comparisons were made with the ribociclib/letrozole cohort (n = 334 patients) in MONALEESA-2. The exploratory objectives included investigating the natural disease trajectory of patients with HR+ HER2- MBC post disease progression, including clinician choice of second and third-line treatment and estimating PFS in immediate line of therapy post ribociclib and AI, where applicable. GraphPad Prism version 8, and Stata version 15 software was used to analyse the data. Overall survival and progression-free survival analyses used Cox proportional-hazards regression. Statistical significance was reported when p<0.05. No multiplicity adjustment was made for the analyses.

      Results

      167 patients from 17 sites participated in the Novartis sponsored ribociclib compassionate MAP were enrolled into KARMA, with a median follow up of 36.5 months. Sites included major tertiary, metropolitan, regional, private and public centres. 7 patients were excluded from analysis with 2 patients found to be oestrogen-receptor negative, 4 patients having received ribociclib and AI as non first-line therapy for MBC and 1 patient receiving ribociclib and AI in the neoadjuvant treatment setting for early breast cancer. A total of 160 patients that met inclusion criteria were available for analysis.

      Patient and Disease Characteristics

      Table 1 demonstrates baseline patient and disease characteristics in KARMA, and where available, compared to MONALEESA-2′s ribociclib/letrozole cohort. As compared to MONALEESA-2, patients in KARMA were numerically younger (54.3 vs. 62 years) and there was a higher proportion of pre and peri-menopausal status (24% vs. 0%). In addition, the KARMA cohort had numerically less disease burden (single site metastasis 61% vs. 30%), with more bone-only metastases (31% vs. 21%), and less visceral metastases (36% vs. 59%). The distribution of ECOG status, oestrogen, and progesterone positivity appeared similar, however data was incomplete.
      Table 1Baseline patient and disease characteristics
      Baseline CharacteristicsKARMA (n=160)MONALEESA-2’s ribociclib/letrozole cohort (n=334)
      Age
      Mean (years)54.3 (range 32-94 years)62 (range 23-91 years)
      ≥ 65 years32 (20%)Not available
      Menopausal status at diagnosis of MBC
      Pre and peri-menopausal37 (24%)0
      Post-menopausal121 (76%)334 (100%)
      Unknown2 (1%)0
      ECOG performance status
       • 088 (55%)205 (61%)
       • 149 (31%)129 (39%)
       • 2 or more5 (3%)0
       • Unknown18 (11%)0
      Sites of metastases
      Bone
       • Any104 (65%)246 (74%)
       • Only49 (31%)69 (21%)
      Visceral58 (36%)197 (59%)
      Nodal49 (31%)133 (40%)
      Brain/leptomeningeal6 (4%)0
      Number of metastatic sites
      197 (61%)100 (30%)
      241 (26%)118 (35%)
      3+22 (14%)114 (34%)
      Tumour characteristics
      ER±
       • Positive160 (100%)332 (99%)
       • Negative02 (1%)
      PR±
       • Positive132 (83%)271 (81%)
       • Negative21 (13%)63 (19%)
       • Unknown7 (4%)Not available
      Table 2 demonstrates the use of prior adjuvant therapy in the 118 patients with relapsed metastatic disease. Where available, data from KARMA was also compared to the 145 relapsed metastatic disease patients in the MONALEESA-2′s ribociclib/letrozole cohort. Notably, 23 (19%) relapsed metastatic patients in KARMA had not received adjuvant ET.
      Table 2Adjuvant therapy and disease-free interval in patients with relapsed metastatic disease
      CharacteristicsKARMAMONALEESA-2’s ribociclib/letrozole cohort
      De novo metastatic disease42 (26%)114 (34%)
      Relapsed metastatic disease118 (74%)220 (66%)
      (Neo)Adjuvant chemotherapy
      Of those who received neo(adjuvant) chemotherapy, the most common regimens used were 5-fluorouracil, epirubicin, cyclophosphamide and docetaxel (FEC-D) 35%, followed by doxorubicin or epirubicin, cyclophosphamide and paclitaxel (AC/EC +T) 28%.
      74 (63%)145 (66%)
      Adjuvant endocrine therapy
      Some patients received more than 1 adjuvant endocrine therapy.
       • Total95 (81%)Not available
       • Tamoxifen72 (61%)140 (64%)
       • Letrozole30 (25%)34 (15%)
       • Anastrozole38 (32%)47 (21%)
       • Exemestane9 (8%)19 (9%)
       • Ovarian suppression7 (6%)6 (3%)
      Disease free interval
       • <12 months6 (5%)4 (2%)
       • 12-24 months8 (7%)14 (6%)
       • >24 months104 (88%)202 (92%)
      Endocrine treatment free interval
       • <12 months (or relapsed on adjuvant endocrine therapy)37 (31%)Not available
       • 12-24 months8 (7%)Not available
       • >24 months47 (40%)Not available
       • Unknown2 (2%)Not available
       • Oophrectomy alone1 (1%)Not available
      low asterisk Of those who received neo(adjuvant) chemotherapy, the most common regimens used were 5-fluorouracil, epirubicin, cyclophosphamide and docetaxel (FEC-D) 35%, followed by doxorubicin or epirubicin, cyclophosphamide and paclitaxel (AC/EC +T) 28%.
      ^ Some patients received more than 1 adjuvant endocrine therapy.

      Treatment With Ribociclib and Aromatase Inhibitor

      At time of analysis, 63 of 160 (39%) patients remain on ribociclib and an AI. Median duration of treatment was 24.5 months, as compared to 20.2 months in MONALEESA-2′s ribociclib/letrozole cohort. 85 (53%) patients in KARMA experienced at least 1 ribociclib interruption (vs. 77% in MONALEESA-2), with the most common reason being neutropenia (54 of 85, 64%), followed by abnormal liver function tests (13 of 85, 15%). Four patients (2.5%) had ribociclib interruption due to QTc prolongation. With regards to dose reductions, 90 (56%) patients experienced at least 1 ribociclib dose reduction (vs. 54% in MONALEESA-2) with 71 (44%) patients required only 1 dose reduction and 19 (12%)2 dose reductions. The most common reason for dose reductions was neutropenia (68%), followed by abnormal liver function tests (14%) and fatigue (8%). Other reasons included nausea and vomiting (2%), rash and pruritis (3%) and diarrhoea (2%).
      A total of 97 of 160 (61%) patients discontinued ribociclib with 74 (46%) due to disease progression and 17 (11%) due to toxicity (vs. 8% in MONALEESA-2). Of the 17 patients who experienced toxicity leading to drug discontinuation, this was due to abnormal liver function tests (n = 6), fatigue (n = 3), neutropenia (n = 2), rash and pruritis (n = 2), QTc prolongation (n = 1), allergic reaction (n = 1), headache (n = 1) and infection (n = 1). There were no deaths due to toxicity. The subsequent treatment for these 17 patients, included 4 patients with palbociclib and endocrine treatment, 9 patients continued on an AI alone, 2 commenced capecitabine and 2 did not receive any further active treatment.

      Survival Outcomes

      At time of analysis, 45 of 160 (28%) patients had died. Median PFS was not reached (95% CI 29.9-NR), thus greater than the median follow up time of 36.5 months, as demonstrated in Figure 1. This is longer than MONALEESA-2 ribociclib/letrozole cohort's median PFS of 25.3 months (95% CI 23.0-30.3). Landmark PFS at 12 months and 18 months were 76% and 67% respectively as compared to 73% and 63% in MONALEESA-2.
      Univariate analysis and multivariate analysis for progression free survival was performed as prespecified (Table 3 and Table 4). There was a trend that post-menopausal patients had improved PFS as compared to pre- or peri-menopausal patients (HR 0.59, P= .06). There was also a trend that patients with de novo metastatic breast cancer (HR 0.47, P = .06) and patients with an ET free interval of > 12 months (HR 0.59, P = .09) had an improved progression free survival when compared to patients with an ET free interval of ≤ 12 months or who relapsed on adjuvant endocrine treatment.
      Table 3Univariate analysis for progression free survival
      PFSHazard ratioP95% confidence interval
      Age ≥ 65 years0.800.480.43-1.49
      Post-menopausal status0.620.070.37-1.04
      Presence of visceral metastases1.430.220.81-2.53
      Patients that received adjuvant chemotherapy1.210.430.75-1.94
      Compared to patients that had an endocrine therapy free interval12 months or relapsed on adjuvant endocrine therapy:
      Endocrine therapy free interval > 12 months0.590.080.32-1.07
      Patients with relapsed breast cancer that did not receive adjuvant endocrine therapy0.980.950.48-1.98
      Patients with de novo metastatic breast cancer0.520.050.27-1.00
      Table 4Multivariate analysis for progression free survival
      PFSHazard ratioP95% confidence interval
      Age ≥ 65 years1.001.000.51-1.97
      Post-menopausal status0.590.060.34-1.03
      Presence of visceral metastases1.520.160.85-2.72
      Patients that received adjuvant chemotherapy0.990.980.56-1.75
      Compared to patients that had endocrine therapy free interval12 months or relapsed on adjuvant endocrine therapy:
      Endocrine therapy free interval > 12 months0.590.090.32-1.09
      Patients with relapsed breast cancer that did not receive adjuvant endocrine therapy0.940.860.45-1.93
      Patients with de novo metastatic breast cancer0.470.060.22-1.02
      Figure 2 demonstrates 4 subgroups of patients and first line PFS,
      • Cancer of the Breast (Female) – Cancer Stat Facts
      patients that had an ET free interval of ≤ 12 months or relapsed on adjuvant ET (n = 37),
      • Gennari A
      • André F
      • Barrios C
      • et al.
      ESMO Clinical Practice Guideline for the diagnosis, staging and treatment of patients with metastatic breast cancer.
      patients that had an ET free interval > 12 months (n = 55),
      • Hortobagyi GN
      • Stemmer SM
      • Burris HA
      • et al.
      Ribociclib as first-line therapy for HR-positive, advanced breast cancer [published correction appears in N Engl J Med. 2018 Dec 27;379:2582].
      patients with relapsed breast cancer who did not receive adjuvant ET (n = 23),
      • Hortobagyi GN
      • Stemmer SM
      • Burris HA
      • et al.
      Overall survival with ribociclib plus letrozole in advanced breast cancer.
      patients with de novo metastatic breast cancer (n = 42). Median PFS was 24.6 months, not reached, 30.1 months and not reached for subgroups 1, 2, 3, and 4 respectively. Landmark 12-month PFS and 24-month PFS were 70% and 51% for subgroup 1, 78% and 70% for subgroup 2, 65% and 51% for subgroup 3, 88% and 74% for subgroup 4 respectively.
      Figure 2
      Figure 2Relapsed and de novo metastatic breast cancer subgroups in progression free survival
      <12m ETFI’ = patients that had an Endocrine Therapy Free Interval ≤ 12 months or relapsed on adjuvant endocrine therapy, >12m ETFI = patients that had an Endocrine Therapy Free Interval > 12 months, ‘No aET’ = patients with relapsed breast cancer that did not receive adjuvant endocrine therapy, ‘De novo MBC’ = patients with de novo metastatic breast cancer.

      Subsequent Treatment After Disease Progression

      Of the 74 patients that had disease progression on first line ribociclib and an AI, 65 (88%) patients received second-line treatment. Three patients died within 30 days of discontinuation of ribociclib and aromatase inhibitor and 6 patients did not receive further systemic treatment. Forty-two of 65 (65%) patients received chemotherapy in the second-line treatment setting, with capecitabine being the most commonly prescribed regimen (Figure 3).
      A total of 57 of 65 patients ceased second-line treatment with 51 due to disease progression and 4 patients ceased due to toxicity. Median overall second-line PFS was 4.7 months (95% CI 3.6-5.7 months). A total of 44 of the 51 patients who developed disease progression on second-line treatment subsequently received third-line treatment with 36 (82%) receiving chemotherapy (capecitabine 44%, nab-paclitaxel 28%, eribulin 14% and other 14%), 2 (4%) everolimus and exemestane, 2(4%) fulvestrant, 2 (4%) olaparib and 2 (4%) were treated on a clinical trial.

      Discussion

      KARMA is a multicentre Australian real-world study of ribociclib partnered with an AI captured alongside a Medicine Access Program in the first line treatment of HR+ HER2- metastatic breast cancer. This study indicates the safety and tolerability of the treatment combination with rates of drug interruptions, reductions and discontinuations in this setting is consistent with clinical trial data. The KARMA registry's median PFS of routine care patients on ribociclib and AI was numerically higher than that observed both in the post-menopausal ribociclib + letrozole cohort of MONALEESA-2 and the peri- and pre-menopausal ribociclib + ET cohort of MONALEESA-7.
      • Tripathy D
      • Im SA
      • Colleoni M
      • et al.
      Ribociclib plus endocrine therapy for premenopausal women with hormone-receptor-positive, advanced breast cancer (MONALEESA-7): a randomised phase 3 trial.
      This study also provided valuable insight into the management of a subgroup of relapsed metastatic disease patients whose treatment outcomes may be impacted by the timing of progression following cessation of adjuvant ET, as well as treatment selection in second line and beyond after progression on CDK4/6 inhibitor and AI in routine clinical practice. Moreover, the KARMA registry demonstrates the feasibility of comprehensive safety and efficacy data collection alongside a medicine access program.
      As reported in the pivotal clinical trials, our study confirmed that the combination of ribociclib and AI is well tolerated by routine care patients with the main toxicities being neutropenia and liver function derangement. Clinically significant cardiac toxicity with QTc prolongation of more than 600 miliseconds led to treatment discontinuation in 1 of 160 patients which, which mirrors the results of 1% of the 1054 patients in combined MONALEESA-2, MONALEESA-3,
      • Slamon DJ
      • Neven P
      • Chia S
      • et al.
      Phase III randomized study of ribociclib and fulvestrant in hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: MONALEESA-3.
      and MONALEESA-7 studies who also experienced a significant grade QTc interval prolongation (>500 miliseconds).
      • Jin Y
      • Xu Z
      • Yan H
      • He Q
      • Yang X
      • Luo P.
      A Comprehensive review of clinical cardiotoxicity incidence of FDA-approved small-molecule kinase inhibitors.
      RIBANNA, an ongoing prospective, non-interventional study of German patients on first line treatment for HR+, HER2- advanced breast cancer, included 1016 patients at third interim analysis treated with ribociclib plus an AI or fulvestrant. Key all-grade adverse events for patients on ribociclib included neutropenia (19%), nausea (19%), and fatigue (17%), however, data has not been presented as to whether these have led to dose interruption, reduction or cessation.
      • Wöckel A
      • Brucker C
      • Decker T
      • et al.
      Abstract PS10-16: Real-world efficacy of ribociclib + aromatase inhibitor/fulvestrant, or endocrine monotherapy, or chemotherapy as first-line treatment in women with HR-positive, HER2-negative locally advanced or metastatic breast cancer: Third interim analysis from the RIBANNA study.
      Two small real world studies of 28 and 31 patients
      • García-Trevijano Cabetas M
      • Lucena Martínez P
      • Jiménez Nácher I
      • Díaz Almirón M
      • Zamora Auñón P
      • Herrero Ambrosio A
      Real-world experience of palbociclib and ribociclib: novel oral therapy in metastatic breast cancer.
      ,
      • Nawaz A
      • Zekri J
      • Rasool H.
      Initial real life experience with ribociclib in breast cancer: outcome with focus on tolerance and cardiac toxicity.
      reported on incidence of dose reductions and interruptions, mirroring our findings that ribociclib is safe to prescribe in routine care setting with associated cardiac toxicity appropriately managed with careful monitoring.
      Our study suggested a numerically longer PFS of patients on ribociclib and an AI (>36.5 months) as compared to both MONALEESA-2 (25.3 months) and MONALEESA-7 (23.8 months). Notably, whilst the KARMA registry results were initially planned to be compared solely to MONALEESA-2, our study found that 1 in 4 patients enrolled were either pre or peri-menopausal which aligned with the patient population in MONALEESA-7. Potentially contributing to the observed numerically higher PFS is the KARMA registry's favourable baseline patient and disease characteristics (younger cohort, low burden of metastases and higher proportion of bone only metastases). Other potential explanations include less frequent or stringent restaging scans to monitor disease progression in routine practice as compared to strict pre-specified restaging scan windows in clinical trials. An improved understanding of the optimal use of ribociclib (and other CDK 4/6 inhibitors) over time may have led to better patient selection as well as monitoring and management of adverse events. Real world studies of first-line CDK 4/6 inhibitor use (palbociclib and ribociclib) with endocrine therapies, have demonstrated a median PFS ranging from 18.7 to 21.3 months.
      • DeSouza K
      • Yeo D
      • Diossy M
      • et al.
      Real-world outcomes from the systemic use of CDK 4/6 inhibitors (CDKIs) in the management of ER positive (+) HER2 negative (-) metastatic breast cancer (mBC).
      ,
      • Fountzilas E
      • Koliou GA
      • Vozikis A
      • et al.
      Real-world clinical outcome and toxicity data and economic aspects in patients with advanced breast cancer treated with cyclin-dependent kinase 4/6 (CDK4/6) inhibitors combined with endocrine therapy: the experience of the Hellenic Cooperative Oncology Group.
      Real world evidence for specifically palbociclib and AI in the first line setting have been reported with median PFS ranging from 13.3 to 29.4 months. While there have not been any real-world studies thus far examining survival outcomes of ribociclib specifically with ET in first-line setting, our novel KARMA registry study illustrates that the ribociclib and AI results in robust PFS outcomes in the first-line routine care setting.
      In our multivariate subgroup analysis, there was a trend towards longer PFS among patients with an ET free interval > 12 months (HR 0.59, P= .09) or de novo metastatic breast cancer patients (HR 0.47, P= .06) compared to those with an ET free interval of < 12 months or those who relapsed on adjuvant ET. Subgroup analyses from the MONALEESA-2 trial concluded that ribociclib is equally effective in patients who received prior ET as compared to those who had not; however, patient ET free interval data is not available for analysis.
      • Hortobagyi GN.
      Ribociclib for the first-line treatment of advanced hormone receptor-positive breast cancer: a review of subgroup analyses from the MONALEESA-2 trial.
      Although all subgroups appear to benefit from ribociclib and ET in the MONALEESA-7 trial, the exploratory analysis in the most recent updated OS analysis suggests that patients who are not ET naïve benefit from the treatment combination to a lesser degree.
      • Im SA
      • Lu YS
      • Bardia A
      • et al.
      Overall Survival with Ribociclib plus Endocrine Therapy in Breast Cancer.
      ,
      • Lu YS
      • Im SA
      • Colleoni M
      • et al.
      Updated overall survival of ribociclib plus endocrine therapy versus endocrine therapy alone in pre- and perimenopausal patients with HR+/HER2- Advanced Breast Cancer in MONALEESA-7: A Phase III Randomized Clinical Trial.
      In a British real world retrospective study abstract examining use of CDK 4/6 inhibitors in combination with endocrine therapies (AI and fulvestrant), significantly poorer outcomes were demonstrated in patients that had an ET free interval < 12 months as compared to those with an ET free interval > 12 months (12.1 vs. 28.4 months, HR 0.50 95%, CI 0.30-0.84).
      • Fountzilas E
      • Koliou GA
      • Vozikis A
      • et al.
      Real-world clinical outcome and toxicity data and economic aspects in patients with advanced breast cancer treated with cyclin-dependent kinase 4/6 (CDK4/6) inhibitors combined with endocrine therapy: the experience of the Hellenic Cooperative Oncology Group.
      Similarly, a Greek study demonstrated that "endocrine-therapy resistant" patients treated with first line CDK 4/6 inhibitor and ET had a shorter PFS than "endocrine-therapy sensitive" patients (median PFS 18.1 months vs not reached).
      • Harbeck N
      • Bartlett M
      • Spurden D
      • et al.
      CDK4/6 inhibitors in HR+/HER2- advanced/metastatic breast cancer: a systematic literature review of real-world evidence studies.
      Further research is required to demonstrate if patients with an ET free interval of <12 months or who relapse on adjuvant ET represent a poor prognostic subgroup, and if these patients would be better treated with upfront with a CDK 4/6 inhibitor and fulvestrant or with alternative first line treatment strategies.
      Optimal therapy after first line use of CDK 4/6 inhibitors is largely unknown. Current treatment guidelines recommend at least 2 lines of endocrine-based therapies before sequencing onto chemotherapy.
      • Gennari A
      • André F
      • Barrios C
      • et al.
      ESMO Clinical Practice Guideline for the diagnosis, staging and treatment of patients with metastatic breast cancer.
      ,
      • Burstein HJ
      • Somerfield MR
      • Barton DL
      • et al.
      Endocrine treatment and targeted therapy for hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer: ASCO Guideline Update.
      Our study found that of patients who progressed on first line ribociclib and AI and received second-line systemic therapy, around two-thirds received chemotherapy, with the preferred agent being capecitabine. Whilst sequential treatment data was not available for analysis from MONALEESA-2, in MONALEESA-7′s ribociclib cohort, just under half of patients received chemotherapy in the second line setting with again the most common agent being capecitabine.
      • Lu YS
      • Im SA
      • Colleoni M
      • et al.
      Updated overall survival of ribociclib plus endocrine therapy versus endocrine therapy alone in pre- and perimenopausal patients with HR+/HER2- Advanced Breast Cancer in MONALEESA-7: A Phase III Randomized Clinical Trial.
      Our study's real-world overall second-line median PFS was shorter than the duration of second-line treatment demonstrated in MONALEESA-7 (4.7 months vs. 7.5 months). Plausible explanations include the older median age of patients in our study, or that a greater proportion of our patients were sequenced onto chemotherapy rather than endocrine therapies, potentially representing patients in the second-line setting with a greater disease burden. This trend was also seen in a US population-based study which suggested that patients transitioning from CDK 4/6 inhibitor first line therapy to chemotherapy, as compared to nonchemotherapy regimens, had a trend of being more likely to have rapidly progressing disease.
      • Princic N
      • Aizer A
      • Tang DH
      • Smith DM
      • Johnson W
      • Bardia A.
      Predictors of systemic therapy sequences following a CDK 4/6 inhibitor-based regimen in post-menopausal women with hormone receptor positive, HEGFR-2 negative metastatic breast cancer.
      Given this was an exploratory analysis, we did not investigate for number of sites of metastases prior to receipt of second-line systemic treatment. Further real-world evidence studies are required to explore outcomes of second-line chemotherapy agents after receipt of CDK 4/6 inhibitors.
      Evidence for sequential non-chemotherapy options in patients who have progressed on first-line CDK4/6 inhibitors and AIs are limited as many therapies were developed in the pre CDK4/6 inhibitor era and little is known about potential cross-resistance.
      • Mavratzas A
      • Marmé F.
      Treatment of Luminal Metastatic Breast Cancer beyond CDK4/6 Inhibition: Is There a Standard of Care in Clinical Practice?.
      Our study demonstrated that clinicians favoured chemotherapy options in the second-line setting over non chemotherapy options, with everolimus and exemestane combination only compromising of 8% of second-line treatment regimens. Everolimus and exemestane combination as second line therapy was seen as the most common choice in an ongoing recruiting Canadian prospective real world observational study,
      • Doyle C
      • Vandenberg T
      • Ferrario C
      • et al.
      326P Exploratory analysis of TreatER+ight: A Canadian prospective real-world observational study in HR+ advanced breast cancer.
      with small scale retrospective studies demonstrating that efficacy and tolerability of everolimus and exemestane combination therapy is not affected by prior CDK 4/6 inhibitor use.
      • Nakayama T
      • Fujisawa F.
      Therapy options after CDK4/6 inhibitors for HR+, HER2- postmenopausal metastatic/recurrent breast cancer in Japan: a role for mammalian target of rapamycin inhibitors?.
      Aside from the everolimus-exemestane combination, there are ongoing studies evaluating the potential benefit of continuing CDK4/6 inhibition and switching ET at progression,
      • Mayer E
      • Wander S
      • Regan M
      • et al.
      Palbociclib after CDK and endocrine therapy (PACE): A randomized phase II study of fulvestrant, palbociclib, and avelumab for endocrine pre-treated ER+/HER2- metastatic breast cancer.
      ,
      • Kalinsky K
      • Layman R
      • Kaufman P
      • et al.
      postMONARCH: A phase 3 study of abemaciclib plus fulvestrant versus placebo plus fulvestrant in patients with HR+, HER2-, metastatic breast cancer following progression on a CDK4 & 6 inhibitor and endocrine therapy.
      with the recently presented Phase 2 MAINTAIN trial demonstrating efficacy of fulvestrant or exemestane with ribociclib after progression on CDK4/6 inhibitor.
      • Kalinsky K
      • Accordino M
      • Chiuzan C
      • et al.
      A randomized, phase II trial of fulvestrant or exemestane with or without ribociclib after progression on anti-estrogen therapy plus cyclin-dependent kinase 4/6 inhibition (CDK 4/6i) in patients (pts) with unresectable or hormone receptor–positive (HR+), HER2-negative metastatic breast cancer (MBC): MAINTAIN trial.
      For patients with PIK3Cα mutant tumours, use of alpelisib in combination with fulvestrant, after treatment with a CDK4/6 inhibitor demonstrated efficacy in the Phase 2 ByLieve study,
      • Rugo HS
      • Lerebours F
      • Ciruelos E
      • et al.
      Alpelisib plus fulvestrant in PIK3CA-mutated, hormone receptor-positive advanced breast cancer after a CDK4/6 inhibitor (BYLieve): one cohort of a phase 2, multicentre, open-label, non-comparative study [published correction appears in Lancet Oncol. 2021 May;22(5):e184].
      with 50% PFS at 6 months. Further evolving research are examining mutational targets such as AKT
      • Jones RH
      • Casbard A
      • Carucci M
      • et al.
      Fulvestrant plus capivasertib versus placebo after relapse or progression on an aromatase inhibitor in metastatic, oestrogen receptor-positive breast cancer (FAKTION): a multicentre, randomised, controlled, phase 2 trial.
      and ESR1 mutations,
      • Bidard F
      • Callens C
      • Dalenc F
      • et al.
      Prognostic impact of ESR1 mutations in ER+ HER2- MBC patients prior treated with first line AI and palbociclib: an exploratory analysis of the PADA-1 trial.
      other novel oral selective oestrogen receptor degrader approaches such as HDAC inhibitors
      • Jiang Z
      • Li W
      • Hu X
      • et al.
      Tucidinostat plus exemestane for postmenopausal patients with advanced, hormone receptor-positive breast cancer (ACE): a randomised, double-blind, placebo-controlled, phase 3 trial.
      and antibody drug conjugates such as sacituzumab govitecan.
      • Rugo HS
      • Bardia A
      • Tolaney SM
      • et al.
      TROPiCS-02: a Phase III study investigating sacituzumab govitecan in the treatment of HR+/HER2- metastatic breast cancer.
      With ongoing extensive research into new targeted therapies for management of HR+ HER2- MBC patients, we suggest that continued monitoring of the uptake and outcomes of these therapies in the real-world setting remains integral to best practice.
      Limitations of our study include that data was collected retrospectively and patients were not followed according to a strict protocol, which may have impacted the reported rates of adverse events and PFS. Data was only collected from a selection of sites that participated in the ribociclib MAP, potentially introducing a bias with respect to which patients were included. Moreover, despite the ribociclib MAP setting out clear eligibility criteria to mirror that of MONALEESA-2, inevitably a small proportion of community clinicians enrolled pre- and peri-menopausal patients on the MAP, reflecting real world practice.

      Conclusion

      First-line ribociclib and AI treatment for HR+ HER2- metastatic breast cancer in routine-care setting was safely delivered and well tolerated with similar rates of dose reductions and treatment discontinuations due to toxicity when compared to the clinical trial setting. This real-world registry cohort achieved a numerically higher median progression free survival as compared to MONALEESA-2, potentially explained in part by a younger population with more favorable baseline disease characteristics, including fewer disease sites and higher rates of bone-only metastases. Less rigid monitoring of disease progression may also have contributed. All subgroups including older patients, those with visceral metastases and receipt of prior adjuvant chemotherapy benefitted from first line treatment of ribociclib and AI. There was a trend for patients with an ET free interval of <12 months and those who relapsed on adjuvant ET to have a poorer prognosis. Our study further demonstrates the feasibility of comprehensive safety and efficacy data collection alongside a medicine access program and it is encouraging to find that drug tolerability and efficacy can be replicated in a non-trial patient population.

      Clinical Practice Points

      • Combination ribociclib and letrozole is a standard first-line treatment option for hormone-positive, HER2-negative metastatic breast cancer as demonstrated by MONALEESA-2 trial.
      • KARMA, an Australian registry, is the first real-world study, developed alongside a Medicine Access Program, to report firstline ribociclib and AI treatment outcomes.
      • Our study found similar rates of dose reduction (56%) and treatment discontinuation (11%) due to toxicity as compared to MONALEESA-2.
      • This real-world registry cohort had a longer median duration of treatment (24.5 vs 20.2 months) and superior progression free survival (>36.5 vs 25.3 months) as compared to MONALEESA-2.
      • Real world evidence continues to be valued by clinicians to see drug tolerability and efficacy replicated in populations not always captured by trial settings.

      Acknowledgments

      This Research Collaboration was supported by Novartis.

      Disclosure

      Vanessa Wong has received speaker honoraria from Amgen and Janssen, and her affiliated institution is the recipient of research grant funding from Pierre-Fabre, Amgen, Roche, MSD, AstraZeneca and Merck. Richard de Boer is on the Australian advisory board for Eli Lilly, Novartis and Pfizer, received speaker honoraria from Novartis and Eli Lilly, and research funding from Novartis and Pfizer. Katharine Cuff has received speaker honoraria from Novartis, is on the advisory board for Novartis, Pfizer and Ipsen, and is part of Amgen education support. Sheau Wen Lok's breast research team has received funding from Novartis, AstraZeneca, Roche and Amgen.

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