The Breast 66 (2022) 77–84 Contents lists available at ScienceDirect The Breast journal homepage: www.journals.elsevier.com/the-breast Safety and efficacy of ribociclib plus letrozole in patients with HR+, HER2– advanced breast cancer: Results from the Spanish sub-population of the phase 3b CompLEEment-1 trial Javier Salvador Bofill a, *, Fernando Moreno Anton b, Cesar Augusto Rodriguez Sanchez c, Elena Galve Calvo d, Cristina Hernando Melia e, Eva Maria Ciruelos Gil f, Maria Vidal g, Begoña Jiménez-Rodriguez h, Luis De la Cruz Merino i, Noelia Martínez Jañez j, Rafael Villanueva Vazquez k, Ruben de Toro Salas l, Antonio Anton Torres m, Isabel Manuela Alvarez Lopez n, Joaquin Gavila Gregori o, Vanesa Quiroga Garcia p, Elena Vicente Rubio q, Juan De la Haba-Rodriguez r, Santiago Gonzalez-Santiago s, Nieves Diaz Fernandez t, Agusti Barnadas Molins u, Blanca Cantos Sanchez de Ibargüen v, Juan Ignacio Delgado Mingorance w, Meritxell Bellet Ezquerra x, Sonia de Casa y, Asuncion Gimeno y, Miguel Martin z a Hospital Universitario Virgen del Rocío, Instituto de Biomedicina de Sevilla (IBIS), Sevilla, Spain b Hospital Clínico San Carlos, Madrid, Spain c Departamento de Oncología Médica, Hospital Universitario de Salamanca-IBSAL, Salamanca, Spain d Hospital Universitario de Basurto, Bilbao, Spain e Servicio de Oncología, Hospital Clínico Universitario de Valencia e Instituto de Investigación Sanitaria INCLIVA, Valencia, Spain f Hospital Universitario 12 de Octubre, Madrid, Spain g Department of Medical Oncology, Hospital Clinic, Barcelona, Spain; Translational Genomics and Targeted Therapies in Solid Tumors, IDIBAPS, Barcelona, Spain; Department of Medicine, University of Barcelona, Barcelona, Spain h UGCI Oncología Médica Hospitales Regional y Virgen de la Victoria, Málaga, Spain i Hospital Universitario Virgen de la Macarena, Sevilla, Spain j Hospital Universitario Ramón y Cajal, Madrid, Spain k Institut Català d’Oncologia, Hospital Duran i Reynals, Barcelona, Spain l Hospital Universitario de Jerez, Jerez, Spain m Hospital Universitario Miguel Servet, Zaragoza, Spain n Hospital Universitario Donostia-BioDonostia, Donostia, Spain o Fundación Instituto Valenciano de Oncología, Valencia, Spain p Departamento de Oncología, Badalona-Applied Research Group in Oncology (B-ARGO Group), Institut Català d’Oncologia, Badalona, Spain q Hospital Universitario Insular Gran Canaria, Gran Canaria, Spain r Instituto Maimonides de Investigacion Biomedica (IMIBIC), Hospital Reina Sofía, Universidad de Córdoba, Spain s Hospital Universitario San Pedro de Alcántara, Cáceres, Spain t Hospital Universitario San Juan de Alicante, Alicante, Spain u Hospital Universitari Santa Creu i Sant Pau and CIBERONC Breast Cancer Programme, Department of Medicine, Universitat Autonoma Barcelona, Barcelona, Spain v Hospital Puerta de Hierro Majadahonda, Madrid, Spain w Hospital Universitario Infanta Cristina, Badajoz, Spain x Hospital Universitari Vall d’Hebron, Barcelona and Institut Oncològic Vall d’Hebron (VHIO), Barcelona, Spain y Novartis Pharmaceuticals Spain, Barcelona, Spain z Hospital Universitario Gregorio Marañón, Madrid, Spain Abbreviations: ABC, advanced breast cancer; AE, adverse event; AESI, adverse event of special interest; ALT, alanine aminotransferase; AST, aspartate amino­ transferase; CBR, clinical benefit rate; CDK4/6, cyclin-dependent kinase 4/6; CI, confidence interval; CNS, central nervous system; CR, complete response; ECOG, Eastern Cooperative Oncology Group; ET, endocrine therapy; FACT-B, Functional Assessment of Cancer Therapy–Breast Cancer; FAS, full analysis set; FPFV, First Patient First Visit; HER2− , human epidermal growth factor receptor 2-negative; HR+, hormone receptor-positive; HRQoL, health-related quality of life; LPFV, last patient first visit; LPLV, last patient last visit; NE, not estimable; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PR, partial response; PRO, patient-reported outcome; QTcF, QT interval corrected for heart rate using Fridericia’s formula; RECIST, Response Evaluation Criteria in Solid Tumors; SAE, serious adverse event; SD, stable disease; SS, safety set; TTP, time to progression. * Corresponding author. Unidad de Oncología, Servicio de Oncología, Hospital Universitario Virgen del Rocío, Av. Manuel Siurot, s/n, 41013 Sevilla, Spain. E-mail address: franciscoj.salvador.sspa@juntadeandalucia.es (J. Salvador Bofill). https://doi.org/10.1016/j.breast.2022.09.006 Received 21 July 2022; Received in revised form 20 September 2022; Accepted 24 September 2022 Available online 28 September 2022 0960-9776/© 2022 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). J. Salvador Bofill et al. The Breast 66 (2022) 77–84 A R T I C L E I N F O A B S T R A C T Keywords: Background: Breast cancer is the most common malignancy and the second leading cause of cancer-related Advanced breast cancer mortality in Spanish women. Ribociclib in combination with endocrine therapy (ET) has shown superiority in Ribociclib prolonging survival in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor CDK4/6 inhibitor 2-negative (HER2− ) advanced breast cancer (ABC) vs. ET alone. Postmenopausal Premenopausal Methods: CompLEEment-1 is a single-arm, open-label phase 3b trial evaluating ribociclib plus letrozole in a broad population of patients with HR+, HER2– ABC. The primary endpoints were safety and tolerability. Here we report data for Spanish patients enrolled in CompLEEment-1. Results: A total of 526 patients were evaluated (median follow-up: 26.97 months). Baseline characteristics showed a diverse population with a median age of 54 years. At study entry, 56.5% of patients had visceral metastases and 8.7% had received prior chemotherapy for advanced disease. Rates of all-grade and Grade ≥3 adverse events (AEs) were 99.0% and 76.2%, respectively; 21.3% of patients experienced a serious AE, and 15.8% of AEs led to treatment discontinuation. AEs of special interest of neutropenia, increased alanine aminotransferase, increased aspartate aminotransferase and QTcF prolongation occurred in 77.8%, 14.8%, 11.4% and 4.0% of patients, respectively. Patients aged >70 years experienced increased rates of all-grade and Grade ≥3 neutropenia and anemia. Efficacy results were consistent with the global study. Conclusions: Results from Spanish patients enrolled in CompLEEment-1 are consistent with global data showing efficacy and a manageable safety profile for ribociclib plus letrozole treatment in patients with HR+, HER2− ABC, including populations of interest (NCT02941926). Trial registration: ClinicalTrials.gov NCT02941926 1. Introduction MONALEESA-7, the CompLEEment-1 trial population included patients who were male, had CNS metastases, and/or an Eastern Cooperative Breast cancer is the most common malignancy in Spanish women, Oncology Group (ECOG) performance status of 2. Furthermore, with approximately 33,000 new cases estimated to be diagnosed in CompLEEment-1 also included patients who had received prior 2021; it is also the second leading cause of cancer-related mortality for chemotherapy for advanced disease, who are frequently excluded from Spanish women [1]. Invasive breast cancer cases represent just under clinical trials despite clinical data showing that a significant number of 30% of all invasive cancers diagnosed in Spanish women [2,3]. Breast patients with HR+, HER2– ABC receive chemotherapy as first-line cancer rates in Spain have remained stable over the past decades with an treatment [19]. Safety and efficacy data for ribociclib in incidence of ~88 per 100,000, which is lower than the European CompLEEment-1 were consistent with those of MONALEESA-2 and -7; average (108.8 per 100,000) [2]. Approximately 19% of women diag­ the median time to progression was 27.1 months (95% confidence in­ nosed with breast cancer in Spain were aged under 45 years [4]. terval [CI], 25.7 to not reached) [18]. Although tumor biology in younger, premenopausal women tends to be Here, we present a detailed analysis of the efficacy and safety of more aggressive than in older ones, these women are often underrep­ ribociclib plus letrozole in a broad population of Spanish patients with resented in clinical trials [5,6]. HR+, HER2− ABC enrolled in the CompLEEment-1 trial. Hormone receptor-positive (HR+) breast cancer is the most common subtype, representing up to 75% of breast cancer cases [7,8]. Endocrine 2. Methods therapy (ET) is a long-established first-line treatment for HR + advanced breast cancer (ABC); however, the effectiveness of ET is limited by the 2.1. Study design and treatment development of endocrine resistance, which prevents patients from achieving long-term clinical benefit [9]. The combination of ET with CompLEEment-1 (NCT02941926) is an open-label, single arm, cyclin-dependent kinase 4/6 (CDK4/6) inhibitors has resulted in pro­ multicenter phase 3b study assessing the overall safety, tolerability, and longed clinical benefit in patients with HR+, human epidermal growth clinical efficacy of ribociclib in combination with letrozole in men, and factor receptor 2-negative (HER2− ) ABC, and is now the recommended pre- and postmenopausal women with HR+, HER2− ABC who did not first-line treatment for these patients as per the ESO-ESMO and NCCN receive prior ET for advanced disease [18]. The study consists of 2 guidelines [10,11]. phases (Supplementary Fig. 1): a core phase running from the First Pa­ Ribociclib, an orally bioavailable, highly selective CDK4/6 inhibitor, tient First Visit (FPFV) until 18 months after the Last Patient First Visit is currently approved by Spanish Health Authorities in combination (LPFV), and an extension phase running from 18 months after LPFV (end with an aromatase inhibitor or fulvestrant as first-line treatment for of the core phase) to the Last Patient Last Visit (LPLV). Patients transi­ pre-/postmenopausal patients with HR+, HER2− ABC [12]. The phase 3 tioned to the extension phase only if they were still obtaining clinical MONALEESA-2, -3 and -7 trials have established the efficacy and safety benefit from the treatment at the end of the core phase and had no access of ribociclib in combination with ET in patients with HR+, HER2− ABC to ribociclib outside of the clinical trial. [13–17], showing superiority vs. ET alone in prolonging both Patients received ribociclib at a total daily starting dose of 600 mg (3 progression-free survival (PFS) and overall survival (OS), regardless of tablets of 200 mg) on a 3 weeks on/1 week off schedule, with or without ET partner, line of therapy, or menopausal status. food. Additionally, patients received 2.5 mg letrozole orally once a day Despite these positive results, evidence for the safety and efficacy of on a continuous schedule through a 28-day cycle. Male patients and ribociclib plus ET in a broader patient population is lacking, as patients premenopausal female patients also received 3.6 mg goserelin (as an with poor performance status, central nervous system (CNS) metastases injectable subcutaneous implant) or 7.5 mg leuprolide (as an intra­ and those who have received chemotherapy for ABC are frequently muscular injection) once per cycle. Treatment continued until disease excluded from clinical trials. The phase 3b CompLEEment-1 trial progression, unacceptable toxicity, death, or discontinuation from study assessed the safety and tolerability of ribociclib plus letrozole in a larger treatment for any reason. All patients were followed for 30 days and broader population of patients with HR+, HER2− ABC than those following the last ribociclib dose. Dose reduction, dose interruption, eligible for previous phase 3 trials [18]. Unlike MONALEESA-2 and and/or discontinuation of ribociclib were permitted for the management 78 J. Salvador Bofill et al. The Breast 66 (2022) 77–84 of severe adverse events (AEs), whereas dose reductions were not electronic devices at Day 1 of each cycle up to Cycle 6, every 2 cycles up permitted for letrozole, goserelin or leuprolide [18]. Data cutoff was 8 to Cycle 12 and every 3 cycles thereafter. November 2019. 2.2. Key inclusion and exclusion criteria 2.4. Statistical analysis Eligible patients included adult males, pre- and postmenopausal fe­ Demographic and other baseline data including disease characteris­ males aged ≥18 years with locoregionally recurrent or metastatic HR+, tics were summarized descriptively for the Full Analysis Set (FAS) of the HER2– ABC not amenable to curative therapy. Only those patients who Spanish patients’ subgroup. The FAS included all patients who received had received ≤1 line of chemotherapy and no prior ET for advanced at least one dose of study treatment (either ribociclib or letrozole or disease were enrolled in this study. Patients with a treatment-free in­ goserelin/leuprolide [if applicable] in the core phase). terval (TFI) > 12 months from completion of (neo)adjuvant therapy The safety analysis was conducted using the Safety Set (SS) of the with letrozole or anastrozole and those who had received treatment in Spanish patients’ subgroup, which included all patients in the FAS. The the metastatic setting with letrozole or anastrozole for ≤28 days prior to primary safety variables (AEs, SAEs, AESIs, AEs leading to dose reduc­ enrollment were eligible. All enrolled patients displayed adequate bone tion or interruption, and AEs leading to discontinuation and deaths) marrow and organ function and had an ECOG performance status of ≤2. were summarized by count and percentage. At screening, eligible patients had corrected QT interval (QTc) <450 ms The clinical efficacy analysis was conducted using the FAS. ORR and as measured by Fridericia’s correction (QT interval corrected for heart CBR were calculated and summarized using frequency tables with rate using Fridericia’s formula, QTcF), and a resting heart rate of ≥50 associated 2-sided exact 95% CI, whereas TTP was estimated using the beats per minute. Kaplan-Meier method. The patient-reported outcome (PRO) analysis set Key exclusion criteria included receipt of any prior CDK4/6 inhibitor consisted of all female patients in the FAS population for whom baseline or systemic hormonal therapy for ABC or concurrent use of other anti­ and at least one postbaseline measurements were available. cancer therapy; known history of HIV infection; clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormalities; and concurrent malignancy or malignancy within 3 years prior to 2.5. Ethics starting study drug (except requisitely treated basal cell or squamous cell carcinoma, non-melanoma skin cancer; or curatively resected cer­ The study was designed, implemented, and reported in accordance vical cancer). Patients with CNS metastases were also excluded, unless with the International Council for Harmonisation of Technical Re­ the patient had completed any prior therapy for CNS disease 4 weeks quirements for Pharmaceuticals for Human Use (ICH) Harmonized before the start of study treatment and CNS lesions were clinically Tripartite Guidelines for Good Clinical Practice, with applicable local stable. regulations, and with the ethical principles laid down in the Declaration of Helsinki. The protocol and informed consent form were reviewed and 2.3. Endpoints and study assessments approved by a properly constituted Institutional Review Board/Inde­ pendent Ethics Committee/Research Ethics Board before study The primary objective of this study was to assess the safety and commencement. Written informed consent was obtained from all pa­ tolerability of ribociclib in combination with letrozole in a broad patient tients. A steering committee oversaw the conduct of the trial as per the population. Primary endpoints included the number of patients experi­ approved protocol. Representatives of the trial sponsor, Novartis Phar­ encing any adverse events (AEs); grade 3/4 AEs; serious AEs (SAEs); maceuticals (East Hanover, NJ), collected and analyzed the data. adverse events of special interest (AESIs); AEs leading to dose reduction, interruption, or discontinuation; and AE-related deaths. AESIs were 3. Results defined according to ongoing reviews of ribociclib safety data, and included neutropenia, QTcF prolongation, and hepatobiliary toxicity 3.1. Patient demographics and baseline characteristics (measured as elevation of aspartate aminotransferase [AST] and alanine aminotransferase [ALT] blood levels). Safety assessments involved Patient disposition and baseline characteristics of all patients monitoring and recording all AEs, grade 3/4 AEs and SAEs, AESIs, AEs enrolled in the global study have been described previously [18]. leading to drug discontinuation and deaths. MedDRA version 22.1 and Overall, 526 Spanish patients were enrolled and received at least one CTCAE version 4.03 were used to define AESIs and AEs (preferred term), dose of study treatment between April 2017 and November 2019. The respectively. median follow-up time was 26.97 months (range, 21.4–33.84). The Secondary endpoints related to the clinical efficacy of ribociclib plus median duration of exposure to ribociclib was 18.6 months, while this letrozole included time-to-progression (TTP) based on investigators’ was 18.8 months for letrozole (n = 526) and 16.8 months for goserelin assessment (defined as time from date of treatment initiation to the date (n = 173); no Spanish patients received leuprolide. The median average of event); overall response rate (ORR) for patients with measurable daily dose of ribociclib was 600.0 mg (240.0–600.0), while the median disease (defined as the proportion of patients with a best overall dose intensity was 576.7 mg/day (204.5–682.4). Overall, 58.0% of pa­ response of complete response [CR] or partial response [PR]); and tients discontinued study treatment (Supplementary Table 1); the most clinical benefit rate (CBR), defined as the proportion of patients with a common reasons for treatment discontinuation were progressive disease best overall response of CR or PR, or an overall lesion response of stable (33.8%) and AEs (15.0%). disease (SD), lasting for at least 24 weeks, as per local review. Tumor Baseline patient characteristics showed a diverse population in terms response, which was assessed locally, was based on Response Evaluation of age and disease characteristics (Tables 1 and 2). The median age was Criteria in Solid Tumors (RECIST) v1.1 criteria. Tumor assessments were 54 years (range, 24–85), and 15.8% of patients were aged >70 years performed according to the current standard of care; assessments were (Table 1). The vast majority of patients were female (99.2%, with 4 male recommended to take place every 12 weeks until disease progression. patients [0.8%] enrolled), and 64.4% were postmenopausal women; Another secondary endpoint was health-related quality of life most patients (97.7%) had an ECOG performance status of ≤1. (HRQoL) using the Functional Assessment of Cancer Therapy–Breast At baseline, 56.5% of patients had visceral metastases, whereas 1.5% Cancer (FACT-B) questionnaire [20], translated into Spanish. This was of patients had CNS metastases (Table 2). Overall, 37.3% of patients had only completed by female patients due to the nature of the question­ ≥3 metastatic sites at baseline, whereas 8.7% of patients had received naire. Responses to the FACT-B questionnaire were collected using prior chemotherapy for advanced disease. 79 J. Salvador Bofill et al. The Breast 66 (2022) 77–84 Table 1 Table 3 Baseline patient characteristics. Safety overview. Characteristic All Patients Spanish Patients Category Spanish Patients, N = 526 N = 3246 N = 526 All Grades n (%) Grade ≥3 n (%) Median age, years (range) 58.0 (20–92) 54.0 (24–85) AEs 521 (99.0) 401 (76.2) Age category, years, n (%) Treatment-related 494 (93.9) 352 (66.9) <70 years 2613 (80.5) 443 (84.2) SAEs 112 (21.3) 93 (17.7) 70 to ≥75 years 633 (19.5) 83 (15.8) Treatment-related 19 (3.6) 16 (3.0) Gender, n (%) Fatal SAEs 10 (1.9) 10 (1.9) Female 3207 (98.8) 522 (99.2) Treatment-related 2 (0.4) 2 (0.4) Female, postmenopausal 2485 (76.6) 339 (64.4) AEs leading to discontinuation 83 (15.8) 47 (8.9) ECOG PS, n (%) Treatment-related 63 (12.0) 36 (6.8) 0 1964 (60.5) 346 (65.8) AEs leading to dose adjustment/interruption 390 (74.1) 350 (66.5) 1 1161 (35.8) 168 (31.9) Treatment-related 351 (66.7) 324 (61.6) 2 112 (3.5) 7 (1.3) Missing 9 (0.3) 5 (1.0) A patient with multiple severity grades for an AE is only counted under the ECOG PS, Eastern Cooperative Oncology Group Performance Status. maximum grade. AE, adverse event; SAE, serious adverse event. 8.9%) led to treatment discontinuation, while 74.1% (Grade ≥3, 66.5%) Table 2 required dose adjustment or interruption. Disease characteristics. The majority of AEs were assessed as treatment-related (all grade, Characteristic All Patients Spanish 93.9%; Grade ≥3, 66.9%), but the rates of SAEs assessed as related to N = 3246 Patients treatment were low (all grade, 3.6%; Grade ≥3, 3.0%). Two deaths were N = 526 assessed as resulting from treatment-related AEs: the causes were Median time since initial diagnosis, months 42.5 46.8 pneumonitis, and pancytopenia and sepsis (it should be noted that the (range) (0.1–469.9) (0.1–412.8) latter patient was concomitantly receiving metamizole). Disease-free interval, n (%) The most common AEs reported were neutropenia (all grade, 77.4%; De novoa 1041 (32.1) 158 (30.0) Non-de novob 2201 (67.8) 368 (70.0) Grade ≥3, 59.5%), asthenia (all grade, 37.8%; Grade ≥3, 1.9%), nausea ≤24 months 382 (11.8) 62 (11.8) (all grade, 28.1%; Grade ≥3, 0.6%), arthralgia (all grade, 24.0%; Grade >24 months 1819 (56.0) 306 (58.2) ≥3, 0%), and anemia (all grade, 20.3%; Grade ≥3, 1.9%) (Table 4). Hormone receptor status, n (%) Rates of all-grade neutropenia were similar across patient subgroups of Estrogen receptor-positive 3231 (99.5) 525 (99.8) Progesterone receptor-positive 2608 (80.3) 417 (79.3) interest (patients aged >70 years, patients who received prior chemo­ Site of metastases, n (%) therapy for advanced disease, and patients with visceral metastases at Bone 2409 (74.2) 401 (76.2) diagnosis), although increased proportions of patients aged >70 years Bone-only 704 (21.7) 151 (28.7) experienced Grade ≥3 neutropenia (64.0% vs. 59.5% in all patients) Breast 183 (5.6) 29 (5.5) (Table 4). The reported frequency of anemia was also increased in pa­ CNS 51 (1.6) 8 (1.5) Visceral 1992 (61.4) 297 (56.5) tients aged >70 years compared with all patients (all grade, 37.3% vs. Liver 862 (26.6) 143 (27.2) 20.3%; Grade ≥3, 5.3% vs. 1.9%). Increased proportions of these elderly Lung 1416 (43.6) 196 (37.3) patients also experienced constipation (22.7% vs. 16.9%), alopecia Other 295 (9.1) 36 (6.8) (26.7% vs. 16.7%), vomiting (22.7% vs. 15.4%), and decreased appetite Skin 110 (3.4) 8 (1.5) Lymph nodes 1250 (38.5) 180 (34.2) (25.3% vs. 11.0%) compared with the whole patient population; the Other 163 (5.0) 15 (2.9) majority of these events were grade 1 or 2. Meanwhile, patients who had Metastatic sites, n (%) received prior chemotherapy for advanced disease reported increased 0 15 (0.5) 2 (0.4) rates of all-grade arthralgia (32.6% vs. 24.0% in all patients). 1 903 (27.8) 175 (33.3) Most cases of neutropenia were managed with dose interruption or 2 923 (28.4) 153 (29.1) 3 644 (19.8) 99 (18.8) dose reduction, while nearly half of hypertransaminasemia cases were 4 375 (11.6) 55 (10.5) managed with dose reduction; on the other hand, few cases of QTcF ≥5 386 (11.9) 42 (8.0) prolongation required this approach (Table 5). The numbers of patients Prior (neo)adjuvant ET, n (%) who required permanent drug withdrawal due to neutropenia, ALT in­ Anti-estrogenc 1156 (35.6) 207 (39.4) Aromatase inhibitorsd 1091 (33.6) 117 (22.2) crease, AST increase and QTcF prolongation were 4 (0.8%), 29 (5.5%), Prior chemotherapy for advanced disease, 194 (6.0) 46 (8.7) 25 (4.8%) and 0, respectively. The rates of recovery/resolution were n (%) greater than the rates of non-recovery/non-resolution for all AESIs a De novo includes patients with no date of first recurrence/progression or except transaminase increase. AESIs very rarely led to hospitalization with a first recurrence/progression within 90 days of initial diagnosis without (0–0.2% of patients) and no fatal AESIs were recorded. prior antineoplastic medication. At data cutoff, 10 patients (1.9%) had died, most of them as a result b Non-de novo disease was calculated as the time from initial diagnosis to first of disease progression (n = 5, 1.0%). Other causes of death were em­ recurrence/progression, categorized as ≤12 months, >12 to ≤24 months, and bolism, hepatic failure, pneumonitis, respiratory failure and sepsis (one ≥24 months. patient each); of these, the deaths due to pneumonitis and sepsis were c Includes tamoxifen. assessed as related to treatment. d Includes anastrozole, exemestane and letrozole. CNS, central nervous sys­ tem; ET, endocrine therapy. 3.3. Efficacy 3.2. Safety The median TTP was not estimable (NE; 95% CI: 23.5, NE; n = 180), Nearly all patients experienced an AE (99.0%), with Grade ≥3 AEs while the Kaplan-Meier estimated event-free probability was 77.0% occurring in 76.2% of patients (Table 3) and all-grade SAEs occurring in (95% CI: 72.8, 80.7) at 12 months and 54.9% (95% CI: 49.5, 60.0) at 24 21.3% (Grade ≥3 SAEs, 17.7%). Only 15.8% of all-grade AEs (Grade ≥3, months (Fig. 1). ORR and CBR for patients with measurable disease at baseline were 80 J. Salvador Bofill et al. The Breast 66 (2022) 77–84 Table 4 Adverse events reported in >15% of patients in subgroups of interest. Preferred Term All patients Age >70 years Prior chemotherapy Visceral metastases N = 526 N = 75 N = 46 N = 297 All Grades n Grade ≥3 n All Grades n Grade ≥3 n All Grades n Grade ≥3 n All Grades n Grade ≥3 n (%) (%) (%) (%) (%) (%) (%) (%) Number of patients with >1 521 (99.0) 401 (76.2) 75 (100.0) 63 (84.0) 45 (97.8) 31 (67.4) 293 (98.7) 224 (75.4) event Neutropenia 407 (77.4) 313 (59.5) 58 (77.3) 48 (64.0) 35 (76.1) 24 (52.2) 226 (76.1) 169 (56.9) Asthenia 199 (37.8) 10 (1.9) 31 (41.3) 4 (5.3) 10 (21.7) 0 109 (36.7) 7 (2.4) Nausea 148 (28.1) 3 (0.6) 21 (28.0) 0 12 (26.1) 0 89 (30.0) 2 (0.7) Arthralgia 126 (24.0) 0 12 (16.0) 0 15 (32.6) 0 67 (22.6) 0 Anemia 107 (20.3) 10 (1.9) 28 (37.3) 4 (5.3) 9 (19.6) 1 (2.2) 63 (21.2) 8 (2.7) Constipation 89 (16.9) 1 (0.2) 17 (22.7) 1 (1.3) 4 (8.7) 0 47 (15.8) 1 (0.3) Alopecia 88 (16.7) 0 20 (26.7) 0 1 (2.2) 0 48 (16.2) 0 Diarrhea 83 (15.8) 4 (0.8) 12 (16.0) 0 9 (19.6) 1 (2.2) 45 (15.2) 2 (0.7) Vomiting 81 (15.4) 4 (0.8) 17 (22.7) 1 (1.3) 6 (13.0) 0 46 (15.5) 2 (0.7) Decreased appetite 58 (11.0) 1 (0.2) 19 (25.3) 1 (1.3) 1 (2.2) 0 36 (12.1) 1 (0.3) A patient with multiple severity grades for an adverse event is only counted under the maximum grade. prior chemotherapy treatment for advanced disease had substantially Table 5 higher ORR and CBR rates compared with those exposed to chemo­ Adverse events of special interest. therapy at baseline (48.5% and 69.5% vs 31.3% and 59.4%, respec­ n (%)a Neutropenia Liver Enzyme QTcF tively), largely driven by higher rates of PR (45.1% vs. 28.1% in patients Elevation Prolongationb with prior chemotherapy treatment). ALT AST In terms of PROs, HRQoL remained stable throughout the study All-grade events 409 (77.8) 78 60 21 (4.0) without any major changes (Supplementary Fig. 2); median (SD) FACT- (14.8) (11.4) B scores were recorded as 101.2 (16.45) at baseline and 93.3 (19.65) at Leading to dose 299 (56.8) 34 (6.5) 25 (4.8) 2 (0.4) end of treatment, with a median change from baseline of − 7.3. interruption Leading to dose 90 (17.1) 6 (1.1) 3 (0.6) 2 (0.4) reduction 4. Discussion Leading to dose 4 (0.8) 29 (5.5) 25 (4.8) 0 withdrawal Our results support the clinical safety, tolerability and efficacy of Leading to 0c 0 0 1 (0.2) hospitalization treatment with ribociclib in combination with letrozole in a broad Medication or therapy 15 (2.9) 2 (0.4) 4 (0.8) 1 (0.2) population of Spanish patients with HR+, HER2− ABC who had not taken previously received ET for their advanced disease. Overall, the data are Not recovered/not 242 (46.0) 44 (8.4) 35 (6.7) 2 (0.4) consistent with those reported in the global CompLEEment-1 study [18] resolved Recovering/resolving 223 (42.4) 37 (7.0) 34 (6.5) 1 (0.2) and support the use of ribociclib plus letrozole in the first-line setting for Recovered/resolved 376 (71.5) 46 (8.7) 33 (6.3) 19 (3.6) patients with HR+, HER2− ABC. Moreover, these results demonstrate With sequelae 9 (1.7) 0 1 (0.2) 0 the reproducibility and robustness of treatment with ribociclib and Leading to death 0 0 0 0 letrozole in this patient population across different environments and a Percentage value calculated based on 526 patients. A patient is counted no local settings. more than once in each AE outcome. If a patient has AEs with different out­ The Spanish patient population enrolled in CompLEEment-1 repre­ comes, the patient will be counted in several outcomes. If the patient has several sented 14% of the global population of the study and reflected a broad events with the same outcome, he/she will be counted only once in the corre­ group of patients with HR+, HER2− ABC that was more representative sponding outcome line. of a real-world patient population than subjects included in other ran­ b Includes “Electrocardiogram QT prolonged”, “Electrocardiogram QT inter­ domized phase 3 trials of CDK4/6 inhibitors in combination with aro­ val abnormal”, “Syncope” and “Long QT syndrome”. matase inhibitors; in particular, a substantial proportion of patients in c 4 (0.8) cases with febrile neutropenia led to hospitalization. AE, adverse this trial had received chemotherapy for advanced disease [13,15,21]. event; AESI, adverse event of special interest; ALT, alanine aminotransferase; Interim safety results from the Spanish population subset in AST, aspartate aminotransferase; QTcF, QT interval corrected for heart rate using Fridericia’s formula. CompLEEment-1 reported using an earlier cut-off date were consistent with previous data from MONALEESA-2, MONALEESA-7, and the CompLEEment-1 global cohort, and confirmed the predictable and 46.6% (95% CI: 40.9, 52.5) and 68.5% (95% CI: 62.8, 73.7), respectively manageable safety profile of ribociclib in combination with letrozole as (Supplementary Table 2). Overall, 3.4% of patients experienced a CR first-line treatment for patients with HR+, HER2− ABC [22]. Spanish and 43.3% a PR. ORR and CBR were higher for patients aged <50 years CompLEEment-1 patients had a lower median age compared with those than for those aged ≥50 years. Patients aged <50 years also had enrolled in the global study (54.0 vs 58.0 years, respectively); the pro­ increased CR rates (5.1% vs. 2.5% for age ≥50 years). In terms of portion of patients aged <65 years was also larger among the Spanish menopausal status, ORR and CBR were similar for pre- and post­ subset (76.0% vs 66.9% in the global study). Consistent with this menopausal women, although CR rates were higher for premenopausal observation, a lower proportion of Spanish patients were post­ women (Supplementary Table 2). Metastatic status also affected efficacy menopausal (64.4% vs 76.6% in the global study). Similar proportions of rates, with patients presenting with visceral metastases having higher patients had ECOG ≤1 (97.7% vs 96.3% in the global study), while more ORR rates compared with patients with no visceral metastases at base­ Spanish patients had <3 metastatic sites at baseline (62.7% vs 56.7% in line (47.7% vs 43.6%, respectively; Supplementary Table 3); the number the global study). Overall, 8.7% of Spanish patients had received of metastatic sites also affected efficacy rates, with patients with <3 chemotherapy for advanced disease, compared with 6.0% in the global metastatic sites more likely to experience a CR (5.2% vs. 1.4% for pa­ study; this slightly higher percentage could reflect a more aggressive tients with ≥3 metastatic sites at baseline). Finally, patients with no treatment approach for Spanish women, which could be explained by 81 J. Salvador Bofill et al. The Breast 66 (2022) 77–84 Fig. 1. Time to progression in Spanish patients and all patients enrolled in the CompLEEment-1 study. Red, Spanish patients; black, all patients enrolled in the global study. Squares denote censored events. CI, confidence interval; NE, not estimable. the Spanish population being younger on average than the overall study reported for MONALEESA-2 (25.3 months [95% CI: 23.0, 30.3] with a population. median follow-up of 26.4 months) and MONALEESA-7 (23.8 months The reported AE profile among Spanish CompLEEment-1 patients [95% CI: 19.2, not reached], with a median follow-up of 19.2 months). was consistent with that reported in previous ribociclib trials [13,15], The similarity of median PFS measures across studies is of note as the and no new safety signals were identified. Rates of AEs and SAEs were CompLEEment-1 study enrolled a much broader patient population, similar to those reported for the global study (99.0% and 21.3% vs including patients who had received chemotherapy for advanced disease 98.7% and 21.6%, respectively), as were the rates of treatment discon­ [13,15]; these results highlight the efficacy of ribociclib in a patient tinuation due to AEs (15.8% vs 16.3% in the global study). This was population more representative of real-world patients. despite a numerically, albeit not significantly higher median dose in­ ORR and CBR for Spanish patients with measurable disease at tensity (576.7 mg/day [204.5–682.4] vs 571.4 mg/day [120.0–800.0] baseline were similar to those reported in the global study (46.6% and in the global study). 68.5% vs 43.6% and 69.1%, respectively). The ORR was lower than Neutropenia was the most common AE reported in Spanish patients, those reported in the MONALEESA-2 and MONALEESA-7 trials for pa­ as in the global study, followed by asthenia and nausea. Spanish patients tients with measurable disease at baseline (54.5% and 51.0%, respec­ aged >70 years reported increased rates of all-grade and grade ≥3 tively) [13,15]. This may be due to the differences in patient population neutropenia and anemia, as well as increased rates of certain non- enrolled in CompLEEment-1, although it should also be noted that hematologic AEs (constipation, alopecia, vomiting and decreased response assessment in this study was not centralized, but rather appetite). These results are similar to those from patients aged ≥65 years depended on the local standard of care. Age <50 years, presence of enrolled in the MONALEESA-2 trial [23]; these patients experienced visceral metastases at baseline, <3 metastatic sites and no prior increased rates of neutropenia and anemia, and the most frequent chemotherapy treatment for advanced disease all correlated with higher non-hematologic AEs (including nausea, fatigue, alopecia, vomiting, ORR and CBR in Spanish patients, while rates were similar for pre- and and diarrhea) were predominantly grade 1–2. Our results support the postmenopausal women. It should be noted that patients with visceral safety of ribociclib in combination with letrozole in Spanish patients metastases are more likely to have measurable disease and thus be aged >70 years, a population that is under-represented in clinical trials evaluable for response, which could explain the higher ORR and CBR and which may present challenges to treatment due to a high incidence rates in patients with visceral metastases at baseline. FACT-B scores of pre-existing comorbidities [24,25]. No notable differences in rates of were maintained relative to baseline, reflecting preservation of HRQoL. the most common AEs were detected for patients who had received prior A potential limitation of CompLEEment-1 is that tumor assessments chemotherapy for advanced disease or those with visceral metastases at were performed according to the current standard of care in different baseline, supporting the safety of ribociclib plus letrozole in these pa­ locations; response assessment timings may have varied, with different tient populations. intervals according to the local standard of care. However, we believe AESIs were managed by dose reduction or interruption, and rarely this is an actual strength of the study, showing the robustness of led to hospitalization. The rates of resolved events were higher than response to ribociclib and supporting the utility of this type of analysis in rates of non-resolved events for all AESIs except ALT and AST increase. a local population. Efficacy and PRO data should be interpreted with The relatively high percentage of non-resolved or resolving AESIs could some caution given the lack of randomization and a control arm. be due to the mild nature of the AEs; in the case of ALT/AST increase, Overall, these findings support the efficacy and manageable safety this could also be explained by the resolution time determined in the profile of ribociclib in combination with letrozole as first-line treatment protocol (28 days) being too short to allow for complete resolution of in a population of Spanish patients with HR+/HER2− ABC approaching transaminitis. that of a real-world setting. Median TTP was not estimable, but the Kaplan-Meier estimated probabilities at 12 and 24 months among Spanish CompLEEment-1 pa­ Funding tients were similar to those reported in the global study (77.0% at 12 months and 54.9% at 24 months vs 75.1% at 12 months and 54.7% at 24 This study was funded by Novartis Pharmaceuticals. The sponsor was months, respectively). The lack of event-free survival data at 33 months involved in the study design, the collection, analysis, and interpretation is likely due to the fact that the study opened in Spain later than in other of data, and the writing of the manuscript. locations. Median PFS was 26.7 months (95% CI: 24.8, 30.1) for the total population in the global CompLEEment-1 study, with a median follow- up of 25.4 months [18]; this was comparable to the median PFS 82 J. Salvador Bofill et al. The Breast 66 (2022) 77–84 Conflict of interest/disclosures Guidelines for Good Clinical Practice, with applicable local regulations, and with the ethical principles laid down in the Declaration of Helsinki. JSB has received research grants from AstraZeneca, Lilly, Pfizer and The protocol and informed consent form were reviewed and approved Roche; consulting fees from AstraZeneca, Daiichi Sankyo, Gilead, Lilly, by a properly constituted Institutional Review Board/Independent Pfizer, Roche and Seagen; honoraria from Lilly, Novartis and Pfizer. Ethics Committee/Research Ethics Board before study commencement. FMA has received research grants from Pfizer; consulting fees from Written informed consent was obtained from all patients. A steering AstraZeneca, Daiichi Sankyo, Eisai, MSD, Pfizer, Roche and Seagen; committee oversaw the conduct of the trial as per the approved protocol. honoraria from Pfizer; travel grants from Daiichi Sankyo, Novartis and Representatives of the trial sponsor, Novartis Pharmaceuticals (East Pfizer. EGC has received research grants from Pfizer; consulting fees Hanover, NJ), collected and analyzed the data. from AstraZeneca, Daiichi Sankyo, Gilead, Pfizer, Pharmamar, Roche and Seagen; honoraria from Eisai, Novartis and Pfizer; travel grants from Data sharing statement Novartis, Pfizer and Roche. CHM has received honoraria from Novartis; travel grants from Novartis, Pfizer and Roche. EMCG has received Novartis is committed to sharing with qualified external researchers, honoraria from AstraZeneca, Daiichi Sankyo, Lilly, Novartis, Pfizer, access to patient-level data and supporting clinical documents from Roche and Seagen; travel grants from AstraZeneca, Daiichi Sankyo, eligible studies. These requests are reviewed and approved by an inde­ Novartis and Pfizer; has participated in advisory boards for AstraZeneca, pendent review panel on the basis of scientific merit. All data provided is Daiichi Sankyo, Lilly, Novartis, Pfizer, Roche and Seagen. MV has anonymized to respect the privacy of patients who have participated in received honoraria from Daiichi Sankyo, Novartis, Pfizer and Roche; the trial in line with applicable laws and regulations. This trial data travel grants from Pfizer and Roche; has participated in advisory boards availability is according to the criteria and process described on www. for Novartis and Roche. LDLCM has received honoraria from AstraZe­ clinicalstudydatarequest.com. neca, BMS, Incyte, MSD and Roche; travel grants from Roche. RVV has received consulting fees from Novartis; honoraria from Eisai, Lilly and Acknowledgements Novartis; payment for expert testimony from Novartis; travel grants from Lilly, Novartis and Roche; has participated in advisory boards for The authors would like to thank Vanesa Martinez Lopez, PhD, of Novartis. AAT has taken advisory/consultancy roles for Eli Lilly and Novartis Ireland Ltd, for medical writing support, which was funded by Gilead; has received honoraria from AstraZeneca-Daichii-Sanykio, Eli Novartis Farma S.A. in accordance with Good Publication Practice Lilly, Pfizer and Seagen. IMAL has received institutional grants from (GPP3) guidelines (http://www.ismpp.org/gpp3). Novartis; honoraria from Novartis. JGG has received honoraria from AstraZeneca, Daiichi Sankyo, Lilly, Novartis, Pfizer, Roche and Seagen; Appendix A. Supplementary data travel grants from AstraZeneca, Daiichi Sankyo, Lilly, Novartis, Pfizer, Roche and Seagen; has participated in advisory boards for AstraZeneca, Supplementary data to this article can be found online at https://doi. Daiichi Sankyo, Lilly, Novartis, Pfizer, Roche and Seagen. VQG has been org/10.1016/j.breast.2022.09.006. an invited speaker for Novartis and is a steering committee member for Roche. EVR has received honoraria from Lilly, Novartis, Pfizer and References Roche; travel grants from Lilly, Novartis, Pfizer and Roche. JDLHR has received consulting fees from Lilly, Novartis, Pfizer, Roche and Seagen; [1] SEOM. Las cifras del cáncer en España. 2021. [2] Galceran J, Ameijide A, Carulla M, Mateos A, Quirós JR, Rojas D, et al. Cancer honoraria from Lilly, Novartis, Pfizer, Roche and Seagen; payment for incidence in Spain, 2015. 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