Abemaciclib In Combination Research Articles

A Phase II Study of Fulvestrant plus Abemaciclib in Hormone Receptor-Positive Advanced or Recurrent Endometrial Cancer.

Inhibition of the cyclin D-cyclin dependent kinase (CDK)4/6-INK4-retinoblastoma pathway can overcome acquired or de novo treatment resistance to endocrine monotherapy. Responses to endocrine monotherapy in advanced endometrial cancer (EC) are suboptimal, perhaps due to genomic alterations that promote estrogen receptor (ER)-independent cyclin D1-CDK4/6 activation. We hypothesized that addition of abemaciclib, a CDK4/6 kinase inhibitor, to antiestrogen therapy with fulvestrant will be an effective therapeutic strategy in patients with advanced or recurrent EC. In this phase II study, patients with advanced or recurrent EC received 150 mg of abemaciclib orally twice daily with 500 mg of fulvestrant intramuscularly monthly with a 2-week loading dose. Eligibility included ER or progesterone receptor expression ³1% by immunohistochemistry, measurable disease, £2 prior lines of chemotherapy, and £1 prior line of hormonal therapy. The primary endpoint was objective response rate (ORR) by RECIST v1.1. Twenty-seven patients initiated therapy and 25 were evaluable for efficacy. Eleven patients achieved partial response; 10 responses (91%) were in copy number-low/no specific molecular profile tumors, 1 (9%) was in a microsatellite instability-high tumor, and no responses were observed in copy number-high/TP53abnormal tumors. The ORR was 44% (90% CI, 27.0%-62.1%). Median duration of response was 15.6 months. Median progression-free survival was 9.0 months (90% CI: 1.8-20.4). The most common grade ³3 treatment-related adverse events were neutropenia (26%) and anemia (19%); no new safety signals were identified. The combination of abemaciclib and fulvestrant has promising activity with durable responses in advanced or recurrent EC; a randomized trial is planned.

Cost-effectiveness of early vs delayed use of abemaciclib combination therapy for patients with high-risk hormone receptor-positive/human epidermal growth factor receptor 2-negative early breast cancer.

Abemaciclib was newly approved for hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) high-risk early breast cancer (EBC). Clinical guidelines recommended abemaciclib as the first-line treatment for HR+/ HER2- EBC (early use) or HR+/ HER2- metastatic breast cancer (MBC) (delayed use). To compare the cost-effectiveness of early vs delayed use of abemaciclib for treatment of HR+/HER2- high-risk EBC. Early use was defined as combined abemaciclib and endocrine therapy as first-line therapy for EBC, followed by treatment with fulvestrant for MBC. Delayed use was defined as endocrine therapy for EBC, followed by combined abemaciclib and fulvestrant therapy for MBC. A 5-state model was developed to estimate lifetime costs, life-years (LYs), and quality-adjusted life-years (QALYs) of hypothetical patients with HR+/ HER2- EBC from a third-party US payer's perspective. Key clinical and safety data were derived from the monarchE and MONARCH 2 clinical trials. Costs, utilities, and disutility values of adverse events were obtained from the literature. We calculated the incremental cost-effectiveness ratio (ICER) of early vs delayed abemaciclib use and compared it with a willingness-to-pay (WTP) threshold of $100,000 per LY or QALY. Deterministic and probabilistic sensitivity analyses (PSAs) were performed to test the robustness of the base-case model. Base-case analysis showed early use yielded 21.08 LYs and 17.93 QALYs for $586,213 and delayed use yielded 11.14 LYs and 9.38 QALYs for $157,576. The ICER of early vs delayed use was $43,136/LY and $50,104/QALY, which was cost-effective at the WTP threshold of $100,000. The PSA result indicated that a 94.6% likelihood of early use (vs delayed use) was cost-effective at the WTP threshold of $100,000 per QALY. This study suggests that giving abemaciclib in the early stage rather than waiting until patients develop metastatic disease (current standard of care in MBC) is a cost-effective strategy.

Abemaciclib plus endocrine therapy for HR+, HER2-, node-positive, high-risk early breast cancer: a plain language summary of the monarchE study.

This article summarizes the most recent results of the monarchE study. This study was completed in participants with a type of breast cancer called HR+, HER2-, node-positive, high-risk early breast cancer. In this study, abemaciclib, a non-chemotherapy treatment, was administered with standard of care endocrine therapy after curative surgery. Most participants had received prior chemotherapy and/or radiotherapy. The study investigated if abemaciclib helped participants live longer without their cancer returning compared with participants who only received standard of care endocrine therapy. The study participants were assigned to 1 of 2 treatment groups. Participants in Group A were assigned to receive standard of care endocrine therapy with abemaciclib for 2years, followed by endocrine therapy for a total of at least 5years. Participants in Group B were assigned to receive standard of care endocrine therapy only for at least 5years. The effect of treatment was compared between these 2 groups. Overall, the results showed that the cancer was 34% less likely to come back after surgery in the participants in Group A (abemaciclib plus endocrine therapy) compared with those in Group B (endocrine therapy only). At 4years since the start of the study treatment, more participants who received the combination of abemaciclib plus endocrine therapy remained free of cancer compared with participants who received endocrine therapy alone (86% versus 79%). Participants who received abemaciclib plus endocrine therapy had more side effects than those who received endocrine therapy alone, but most of these effects were mild to moderate and reversible upon the end of therapy. The most common side effects in the abemaciclib group were diarrhea, infections, low number of white blood cells, and tiredness. This study found that administering abemaciclib in combination with standard endocrine therapy after curative breast surgery helped lower the risk of cancer returning in people with HR+, HER2-, node-positive, high-risk early breast cancer. Abemaciclib is a new treatment option for people with this diagnosis. People with high-risk early breast cancer should always talk to their doctors and nurses before making any decisions about their treatment.Clinical Trial Registration: NCT03155997 (monarchE study).

Concurrent Use of Abemaciclib and Radiotherapy in Metastatic Breast Cancer Patients: A Single-Center Experience.

There is little evidence regarding the safety and efficacy of the combination of abemaciclib plus radiotherapy (RT). The majority of studies investigated the combination of RT with palbociclib or ribociclib reporting that hematological toxicity is common. Given the unique toxicity profile of abemaciclib with greater gastrointestinal toxicity compared to hematological toxicity, we wanted to evaluate the toxicity of the combination with RT in metastatic breast cancer (BC) patients. Patients with histologically proven metastatic or locally advanced BC treated with RT and concurrent abemaciclib were selected. Toxicity was assessed according to the NCI-CTCAE V4.0. Thirty-two metastatic sites were treated in 19 patients and analyzed. All patients received abemaciclib during the RT course. A total of 68% of patients received a full dose of abemaciclib during RT. Also, 71.9% of patients received a palliative intent (median dose = 30 Gy, range = 8-30 Gy), and 26.3% were treated for 9 oligo-metastatic or oligo-progressive sites of disease with stereotactic body RT (median dose = 30 Gy, range 21-30 Gy, given in 3-5 fractions). Overall, the rate of G3 toxicity was 15.7%. The rate of G3 hematological toxicity was 10.6% (2/19 patients, one G3 neutropenia and one G3 anemia). No patient presented diarrhea, including those treated for RT sites close to the bowel. One patient developed G3 skin toxicity. Pain significantly improved after RT (mean value NRS pre-RT = 3.9, SD = 3.07; mean value NRS after RT = 0.9, SD = 0.46; p < 0.0001). Abemaciclib and concomitant RT seem well tolerated showing acceptable toxicity.

Abstract PO4-27-06: Design of Active Phase 3 ENABLAR-2 Study Evaluating Enobosarm +/- Abemaciclib in Patients with AR+ER+HER2- 2nd-Line Metastatic Breast Cancer Following Tumor Progression on an Estrogen Blocking Agent Plus Palbociclib or Ribociclib

Abstract Background: Targeting the androgen receptor (AR) with an oral selective agonist, enobosarm, is a novel approach to overcome ER and CDK4/6 resistance to suppress metastatic breast cancer (mBC). Preclinical studies in CDK4/6 inhibitor and estrogen blocking agent resistant PDX mBC models demonstrated that enobosarm alone or in combination with another CDK 4/6 inhibitor suppressed PDX mBC growth. In a subgroup analysis from a Phase 2 study, enobosarm demonstrated efficacy in the treatment of AR+ ER+ HER2- metastatic breast cancer in patients who had tumor progression on estrogen blocking agent and a CDK 4/6 inhibitor with a best overall response rate of 30% (2CRs and 1 PR). A Phase 3 ENABLAR-2 multi-center, open label, study evaluating enobosarm +/- abemaciclib is open and active for the treatment of HR+HER2- mBC. Methods: The two-staged Phase 3 ENABLAR-2, open-label, randomized, multicenter study is being conducted in AR+ER+ HER2- 2nd-line mBC who have progressed on estrogen blocking agent plus palbociclib or ribociclib. In the Stage 1 of the study (160 patients), five treatment arms will be assessed with the primary efficacy endpoint of ORR: enobosarm 9 mg QD, enobosarm 1 mg QD + abemaciclib, enobosarm 3 mg QD + abemaciclib, enobosarm 9 mg QD + abemaciclib, and an estrogen blocking agent, active control (a nonsteroidal AI, exemestane +/- everolimus, or SERD). Secondary efficacy endpoints include progression-free survival (PFS). In Stage 2 of the study, patients will be randomized to receive enobosarm +/- abemaciclib (based on outcome of ORR in Stage 1) or estrogen blocking agent, active control, with the primary endpoint of PFS and secondary efficacy endpoints including, ORR, CBR, OS, as well as changes in quality-of-life measurements (SPPB, EORTC-QLQ, body composition measured by DEXA). Randomization will be stratified by AR% nuclei staining and by line of treatment for metastatic disease. Subjects will receive study drug until disease progression is observed. Preliminary Results: To date, 3 patients have been treated with enobosarm 9 mg in combination with abemaciclib. The combination therapy was well tolerated with no new safety findings. There were no drug-drug interactions between enobosarm and abemaciclib. Two patients have achieved BOR of a partial response with up to 79% and 56% reduction in their target lesion recorded by local reads on day 224 post-treatment initiation (PTI). The third patient has achieved a stable disease and continues to receive treatment (on study 10+ months). Conclusions: Preliminary data of efficacy and safety of enobosarm in combination with abemaciclib are encouraging. The Phase 3 ENABLAR-2 study is underway to further evaluate enobosarm monotherapy or in abemaciclib combination therapy in 2nd-line metastatic breast cancer population. Clinical trial information: NCT05065411. Research Sponsor: Veru Inc Citation Format: Kristine Rinn, Hannah Linden, Lee Schwartzberg, Gary Barnette, Domingo Rodriguez, Itay Shalev, Mitchell Steiner, Adam Brufsky, Joyce O'Shaughnessy. Design of Active Phase 3 ENABLAR-2 Study Evaluating Enobosarm +/- Abemaciclib in Patients with AR+ER+HER2- 2nd-Line Metastatic Breast Cancer Following Tumor Progression on an Estrogen Blocking Agent Plus Palbociclib or Ribociclib [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-27-06.

Abstract 4610: Dual inhibition of CDK4/6 and IL-6 pathways as a novel therapeutic approach for triple-negative breast cancer cells

Abstract Triplenegative breast cancer (TNBC) is highly aggressive and associated with poor clinical outcomes. TNBC stands as a major cause of death among breast cancer patients and offers only a few therapeutic options. Abemaciclib, a cyclin dependent kinase 4/6 (CDK4/6) inhibitor, has received FDA approval for use in hormone receptor-positive, HER2-negative, and metastatic breast cancers. However, acquired resistance to CDK4/6 inhibitors in treating TNBC is becoming an increasing concern. Our recent results indicated that CDK4/6 inhibitors can induce IL-6 levels in TNBC cells as a potential resistance mechanism by augment IL-6 signaling axis, and that targeting IL-6 signaling can sensitize TNBC cells to CDK4/6 inhibitor therapy. In this study, combination of Abemaciclib with an IL-6/GP130 inhibitor (bazedoxifene) was tested in TNBC cells. We examined the effect of the combination on cell viability, cell migration, and invasion of human and mouse TNBC cell lines. Our data demonstrated that the bazedoxifene and abemaciclib combination treatment synergistically inhibited TNBC cell viability, cell migration, and invasion in vitro. These results support dual inhibition of CDK4/6 and IL-6 as a novel therapeutic approach for TNBC. Citation Format: Kailey Caroland, Changyou Shi, Hui-Wen Lo, Jiayuh Lin. Dual inhibition of CDK4/6 and IL-6 pathways as a novel therapeutic approach for triple-negative breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4610.

A network meta-analysis of efficacy and safety for first-line and second/further-line therapies in postmenopausal women with hormone receptor-positive, HER2-negative, advanced breast cancer

BackgroundHormone receptor-positive/human epidermal growth factor receptor 2-negative (HR + /HER2 −) advanced breast cancer is a prevalent subtype among postmenopausal women. Despite the growing number of randomized clinical trials (RCTs) exploring this topic, the efficacy and safety of first-line and second/further-line treatments remain uncertain. Accordingly, our aim was to conduct a comprehensive evaluation of the efficacy and safety of these therapies through network meta-analysis.MethodsRCTs were identified by searching Pubmed, Embase, and major cancer conferences. The efficacy of interventions was assessed using the hazard ratios (HRs) of progression-free survival (PFS) and overall survival (OS), while safety was indicated by the incidence of any grade adverse events (AEs), grade 3–5 AEs, AEs leading to treatment discontinuation, and AEs leading to death. Both time-variant HRs fractional polynomial models and time-invariant HRs Cox-proportional hazards models were considered for handling time-to-event data. Safety indicators were analyzed using Bayesian network meta-analysis. Additionally, subgroup analyses were conducted based on patient characteristics.ResultsA total of 41 RCTs (first-line 17, second/further-lines 27) were included in the analysis. For first-line treatment, the addition of Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors to endocrine therapy significantly improved therapeutic efficacy in terms of both PFS and OS, demonstrating the best performance across all mechanisms. Specifically, the combination of Abemaciclib and Letrozole demonstrated the most favorable performance in terms of PFS, while Ribociclib plus Fulvestrant yielded the best outcomes in OS. Incorporating the immune checkpoint inhibitor Avelumab into the regimen with CDK4/6 inhibitors and selective estrogen receptor degraders significantly enhanced both PFS and OS in second-line or later treatments. Regarding safety, endocrine monotherapy performed well. Regarding safety, endocrine monotherapy performed well. There is mounting evidence suggesting that most CDK4/6 inhibitors may demonstrate poorer performance with respect to hematologic AEs. However, additional evidence is required to further substantiate these findings.ConclusionsCDK4/6 inhibitors, combined with endocrine therapy, are pivotal in first-line treatment due to their superior efficacy and manageable AEs. For second/further-line treatment, adding immune checkpoint inhibitors to CDK4/6 inhibitors plus endocrine therapy may produce promising results. However, to reduce the results’ uncertainty, further trials comparing these novel treatments are warranted.Trial registrationRegistration number: PROSPERO (CRD42022377431).

284TiP CYCLONE 3: A phase III, randomized, double-blind, placebo-controlled study of abemaciclib in combination with abiraterone plus prednisone in men with high-risk metastatic hormone-sensitive prostate cancer

284TiP CYCLONE 3: A phase III, randomized, double-blind, placebo-controlled study of abemaciclib in combination with abiraterone plus prednisone in men with high-risk metastatic hormone-sensitive prostate cancer

Late onset toxicities associated with the use of CDK 4/6 inhibitors in hormone receptor positive (HR+), human epidermal growth factor receptor-2 negative (HER2-) metastatic breast cancer patients: a multidisciplinary, pan-EU position paper regarding their optimal management. The GIOCONDA project

The personalization of therapies in breast cancer has favoured the introduction of new molecular-targeted therapies into clinical practice. Among them, cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors have acquired increasing importance, with the approval in recent years of palbociclib, ribociclib, and abemaciclib in combination with endocrine therapy. Currently, no guidelines are available to monitor and manage potential long-term toxicities associated with the use of these drugs. A multidisciplinary panel of European oncologists, was supported by a pharmacologist, a hematologist, a hepatologist and a pulmonologist to discuss the management of long-term toxicities, based on the literature review and their clinical experience. The panel provided detailed roadmaps to manage long-term toxicities associated with the use of CDK4/6 inhibitors in clinical practice. Knowing the frequency and characteristics of the toxicity profile associated with each CDK4/6 inhibitor is important in the decision-making process to match the right drug to the right patient.

Resistance to abemaciclib is associated with increased metastatic potential and lysosomal protein deregulation in breast cancer cells.

Cyclin dependent kinase 4 and 6 inhibitors such as abemaciclib are routinely used to treat metastatic estrogen receptor positive (ER+) breast cancer. However, adaptive mechanisms inhibit their effectiveness and allow for disease progression. Using ER+ breast cancer cell models, we show that acquired resistance to abemaciclib is accompanied by increase in metastatic potential. Mass spectrometry-based proteomics from abemaciclib sensitive and resistant cells showed that lysosomal proteins including CTSD (cathepsin D), cathepsin A and CD68 were significantly increased in resistant cells. Combination of abemaciclib and a lysosomal destabilizer, such as hydroxychloroquine (HCQ) or bafilomycin A1, resensitized resistant cells to abemaciclib. Also, combination of abemaciclib and HCQ decreased migration and invasive potential and increased lysosomal membrane permeability in resistant cells. Prosurvival B cell lymphoma 2 (BCL2) protein levels were elevated in resistant cells, and a triple treatment with abemaciclib, HCQ, and BCL2 inhibitor, venetoclax, significantly inhibited cell growth compared to treatment with abemaciclib and HCQ. Furthermore, resistant cells showed increased levels of Transcription Factor EB (TFEB), a master regulator of lysosomal-autophagy genes, and siRNA mediated knockdown of TFEB decreased invasion in resistant cells. TFEB was found to be mutated in a subset of invasive human breast cancer samples, and overall survival analysis in ER+, lymph node-positive breast cancer showed that increased TFEB expression correlated with decreased survival. Collectively, we show that acquired resistance to abemaciclib leads to increased metastatic potential and increased levels of protumorigenic lysosomal proteins. Therefore, the lysosomal pathway could be a therapeutic target in advanced ER+ breast cancer.

Abemaciclib plus trastuzumab with or without fulvestrant versus trastuzumab plus standard-of-care chemotherapy in women with HR+, HER2+ advanced breast cancer: plain language summary of the monarcHER study.

This article summarizes the results of a study called monarcHER. The study included participants with a certain type of aggressive breast cancer called HR+, HER2+ advanced breast cancer (ABC) that had their disease worsen or return after multiple previous therapies. This summary intends to help you understand the impact of a non-chemotherapy treatment called abemaciclib in people with HR+, HER2+ ABC. When the study was planned, HER2-targeted therapy (ie trastuzumab) was standard treatment and was typically combined with chemotherapy and endocrine therapy (ie fulvestrant). However drug resistance can develop when HER2+ targeted therapy is used for a long time, making it less effective and allowing cancer to grow or spread to other parts of the body. When this happens, few chemotherapy-free options are available. Because of the chemotherapy side effects, this is not desirable. There is an urgent need to develop new, effective, safe, and tolerable treatment options for patients with HR+, HER2+ ABC. The monarcHER study compared the effects of abemaciclib plus trastuzumab with or without fulvestrant compared to the standard of care treatment. Participants were randomly assigned to 1 of 3 groups: Group A (abemaciclib, trastuzumab and fulvestrant), Group B (abemaciclib and trastuzumab), or Group C (trastuzumab and standard of care chemotherapy). The study compared the length of time patients took study treatments without worsening or dying from their breast cancer. This is called the progression free survival (PFS). Participants in Group A had a longer median PFS than those in groups B and C (8.3months, 5.7months and 5.7months respectively). There was no notable difference in PFS between participants in Groups B and C. Additionally, the study looked at the side effects with each treatment group. The most common side effect which is considered severe or lifethreatening was neutropenia, defined as decreased white blood cell levels. Neutropenia may lead to an increased risk of getting infections. However, the percentage of patients experiencing neutropenia was similar in all groups A, B and C (27%, 22% and 26%, respectively). Patients in groups A (79%) and B (78%) who received abemaciclib experienced similar rates of diarrhea. The data from the monarcHER study suggest that the combination of abemaciclib, trastuzumab, and fulvestrant may offer a chemotherapy-free option for patients with HR+, HER2+ ABC who have experienced worsening of disease despite multiple prior therapies.

Combined CDK4/6 and ERK1/2 Inhibition Enhances Antitumor Activity in NF1-Associated Plexiform Neurofibroma.

Plexiform neurofibromas (PNF) are peripheral nerve sheath tumors that cause significant morbidity in persons with neurofibromatosis type 1 (NF1), yet treatment options remain limited. To identify novel therapeutic targets for PNF, we applied an integrated multi-omic approach to quantitatively profile kinome enrichment in a mouse model that has predicted therapeutic responses in clinical trials for NF1-associated PNF with high fidelity. Utilizing RNA sequencing combined with chemical proteomic profiling of the functionally enriched kinome using multiplexed inhibitor beads coupled with mass spectrometry, we identified molecular signatures predictive of response to CDK4/6 and RAS/MAPK pathway inhibition in PNF. Informed by these results, we evaluated the efficacy of the CDK4/6 inhibitor, abemaciclib, and the ERK1/2 inhibitor, LY3214996, alone and in combination in reducing PNF tumor burden in Nf1flox/flox;PostnCre mice. Converging signatures of CDK4/6 and RAS/MAPK pathway activation were identified within the transcriptome and kinome that were conserved in both murine and human PNF. We observed robust additivity of the CDK4/6 inhibitor, abemaciclib, in combination with the ERK1/2 inhibitor, LY3214996, in murine and human NF1(Nf1) mutant Schwann cells. Consistent with these findings, the combination of abemaciclib (CDK4/6i) and LY3214996 (ERK1/2i) synergized to suppress molecular signatures of MAPK activation and exhibited enhanced antitumor activity in Nf1flox/flox;PostnCre mice in vivo. These findings provide rationale for the clinical translation of CDK4/6 inhibitors alone and in combination with therapies targeting the RAS/MAPK pathway for the treatment of PNF and other peripheral nerve sheath tumors in persons with NF1.

Recommended phase 2 dose (RP2D) for abemaciclib in combination with irinotecan (IRN) and temozolomide (TMZ) in pediatric patients with relapsed/refractory solid tumors (JPCS Part A).

10039 Background: There remains an unmet need to improve outcomes for pediatric patients (pts) with relapsed/refractory solid tumors. Abemaciclib is an orally administered, selective cyclin-dependent kinase (CDK) 4 & 6 inhibitor approved for breast cancer. Based upon preclinical data and the role of CDK4 & 6 in multiple pediatric solid tumor types, we hypothesized that abemaciclib in combination with IRN and TMZ would demonstrate clinical activity to support further pediatric development. This Phase 1b study aimed to determine the RP2D of abemaciclib in combination with IRN and TMZ in this pt population. Methods: This dose escalation study was part A of study JPCS (NCT04238819), and enrolled pts ≤18 years, weighing ≥10 kg, with a body-surface area ≥0.5 m2, and with relapsed/refractory solid tumors, including CNS tumors, that progressed on standard treatment or experienced disease recurrence. IRN (50 mg/m2) and TMZ (100 mg/m2) were administered on days 1-5 of 21-day cycles and remain the same for all dose levels, while abemaciclib was tested on four dose levels: 55, 70, 90, and 115 mg/m2 twice daily (BID). The starting dose was 70 mg/m2 BID for abemaciclib. The maximum tolerated dose was defined as the highest dose level at which < 33% of pts experienced a dose-limiting toxicity (DLT) during Cycle 1. The primary objective, determination of the abemaciclib RP2D, was defined based on the totality of safety, tolerability, and pharmacokinetic (PK) results, and confirmed in an expansion cohort. Secondary objectives included safety and response assessments. Results: At the data cut-off of 13 June 2022, a total of 20 pts received abemaciclib at 70 mg/m2 (n = 7) or 55 mg/m2 (n = 13). The most frequent diagnoses (≥3 pts) were medulloblastoma (n = 4), malignant glioma (n = 3), and rhabdomyosarcoma (n = 3). At the starting dose of 70 mg/m2, DLTs were experienced by 3 pts (neutropenia [n = 3; 43%]; gamma glutamyltransferase increased [n = 1; 14%]). The dose was de-escalated to 55 mg/m2, at which one pt (8%) experienced a DLT (thrombocytopenia). High grade adverse events (AEs) were mostly hematological. Discontinuations due to AEs occurred in 2 pts (29%) at 70 mg/m2 and 0 pts at 55 mg/m2. Five pts (71%) at 70 mg/m2 and 4 pts (31%) at 55 mg/m2 achieved a best overall response of stable disease; 1 pt (8%) at 55 mg/m2 achieved a complete response (rhabdomyosarcoma). No partial responses were observed. PK concentrations of abemaciclib at 55 mg/m2 achieved average plasma abemaciclib concentrations of ~150 ng/mL and the abemaciclib Ctrough concentrations appeared reasonably constant over time at ~100 ng/mL. PK concentrations of IRN and TMZ were as expected. Conclusions: The RP2D of abemaciclib is 55mg/m2 BID in combination with IRN and TMZ. This combination appears tolerable with plasma concentrations within the range associated with efficacy in adult studies. Clinical trial information: NCT04238819 .

Phase 1b/2 study of abemaciclib combined with chemoimmunotherapy in pediatric and young adult patients with relapsed/refractory neuroblastoma (JPCS Part C).

TPS10068 Background: Survival for high-risk neuroblastoma (NBL) remains poor with over 50% of patients experiencing disease relapse. The addition of dinutuximab (DIN) and granulocyte macrophage colony-stimulating factor (GM-CSF) to irinotecan (IRN) and temozolomide (TMZ) in patients with first relapse achieved an overall response rate of 42% in the study ANBL12211 and is now standard of care. However, there remains a significant unmet need to improve outcomes for children with relapsed/refractory NBL. Deregulation of the Cyclin D/cyclin-dependent kinase (CDK) 4 & 6 pathway has been observed in NBL, rendering CDK4 & 6 inhibition logical to explore. Abemaciclib is an orally administered, selective CDK4 & 6 inhibitor approved to treat breast cancer. JPCS (NCT04238819) is designed to assess the pharmacokinetics, safety, and tolerability of abemaciclib added to standard treatment regimens for relapsed/refractory pediatric solid tumors. Part A defined the recommended phase 2 dose (RP2D) of abemaciclib in combination with IRN and TMZ. In Part C, the addition of DIN + GM-CSF to the JPCS Part A regimen will be evaluated. The co-primary objectives of Part C are to determine the RP2D and to estimate the anti-tumor activity of abemaciclib added to the ANBL1221 chemoimmunotherapy backbone in patients with first relapse/refractory NBL. Methods: JPCS Part C is a two-stage, non-randomized, open-label, Phase 1b/2 study for patients < 21 years of age with first relapse/refractory NBL. Stage 1 aims to identify the maximum tolerated dose (MTD) of abemaciclib at a starting dose of 55 mg/m2 combined with DIN, GM-CSF, IRN and TMZ using a 3+3 design. One dose de-escalation (30 mg/m2) will be possible if the starting dose is not tolerated. Further tolerability and initial anti-tumor activity will be evaluated in an expansion cohort at the MTD. Up to 11 evaluable patients will enroll in Stage 1 at the MTD; the MTD will be declared the RP2D if adequate safety and tolerability are observed and ≥6 patients achieve minimal response or better per International Neuroblastoma Response Criteria (INRC). Following determination of the RP2D, Stage 2 will enroll 35 patients. If ≥26 of 46 total patients achieve an INRC minimum response or better, further investigation of this regimen could be warranted. As of 31 Jan 2023, Part C is open for enrollment at one site (US) and additional sites are being evaluated.

PO-1270 Safety of Combination of Abemaciclib and Radiotherapy in metastatic breast cancer patients

PO-1270 Safety of Combination of Abemaciclib and Radiotherapy in metastatic breast cancer patients

Letter in Reply: indirect comparison of quality-of-life scores between patients with advanced breast cancer receiving palbociclib and abemaciclib in combination with fulvestrant.

Letter in Reply: indirect comparison of quality-of-life scores between patients with advanced breast cancer receiving palbociclib and abemaciclib in combination with fulvestrant.

Abstract CT159: CYCLONE 1: abemaciclib in men with heavily pretreated metastatic castration-resistant prostate cancer (mCRPC)

Abstract Background: Treatment options for patients (pts) with heavily pretreated mCRPC are limited. Augmenting endocrine therapy by targeting CDK4/6 with abemaciclib has dramatically improved outcomes in HR+ breast cancer. Similar to ER, AR signaling activates CDK4 & 6 and abemaciclib showed preclinical anti-tumor activity in prostate cancer (PC). This signal seeking single arm Phase 2 study evaluated the safety and clinical activity of abemaciclib monotherapy in pts with heavily pretreated poor prognosis mCRPC who progressed after both a novel hormonal agent (NHA) and two taxanes. Methods: Eligible pts had progressive mCRPC, measurable disease by RECIST1.1, and previously received ≥1 NHA, docetaxel, and cabazitaxel for metastatic PC. Abemaciclib was administered at 200 mg BID on a continuous 28-day dosing schedule. The primary endpoint was investigator-assessed objective response rate without concurrent bone progression (ORR). A target ORR of ≥12.5% was deemed suitable to support further evaluation of abemaciclib monotherapy in this refractory mCRPC setting. Key secondary endpoints included disease control rate (DCR), time to PSA progression, radiographic progression-free survival (rPFS), overall survival (OS), and safety. Results: Forty-four pts (median age 68 yrs; 75% ECOG PS 1, median PSA of 96 ng/mL) were enrolled. In total, 46.5% had visceral metastasis, including 27.9% with liver metastases. Median time from development of mCRPC to study entry was 2.1 yrs and the median number of prior systemic regimens for mCRPC was 3. Median number of treatment cycles was 3 (1-13). Five pts (11.8%) had soft tissue response. The ORR without concurrent bone progression was 6.8%. Eighteen pts (40.9%) had stable disease, of which 6 (13.6%) lasted ≥6 months (mos); DCR was 47.7%. Median rPFS was 2.7 mos (95% CI 1.9, 3.7); 6-mos rPFS rate was 24.9% (95% CI 12.4, 39.5); median time to PSA progression was 6.5 mos. Median OS was 7.6 mos (95% CI 5.6, NE). Any grade (G) TRAEs experienced by ≥50% of pts were diarrhea (79.5%), decreased appetite (52.3%) and fatigue (50%); majority were G1/2. G3 TRAEs in ≥ 5% of pts were neutropenia (22.7%), anemia (6.8%), fatigue (6.8%) and diarrhea (6.8%). There were no G4 or G5 TRAEs. Discontinuation rate due to AE was 13.6%. Conclusions: Abemaciclib demonstrated modest but objective single-agent clinical activity in pts with very heavily pretreated progressive mCRPC. The safety profile of abemaciclib was consistent with the experience in breast cancer. Although the primary endpoint was not formally met, the single agent activity observed in this late line mCRPC setting validates CDK4/6 as a therapeutic target in advanced PC. The CYCLONE 2 and CYCLONE 3 studies are currently evaluating abemaciclib in combination with abiraterone/prednisone to leverage synergy of combined CDK4/6 and hormonal inhibition in first line mCRPC and mHSPC settings, respectively. Citation Format: Neeraj Agarwal, Daniel Castellano Guana, Teresa A. Gordoa, Jose A. Arija, Emeline Colomba, Gwenaelle Gravis, Loic Mourey, Stephanie Oudard, Aude Flechon, Macarena Gonzalez, Pablo Maroto-Rey, Michael Schweizer, Enrique Gallardo, Karim Nacerddine, Adams K. Appiach, Arjun Balar, Erica Johnston, José M. Piulats. CYCLONE 1: abemaciclib in men with heavily pretreated metastatic castration-resistant prostate cancer (mCRPC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT159.

Abstract 4364: Cost-effectiveness analysis of abemaciclib and endocrine therapy combination for the adjuvant treatment of HR+/HER2-, node-positive, high-risk, early breast cancer

Abstract Background: Abemaciclib is the only approved cyclin-dependent kinase 4/6 (CDK4/6) inhibitor approved for adjuvant treatment of hormone receptor-positive, human epidermal growth factor receptor-2-negative (HR+/HER2-), node-positive, high-risk early breast cancer (EBC) patients. However, the addition of abemaciclib to the standard of care endocrine therapy (ET, such as tamoxifen or aromatase inhibitors) results in a drastic increase to the overall healthcare costs. Objective: In this study, we aimed to evaluate the cost-effectiveness of abemaciclib and ET combination versus ET monotherapy for the adjuvant treatment of HR+/HER2-, EBC from the U.S. third-party payer perspective. Methods: A Markov-based decision analytic model using TreeAge Software was developed. The model simulated lifetime costs and health outcomes over a lifetime. The model incorporated the disease course of the progression-free disease, progressive disease, death due to disease, and mortality due to other causes. All clinical data and utilities were derived from the literature and clinical trial: monarchE. Notable adverse events such as neutropenia, leucopenia, anemia, and diarrhea were included. Age-specific mortality risk was calculated from the U.S. life tables. The outcomes were measured by costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio (ICER). The willingness-to-pay threshold was set at $100,000 per QALY gained. Results: We simulated our analysis on patients assigned to either abemaciclib + ET or ET alone groups as per the monarchE trial. The median age of the patients was 51 years. In base case analysis, the total costs for abemaciclib plus ET and ET alone treatment, were USD 122,052.11 and USD 40,344.87, respectively. Abemaciclib plus ET treatment produced 4.5 QALYs, while the ET treatment alone produced 4.31 QALYs. Overall, abemaciclib plus ET was marginally more effective than ET with an additional 0.20 QALYs but much costlier with an ICER of $417,780.18/QALY. For utilities ranging from 0.41 to 0.69, the ICERs ranged from USD 36,5950 to USD 4,463,866.59 per QALY, which exceeded the WTP threshold. Using probabilistic sensitivity analysis, we estimated that the combination of abemaciclib plus ET was a cost-effective strategy at the willingness-to-pay threshold of $500,000 per QALY or higher for the base case population. Conclusion: At current costs, abemaciclib plus ET is not cost-effective as compared to ET monotherapy for patients with node-positive, high-risk, HR+/HER2- EBC in the US healthcare system from the third-party payer perspective. Citation Format: Ashna Talwar, Ashish Deshmukh, Meghana Trivedi, Rajender R. Aparasu. Cost-effectiveness analysis of abemaciclib and endocrine therapy combination for the adjuvant treatment of HR+/HER2-, node-positive, high-risk, early breast cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4364.

Recurrence rate in patients with stage IV breast cancer: a retrospective cohort study

Abstract Introduction: Metastatic breast cancer (mBC) remains incurable, with a median overall survival (OS) of approximately 3 years and a 5-year survival rate of approximately 25%, irrespective of the economic classification of the country where treatment is received. Cyclin-dependent kinase (CDK) inhibitors increase overall survival in both first and second-line settings in the treatment of hormone receptor–positive, human epidermal growth factor receptor 2–negative mBC. This retrospective cohort study investigated the progression-free survival in women with mBC receiving combination therapy with abemaciclib (CDK4/CDK6 inhibitor) and letrozole or fulvestrant as opposed to abemaciclib only. Methods: The study included all eligible women with stage IV breast cancer treated with abemaciclib at a private oncology facility in Johannesburg over the study period. Data were collected from medical records from April 1, 2019 to March 31, 2021. Analyses were conducted to assess the overall survival rate, progression-free survival probability, and safety of abemaciclib in women with stage IV breast cancer. Results: Thirty-two patients were eligible for inclusion in this study. The progression-free survival probability was 60% after a period of 17 months, irrespective of treatment options. After 17 months, the OS of women on a combination of abemaciclib and letrozole was 80%, on a combination of abemaciclib and fulvestrant was 80%, and on abemaciclib monotherapy was 70%. The most noted adverse effects were diarrhea (92.0%), neutropenia (92.0%), fatigue (48.0%), and hepatotoxicity (16.0%). Discussion: Abemaciclib with endocrine therapy or an aromatase inhibitor provided an improvement in the OS compared with abemaciclib monotherapy. These findings are representative of the use of abemaciclib in a local population and are similar to those of larger studies conducted internationally.

Characteristics and Outcomes in Cases of US Male Patients with Metastatic Breast Cancer Receiving Abemaciclib in Routine Clinical Practice.

Breast cancer in males constitutes approximately 1% of all breast cancer cases globally. Despite extensive treatment experience with abemaciclib in women with metastatic breast cancer (MBC), real-world evidence in male MBC is lacking. This analysis was a part of a broader, retrospective study that analyzed electronic medical records and charts of 448 men and women with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) MBC who initiated an abemaciclib-containing regimen from January 2017 through September 2019. Data were collected from the Florida Cancer Specialists & Research Institute and the Electronic Medical Office Logistics Health Oncology Warehouse Language™ databases and summarized descriptively. Real-world best response was described: complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD). Data for six male patients with MBC who were treated with abemaciclib in combination with an aromatase inhibitor (AI) or fulvestrant are presented. Four patients were aged≥75years, and four patients had≥3 metastatic sites, including visceral involvement. Abemaciclib was initiated in/after third-line (≥3L) in four patients, and patients had history of treatment with AI (n=4), chemotherapy (n=3), and/or prior cyclin-dependent kinase 4 and 6 inhibitors (n=2) in the metastatic setting. Abemaciclib+fulvestrant was the most common abemaciclib-containing regimen (n=4). Best responsewas documented in four patients: 1 each with CR, PR, SD, and PD. Prevalence of male MBC in this dataset was consistent with expected prevalence in the broader population. Mostmale patients received an abemaciclib-containing regimen in≥3L, with anti-cancer activity observed despite heavy metastatic burden and prior treatments in a metastatic setting.