Safety Of Abemaciclib Research Articles

Efficacy and Safety of Abemaciclib in Combination With Endocrine Therapy for HR+/HER2- Advanced or Metastatic Breast Cancer: A Systematic Review and Meta-Analysis.

Breast cancer, particularly the hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-) subtype, remains a major global health concern. Abemaciclib, a CDK4/6 inhibitor, has shown promising results in treating advanced cases. This study comprehensively assesses the efficacy and safety of abemaciclib in combination with endocrine therapy for HR+/HER2- advanced or metastatic breast cancer. Following PRISMA guidelines, a systematic review and meta-analysis was conducted. A thorough literature search was conducted on PubMed, EMBASE, Cochrane Library, and ClinicalTrials.gov til December 2023. Inclusion criteria encompassed randomized controlled trials and retrospective cohort studies reporting on abemaciclib in approved doses, either as monotherapy or in combination. Outcome assessments included progression-free survival (PFS), overall response rate (ORR), side effects/adverse effects (SE/AE), and overall survival (OS). Quality assessment utilized Cochrane's revised risk of bias tool and Newcastle-Ottawa scale. Pooled results of 22 studies involving 14,010 patients revealed that abemaciclib significantly improved PFS (hazard ratio=0.53; 95% CI: 0.48-0.59; P=0.00; I2=0%), ORR (risk ratio=2.31; 95% CI: 1.93-2.75; P=0.00; I2=0%), and OS (risk ratio=0.76 (95% CI: 0.65-0.87; P=0.001; I2=0%). However, abemaciclib increased the risk of adverse events in the fulvestrant and nonsteroidal aromatase inhibitor (NSAI) combinations, respectively. Abemaciclib, particularly in combination with fulvestrant, emerges as an effective therapeutic option for HR+/HER2- advanced or metastatic breast cancer, improving PFS and OS. The higher toxicity profile warrants cautious use, especially in treatment-naive patients.

Clinical impact of drug-drug interactions on abemaciclib in the real-world experience of AB-ITALY study

Abemaciclib demonstrated clinical benefit in women affected by HR+/HER2− advanced breast cancer (aBC). Drug-drug interactions (DDIs) can lead to reduced treatment efficacy or increased toxicity. This retro-prospective study aimed to evaluate outcomes, DDIs’ impact, and toxicities of abemaciclib combined with endocrine therapy in a real-world setting. Patients from 12 referral Italian hospitals with HR+/HER2− aBC who received abemaciclib were included. Clinical data about comorbidities, concurrent medications, outcomes, and adverse events (AE) were collected. Drug-PIN® (Personalized Interactions Network) is a tool recognizing the role of multiple interactions between active and/or pro-drug forms combined with biochemical and demographic patient data. The software was used to define the Drug-PIN score and Drug-PIN tier (green, yellow, dark yellow, and red) for each patient. Univariate and multivariate analyses were performed to identify predictors of patients’ PFS or toxicity. One hundred seventy-three patients were included. 13% of patients had >75years. The overall response rate (ORR) was 63%. The general population’s median PFS (mPFS) was 22 months (mo), while mOS were not reached. Patients treated with abemaciclib in combination with AI and fulvestrant had a mPFS of 36 and 19 mo, respectively. The most common toxicities were diarrhea, asthenia, and neutropenia detected in 63%,49%, and 49% of patients. The number of concomitant medications and comorbidities were not associated with survival outcomes (22 vs 17 mo, p = 0.068, p = 0.99). Drug-PIN tier from dark yellow to red and Drug-PIN score >12 were associated with shorter PFS compared to no/low-risk DDIs and score <12 (15 vs 23, p = 0.005, p = 0.0017). Drug interaction was confirmed as an independent biomarker in a multivariate model (p = 0.02). No difference in any grade AE, severe toxicities, and diarrhea were detected among different age subgroups. No association was found between Drug-PIN score or Drug-PIN tier and overall toxicity (p = 0.44), severe AEs (p = 0.11), or drug reduction (p = 0.27). The efficacy and safety of abemaciclib plus ET were confirmed in a real-world setting, even in the elderly population and patients with comorbidities. Evaluation of DDIs with Drug-PIN appears to be an independent predictor of PFS.

Efficacy and safety of abemaciclib in combination with endocrine therapy for HR+/HER2- advanced or metastatic breast cancer: A systematic review and meta-analysis.

e13096 Background: Breast cancer, particularly the HR+/HER2- subtype, remains a major global health concern. Abemaciclib, a CDK4/6 inhibitor, has shown promise in treating advanced cases. This study comprehensively assesses the efficacy and safety of Abemaciclib in combination with endocrine therapy for HR+/HER2- advanced or metastatic breast cancer. Methods: Following PRISMA guidelines, a systematic review and meta-analysis were conducted. A thorough literature search spanning PubMed, EMBASE, Cochrane Library, and ClinicalTrials.gov identified 22 studies. Inclusion criteria encompassed RCTs and retrospective cohort studies reporting on Abemaciclib in approved doses, either as monotherapy or in combination. Outcome assessments included PFS, ORR, SE/AE, and OS. Quality assessment utilized ROB II and NOS tools. Results: Analysis of 22 studies involving 14,010 patients revealed that Abemaciclib significantly improved PFS and ORR, with a 47% and 46% reduction in risk, respectively. A noteworthy 24% reduction in the risk of death was observed in the Fulvestrant combination group. However, Abemaciclib increased the risk of SE/AE by 104% and 304% in the Fulvestrant and NSAI combinations, respectively. Conclusions: Abemaciclib, particularly in combination with Fulvestrant, emerges as an effective therapeutic option for HR+/HER2- advanced or metastatic breast cancer, improving PFS and OS. The higher toxicity profile warrants cautious use, especially in treatment-naïve patients. This review informs future research directions and offers insights for clinical decision-making in the evolving landscape of breast cancer treatment.

Abemaciclib plus endocrine therapy versus chemotherapy after progression on prior palbociclib in HR+/HER2- metastatic breast cancer: A single center real-world study in China.

Cyclin-dependent kinase (CDK) 4/6 inhibitor plus endocrine therapy (ET) become standard-of-care for patients with hormone receptor-positive, human epidermal growth factor receptor-2 negative (HR+/HER2-) metastatic breast cancer (MBC). However, the optimal therapeutic paradigm after progression on CDK4/6 inhibitor remains unclear. This study aimed to evaluate the efficacy and safety of abemaciclib with switching ET versus chemotherapy after progression on prior palbociclib-based ET in Chinese patients with HR+/HER2- MBC. From 414 consecutive patients with HR+/HER2- MBC who had been treated with palbociclib plus ET from September 2018 to May 2022 in Peking University Cancer Hospital, we identified 80 patients who received abemaciclib plus switching ET or chemotherapy after progression on palbociclib, matched for age, original stage at diagnosis, disease-free interval, and tumor burden at 1:1 ratio. The primary endpoint was progression-free survival (PFS) compared using the Kaplan-Meier method. A Cox proportional hazard model was performed to identify clinical factors associated with PFS in the abemaciclib group. The median PFS was 6.0 months (95% confidence interval [CI]: 3.94-8.06) in abemaciclib group and 4.0 months (95% CI, 2.52-5.49) in chemotherapy group (p = 0.667). And, there was no difference in median PFS between the sequential and nonsequential arm (6.0 vs. 6.0 months) in the abemaciclib group though fewer lines of prior systemic therapy and longer PFS from prior palbociclib in the sequential arm. However, patients with prior palbociclib as the first-line therapy had a significantly longer median PFS versus prior palbociclib as ≥2nd-line therapy (11.0 vs. 5.0 months, p = 0.043). Based on multivariable analysis, ER+/PR+ was an independent factor associated with longer PFS. There was no significant difference in overall survival between the abemaciclib and chemotherapy groups (p = 0.069). Our findings indicate that abemaciclib plus switching ET might be one of feasible treatment options for Chinese patients with HR+/HER2- MBC after progression on prior palbociclib-based therapy in addition to chemotherapy.

A phase II, multicenter, open-label study of abemaciclib and letrozole in patients with estrogen receptor-positive rare ovarian cancer: ALEPRO trial

BackgroundLow-grade serous and endometrioid ovarian cancers and adult-type granulosa cell tumors are rare ovarian malignancies that show high estrogen receptor positivity. Recurrences of these subtypes of ovarian cancer are often...

138 (PB-138) Poster - Efficacy and safety of abemaciclib in the treatment of HR+ HER2-advanced breast cancer: real world data

138 (PB-138) Poster - Efficacy and safety of abemaciclib in the treatment of HR+ HER2-advanced breast cancer: real world data

Artículo traducido] Abemaciclib en adyuvancia para el tratamiento del cáncer de mama precoz de alto riesgo

ObjectiveTo adapt the GHEMA report of abemaciclib, an inhibitor of cyclin-dependent kinases 4 and 6. European Medicines Agency authorisation (April 2022) includes, in combination with endocrine therapy, the adjuvant treatment of adult patients with hormone receptor positive, human epidermal growth factor receptor 2 negative, node-positive, early breast cancer at high risk of recurrence. MethodThe efficacy and safety of abemaciclib were evaluated in a randomized, open-label and multicenter phase III study. A total of 5,637 patients diagnosed with early breast cancer with hormone receptor positive, human epidermal growth factor receptor 2 negative, node positive and high risk of recurrence were included. High risk was defined as patients with 4 or more positive axillary lymph nodes, or 1-3positive axillary lymph nodes and at least one of the following: tumor size ≥5 cm, histologic grade 3 or Ki-67 ≥ 20%. Patients were randomized (1:1) to receive adjuvant abemaciclib + endocrine therapy (n = 2,808) or endocrine therapy alone (n = 2,829) for 2 years, with endocrine therapy prescribed for at least 5 years. ResultsWith a median follow-up of 15.5 months, abemaciclib + endocrine therapy demonstrated a statistically significant improvement in invasive disease-free survival versus endocrine therapy alone (HR = 0.747 [95% CI 0.598-0.932], p = 0.0096); achieving an absolute improvement of 3.5% invasive disease-free survival rate at 2-years. These results were maintained, with a median follow-up of 27.7 months: absolute improvement of 2.7% and 5.4% in invasive disease-free survival rate at 2 and 3-years, respectively. All-causality grade 3 or 4 adverse events were 45.9% for abemaciclib and 12.9% for endocrine therapy, and included neutropenia (19.6% vs. 0.8%), leukopenia (11.4% vs. 0.4%) and diarrhea (7.8% vs. 0.2%). ConclusionsThe results of the pivotal trial are sufficient to consider abemaciclib as adjuvant treatment for high-risk early breast cancer in highly selected patients. However, in order to the efficacy results present less uncertainty, we must wait for a evaluation later, in which we can have a mature determination at 3 years (with more patients at risk).

Real-World Analysis of Clinical and Demographic Characteristics, Treatment Patterns, and Outcomes in Predominantly Older Patients with HR+/HER2- Metastatic Breast Cancer Receiving Abemaciclib in Routine Clinical Practice.

Hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) is the most frequently diagnosed metastatic breast cancer (mBC) subtype. Combinations of endocrine therapy (ET) with cyclin-dependent kinase 4/6 inhibitors (CDK4 & 6is) improve outcomes compared with ET alone. The efficacy and safety of abemaciclib among patients with HR+/HER2- mBC has been demonstrated in the MONARCH clinical trials; however, there is a paucity of real-world evidence, particularly in older patients. This retrospective cohort study analyzed the electronic medical record data/charts of adult patients with HR+/HER2- mBC receiving abemaciclib in US-based community oncology settings (1 September 2017 to 30 September 2019). Patients with other primary malignancies, clinical trial enrollment, and incomplete charts were excluded. Patient characteristics, treatment attributes and patterns, and real-world outcomes (clinical benefit rate [CBR] and stable disease among patients with response data available, time to chemotherapy [TTC], time to treatment discontinuation [TTD], and progression-free survival [PFS]) were summarized. Multivariable models evaluated the association between demographic/clinical characteristics and outcomes. Of the 448 final patients, 99% were female, with a median age of 67 years (25% were ≥75 years) and median follow-up of 11 months; most (60%) initiated abemaciclib within 2 years of mBC diagnosis. Patients received a median of 1(P25=0, P75=3) prior line of therapy for mBC before abemaciclib, including other CDK4 & 6is (48%) and prior chemotherapy (31%); most (57%) had visceral disease. The CBR for the overall population was 53%, with 48% achieving stable disease. The median TTC was not reached; median TTD was 249 days (95% confidence interval [CI]: 202, 304). The median PFS was 329 days (95% CI 266, 386). The discontinuation rate of abemaciclib owing to adverse events (30%) trended higher with age (years) (P=0.027): 18-49 (n=42; 19%), 50-64 (n=155; 25%), 65-74 (n=138; 32%), 75-84 (n=82; 37%), ≥85 (n=31; 49%); only 23% of patients overall had a dose hold or reduction prior to discontinuation. These patients were older than those in the MONARCH studies with substantial visceral disease, and prior chemotherapy and CDK4 & 6i use. Discontinuation rates were higher than in previous real-world studies (11.9%), highlighting the need for proactive management to optimize outcomes, particularly in older patients with mBC.

Abemaciclib as adjuvant treatment for high-risk early breast cancer

ObjectiveTo adapt the GHEMA report of abemaciclib, an inhibitor of cyclin-dependent kinases 4 and 6. European Medicines Agency authorization (April 2022) includes, in combination with endocrine therapy, the adjuvant treatment of adult patients with hormone receptor positive, human epidermal growth factor receptor 2 negative, node-positive, early breast cancer at high risk of recurrence. MethodThe efficacy and safety of abemaciclib were evaluated in a randomized, open-label, and multicenter phase III study. A total of 5637 patients diagnosed with early breast cancer with hormone receptor positive, human epidermal growth factor receptor 2 negative, node positive, and high risk of recurrence were included. High risk was defined as patients with 4 or more positive axillary lymph nodes, or 1–3 positive axillary lymph nodes and at least one of the following: tumor size ≥5 cm, histologic grade 3, or Ki-67≥20%. Patients were randomized (1:1) to receive adjuvant abemaciclib+endocrine therapy (n = 2808) or endocrine therapy alone (n = 2829) for 2 years, with endocrine therapy prescribed for at least 5 years. ResultsWith a median follow-up of 15.5 months, abemaciclib+endocrine therapy demonstrated a statistically significant improvement in invasive disease-free survival versus endocrine therapy alone [HR = 0.747 (95% CI 0.598–0.932), P = 0.0096]; achieving an absolute improvement of 3.5% invasive disease-free survival rate at 2-years. These results were maintained, with a median follow-up of 27.7 months: absolute improvement of 2.7% and 5.4% in invasive disease-free survival rate at 2 and 3 years, respectively. All-causality grade 3 or 4 adverse events were 45.9% for abemaciclib and 12.9% for endocrine therapy, and included neutropenia (19.6% vs. 0.8%), leukopenia (11.4% vs. 0.4%), and diarrhea (7.8% vs. 0.2%). ConclusionsThe results of the pivotal trial are sufficient to consider abemaciclib as adjuvant treatment for high-risk early breast cancer in highly selected patients. However, in order to the efficacy results present less uncertainty, we must wait for a evaluation later, in which we can have a mature determination at 3 years (with more patients at risk).

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.

Efficacy and safety results by menopausal status in monarchE: adjuvant abemaciclib combined with endocrine therapy in patients with HR+, HER2-, node-positive, high-risk early breast cancer.

Abemaciclib is the first and only cyclin-dependent kinases 4 and 6 inhibitor approved for adjuvant treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), node-positive, and high-risk early breast cancer (EBC), with indications varying by geography. Premenopausal patients with HR+, HER2- tumors may have different tumor biology and treatment response compared to postmenopausal patients. We describe the efficacy and safety of abemaciclib plus endocrine therapy (ET) for the large subgroup of premenopausal patients with HR+, HER2- EBC in monarchE. Randomized patients (1:1) received adjuvant ET with or without abemaciclib for 2 years plus at least 3 additional years of ET as clinically indicated. Patients were stratified by menopausal status (premenopausal versus postmenopausal) at diagnosis. Standard ET (tamoxifen or aromatase inhibitor) with or without gonadotropin-releasing hormone agonist was determined by physician's choice. Invasive disease-free survival (IDFS) and distant relapse-free survival (DRFS) by menopausal status were assessed at data cutoff on 1 April 2021 (median follow-up of 27 months). Among randomized patients, 2451 (43.5%) were premenopausal and 3181 (56.4%) were postmenopausal. The choice of ET for premenopausal patients varied considerably between countries. Treatment benefit was consistent across menopausal status, with a numerically greater effect size in premenopausal patients. For premenopausal patients, abemaciclib with ET resulted in a 42.2% and 40.3% reduction in the risk of developing IDFS and DRFS events, respectively. Absolute improvement at 3 years was 5.7% for IDFS and 4.4% for DRFS rates. Safety profile for premenopausal patients was consistent with the overall safety population. Abemaciclib with ET demonstrated clinically meaningful treatment benefit for IDFS and DRFS versus ET alone regardless of menopausal status and first ET, with a numerically greater benefit in the premenopausal compared to the postmenopausal population. Safety data in premenopausal patients are consistent with the overall safety profile of abemaciclib.

Abemaciclib: The First FDA-Approved CDK4/6 Inhibitor for the Adjuvant Treatment of HR+ HER2- Early Breast Cancer.

To review the new indication of cyclin-dependent kinase (CDK4/6) inhibitor abemaciclib for the adjuvant treatment of hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-), axillary lymph node (LN) positive early breast cancer (EBC) at high risk of recurrence and a Ki-67 ≥20%. A literature search was performed through PubMed, ClinicalTrials.gov, and Food and Drug Administration (FDA) website (February 1, 2018, to December 23, 2021) to identify relevant information. Human and animal studies related to pharmacology, pharmacokinetics, efficacy, and safety of abemaciclib were identified. Addition of abemaciclib to standard of care endocrine therapy (ET) for patients with high-risk clinicopathologic features and Ki-67 ≥20% demonstrated 30% reduction in the risk of developing invasive disease and distant recurrence. At 15.5 months, abemaciclib + ET demonstrated a significant improvement in invasive disease-free survival (IDFS) vs ET alone (hazard ratio [HR], 0.75; 95% confidence interval [CI], 0.60-0.93, P = 0.01). At 27 months, IDFS benefit was maintained (HR, 0.70; 95% CI, 0.59-0.82, P < 0.0001). Diarrhea occurred in more than 80% of patients in the abemaciclib arm. This review describes the clinical applicability of adjuvant abemaciclib for patients with HR+, HER2- EBC at high risk for recurrence. Adjuvant abemaciclib significantly reduces the risk for early development of invasive disease and distant recurrence in patients with HR+, HER2- node positive EBC. Longer follow-up is needed to determine the impact of adjuvant abemaciclib on late disease recurrence and survival outcomes.

MONARCH-plus: the evidence of efficacy and safety of abemaciclib in countries with limited clinical research opportunities

MONARCH-plus: the evidence of efficacy and safety of abemaciclib in countries with limited clinical research opportunities

A Randomized Phase III Study of Abemaciclib Versus Erlotinib in Patients with Stage IV Non-small Cell Lung Cancer With a Detectable KRAS Mutation Who Failed Prior Platinum-Based Therapy: JUNIPER.

IntroductionJUNIPER compared the efficacy and safety of abemaciclib, a selective cyclin-dependent kinase 4 and 6 inhibitor, with erlotinib in patients with non-small cell lung cancer (NSCLC) harboring a Kirsten rat sarcoma (KRAS) mutation.MethodsJUNIPER was a Phase III, multicenter, randomized, open-label trial of abemaciclib versus erlotinib in patients with stage IV NSCLC and a detectable mutation in codons 12 or 13 of the KRAS oncogene, who progressed after platinum-based chemotherapy and 1 additional therapy (could include immune checkpoint inhibitor therapy). Randomized patients (3:2) received either 200 mg abemaciclib twice daily or 150 mg erlotinib once daily with best supportive care until disease progression or unacceptable toxicity. The primary endpoint was overall survival (OS); secondary endpoints included overall response rate (ORR), progression-free survival (PFS), and safety.ResultsBetween December 2014 and April 2017, 453 patients were randomly assigned to receive abemaciclib (N = 270) or erlotinib (N = 183). Median OS was 7.4 months (95% confidence interval [CI]: 6.5, 8.8) with abemaciclib and 7.8 months (95% CI: 6.4, 9.5) with erlotinib (hazard ratio [HR] = 0.968 [95% CI: 0.768, 1.219]; p = .77). Median PFS was 3.6 months (95% CI: 2.8, 3.8) with abemaciclib and 1.9 months (95% CI: 1.9, 2.0) with erlotinib (HR = 0.583 [95% CI: 0.470, 0.723]; p <.000001). ORR was 8.9% and 2.7% (p = .010), and the disease control rate was 54.4% and 31.7% (p <.001) with abemaciclib and erlotinib, respectively. Safety results reflected the known safety profiles of abemaciclib and erlotinib.ConclusionsIn this study, the primary endpoint of OS was not met; PFS and ORR were improved with manageable toxicity in the abemaciclib arm. The increases in response rates and PFS support further investigation of abemaciclib in other NSCLC subpopulations or in combination with other agents.Clinical Trial Registration www.ClinicalTrials.gov, identifier: NCT02152631

Abemaciclib Combined With Endocrine Therapy for the Adjuvant Treatment of HR+, HER2−, Node-Positive, High-Risk, Early Breast Cancer (monarchE)

PURPOSEMany patients with HR+, HER2− early breast cancer (EBC) will not experience recurrence or have distant recurrence with currently available standard therapies. However, up to 30% of patients with high-risk clinical and/or pathologic features may experience distant recurrence, many in the first few years. Superior treatment options are needed to prevent early recurrence and development of metastases for this group of patients. Abemaciclib is an oral, continuously dosed, CDK4/6 inhibitor approved for HR+, HER2− advanced breast cancer (ABC). Efficacy and safety of abemaciclib in ABC supported evaluation in the adjuvant setting.METHODSThis open-label, phase III study included patients with HR+, HER2−, high-risk EBC, who had surgery and, as indicated, radiotherapy and/or adjuvant/neoadjuvant chemotherapy. Patients with four or more positive nodes, or one to three nodes and either tumor size ≥ 5 cm, histologic grade 3, or central Ki-67 ≥ 20%, were eligible and randomly assigned (1:1) to standard-of-care adjuvant endocrine therapy (ET) with or without abemaciclib (150 mg twice daily for 2 years). The primary end point was invasive disease-free survival (IDFS), and secondary end points included distant relapse–free survival, overall survival, and safety.RESULTSAt a preplanned efficacy interim analysis, among 5,637 randomly assigned patients, 323 IDFS events were observed in the intent-to-treat population. Abemaciclib plus ET demonstrated superior IDFS versus ET alone (P = .01; hazard ratio, 0.75; 95% CI, 0.60 to 0.93), with 2-year IDFS rates of 92.2% versus 88.7%, respectively. Safety data were consistent with the known safety profile of abemaciclib.CONCLUSIONAbemaciclib when combined with ET is the first CDK4/6 inhibitor to demonstrate a significant improvement in IDFS in patients with HR+, HER2− node-positive EBC at high risk of early recurrence.

Abstract 6322: The role of multidrug efflux transporters and CYP3A in the pharmacokinetics and tissue distribution of abemaciclib and its active metabolites

Abstract Abemaciclib is the third CDK4/6 inhibitor approved by the U.S. Food and Drug Administration to treat some types of breast cancer in combination with an aromatase inhibitor. Currently it is also in clinical development to treat other types of cancer, including lung and brain cancers. Abemaciclib is mainly metabolized by CYP3A4, with the formation of three active metabolites with similar potency to abemaciclib, including N-desethylabemaciclib (M2), hydroxyabemaciclib (M20) and N-desethylhydroxyabemaciclib. The systemic exposure and/or tissue distribution of these active compounds could be affected by drug transporters and CYP3A enzymes, and hence the efficacy and safety of abemaciclib. In this study we aimed to determine the effect of P-glycoprotein (ABCB1), breast cancer resistance protein (ABCG2), and CYP3A on the pharmacokinetics and tissue distribution of abemaciclib and its active metabolites. We performed pharmacokinetic experiments in several mouse models, including ABC transporter knockout (Abcb1a/1b-/-;Abcg2-/-), Cyp3a knockout (Cyp3a-/-), a humanized mouse model with the expression of human CYP3A4 in liver and small intestine in a Cyp3a-/- background (Cyp3aXAV), and wild-type mice. To support these studies, we set up a bioanalytical method using LC-MS/MS for the (semi-)quantification of abemaciclib and its metabolites. After a single oral administration of abemaciclib at 10 mg/kg, the plasma exposure (AUC0-24h) of abemaciclib was not significantly different, but the AUC0-24h of N-desethylabemaciclib increased 5.3-fold in Abcb1a/1b-/-;Abcg2-/- compared to the wild-type mice. In Abcb1a/1b-/-;Abcg2-/- mice also the brain-to-plasma ratio of abemaciclib and N-desethylabemaciclib increased respectively 25- and 4-fold relative to wild-type mice. Regarding CYP3A, the abemaciclib plasma exposure increased 3.1-fold in Cyp3a-/- compared to the wild-type mice, and it decreased 7.6-fold in Cyp3aXAV compared to the Cyp3a-/- mice. However, the plasma exposure of N-desethylabemaciclib was not significantly different among these mouse strains. No other meaningful differences were observed including the distribution of abemaciclib and N-desethylabemaciclib in other tissues. Based on our preliminary data, Abcb1a/1b and/or Abcg2 limit the penetration of abemaciclib and N-desethylabemaciclib into the brain, and they also decrease the oral exposure of the active metabolite N-desethylabemaciclib. CYP3A4 extensively metabolizes abemaciclib, restricting the plasma exposure of the parental drug, but without significantly altering the plasma exposure of N-desethylabemaciclib. It therefore might be important to consider the high risk of variation in oral exposure of abemaciclib due to variable CYP3A4 activity. The insights gained from this study may be useful to optimize the clinical use of abemaciclib, especially for the treatment of brain tumors. Citation Format: Alejandra Martinez Chavez, Matthijs M. Tibben, Maria C. Lebre, Hilde Rosing, Jos H. Beijnen, Alfred H. Schinkel. The role of multidrug efflux transporters and CYP3A in the pharmacokinetics and tissue distribution of abemaciclib and its active metabolites [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6322.

Abstract PR06: Combinations with CDK4/6 inhibitors to treat cancers with mutations in both KRAS and CDKN2A

Abstract Oncogenic KRAS mutations commonly co-occur with loss of CDKN2A in pancreas and lung cancer. Both mutations are known to activate D-cyclin dependent kinases and therefore may confer sensitivity to drugs that inhibit CDK4 and CDK6 (CDK4/6i). Indeed, preclinical studies have shown that KRAS/CDKN2A double-mutant cancers are reasonably sensitive to CDK4/6 inhibitors and the CDK4/6i abemaciclib showed evidence of benefit in clinical studies of KRAS-mutant NSCLC (1) (http://www.ascopost.com/News/58135). However, despite the encouraging result, abemaciclib did not meet a prespecified overall survival endpoint in the JUNIPER trial, and it has been shown that failure to suppress CDK2 activity diminishes the antiproliferative activity of CDK4/6i in KRAS/CDKN2A mutant cancer cells (2). Since CDK2-specific inhibitors are not available for clinical combination strategies, it is unclear how to exploit this discovery. We employed CRISPR and shRNA genome-wide library screens to identify alternate mechanisms to potentiate the CDK4/6 inhibitor abemaciclib in this class of cancer. Depletion of Src family or Ras-MAPK pathway genes emerged as consistent hits in both lung and pancreas cancer cells with KRAS/CDKN2A mutations. Inhibitors of Src family or Ras-MAPK pathway kinases led to a strong suppression of CDK2 activity and apoptosis when combined with abemaciclib. Across a panel of cancer cell lines, ERKi LY3214996 combined with abemaciclib potently inhibited the growth of KRAS/CDKN2A mutant cancer cells. The combination of LY3214996 with abemaciclib was well tolerated in vivo and caused regressions in mice bearing human KRAS/CDKN2A mutant tumor xenografts, supporting the clinical examination of this drug combination.

Abstract OT2-02-05: A randomized trial of abemaciclib in combination with fulvestrant compared to chemotherapy in women with HR+, HER2- advanced breast cancer with visceral metastases

Abstract Background: Abemaciclib is a potent oral cyclin-dependent kinase (CDK) 4 and 6 inhibitor that demonstrated statistically significant improvement in progression-free survival (PFS) and objective response rate (ORR) in combination with endocrine therapy (ET) in hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) advanced and metastatic breast cancer patients in Phase 3 studies. In contrast to NCCN guidelines, cytotoxic chemotherapy is still often initiated early in the course of HR+, HER2- advanced breast cancer despite absence of visceral crises, potentially denying patients effective and tolerable standard-of-care regimens containing ET. The current study aims to compare the efficacy and safety of abemaciclib in combination with ET to chemotherapy in patients with HR+, HER2- advanced breast cancer with ≥1 site of visceral metastases. Trial design: I3Y-MC-JPCU is a multicenter, open-label, randomized, controlled study of abemaciclib in combination with fulvestrant compared to physician’s choice of chemotherapy in women with HR+, HER2- locally advanced or metastatic breast cancer who have poor prognosis due to visceral metastases. Approximately 300 patients will be randomized 1:1 to Arm A (abemaciclib, 150 mg BID, in combination with fulvestrant, n=150) or Arm B (physician’s choice of chemotherapy [capecitabine, docetaxel, nab-paclitaxel, or paclitaxel], n=150). Stratification factors will include liver metastasis, sensitivity to endocrine therapy (sensitive vs primary resistance vs secondary resistance, and postmenopausal status (natural/surgical/therapeutic radiation vs GnRH use). It will be conducted in the USA. Accrual is planned to start in 2019. Eligibility: Key inclusion criteria are postmenopausal HR+, HER2- patients with locally advanced recurrent and unresectable or metastatic HR+, HER2- breast cancer and ≥1 site of visceral metastasis as well as disease progression after ≥1 line of ET in (neo)adjuvant or metastatic setting. Individuals will be excluded if they have visceral crisis, have received prior systemic therapy other than ET for metastatic disease, have received &amp;gt;1 prior ET for metastatic disease, and/or have been treated with fulvestrant or any CDK 4 and F6 inhibitor for any duration. Objectives: The primary objective is ORR. Secondary objectives include PFS, time to response, duration of response, time to second disease progression (PFS2), and safety. Exploratory objectives include healthcare resource utilization, patient reported outcomes, and relationship of pharmacogenomics/biomarkers to clinical outcomes. Statistical Methods: Comparability of abemaciclib in combination with fulvestrant to chemotherapy will be evaluated with respect to ORR and PFS. The study is designed to demonstrate comparability using a 10% ORR margin and a 20% PFS margin. Comparability will declared if the posterior probability the true difference is less than the comparability margin is at least 80%. PFS comparability will be assessed only if ORR comparability is declared after a gatekeeping testing strategy. The tested hypotheses will be 1) ORR comparability: ≥80% posterior probability that true ORRArm B - true ORRArm A &amp;lt;10% with 10% the defined margin for ORR comparability; and 2) PFS comparability (gated secondary endpoint): ≥80% posterior probability that true PFS hazard ratioArm A/Arm B - 1 &amp;lt;0.2, with 0.2 being the defined margin for PFS comparability. Citation Format: Peter Kaufman, John Glaspy, Wei Zhang, Andrew Koustenis, Yanyun Chen, Adam Brufsky. A randomized trial of abemaciclib in combination with fulvestrant compared to chemotherapy in women with HR+, HER2- advanced breast cancer with visceral metastases [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT2-02-05.

RBTT-05. A SINGLE-ARM, OPEN-LABEL, PHASE II STUDY EVALUATING THE EFFICACY AND SAFETY OF ABEMACICLIB IN PATIENTS WITH RECURRENT OLIGODENDROGLIOMA: TRIALS IN PROGRESS

Abstract BACKGROUND Oligodendroglioma is a rare primary brain tumor characterized by mutation in the IDH1/IDH2 genes and codeletion of chromosomes 1p and 19q. Although median overall survival extends beyond 10 years for patients with oligodendroglioma who receive adjuvant radiation and alkylating chemotherapy, the disease uniformly relapses and has no other effective treatments. The CIC gene, which encodes a high-mobility group box transcriptional repressor, is mutated in about 70% of oligodendrogliomas and is associated with worse prognosis and overexpression of cyclin D1 (CCND1). Cyclin D1 assembles with the cyclin-dependent kinases CDK4 and CDK6 to cause phosphorylation of Rb protein and subsequent cell cycle progression from the G1 to S phase. Therapeutic inhibition of CDK4/6 activity, which leads to Rb dephosphorylation and cell cycle arrest, has revolutionized the care of breast cancer. The current phase 2 study will investigate the efficacy and safety of abemaciclib, a selective and potent small molecule inhibitor of CDK4 and CDK6 with significant brain-brain barrier penetration, in patients with 1p/19q codeleted oligodendroglioma that has recurred after standard radiation and alkylating chemotherapy. METHODS This protocol (NCT03969706) has a single-arm, open-label, single-stage phase 2 design. Subjects will be treated with abemaciclib 200mg tablet twice daily on 28-day cycles until disease progression or unacceptable toxicity. Tumor response will be assessed according to modified Response Assessment in Neuro-Oncology (mRANO) criteria. The primary objective of the study is to determine the efficacy of abemaciclib for recurrent oligodendroglioma. The primary endpoint is the progression-free survival status of the subject at 6 months after enrollment (PFS-6). The alternative hypothesis is that the proportion of subjects without an event at 6 months will be ³85%. We will test this hypothesis against a null hypothesis of PFS-6 = 50%. With enrollment of 10 planned subjects, the power to detect this difference is 82% (one-sided alpha = 0.05).

LBA25 - MONARCHplus: A phase III trial of abemaciclib plus nonsteroidal aromatase inhibitor (NSAI) or fulvestrant (F) for women with HR+/HER2- advanced breast cancer (ABC)

BackgroundAbemaciclib is an oral, selective CDK4 & 6 inhibitor dosed on a continuous schedule and approved in combination with endocrine therapy (ET) for HR+/HER2- ABC patients (pts) outside of China in more than 50 countries. MONARCHplus evaluated the efficacy and safety of abemaciclib plus ET in predominantly Chinese pts with HR+/HER2- ABC.Table: LBA25Summary of PFS and ORR in ITT populationTable: LBA25Cohort ACohort BAbemaciclib + NSAI (n=207)P + NSAI (n=99)Abemaciclib + F (n=104)P + F (n=53)Median PFS(months)NR*14.7311.475.59HR (95% CI)0.499 (0.346, 0.719)0.376 (0.240, 0.588)p-value.0001<.0001ORR (%)56.030.338.57.5p-value<.0001<.0001*NR= not reached. MethodsMONARCHplus was a randomized-controlled, double-blind phase III trial for postmenopausal women with endocrine sensitive (Cohort A) or endocrine resistant (Cohort B) HR+/HER2- ABC. In Cohort A, pts received abemaciclib (150mg Q12h)/ placebo (P) + NSAI (anatrozole or letrozole) as first-line ET. In Cohort B, pts received abemaciclib/P + F following progression to ET. Both cohorts were randomized at a 2:1 ratio. The primary objective was PFS in Cohort A with a key secondary objective of PFS in Cohort B. The trial was powered for Cohort A to 80% at 1-sided α=.025 assuming a hazard ratio (HR) of 0.626 in favor of abemaciclib + NSAI, with analyses at 119 and 170 PFS events. ResultsAt the pre-specified interim, 119 PFS events were observed in Cohort A (n=306) and 82 events in Cohort B (n=157). Abemaciclib +NSAI and abemaciclib + F statistically and significantly improved PFS and ORR (see Table). PFS benefit was consistent within all stratification factors and pre-specified sensitivity analyses. The safety profile for both abemaciclib arms was consistent with previous reports for abemaciclib plus ET and included neutropenia, diarrhea, leukopenia, and anemia as the most frequent adverse events (AEs). ConclusionsAbemaciclib in combination with NSAI or fulvestrant provided a statistically significant and clinically meaningful improvement in PFS in predominantly Chinese postmenopausal women with HR+/HER2- ABC with no new safety signals observed. The MONARCHplus interim analysis demonstrated benefit consistent with the MONARCH 2 and 3 studies. Clinical trial identificationNCT02763566. Legal entity responsible for the studyEli Lilly and Company. FundingEli Lilly and Company. DisclosureAll authors have declared no conflicts of interest.