Earlier this year, the US Food and Drug Administration (FDA) approved an expanded indication for abemaciclib (Verzenio®; Eli Lilly & Co; previously known as LY2835219) in combination with endocrine therapy (ET), for the adjuvant treatment of adult patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), node-positive, early breast cancer (EBC) at a high risk of recurrence.

This label expansion is supported by four-year data from the Phase 3 monarchE trial of adjuvant abemaciclib in combination with ET, which showed a deepened benefit in invasive disease-free survival (IDFS) beyond the two-year treatment course with adjuvant abemaciclib.

These four-year monarchE data were presented at the 2022 San Antonio Breast Cancer Symposium and simultaneously published in The Lancet Oncology. [1]

During the annual meeting of the American Society of Clinical Oncology (ASCO) held June 2, -6, 2023 in Chicago, Illinois, and online, cancer researchers and clinicians from around the world will gather to discuss the latest research and how to ensure that all people receive the cancer care they need.

During the annual meeting, updates will be presented discussing novel treatment options for patients with HR+, HER2–, node-positive, early breast cancer with a high risk of coming back, or certain types of HR+, HER2– metastatic breast cancer.

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Abstract #501
An oral presentation (Abstract #501) will highlight efficacy and safety results from age-based subgroup analyses from the Phase 3 monarchE study of the CDK4/6 inhibitor abemaciclib (Verzenio®; Eli Lilly & Co) in combination with endocrine therapy (ET) in patients with HR+, HER2-, node-positive EBC at a high risk of recurrence.

Previously reported four-year data from monarchE demonstrated that, with all patients off abemaciclib, abemaciclib with ET compared to ET alone reduced the risk of recurrence by 34% and the risk of distant relapse by 34% in this node positive, high risk EBC population, with a persistent and growing benefit demonstrated beyond the two-year treatment period with abemaciclib – supporting the goal of eradicating micrometastatic disease to prevent recurrence even after patients have completed treatment.[1]

The new analyses show similar efficacy across age groups and in patients who had dose adjustments. Adjuvant abemaciclib plus ET demonstrated an absolute benefit in invasive disease-free survival (IDFS) rate of 5.9% in those age 65 and older (n=850) and 6.4% in patients under 65 (n=4,787). Rates of adverse events (AEs) were also similar between age groups; 54% of patients 65 and older experienced Grade 3 and above AEs compared with 49% of patients under 65. Dose adjustments due to AEs were more common in patients age 65 and older. The impact of dose adjustments was evaluated among all patients enrolled in monarchE, regardless of age. In this analysis, patients were classified into three equal-sized subgroups according to their relative dose intensity (RDI) of abemaciclib. IDFS outcomes at four years were similar across RDI subgroups (RDI from lowest dose intensity group to highest: 87.1%, 86.4%, 83.7%), showing treatment benefit is maintained despite dose modifications.

Patient-reported quality of life (QoL) data collected at baseline, 3, 6, 12, 18, and 24 months during the treatment period will also be presented, across all patients in monarchE. These results demonstrated overall QoL scores were similar for patients taking abemaciclib plus ET and patients taking ET alone and were maintained in all age subgroups during the two-year abemaciclib treatment period.

Other key presentations
During the annual meeting also expect to see updates about pirtobrutinib (Jaypirca™ Eli Lilly & Co; previously know as LOXO-305), the first BTK inhibitor of any kind specifically approved for patients with Mantle Cell Lymphoma (MCL) previously treated with a covalent BTK inhibitor (cBTKi). [3][4]

BTK inhibitors work by interfering with the B-cell receptor signaling pathway.

Current treatment options for MCL include ibrutinib, acalabrutinib, zanubrutinib and pirtobrutinib are approved to treat patients with mantle cell lymphoma that has relapsed and/or not responded to other treatment.

And while BTK, a non-receptor tyrosine kinase, is a major therapeutic target for B-cell driven malignancies, and approved and commercially available covalent BTK inhibitors has shown remarkable efficacy in B cell malignancies, covalent BTK inhibitors are generally associated with treatment limitations and treatment failure to off-target adverse events, suboptimal oral pharmacology, and development of resistance mutations that prevent inhibitor binding.

To improve treatment outcomes, using non-covalent BTK inhibitor like pirtobrutinib, a highly selective and potent, non-covalent (reversible) BTK inhibitor, is one strategy to help overcome drug resistance and reduce adverse events. 

Abstract #7514
During ASCO, a poster presentation (Abstract #7514) will highlight efficacy data with a median survival follow-up time of two years for pirtobrutinib in relapsed or refractory MCL from the BRUIN Phase 1/2 clinical trial. The presentation uses a July 29, 2022 data cutoff date, providing an additional six months of follow-up from the data recently published in the Journal of Clinical Oncology and presented at the 2022 American Society of Hematology (ASH) Annual Meeting.[3][4][5]

The dataset includes the first 90 MCL patients enrolled who had received a prior covalent Bruton’s tyrosine kinase (BTK) inhibitor. Patients had received a median of three prior lines of therapy (range 1-8). Efficacy and safety results were consistent with previously reported data.

Abstract #7513
A second poster presentation (Abstract #7513) will highlight clinical safety data in patients with relapsed or refractory B-cell malignancies, inclusive of subtypes still under investigational use, from the Phase 1/2 BRUIN trial who received long-term (≥12 months) pirtobrutinib treatment. These safety data, based on longer-term pirtobrutinib therapy, are consistent with the overall safety profile, without evidence of new or worsening toxicity signals. In this long-term safety cohort (n=326), the most common TEAEs, regardless of attribution, were fatigue (32%), diarrhea (31%), COVID-19 (29%), contusion (26%), cough (25%), and back pain (21%). With continued treatment (median of 19 months), the rates of select AEs of special interest including atrial fibrillation remained low and did not show clinically meaningful increases, particularly Grade ≥3. [6]

Clinical trials
Endocrine Therapy With or Without Abemaciclib (LY2835219) Following Surgery in Participants With Breast Cancer (monarchE) – NCT03155997
A Study of Oral LOXO-305 in Patients With Previously Treated CLL/SLL or NHL – NCT03740529

Highlights of prescribing information
Abemaciclib (Verzenio®; Eli Lilly & Co) [Prescribing Information]
Pirtobrutinib (Jaypirca™ Eli Lilly & Co)[Prescribing Information]

[1] Johnston SRD, Toi M, O’Shaughnessy J, Rastogi P, et al. Abemaciclib plus endocrine therapy for hormone receptor-positive, HER2-negative, node-positive, high-risk early breast cancer (monarchE): results from a preplanned interim analysis of a randomised, open-label, phase 3 trial. Lancet Oncol. 2023 Jan;24(1):77-90.
[2] Hamilton EP, Kim JH, Eigeliene N, Mavroudis D, Median DM, Marconato H, Shevnia S, et al. Efficacy and safety results by age in monarchE: Adjuvant abemaciclib combined with endocrine therapy (ET) in patients with HR+, HER2-, node-positive, high-risk early breast cancer (EBC). J Clin Oncol 41, 2023 (suppl 16; abstr 501).
[3] Wang ML, Jurczak W, Zinzani PL, Eyre TA, Cheah CY, Ujjani CS, Koh Y, Izutsu K, Gerson JN, Flinn I, Tessoulin B, Alencar AJ, Ma S, Lewis D, Lech-Maranda E, Rhodes J, Patel K, Maddocks K, Lamanna N, Wang Y, Tam CS, Munir T, Nagai H, Hernandez-Ilizaliturri F, Kumar A, Fenske TS, Seymour JF, Zelenetz AD, Nair B, Tsai DE, Balbas M, Walgren RA, Abada P, Wang C, Zhao J, Mato AR, Shah NN. Pirtobrutinib in Covalent BTK-Inhibitor Pre-treated Mantle Cell Lymphoma. J Clin Oncol. 2023 May 16:101200JCO2300562. doi: 10.1200/JCO.23.00562. Epub ahead of print. PMID: 37192437.
[4] Gomez EB, Ebata K, Randeria HS, Rosendahl MS, Cedervall EP, Morales TH, Hanson LM, Brown NE, Gong X, Stephens JR, Wu W, Lippincott I, Ku KS, Walgren RA, Abada PB, Ballard JA, Allerston CK, Brandhuber BJ. Pirtobrutinib preclinical characterization: a highly selective, non-covalent (reversible) BTK inhibitor. Blood. 2023 Feb 16:blood.2022018674. doi: 10.1182/blood.2022018674. Epub ahead of print. PMID: 36796019.
[5] Shah NN, Jurczak W, Zinzani PL, Eyre TA, Cheah C, Ujjani CS, Izutsu K, et al. Pirtobrutinib in covalent BTK-inhibitor (cBTKi) pre-treated mantle cell lymphoma (MCL): Updated results and subgroup analysis from the phase 1/2 BRUIN study with >3 years follow-up from start of enrollment. J Clin Oncol 41, 2023 (suppl 16; abstr 7514).
[6] Coombs CC, Shah NN, Jurczak W, Woyach JA, Cheah C, Patel K, Maddocks KJ, Wang Y, et al. Long-term safety with ≥12 months of pirtobrutinib in relapsed/refractory (R/R) B-cell malignancies. J Clin Oncol 41, 2023 (suppl 16; abstr 7513).

Featured image: Doctor talks with patient.  Photo courtesy: © 2016 – 2023 Fotolia/Adobe. Used with permission.

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