bims-cyhorp 2023-03-05 papers

Ther Adv Med Oncol. 2023 ;15 17588359231152843

Quality of life with ribociclib versus abemaciclib as first-line treatment of HR+/HER2- advanced breast cancer: a matching-adjusted indirect comparison.

Hope S Rugo, Victoria Harmer, Joyce O'Shaughnessy, Komal Jhaveri, Sara M Tolaney, Fatima Cardoso, Aditya Bardia, Vikalp Kumar Maheshwari, Sandeep Tripathi, Sina Haftchenary, Purnima Pathak, Peter A Fasching.

Background: A cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) + endocrine therapy is recommended as first-line treatment for hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced breast cancer (ABC). Quality of life (QoL) is an important endpoint that affects treatment decisions. Understanding the relevance of CDK4/6i treatment on QoL is gaining importance given use in earlier treatment lines for ABC and an emerging role in treating early breast cancer in which QoL may be more impactful. In the absence of head-to-head trial data, a matching-adjusted indirect comparison (MAIC) permits comparative efficacy between trials.
Objective: In this analysis, patient-reported QoL for MONALEESA-2 [ribociclib + aromatase inhibitor (AI)] and MONARCH 3 (abemaciclib + AI) was compared using MAIC with a focus on individual domains.
Design: An anchored MAIC of QoL comparing ribociclib + AI versus abemaciclib + AI was performed using data from the European Organization for Research and Treatment of Cancer quality of life questionnaire (QLQ)-C30 and BR-23 questionnaires.
Methods: Individual patient data from MONALEESA-2 and published aggregated data from MONARCH 3 were included in this analysis. Time to sustained deterioration (TTSD) was calculated as the time from randomization to a ⩾10-point deterioration with no later improvement above this threshold.
Results: Patients from the ribociclib (n = 205) and placebo (n = 149) arms of MONALEESA-2 were matched with patients from the abemaciclib (n = 328) and placebo (n = 165) arms of MONARCH 3. After weighting, baseline patient characteristics were well balanced. TTSD significantly favored ribociclib versus abemaciclib in appetite loss [hazard ratio (HR), 0.46; 95% confidence interval (CI), 0.27-0.81], diarrhea (HR, 0.42; 95% CI, 0.23-0.79), fatigue (HR, 0.63; 95% CI, 0.41-0.96), and arm symptoms (HR, 0.49; 95% CI, 0.30-0.79). TTSD did not significantly favor abemaciclib compared with ribociclib in any functional or symptom scale of the QLQ-C30 or BR-23 questionnaires.
Conclusions: This MAIC indicates that ribociclib + AI is associated with better symptom-related QoL than abemaciclib + AI for postmenopausal patients with HR+/HER2- ABC treated in the first-line setting.
Trial registration: NCT01958021 (MONALEESA-2) and NCT02246621 (MONARCH 3).

Keywords: CDK4/6 inhibitor; MONALEESA-2; MONARCH 3; abemaciclib; quality of life; ribociclib

DOI: https://doi.org/10.1177/17588359231152843

Anticancer Res. 2023 Mar;43(3): 1291-1299

Abemaciclib-associated Diarrhea: An Exploratory Analysis of Real-life Data.

Vittorio Gebbia, Federica Martorana, Maria Vita Sanò, Maria Rosaria Valerio, Francesco Giotta, Massimiliano Spada, Dario Piazza, Michele Caruso, Paolo Vigneri.

BACKGROUND/AIM: Abemaciclib is a cyclin-dependent kinase 4/6 inhibitor approved in combination with endocrine therapy for treating hormone receptor-positive and human epidermal growth factor receptor 2-negative early and advanced breast cancer patients. The safety profile of abemaciclib is characterized by frequent gastrointestinal toxicity, especially diarrhea. Therefore, we performed an exploratory analysis of clinical factors that may be potentially associated with diarrhea in patients treated with abemaciclib plus endocrine therapy.
PATIENTS AND METHODS: Factors potentially predisposing to diarrhea were selected, such as age ≥70 years, concomitant medications and diseases, diet, and use of laxatives. These variables were correlated with the onset of grade 2/3 diarrhea in a cohort of patients treated with abemaciclib from advanced breast cancer. Univariate and multivariate analysis was performed. Sensitivity and specificity were tested using the ROC curve.
RESULTS: Eighty women with advanced breast cancer were included in the study. The univariate analysis found a statistically significant correlation between grade 2/3 diarrhea and age ≥70 years, polypharmacy, and concomitant gastrointestinal diseases (p<0.05). In the multivariate analysis, the number of risk factors significantly correlated with the outcome of interest (p<0.0001). ROC analysis showed our model's 82% sensitivity and 75% specificity.
CONCLUSION: Taking into account specific pre-existing factors, it is possible to estimate the risk of diarrhea in hormone receptor-positive and human epidermal growth factor receptor 2-negative - advanced breast cancer patients, candidates for abemaciclib plus endocrine therapy. In these subjects, implementing proactive prevention and adopting a dose-escalation strategy may represent practical approaches to decrease the abemaciclib toxicity burden.

Keywords: Abemaciclib; age; comorbidities; diarrhea; diet; polypharmacy

DOI: https://doi.org/10.21873/anticanres.16276

Breast Cancer Res Treat. 2023 Feb 27.

Effective combination treatments for breast cancer inhibition by FOXM1 inhibitors with other targeted cancer drugs.

Valeria Sanabria Guillen, Yvonne Ziegler, Chirag Gopinath, Sandeep Kumar, Parama Dey, Blake N Plotner, Nadia Z Dawson, Sung Hoon Kim, John A Katzenellenbogen, Benita S Katzenellenbogen.

PURPOSE: Few targeted treatment options currently exist for patients with advanced, often recurrent breast cancers, both triple-negative breast cancer (TNBC) and hormone receptor-positive breast cancer. Forkhead box M1 (FOXM1) is an oncogenic transcription factor that drives all cancer hallmarks in all subtypes of breast cancer. We previously developed small-molecule inhibitors of FOXM1 and to further exploit their potential as anti-proliferative agents, we investigated combining FOXM1 inhibitors with drugs currently used in the treatment of breast and other cancers and assessed the potential for enhanced inhibition of breast cancer.
METHODS: FOXM1 inhibitors alone and in combination with other cancer therapy drugs were assessed for their effects on suppression of cell viability and cell cycle progression, induction of apoptosis and caspase 3/7 activity, and changes in related gene expressions. Synergistic, additive, or antagonistic interactions were evaluated using ZIP (zero interaction potency) synergy scores and the Chou-Talalay interaction combination index.
RESULTS: The FOXM1 inhibitors displayed synergistic inhibition of proliferation, enhanced G2/M cell cycle arrest, and increased apoptosis and caspase 3/7 activity and associated changes in gene expression when combined with several drugs across different pharmacological classes. We found especially strong enhanced effectiveness of FOXM1 inhibitors in combination with drugs in the proteasome inhibitor class for ER-positive and TNBC cells and with CDK4/6 inhibitors (Palbociclib, Abemaciclib, and Ribociclib) in ER-positive cells.
CONCLUSION: The findings suggest that the combination of FOXM1 inhibitors with several other drugs might enable dose reduction in both agents and provide enhanced efficacy in treatment of breast cancer.

Keywords: Breast cancer suppression; CDK4/6; FOXM1 inhibitors; Inhibitors; Proteasome inhibitors; Synergy

DOI: https://doi.org/10.1007/s10549-023-06878-3

Lancet Oncol. 2023 Mar;pii: S1470-2045(23)00065-7. [Epub ahead of print]24(3): e104

Abemaciclib plus endocrine therapy for hormone receptor-positive, HER2-negative, node-positive, high-risk, early breast cancer - Authors' reply.

Stephen R D Johnston, Valérie André.

DOI: https://doi.org/10.1016/S1470-2045(23)00065-7

Lancet Oncol. 2023 Mar;pii: S1470-2045(23)00014-1. [Epub ahead of print]24(3): e103

Abemaciclib plus endocrine therapy for hormone receptor-positive, HER2-negative, node-positive, high-risk, early breast cancer.

Kazuki Nozawa, Masataka Sawaki, Hiroji Iwata.

DOI: https://doi.org/10.1016/S1470-2045(23)00014-1

Clin Cancer Res. 2023 Feb 28. OF1-OF7

Phase II Study of Palbociclib (PD-0332991) in CCND1, 2, or 3 Amplification: Results from the NCI-MATCH ECOG-ACRIN Trial (EAY131) Subprotocol Z1B.

PURPOSE: Cyclin D/CDK4/6 is critical in controlling the G1 to S checkpoint. CCND, the gene encoding cyclin D, is known to be amplified in a variety of solid tumors. Palbociclib is an oral CDK4/6 inhibitor, approved in advanced breast cancer in combination with endocrine therapy. We explored the efficacy of palbociclib in patients with nonbreast solid tumors containing an amplification in CCND1, 2, or 3.
PATIENTS AND METHODS: Patients with tumors containing a CCND1, 2, or 3 amplification and expression of the retinoblastoma protein were assigned to subprotocol Z1B and received palbociclib 125 mg once daily for 21 days of a 28-day cycle. Tumor response was assessed every two cycles.
RESULTS: Forty patients were assigned to subprotocol Z1B; 4 patients had outside assays identifying the CCND1, 2, or 3 amplification and were not confirmed centrally; 3 were ineligible and 2 were not treated (1 untreated patient was also ineligible), leaving 32 evaluable patients for this analysis. There were no partial responses; 12 patients (37.5%) had stable disease as best response. There were seven deaths on study, all during cycle 1 and attributable to disease progression. Median progression-free survival was 1.8 months. The most common toxicities were leukopenia (n = 21, 55%) and neutropenia (n = 19, 50%); neutropenia was the most common grade 3/4 event (n = 12, 32%).
CONCLUSIONS: Palbociclib was not effective at treating nonbreast solid tumors with a CCND1, 2, or 3 amplification in this cohort. These data do not support further investigation of single-agent palbociclib in tumors with CCND1, 2, or 3 amplification.

DOI: https://doi.org/10.1158/1078-0432.CCR-22-2150