89 research outputs found
A Phase I/II Study of GSK525762 Combined with Fulvestrant in Patients with Hormone Receptor-positive/HER2-negative Advanced or Metastatic Breast Cancer
No full textFulvestrant; Breast cancerFulvestrant; Cáncer de mamaFulvestrant; Càncer de mamaPurpose:
Endocrine-based therapy is the initial primary treatment option for hormone receptor–positive and human epidermal growth factor receptor 2-negative (HR+/HER2−) metastatic breast cancer (mBC). However, patients eventually experience disease progression due to resistance to endocrine therapy. Molibresib (GSK525762) is a small-molecule inhibitor of bromodomain and extraterminal (BET) family proteins (BRD2, BRD3, BRD4, and BRDT). Preclinical data suggested that the combination of molibresib with endocrine therapy might overcome endocrine resistance. This study aimed to investigate the safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy [objective response rate (ORR)] of molibresib combined with fulvestrant in women with HR+/HER2− mBC.
Patients and Methods:
In this phase I/II dose-escalation and dose-expansion study, patients received oral molibresib 60 or 80 mg once daily in combination with intramuscular fulvestrant. Patients enrolled had relapsed/refractory, advanced/metastatic HR+/HER2− breast cancer with disease progression on prior treatment with an aromatase inhibitor, with or without a cyclin-dependent kinase 4/6 inhibitor.
Results:
The study included 123 patients. The most common treatment-related adverse events (AE) were nausea (52%), dysgeusia (49%), and fatigue (45%). At a 60-mg dosage of molibresib, >90% of patients experienced treatment-related AE. Grade 3 or 4 treatment-related AE were observed in 47% and 48% of patients treated with molibresib 60 mg and molibresib 80 mg, respectively. The ORR was 13% [95% confidence interval (CI), 8–20], not meeting the 25% threshold for proceeding to phase II. Among 82 patients with detected circulating tumor DNA and clinical outcome at study enrollment, a strong association was observed between the detection of copy-number amplification and poor progression-free survival (HR, 2.89; 95% CI, 1.73–4.83; P < 0.0001).
Conclusions:
Molibresib in combination with fulvestrant did not demonstrate clinically meaningful activity in this study.This study was funded by GSK
Metastatic Invasive Breast Cancer Recurrence Following Curative-Intent Therapy for Ductal Carcinoma In Situ
No full textAbstract P6-11-18: Medical, financial and insurance related concerns of metastatic breast cancer patients
No full textAbstract CT011: Circulating tumor DNA (ctDNA) sequencing for <i>HER2</i> mutation (<i>HER2</i>mut) screening and response monitoring to neratinib in metastatic breast cancer (MBC)
No full textAbstract
Introduction: MutHER is a phase II trial that demonstrated the anti-tumor activity of the pan-HER inhibitor neratinib in HER2mut, non-amplified MBC. The major challenges to accrue to this trial were the large number of pts to screen for the 2-3% HER2mut population and the high rate (24%) of poor quality tumor DNA for sequencing. The goals of this ctDNA study were: 1) the concordance of HER2mut detected by ctDNA versus tumor testing; 2) the incidence of ctDNA HER2mut in HER2 non-amplified MBC; 3) changes in HER2mut variant allele frequency (VAF) on neratinib therapy.
Methods: A sample size of 30 negative (neg) controls was needed to ensure 90% confidence if ctDNA testing has &gt;90% specificity in detecting HER2mut. Thus, plasma from MBC pts obtained at screening for MutHER trial (Neg control: 40 pts without HER2mut on tumor testing; Positive (pos) control: 14 pts with known HER2mut who received neratinib) were subjected to Guardant360 ctDNA 70-gene panel sequencing (all exons of HER2 included). ctDNA from the 14 neratinib treated pts were also analyzed at week (wk) 4 and upon progression. ctDNA data from MBC pts clinically tested at Guardant Health were interrogated for HER2mut incidence.
Results: Among the 14 pts with tumor pos for HER2mut, ctDNA sequencing identified the same HER2mut in 11, discrepant HER2mut in 1, and neg in 2. The 2 pts with ctDNA neg for HER2mut had progressive disease (PD) and stable disease (SD &gt; 6 months) on neratinib, respectively. Among the 40 neg controls, 8 were not evaluable (no detectable ctDNA or assay unsuccessful) and all 32 successfully sequenced cases were neg for HER2mut. The sensitivity and specificity of ctDNA for HER2mut detection was 11/14 (79%, 90% CI: 53-94%) and 32/32 (100%, 90% CI: 91-100%), respectively. Among the 11 paired baseline and wk 4 samples, 9 (82%) had lower HER2mut VAFs at wk 4 than at baseline, with 1 complete response (CR), 1 partial response (PR), 5 SD, and 4 PD at wk 8 as best tumor response. Two pts had higher wk 4 ctDNA HER2mut VAFs and both had radiographic PD at wk 8. The absolute HER2mut VAF levels at wk 4 were significantly associated with TTP (Spearman rho=-0.69, p=0.02) and tumor size change (rho=0.67, p=0.05). The HER2mut VAFs were significantly higher at progression than wk 4 in all pts (p&lt;0.01). One pt acquired a new HER2mut T798I, which is analogous to the gate-keeper mutation EGFR T790M. The incidence of HER2mut without amplification in unselected consecutive MBC clinically tested by Guardant360 was 3% (48/1,584), with mutation pattern similar to published tumor testing data.
Conclusions: ctDNA sequencing is sensitive and highly specific in detecting HER2mut, offering a non-invasive method to identify pts for trials of HER2mut-targeted therapy. Decreased HER2mut VAFs at wk 4 was observed in 82% of cases, consistent with the on-target effect of neratinib. Increased HER2mut VAFs at wk 4 is a potential early marker of progression.
Citation Format: Cynthia Ma, Ron Bose, Feng Gao, Rachel Freedman, Melinda Telli, Gretchen Kimmick, Eric Winer, Michael Naughton, Matthew Goetz, Christy Russell, Debu Tripathy, Melody Cobleigh, Andres Forero, Timothy Pluard, Carey Anders, Shana Thomas, Jill Anderson, Caroline Bumb, Kimberly Banks, Richard Lanman, Richard Bryce, Alshad Lalani, John Pfeifer, Daniel Hays, Mark Pegram, Kimberly Blackwell, Philippe Bedard, Hussam Al-Kateb, Matthew Ellis. Circulating tumor DNA (ctDNA) sequencing for HER2 mutation (HER2mut) screening and response monitoring to neratinib in metastatic breast cancer (MBC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT011. doi:10.1158/1538-7445.AM2017-CT011</jats:p
Infusion-Related Reactions in the Phase 3 SOPHIA Trial of Margetuximab + Chemotherapy vs Trastuzumab + Chemotherapy in Patients With Pretreated HER2+ Metastatic Breast Cancer
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Abstract GS01-10: HER2CLIMB-02: Randomized, Double-Blind Phase 3 Trial of Tucatinib and Trastuzumab Emtansine for Previously Treated HER2-Positive Metastatic Breast Cancer
No full textBackground
Tucatinib is a highly selective HER2-directed tyrosine kinase inhibitor approved in combination with trastuzumab and capecitabine for previously treated HER2+ locally advanced or metastatic breast cancer (LA/MBC). Trastuzumab emtansine (T-DM1) is a HER2-directed antibody-drug conjugate approved to treat HER2+ LA/MBC previously treated with trastuzumab and a taxane. This is the first report of HER2CLIMB-02 (NCT03975647), a randomized, double-blind, placebo-controlled phase 3 study assessing the efficacy and safety of tucatinib combined with T-DM1 in patients with previously treated HER2+ LA/MBC.
Methods
Eligible patients had HER2+ LA/MBC previously treated with trastuzumab and a taxane in any setting with ECOG performance status ≤1 and adequate hepatic, renal, hematologic, and cardiac function. Patients with previously treated stable, progressing, or untreated brain metastases (BMs) not requiring immediate local therapy were also eligible. Patients were randomly assigned 1:1 to receive 21-day cycles of either tucatinib (300 mg orally twice a day [PO BID]) or placebo (PO BID), combined with T-DM1 (3.6 mg/kg intravenously every 3 weeks). The primary endpoint was progression-free survival (PFS) by investigator assessment per RECIST v1.1. Alpha-controlled secondary endpoints included overall survival (OS) and objective response rate (ORR) per RECIST v1.1 for the overall population, and PFS and OS for the subset of patients with BMs at baseline. Safety was analyzed as a secondary endpoint.
Results
From October 8, 2019, to June 16, 2022, 463 patients were randomly assigned, comprising 228 to the tucatinib arm (tucatinib + T-DM1) and 235 to the control arm (placebo + T-DM1). The median duration of follow-up (OS) was 24.4 months for the overall population. Patient demographics and baseline characteristics were balanced between the 2 arms. Almost half (44.1%) of the overall population had either active or stable BMs at baseline. As of the data cutoff (June 29, 2023), the study met its primary endpoint with a statistically significant improvement in PFS in the tucatinib arm vs control arm. The risk of progression or death decreased by 24.1% in the tucatinib arm (hazard ratio [HR]=0.759 [95% CI, 0.607-0.950]; P=0.0163). Median PFS was 9.5 months (95% CI, 7.4-10.9) vs 7.4 months (95% CI, 5.6-8.1) for the tucatinib and control arms, respectively. HRs for PFS across all prespecified subgroups were consistent with the HR of the overall population, including patients with BMs at baseline (HR=0.639 [95% CI, 0.459-0.891]). The interim OS results were immature with 134 of 253 total required events (53%) and did not meet the prespecified crossing boundary. The confirmed ORR was numerically higher in the tucatinib arm (42.0%) vs the control arm (36.1%). The most common treatment-emergent adverse events (TEAEs) included nausea (65.4% vs 49.4% for tucatinib and control arms, respectively), diarrhea (56.7% vs 26.6%), and fatigue (48.9% vs 37.3%). The most common grade ≥3 TEAEs in the tucatinib arm were alanine and aspartate aminotransferase elevations, each reported in 38 patients (16.5%) in the tucatinib arm and 6 patients (2.6%) in the control arm. TEAEs associated with any treatment discontinuation occurred in 51 patients (22.1%) in the tucatinib arm and 27 (11.6%) in the control arm. TEAEs leading to deaths occurred in 3 patients (1.3%) in the tucatinib arm and 2 patients (0.9%) in the control arm.
Conclusion
HER2CLIMB-02 demonstrated that the addition of tucatinib to T-DM1 significantly improved median PFS in patients with previously treated HER2+ LA/MBC, including those with BMs. Although discontinuations due to TEAEs were more common in the tucatinib arm, no new safety signals emerged for the combination therapy.
Citation Format: Sara Hurvitz, Sherene Loi, Joyce O'Shaughnessy, Alicia Okines, Sara Tolaney, Joo Hyuk Sohn, Cristina Saura, Xiaofu Zhu, David Cameron, Thomas Bachelot, Erika Hamilton, Giuseppe Curigliano, Antonio Wolff, Nadia Harbeck, Norikazu Masuda, Linda Vahdat, Khalil Zaman, Frances Valdes-Albini, Margaret Block, Timothy Pluard, Tira Tan, Chelsea Gawryletz, Arlene Chan, Philippe Bedard, Rinat Yerushalmi, Binghe Xu, Konstantinos Tryfonidis, Michael Schmitt, Joan Xie, Virginia Borges. HER2CLIMB-02: Randomized, Double-Blind Phase 3 Trial of Tucatinib and Trastuzumab Emtansine for Previously Treated HER2-Positive Metastatic Breast Cancer [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 GS01-10
First-line cyclin-dependent kinase 4 and 6 inhibitors in combination with an aromatase inhibitor for HR+/HER2- metastatic breast cancer: a real-world cost-effectiveness assessment in a US Medicare-eligible population
No full textBACKGROUND: In hormone receptor-positive, human epidermal growth factor 2-negative (HR+/HER2-) metastatic breast cancer (mBC), cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6is) in combination with an aromatase inhibitor (AI) are the preferred first-line (1L) treatment. Although prior cost-effectiveness models comparing CDK4/6is palbociclib, ribociclib, and abemaciclib have used data from placebo-controlled clinical trials, no analyses in the United States have been conducted using real-world evidence (RWE) for a US Medicare-eligible population. OBJECTIVE: To estimate the long-term clinical outcomes and health care costs of 1L CDK4/6i treatment in patients aged 65 years and older using RWE. METHODS: We developed a partitioned survival model to project patient time in progression-free and progressed disease health states. Progression-free survival (PFS) and overall survival (OS) curves for palbociclib + AI were obtained from an analysis of patients aged 65 years and older treated 1L for HR+/HER2- mBC using the Flatiron Health Analytic Database (Flatiron). Adjusted comparative effectiveness estimates vs palbociclib + AI for both ribociclib + AI (PFS hazard ratio = 0.98 [95% CI = 0.86-1.13]; OS hazard ratio = 1.01 [95% CI: 0.87-1.18]) and abemaciclib + AI (PFS hazard ratio = 0.99 [95% CI = 0.86-1.15]; OS hazard ratio = 1.00 [95% CI = 0.84-1.19]) were obtained from the same analysis. All-cause medical costs and CDK4/6i drug costs were based on an analysis of patients aged 65 years and older in Optum Clinformatics DataMart. We used a Medicare perspective over a lifetime horizon for a cohort of patients with mean age of 73.7 years. Sensitivity analyses were performed to assess the robustness of results to plausible variation in input values. RESULTS: Projected life-years (LYs) with palbociclib + AI, ribociclib + AI, and abemaciclib + AI were similar: 5.16 (95% credible range [CR] = 4.94-5.35), 5.12 (95% CR = 4.53-5.82), and 5.16 (95% CR = 4.49-5.90), respectively. Total lifetime health care costs were also similar (807,400-866,800 [95% CR = 965,000], and 809,000-$1,004,600], respectively). Sensitivity analyses further supported no differences in LYs or total costs between CDK4/6is. CONCLUSIONS: Based on effectiveness and cost estimates from real-world data, our analyses suggest that palbociclib, ribociclib, and abemaciclib produce similar life expectancy and health care costs in US patients aged 65 years and older with HR+/HER2- mBC
Margetuximab Versus Trastuzumab in Patients With Previously Treated HER2-Positive Advanced Breast Cancer (SOPHIA): Final Overall Survival Results From a Randomized Phase 3 Trial
No full textClinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.Final overall survival (OS) in SOPHIA (ClinicalTrials.gov identifier: NCT02492711), a study of margetuximab versus trastuzumab, both with chemotherapy, in patients with previously treated human epidermal growth factor receptor 2-positive advanced breast cancer, is reported with updated safety. Overall, 536 patients in the intention-to-treat population were randomly assigned to margetuximab (15 mg/kg intravenously once every 3 weeks; n = 266) plus chemotherapy or trastuzumab (6 mg/kg intravenously once every 3 weeks after a loading dose of 8 mg/kg; n = 270) plus chemotherapy. Primary end points were progression-free survival, previously reported, and OS. Final OS analysis was triggered by 385 prespecified events. The median OS was 21.6 months (95% CI, 18.89 to 25.07) with margetuximab versus 21.9 months (95% CI, 18.69 to 24.18) with trastuzumab (hazard ratio [HR], 0.95; 95% CI, 0.77 to 1.17; P = .620). Preplanned, exploratory analysis of CD16A genotyping suggested a possible improvement in OS for margetuximab in CD16A-158FF patients versus trastuzumab (median OS, 23.6 v 19.2 months; HR, 0.72; 95% CI, 0.52 to 1.00) and a possible improvement in OS for trastuzumab in CD16A-158VV patients versus margetuximab (median OS, 31.1 v 22.0 months; HR, 1.77; 95% CI, 1.01 to 3.12). Margetuximab safety was comparable with trastuzumab. Final overall OS analysis did not demonstrate margetuximab advantage over trastuzumab. Margetuximab studies in patients with human epidermal growth factor receptor 2-positive breast cancer with different CD16A allelic variants are warranted
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