Impact of palbociclib plus letrozole on patient-reported health-related quality of life: results from the PALOMA-2 trial

BackgroundPatient-reported outcomes are integral in benefit–risk assessments of new treatment regimens. The PALOMA-2 study provides the largest body of evidence for patient-reported health-related quality of life (QOL) for patients with metastatic breast cancer (MBC) receiving first-line endocrine-based therapy (palbociclib plus letrozole and letrozole alone).Patients and methodsTreatment-naïve postmenopausal women with estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2−) MBC were randomized 2 : 1 to palbociclib plus letrozole (n = 444) or placebo plus letrozole (n = 222). Patient-reported outcomes were assessed at baseline, day 1 of cycles 2 and 3, and day 1 of every other cycle from cycle 5 using the Functional Assessment of Cancer Therapy (FACT)-Breast and EuroQOL 5 dimensions (EQ-5D) questionnaires.ResultsAs of 26 February 2016, the median duration of follow-up was 23 months. Baseline scores were comparable between the two treatment arms. No significant between-arm differences were observed in change from baseline in FACT-Breast Total, FACT-General Total, or EQ-5D scores. Significantly greater improvement in pain scores was observed in the palbociclib plus letrozole arm (−0.256 versus −0.098; P = 0.0183). In both arms, deterioration of FACT-Breast Total score was significantly delayed in patients without progression versus those with progression and patients with partial or complete response versus those without. No significant difference was observed in FACT-Breast and EQ-5D index scores in patients with and without neutropenia.ConclusionsOverall, women with MBC receiving first-line endocrine therapy have a good QOL. The addition of palbociclib to letrozole maintains health-related QOL and improves pain scores in treatment-naïve postmenopausal patients with ER+/HER2− MBC compared with letrozole alone. Significantly greater delay in deterioration of health-related QOL was observed in patients without progression versus those who progressed and in patients with an objective response versus non-responders.ClinicalTrials.gov: NCT01740427 (https://clinicaltrials.gov/ct2/show/NCT01740427)     

Challenges in the treatment of hormone receptor-positive,HER2-negative metastatic breast cancer with brain metastases

Brain metastases are a major cause of morbidity and mortality for women with hormone receptor (HR)-positive breast cancer, yet little is known about the optimal treatment of brain disease in this group of patients. Although these patients are at lower risk for brain metastases relative to those with HER2-positive and triple-negative disease, they comprise the majority of women diagnosed with breast cancer. Surgery and radiation continue to have a role in the treatment of brain metastases, but there is a dearth of effective systemic therapies due to the poor penetrability of many systemic drugs across the blood-brain barrier (BBB). Additionally, patients with brain metastases have long been excluded from clinical trials, and few studies have been conducted to evaluate the safety and effectiveness of systemic therapies specifically for the treatment of HER2-negative breast cancer brain metastases. New approaches are on the horizon, such as nanoparticle-based cytotoxic drugs that have the potential to cross the BBB and provide clinically meaningful benefits to patients with this life-threatening consequence of HR-positive breast cancer.     

依维莫司联合依西美坦治疗激素受体阳性、HER2阴性复发转移性乳腺癌的安全性及有效性分析

目的:观察依维莫司联合依西美坦治疗非甾体类芳香化酶抑制剂（NSAIs）耐药的激素受体阳性、HER2阴性绝经后晚期乳腺癌的安全性及疗效。方法:2014年8月10日至2016年9月20日收治的绝经后激素受体阳性、HER2阴性,NSAIs治疗后进展的晚期乳腺癌患者46例,随机进入研究组和对照组。研究组23例口服依维莫司10 mg/d及依西美坦2.5 mg/d;对照组23例口服依西美坦单药2.5 mg/d,分析两组患者的肿瘤控制率(DCR)、不良反应发生率、无进展生存期（PFS）。结果:中位随访时间9.5个月,研究组和对照组的DCR率分别为65.2%和34.8%,差异具有统计学意义（P=0.038）。研究组最常见的不良反应为口腔炎（65.2%）和乏力（47.8%）与对照组差异具有统计学意义（P＜0.05）。研究组和对照组的中位PFS分别为6.5个月(95%CI=4.8~8.2)和3.5个月(95%CI=2.7~4.3),差异有统计学意义（P=0.02）。结论:依维莫司联合依西美坦治疗绝经后NSAIs耐药的激素受体阳性、HER2阴性晚期乳腺癌的不良反应可控,可显著提高DCR率及PFS。     

Updated results from MONALEESA-2, a phase III trial of first-line ribociclib plus letrozole versus placebo plus letrozole in hormone receptor-positive,HER2-negative advanced breast cancer

BackgroundThe phase III MONALEESA-2 study demonstrated significantly prolonged progression-free survival (PFS) and a manageable toxicity profile for first-line ribociclib plus letrozole versus placebo plus letrozole in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) advanced breast cancer. Here, we report updated efficacy and safety data, together with exploratory biomarker analyses, from the MONALEESA-2 study.Patients and methodsA total of 668 postmenopausal women with HR+, HER2– recurrent/metastatic breast cancer were randomized (1 : 1; stratified by presence/absence of liver and/or lung metastases) to ribociclib (600 mg/day; 3-weeks-on/1-week-off; 28-day treatment cycles) plus letrozole (2.5 mg/day; continuous) or placebo plus letrozole. The primary end point was locally assessed PFS. The key secondary end point was overall survival (OS). Other secondary end points included overall response rate (ORR) and safety. Biomarker analysis was an exploratory end point.ResultsAt the time of the second interim analysis, the median duration of follow-up was 26.4 months. Median PFS was 25.3 months [95% confidence interval (CI) 23.0–30.3] for ribociclib plus letrozole and 16.0 months (95% CI 13.4–18.2) for placebo plus letrozole (hazard ratio 0.568; 95% CI 0.457–0.704; log-rank P = 9.63 × 10⁻⁸). Ribociclib treatment benefit was maintained irrespective of PIK3CA or TP53 mutation status, total Rb, Ki67, or p16 protein expression, and CDKN2A, CCND1, or ESR1 mRNA levels. Ribociclib benefit was more pronounced in patients with wild-type versus altered receptor tyrosine kinase genes. OS data remain immature, with 116 deaths observed; 50 in the ribociclib arm and 66 in the placebo arm (hazard ratio 0.746; 95% CI 0.517–1.078). The ORR was 42.5% versus 28.7% for all patients treated with ribociclib plus letrozole versus placebo plus letrozole, respectively, and 54.5% versus 38.8%, respectively, for patients with measurable disease. Safety results, after a further 11.1 months of follow-up, were comparable with those reported at the first analysis, with no new or unexpected toxicities observed, and no evidence of cumulative toxicity.ConclusionsThe improved efficacy outcomes and manageable tolerability observed with first-line ribociclib plus letrozole are maintained with longer follow-up, relative to letrozole monotherapy.Clinical trials numberNCT01958021     

Biomarker results from the AVADO phase 3 trial of first-line bevacizumab plus docetaxel for HER2-negative metastatic breast cancer

Background:

Combining bevacizumab with first-line chemotherapy significantly improves progression-free survival (PFS) in HER2-negative metastatic breast cancer (mBC). However, identification of patients benefitting most from bevacizumab remains elusive. The AVADO trial included an extensive optional exploratory biomarker programme.

Methods:

Patients with HER2-negative mBC were randomised to receive docetaxel with placebo or bevacizumab. The primary end point was PFS. Plasma samples were analysed using a multiplex ELISA. Blood mRNA expression was assessed using quantitative PCR. Tumour tissue samples were analysed by immunohistochemistry. Single-nucleotide polymorphisms (SNPs) involved in the VEGF pathway were analysed in germline DNA.

Results:

Samples for biomarker analysis were available from 24–54% of the 736 treated patients (depending on specimen type). The most consistent potential predictive effect was observed with plasma VEGF-A and VEGFR-2; high baseline concentrations were associated with greater treatment effect. Blood mRNA analyses suggested a greater bevacizumab effect in patients with high VEGF₁₂₁. No consistent predictive effect was seen for tumour neuropilin or other candidate tumour markers by immunohistochemistry, or for any of the SNPs investigated.

Conclusion:

Plasma VEGF-A and VEGFR-2 are potential predictive markers for bevacizumab efficacy, supporting findings in gastric and pancreatic cancers. Plasma VEGF-A is being evaluated prospectively in mBC in the MERiDiAN trial.     

Phase II study of bi-weekly irinotecan for patients with previously treated HER2-negative metastatic breast cancer: KMBOG0610B

Background

A trial was conducted to evaluate the feasibility, efficacy, and safety of biweekly administration of irinotecan, a novel topoisomerase I inhibitor, for patients with metastatic breast cancer (MBC) previously treated with either anthracycline-based or taxane-based chemotherapy.

Methods

Eligible patients were HER2-negative, had a performance status of 0 to 2, and had been treated previously with either anthracyclines or taxanes for MBC. Patients received irinotecan intravenously at 150 mg/m² on days 1 and 15 every 4 weeks. The primary end-point was feasibility, and the treatment was considered feasible if a patient was able to receive three administrations of irinotecan within the first 8 weeks, as pre-specified in the protocol.

Results

Eighteen patients (median age 60 years) were enrolled. Fifteen patients received irinotecan more than 3 times within the first 8 weeks, with resulting feasibility of 83.3%. The median number of treatment cycles was 2 (range 1–16) during this period, and the relative dose intensity was 91.2%. Partial response was observed for one patient, so overall response rate was 5.6%. Nine patients (50.0%) had stable disease, and overall disease control was 50.0%. Median progression-free survival and overall survival periods were 3.2 and 9.6 months, respectively. The only grade 3/4 hematological toxicity was neutropenia (22.2%). Grade 3/4 non-hematological toxicities were anorexia (11.2%), diarrhea (11.2%), and fatigue (5.6%). No treatment-related death occurred.

Conclusions

This study demonstrated that biweekly administration of 150 mg/m² irinotecan was feasible for patients with MBC treated previously with anthracyclines or taxanes.     

Phase II trial of the farnesyltransferase inhibitor tipifarnib plus fulvestrant in hormone receptor-positive metastatic breast cancer: New York Cancer Consortium Trial P6205

BackgroundFulvestrant produces a clinical benefit rate (CBR) of ∼45% in tamoxifen-resistant, hormone receptor (HR)-positive metastatic breast cancer (MBC) and 32% in aromatase inhibitor (AI)-resistant disease. The farnesyltransferase inhibitor tipifarnib inhibits Ras signaling and has preclinical and clinical activity in endocrine therapy-resistant disease. The objective of this study was to determine the efficacy and safety of tipifarnib–fulvestrant combination in HR-positive MBC.Patients and methodsPostmenopausal women with no prior chemotherapy for metastatic disease received i.m. fulvestrant 250 mg on day 1 plus oral tipifarnib 300 mg twice daily on days 1–21 every 28 days. The primary end point was CBR.ResultsThe CBR was 51.6% [95% confidence interval (CI) 34.0% to 69.2%] in 31 eligible patients and 47.6% (95% CI 26.3% to 69.0%) in 21 patients with AI-resistant disease. A futility analysis indicated that it was unlikely to achieve the prespecified 70% CBR. Tipifarnib dose modification was required in 8 of 33 treated patients (24%).ConclusionsThe target CBR of 70% for the tipifarnib–fulvestrant combination in HR-positive MBC was set too high and was not achieved. The 48% CBR in AI-resistant disease compares favorably with the 32% CBR observed with fulvestrant alone in prior studies and merit further clinical and translational evaluation.     

Phase III randomized trial of sunitinib versus capecitabine in patients with previously treated HER2-negative advanced breast cancer

Electron paramagnetic resonance (EPR) imaging is an emerging modality that can detect and localize paramagnetic molecular probes (so-called spin probes) in vivo. We previously demonstrated that nitroxide spin probes can be encapsulated in liposomes at concentrations exceeding 100 mM, at which nitroxides exhibit a concentration-dependent quenching of their EPR signal that is analogous to the self-quenching of fluorescent molecules. Therefore, intact liposomes encapsulating high concentrations of nitroxides exhibit greatly attenuated EPR spectral signals, and endocytosis of such liposomes represents a cell-activated contrast-generating mechanism. After endocytosis, the encapsulated nitroxide is liberated and becomes greatly diluted in the intracellular milieu. This dequenches the nitroxides to generate a robust intracellular EPR signal. It is therefore possible to deliver a high concentration of nitroxides to cells while minimizing background signal from unendocytosed liposomes. We report here that intracellular EPR signal can be selectively generated in a specific cell type by exploiting its expression of Human Epidermal Growth Factor Receptor 2 (HER2). When targeted by anti-HER2 immunoliposomes encapsulating quenched nitroxides, Hc7 cells, which are novel HER2-overexpressing cells derived from the MCF7 breast tumor cell line, endocytose the liposomes copiously, in contrast to the parent MCF7 cells or control CV1 cells, which do not express HER2. HER2-dependent liposomal delivery enables Hc7 cells to accumulate 750 μM nitroxide intracellularly. Through the use of phantom models, we verify that this concentration of nitroxides is more than sufficient for EPR imaging, thus laying the foundation for using EPR imaging to visualize HER2-overexpressing Hc7 tumors in animals.