Michelle Kristine Miller

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

Background The 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 methods A 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. Results At 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. Conclusions The 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 number NCT01958021.

Discovery and development of novel therapies in advanced breast cancer: rapid development of ribociclib

The treatment landscape for advanced breast cancer has changed radically over the last 30–40 years with the refinement of surgical and radiographic techniques, approval of a range of chemotherapy regimens in the adjuvant and metastatic settings, and improvements in screening procedures. A deeper understanding of the molecular pathways underpinning tumor growth has led to the identification and development of a number of targeted therapies with particularly high activity in breast cancer. As an example, the prognosis of women with human epidermal growth factor receptor 2-positive (HER2+) breast cancer has improved dramatically since the introduction of HER2-targeted therapies [1]. Meanwhile, in hormone receptor-positive (HR+) breast cancer, the mammalian target of rapamycin (mTOR) inhibitor everolimus has been shown to be effective in combination with exemestane [2]. Overall, these innovations have led to the earlier detection of breast cancers and better treatments, resulting in significant improvements in patient survival and quality of life. Finding future treatments for breast cancer will depend on gaining more insights into the pathways driving tumor growth and the mechanisms of acquired and de novo resistance. Investigational targeted agents currently in clinical development include the phosphatidylinositol 3-kinase (PI3K) inhibitor alpelisib (BYL719) and the cyclin-dependent kinase (CDK) 4/6 inhibitor ribociclib (LEE011).

Ribociclib Bioavailability Is Not Affected by Gastric pH Changes or Food Intake: In Silico and Clinical Evaluations

Ribociclib (KISQALI), a cyclin‐dependent kinase 4/6 inhibitor approved for the first‐line treatment of HR+/HER2– advanced breast cancer with an aromatase inhibitor, is administered with no restrictions on concomitant gastric pH‐elevating agents or food intake. The influence of proton pump inhibitors (PPIs) on ribociclib bioavailability was assessed using 1) biorelevant media solubility, 2) physiologically based pharmacokinetic (PBPK) modeling, 3) noncompartmental analysis (NCA) of clinical trial data, and 4) population PK (PopPK) analysis. This multipronged approach indicated no effect of gastric pH changes on ribociclib PK and served as a platform for supporting ribociclib labeling language, stating no impact of gastric pH‐altering agents on the absorption of ribociclib, without a dedicated drug–drug interaction trial. The bioequivalence of ribociclib exposure with or without a high‐fat meal was demonstrated in a clinical trial. Lack of restrictions on ribociclib dosing may facilitate better patient compliance and therefore clinical benefit.