Breast cancer drug research roundup from ASCO

Among the many poster sessions being presented at the 2015 American Society of Clinical Oncology (ASCO) annual meeting in Chicago, IL, are several on the latest trials that are planned to evaluate potential treatment options for breast cancer. These trials include 1 phase 2 study and 3 phase 3 studies.

Adjuvant endocrine therapy with or without everolimus

A phase 3 randomized, double-blinded, placebo-controlled clinical trial in patients with high-risk, hormone receptor (HR)-positive and HER2-negative breast cancer will evaluate the use of adjuvant endocrine therapy with or without 1 year of everolimus.

Everolimus is an mTOR inhibitor (mTORi) that increases the biologic activity of endocrine therapy. This therapy is pertinent because abnormalities of the PI3kinase/AKT/mTOR signaling network are often present in breast cancer and, in HR-positive tumors, this pathway has been associated with resistance to endocrine therapy.

Related: Phase 3 results show significant pathological complete response for nab-paclitaxel in neoadjuvant breast cancer

The phase 3 trial (S1207) will assess if invasive disease-free survival (DFS) among these patients will be improved by the combination of everolimus and standard adjuvant endocrine therapy. All 3,500 participants will receive the endocrine therapy, but they will be randomized to receive it in combination with everolimus for 1 year or placebo. The dose of everolimus will be 10 mg orally per day.

Detection of an effective hazard ratio (0.75) for everolimus versus placebo, for which the study has 90% power, would indicate an increase of about 4.3% in DFS at 5 years. Follow-up of patients will continue for 10 years.

NEXT: Phase 2 study on the safety of alpelisib or buparlisib plus letrozole

Alpelisib or buparlisib plus letrozole: safety and efficacy

For postmenopausal women who have HR-positive and HER2-negative, PIK3CA mutant or wild-type breast cancer, a phase 2 study will evaluate the safety and efficacy of neoadjuvant treatment with alpelisib or buparlisib plus letrozole.

The double-blind trial will randomize study participants to alpelisib/placebo at 300 mg once daily or buparlisib/placebo at 100 mg once daily (intermittent regimen: 5 days on, 2 days off) plus letrozole (2.5 mg once daily). Stratified by Ki67 level (<14% vs ≥14%) and lymph node status (positive vs negative), treatment will be for 24 weeks until unacceptable toxicity, disease progression, surgery, or study discontinuation for any other reason.

Related: Unprecedented efficacy of latest HER2-targeting agents can extend life but at significant cost

In preclinical studies of HR-positive breast cancer, the phosphatidylinositol 3-kinase (PI3K)-α inhibitor alpelisib and the pan-PI3K inhibitor buparlisib showed significant antitumor effects in vitro and in vivo when these agents were used in combination with hormone therapy. In breast cancer, the PI3K/AKT/mTOR pathway is the most frequently activated signaling pathway. Further, the most common genetic alteration observed in HR-positive breast cancer is PIK3CA-activating mutations. 

The study’s primary end point is pathologic complete response at 24 weeks. An enrollment of 360 patients is planned.

NEXT: Study on buparlisib plus fulvestrant in metastatic breast cancer

Use of buparlisib plus fulvestrant in advanced metastatic breast cancer

Treatment with combination therapy including the pan-PI3K inhibitor buparlisib and fulvestrant will be studied in postmenopausal women with HR-positive and HER2-negative locally advanced metastatic breast cancer. All study participants will have been pretreated with aromatase inhibitors (AIs) and found refractory to treatment based on an mTORi.

The double-blind, placebo-controlled phase 3 study (BELLE-3) will include approximately 420 women who will be randomized to either 100 mg daily of buparlisib or placebo with 500 mg of fulvestrant (on cycle 1, day 1 [C1D1], C1D15, D1 of each subsequent cycle). Visceral disease status will be utilized to stratify patients regarding randomization.

Related:FDA approves Ibrance to treat metastatic breast cancer

Until disease progression (per RECIST guideline v1.1), there will be tumor assessments at intervals of 6 weeks. The primary end point will be progression-free survival (PFS). Overall survival (OS) will be the most important secondary end point.

The most frequent alteration observed in breast cancer is that of PI3K pathway activation, which results in resistance to treatment with endocrine and mTORi therapy. In mTORi-resistant estrogen-receptor-positive xenograft models, buparlisib plus fulvestrant has shown antitumor activity. It is possible that buparlisib bypasses mTORi resistance by blocking upstream PI3K pathway signaling. 

NEXT: Phase 3 study on ribociclib, other agents, for treatment of advanced breast cancer

Ribociclib combined with other agents for treatment of advanced breast cancer

In a phase 3, randomized, double-blind, placebo-controlled study, ribociclib will be combined with tamoxifen and goserelin or a nonsteroidal AI and goserelin to treat premenopausal women with HR-positive and HER2-negative advanced breast cancer.

The study (MONALEESA-7) will randomize approximately 660 patients to 20 mg once daily continuous tamoxifen or 2.5 mg once daily letrozole or 1 mg once daily anastrozole (both nonsteroidal AIs) with a subcutaneous implant of 3.6 mg goserelin (D1 each 28-day cycle) and 600 mg once daily ribociclib (D1-21 each cycle) or matching placebo. Patients will receive ribociclib or placebo combined with either tamoxifen and goserelin or a nonsteroidal AI and goserelin.

Related:New device prevents cancer tumors from coming back

PFS will be the primary study end point, and the most important secondary end point will be OS. Investigators believe this is the first phase 3 study to evaluate use of a cyclin-dependent kinase (CDK) 4/6 inhibitor in only pre- or perimenopausal women with advanced breast cancer.

Although tamoxifen or nonsteroidal AIs with ovarian function suppression are standard first-line endocrine therapies for premenopausal women with HR-positive, HER2-negative advanced breast cancer, resistance ultimately develops. CDK4/6 inhibition, however, may cease endocrine-resistant cell proliferation in subsets of breast cancer. It is postulated that adding ribociclib to standard endocrine therapy may provide therapeutic benefit versus endocrine therapy alone in these patients.