VBCC - March 2014, Volume 5, No 2 - VBCC Perspectives
Phoebe Starr

San Antonio, TX—Many new drugs are currently in development for the treatment of patients with breast cancer. The following is a selection of drugs featured at the 2013 San Antonio Breast Cancer Symposium.

Veliparib, a poly (ADP-ribose) polymerase inhibitor, showed promise in the Investigation of Serial Studies to Predict Your Therapeutic Response with Imaging and Molecular Analysis 2 trial for the neoadjuvant treatment of patients with triple-negative breast cancer in combination with carboplatin (Paraplatin). This combination will move to phase 3 testing in patients with triple-negative breast cancer. Veliparib is also being studied in patients with advanced breast cancer, cervical cancer, and ovarian cancer.

Ridaforolimus, an mTOR inhibitor, is a nonprodrug analog of rapamycin, and dalotuzumab is a monoclonal antibody targeted to insulin-like growth factor 1. These 2 drugs are being studied as a new combination therapy; the scientific rationale for the combination of ridaforolimus and dalotuzumab is upstream and downstream inhibition of molecular targets on the PIK3 pathway. In a phase 2 trial of ridaforolimus plus dalotuzumab in patients with metastatic estrogen receptor–positive breast cancer that progressed with previous treatments, the median progression-free survival (PFS) was similar to that of exemestane (Aromasin), but no survival advantage was shown for the combination. The trial was stopped because of the toxicity level at the doses used, but the investigators concluded that further study is warranted. Lower doses of ridaforolimus will be studied in a new phase 2 clinical trial for high-proliferation estrogen receptor–positive breast cancer that is progressing with previous hormonal therapies. The study will compare the combination of ridaforolimus plus dalotuzumab with ridaforolimus, dalotuzumab, and exemestane alone in this patient population.

Ganetespib, a heat shock protein 90 (hsp90) inhibitor, is now in phase 2 clinical trials as frontline therapy for women with metastatic HER2-positive or triple-negative breast cancer in the ENCHANT-1 trial. Hsp90 inhibitors block multiple oncogenic pathways that play key roles in various breast cancer subtypes. ENCHANT-1 showed that treatment with ganetes­pib was well tolerated, with an acceptable safety profile; diarrhea is the most common side effect. Ganetespib demonstrated promising antitumor activity in the HER2-positive and triple-negative breast cancer subgroups of patients, with durable responses. En­rollment is continuing in the phase 2 trial. Future strategies that will be studied include combinations with other treatments in early- and advanced-stage breast cancer, and biomarker studies will be conducted to try to determine which patients would benefit from this treatment.

Palbociclib, an oral selective cyclin-dependent kinase 4/6 inhibitor, passed the phase 2 clinical trials hurdle and has been designated a breakthrough therapy by the US Food and Drug Administration (FDA). In the phase 2 trial, palbociclib plus letrozole (Femara) improved PFS versus letrozole alone in advanced or metastatic estrogen receptor–positive, HER2-positive breast cancer: the median PFS was 26.1 months versus 7.5 months with letrozole alone.

Palbociclib is now in phase 3 clinical trials in the PENELOPEB trial as adjuvant therapy for patients with hormone receptor–positive, HER2-normal primary breast cancer with high relapse risk after neoadjuvant chemotherapy. After neoadjuvant chemotherapy and surgery, with or without radiation therapy, approximately 800 patients will be randomized to once-daily oral palbociclib versus placebo for 13 cycles. Patients will receive concomitant endocrine therapy according to local standards. The patients will be followed until progression, secondary malignancy, unacceptable toxicity, or withdrawal of consent.

Ramucirumab, a novel monoclonal angiogenesis inhibitor targeted to vascular endothelial growth factor receptor 2, failed to meet its primary end point of PFS in the Ramucirumab Overall Survival Evaluation/Translational Research in Oncology-12 trial when added to docetaxel (Taxotere) in patients with metastatic breast cancer. These findings are disappointing and may put another nail in the coffin of antiangiogenic agents for breast cancer; however, investigators say that they will search for a biomarker to identify subgroups of patients who could benefit from this strategy. Ramucirumab is moving ahead as second-line therapy for gastric cancer, and the FDA has granted ramuciru­mab priority review in this setting.

Entinostat, a novel oral small-molecule inhibitor of benzamide histone deacetylase, was shown to extend PFS when added to exemestane versus exemestane alone in postmenopausal women with advanced estrogen receptor–positive breast cancer that is progressing with a nonsteroidal aromatase inhibitor in the phase 2 ENCORE 301 study. The median PFS was 4.28 months for the combination versus 2.27 months for exemestane alone. Entinostat is now being evaluated in phase 3 clinical trials.

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