- Randomized Phase II data show RAD001 significantly increased efficacy of letrozole tablets in women with newly diagnosed hormone-positive breast cancer

- Phase I studies suggest RAD001 may help overcome a major pathway of resistance to trastuzumab

- Novartis to further explore potential of RAD001 in breast cancer by initiating new trial in early 2009

EAST HANOVER, N.J., June 2 /PRNewswire/ -- Early proof-of-concept studiespresented today show RAD001 (everolimus) may offer a novel treatment strategyfor breast cancer by enhancing the efficacy of, and overcoming resistance to,several commonly used breast cancer treatments.

Findings from a Phase II study show that RAD001 enhances tumor shrinkagewhen given in combination with letrozole tablets (Femara(R)) to postmenopausalwomen with newly diagnosed estrogen receptor-positive (ER+) breast cancer.Further, initial results from two Phase I trials in which RAD001 was combinedwith trastuzumab (Herceptin(R)) and chemotherapy agents suggest that theaddition of RAD001 overcame resistance to trastuzumab. The combination appearshighly active, achieving complete responses in a few patients and partialresponses or stable disease in a majority of patients.

These results were among several studies of RAD001 presented at the 44thannual meeting of the American Society of Clinical Oncology (ASCO) in Chicago,Illinois, US. RAD001 is an investigational once-daily oral therapy that mayoffer a new approach to cancer treatment by continuously inhibiting the mTORprotein, a central regulator of tumor cell division and blood vessel growth incancer cells.

'The mTOR pathway is a major route to resistance in targeted cancertherapies, and the early data in combination with Herceptin and chemotherapydemonstrate proof of concept that by inhibiting mTOR we may be able toovercome resistance to these medicines,' said David Epstein, CEO and Presidentof Novartis Oncology. 'These remarkable early findings support exploring thepotential of RAD001 in addressing unmet medical needs in women with HER2+breast cancer in a larger randomized clinical trial.'

For breast cancer patients whose disease becomes resistant to availabledrugs, identifying the mechanism of resistance is important for restoringactivity to treatment. Preclinical studies have shown that RAD001, aninhibitor of mTOR, acts on the pathway that mediates trastuzumab resistanceand has the potential to help restore response in patients who are refractoryto therapy. RAD001 works through direct antitumor activity as well as throughits influence on two of the most important pathways for breast cancer, theestrogen receptor and the HER2/neu pathways.

Based on these data, Novartis will initiate a new trial to evaluate thepotential of RAD001 in breast cancer in early 2009. Plans for this trial areongoing and will be announced at a later date.

'In patients with hormone-sensitive breast cancer, the results from therandomized Phase II study are exciting because they show that adding RAD001 toinitial treatment with letrozole tablets may improve outcomes for early-stagebreast cancer patients,' said Professor Jose Baselga, MD, Hospital VallD'Hebron, Barcelona, Spain. 'Taken together, the results of the three trialsannounced today indicate that RAD001 has a promising potential across varioussubsets of breast cancer.'

Study results

ABSTRACT #530 - 'Improved clinical and cell cycle response with an mTORinhibitor, daily oral RAD001 (everolimus) plus letrozole versus placebo plusletrozole in a randomized phase II neoadjuvant trial in ER+ breast cancer'

Jose Baselga, MD, Hospital Vall D'Hebron, Barcelona, Spain

This randomized, double-blind, Phase II placebo-controlled trial of 270postmenopausal women found that RAD001 10 mg increased both the clinical andthe cell cycle efficacy of letrozole tablets 2.5 mg in the treatment of newlydiagnosed ER+ breast cancer. The overall clinical response rate with RAD001 incombination with letrozole tablets was clinically important as compared toletrozole tablets alone (68% versus 59%, one-sided P=0.062, respectively). Theresults were also confirmed by ultrasound (58% versus 47%, one-sided P=0.035,respectively). In addition, cell cycle response in the RAD001/letrozoletreatment arm, as measured by major reduction in Ki67, an indication of tumorcell proliferation, was twice that as measured in the placebo/letrozoletreatment arm.

Adverse events in the RAD001/letrozole treatment arm were manageable. Themost frequent grade 3/4 adverse events in the RAD001/letrozole treatment armwere high blood sugar (5%), mouth sores (2%), pneumonitis (2%) and infections(2%). The rate of grade 3/4 adverse events was 23% in the RAD001/letrozoletreatment arm versus 4% in the placebo/letrozole treatment arm.