SAN ANTONIO—In the phase 2 TAMRAD trial, tamoxifen (TAM) with everolimus (RAD) conferred the greatest clinical benefits over tamoxifen alone among patients with secondary hormone resistance after treatment with an aromatase inhibitor (AI).
Everolimus, an oral mammalian target of rapamycin (mTOR) inhibitor, has shown promising activity in an in vitro model of hormone resistance, stated lead investigator Thomas Bachelot, MD, Centre Léon Bérard in Lyon, France, in a presentation. Everolimus has also been shown to significantly increase the neoadjuvant antitumor activity of letrozole.
Although previous randomized trials of first-line hormone therapy plus mTOR inhibition in metastatic breast cancer (mBC) have been disappointing, Bachelot said, selection of mBC patients previously treated with an AI may enrich the study population with subjects whose tumors are driven by activation of the PI3K/AKT/mTOR pathway. Dysregulation of this pathway has been found in a variety of cancer cells, and constitutively active PI3K/AKT signaling has been identified as a major determinant for cell growth and survival in an array of cancers. The TAMRAD trial’s goal was to estimate the clinical benefit rate (CBR) of the tamoxifen/everolimus combination in such a population after 6 months of treatment.
After stratification according to primary or secondary hormone resistance (determined by early or late progression after previous AI treatment), TAMRAD patients were randomized 1:1 to receive either tamoxifen (20 mg/day) alone or tamoxifen/everolimus (everolimus 10 mg/day; tamoxifen 20 mg/day). Among 111 included patients, median age was 64 years (range, 41-86). Previous AI treatment had been given to 34 (31%) patients in the adjuvant setting, 67 (60%) patients in the metastatic setting, and 10 (9%) in both the adjuvant and metastatic setting. The population was poorly hormone sensitive in that all but 10 (9%) patients had progressed either during or within 6 months after adjuvant AI treatment. Furthermore, 57 (51%) patients and 28 (25%) pa tients had received previous chemo therapy in the adjuvant and/or metastatic setting, respectively. The primary end point was CBR, defined as complete response plus partial response plus stable disease at 6 months.
TAMRAD patients (tamoxifen, 57; tamoxifen/everolimus, 54) had a median duration of metastatic disease of ~13.8 months. Patients were divided evenly between those with primary and secondary hormone resistance. In an exploratory analysis after a median follow-up of ~22.5 months, the CBR was 42.1% for the tamoxifen group and 61.1% (P = .045) for the tamoxifen/ everolimus group. Similarly, time to progression (TTP) favored the combination group (tamoxifen 4.5 months vs tamoxifen/everolimus 8.6 months; hazard ratio [HR], 0.53; 95% confidence interval [CI], 0.35-0.81; exploratory log-rank P = .0028), as did overall survival (HR, 0.32; 95% CI, 0.15-0.68; exploratory log-rank P = .0019).
Although adverse event–associated treatment discontinuations were not higher with the combination (7.0% tamoxifen vs 5.6% tamoxifen/everolimus), adverse events overall were higher with the combination, in particular, fatigue, stomatitis, rash, anorexia, and diarrhea, requiring dose reductions in 28% of patients (none for tamoxifen).
Secondary hormone resistance was defined as late relapse (≥6 months) or previous response and subsequent progression to metastatic AI treatment. CBR differences were accentuated in patients with secondary hormone resistance (44.8% for tamoxifen vs 77.8% for tamoxifen/everolimus). Looking at TTP as a function of intrinsic hormone resistance, Bachelot noted that among patients with primary resistance, TTP was 3.9 months for tamoxifen and 5.4 months for the combination (HR, 0.74). Among those with secondary hormone resistance, TTP was 5.0 months for tamoxifen and 17.4 months for tamoxifen/everolimus (HR, 0.38).
TAMRAD results, Bachelot said, confirm the importance of the PI3K/ AKT/ mTOR pathway. “It seems to be very important when they [patients] respond to hormone therapy and then become resistant.”
The phase 3 Breast Cancer Trials of Oral Everolimus (BOLERO-3) is under way, Bachelot noted