Phase II trial of temsirolimus in patients with metastatic breast cancer

Abstract

Preclinical models suggested that activating mutations of the PIK3CA gene are associated with sensitivity to inhibitors of the mammalian target of rapamycin (mTOR). In breast cancers, PIK3CA mutations are associated with estrogen receptor (ER) positivity. We therefore performed an open-label single arm phase II study of the rapamycin analog, temsirolimus, at a dose of 25 mg weekly, in women with pretreated breast cancers that were positive for ER, PR, or HER2. Archived formalin-fixed paraffin embedded tumor was collected for immunohistochemical evaluation of components of the PI3K/Akt/mTOR pathway and PIK3CA mutation analysis. Thirty-one patients were enrolled. There were no major objective responses; however, three patients had stable disease for over 24 weeks. Twenty-three tumor samples were available for mutational analysis. There were five tumors with PIK3CA mutations; no association was found between prolonged stable disease and PIK3CA mutation or any immunohistochemical marker. There was a trend toward improved progression free survival (PFS) for patients with positive nuclear staining for phospho-Akt308. One patient remains on study four and a half years after starting therapy; her tumor did not have a PIK3CA mutation. We conclude that single agent temsirolimus has minimal activity in a population of women with heavily pretreated breast cancer. We found no evidence that either absence of immunohistochemical staining for PTEN or mutations in the hotspot domains of PIK3CA in the primary tumor were associated with clinical benefit.

Randomized Phase III Placebo-Controlled Trial of Letrozole Plus Oral Temsirolimus As First-Line Endocrine Therapy in Postmenopausal Women With Locally Advanced or Metastatic Breast Cancer

“…Single-agent IV temsirolimus weekly at 75 or 300 mg IV weekly was modestly active (RR, 9%) in breast cancer (n ϭ 109), 14 with no responses seen in a smaller study (n ϭ 31, 25 mg IV weekly). 20 Regarding toxicity as a proxy for pharmacodynamic effects, a small randomized, open-label, three-arm phase II study (n ϭ 92) of letrozole Ϯ oral temsirolimus 10 mg daily or 30 mg intermittently showed similar toxicity profiles in both temsirolimus arms (ϳ42% and 57% of patients with any mucositis, respectively), with a doubling of the PFS in the intermittent arm compared with letrozole. 9 Finally, an indirect and limited comparison of the observed toxicities between BOLERO-2 (see its Table 2 19 ) and HORIZON (Table 3 of this article) suggests a similar proportional increase over placebo in the frequency of toxicities often associated with mTOR inhibitors.…”

Temsirolimus improves cytotoxic efficacy of cisplatin and gemcitabine against urinary bladder cancer cell lines

“…In 2012, Sun et al [8] presented a study in which they tested temsirolimus in phase II studies in East Asian patients with advanced RCC, having obtained promising results. This drug has also been used to treat cancer in multiple clinical studies, such as breast cancer [9], glioma [10], endometrial [11], and mantle cell lymphoma [12], as well as in preclinical studies, such as ovarian, lung, colon, breast, and prostate cell lines [13]. To enhance its action, combinations of temsirolimus with other antineoplastic drugs, such as sorafenib, bevacizumab, and tivozanib, have been explored in clinical trials in patients with metastatic RCC [14].…”

mTOR inhibitors in breast cancer: A systematic review

“…All studies reported detailed outcomes pertaining to efficacy and/or safety [10,12,13,15,17,[20][21][22][23][24][25][26][27][28][31][32][33]. Further details are provided in Tables 1-4. There were seven studies examining temsirolimus (1245 patients, 8 articles; one study was described in two distinct articles [14,16]) [11,14,16,19,29,30,34,35]. Three studies described the results of phase I trials [14,16,19,30], three described those of phase II trials [11,29,35] and one study involved a phase III design [34].…”

“…Further details are provided in Tables 1-4. There were seven studies examining temsirolimus (1245 patients, 8 articles; one study was described in two distinct articles [14,16]) [11,14,16,19,29,30,34,35]. Three studies described the results of phase I trials [14,16,19,30], three described those of phase II trials [11,29,35] and one study involved a phase III design [34]. All of them dealt with recurrent, metastatic or refractory breast cancer patients [11,14,16,19,29,30,34,35].…”