PD09-08: Combined Inhibition of mTORC1 with Temsirolimus and HER2 with Neratinib: A Phase I/II Study in Patients with Metastatic HER2−Amplified or Triple-Negative Breast Cancer.

Abstract

Background: Hyperactivation of the PI3K-AKT-mTOR pathway is a postulated mechanism of resistance to anti-HER2 therapies and has also been described in triple-negative breast tumors. In HER2−amplified (HER2+) laboratory models, inhibition of this pathway induces activation of upstream receptor tyrosine kinases such as HER3. In triple-negative breast cancer (TN), HER1 overexpression has been identified and models show sensitivity to combined HER1 and mTOR inhibition. We hypothesize that dual inhibition of the PI3K pathway, HER1/2, and induced HER3 may be highly effective in patients with HER2+ or TN breast cancer (BC). This phase I/II trial is designed to determine the tolerability and possible efficacy of the mTOR inhibitor temsirolimus (T) plus the HER1/2 inhibitor neratinib (N) in patients with trastuzumab-refractory, HER2+ or TN BC. We will also explore mutational activation of the PI3K pathway in trastuzumab-refractory tumors as it relates to response to the T-N combination. Methods: The phase I dose-escalation study evaluated T (flat dose IV weekly) plus N (240 mg oral daily) in patients with metastatic HER2+ or TN BC. Cycle length was 4 weeks. Phase I end points included definition of maximum tolerated dose (MTD) and response rate (RR) per RECIST. The phase II study has a Simon two-stage design and evaluates the HER2+ and TN patients separately. Phase II endpoints include progression free survival and duration of response. Response was evaluated radiographically every 8 weeks, toxicity assessed every 2 weeks. All patients underwent biopsy of metastatic disease for biomarker assessment. Activating mutations in PIK3CA were assayed using the Sequenom MassARRAY system. Expression of PTEN was assessed by immunohistochemistry utilizing a published scoring system. Results: The phase I study enrolled 8 HER2+ patients who received a median of 5 (1-13) cycles of therapy. All patients had received trastuzumab and a median of 5.5 (2-12) prior lines of therapy. Frequent treatment-related grade 2 events were: hyperglycemia (4/8), elevated CPK (3/8), diarrhea (2/8), and rash (2/8). Grade 3 diarrhea was the dose-limiting toxicity. Other grade 3 toxicity was hyperglycemia (1/8); hematologic toxicities were not observed. The MTD of temsirolimus with neratinib is 8 mg IV weekly. Six patients treated at MTD were evaluable for response; 4 patients had PR, 1 had SD for a RR of 67%. PI3K pathway activation, through PIK3CA mutational activation or PTEN loss, was identified in 4/6 tumors analyzed and did not preclude response to temsirolimus and neratinib. Updated results reflecting the phase II patients will be reported. Conclusions: Temsirolimus plus neratinib is active in trastuzumab-refractory HER2+ patients. The phase II study is ongoing and additional efficacy and safety data in both HER2−amplified and triple-negative breast cancer patients will be presented. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr PD09-08.

Treating Breast Cancer in the 21st Century: Emerging Biological Therapies

“…To date, there have been two reported trials involving temsirolimus, one phase II trial 138 and one phase I 139. Of the 31 patients in the phase II trial, none had an objective response to temsirolimus.…”

Advances in Small-Molecule Drug Discovery for Triple-Negative Breast Cancer

“…A Phase II trial of erlotinib with chemotherapy is currently underway to assess the pathological clinical response of neoadjuvant chemotherapy plus erlotinib in patients with TNBC (NCT00491816). Figure 3) [59], and neratinib, a substituted quinolone inhibitor (9, Figure 3) [60]. Both compounds are orally bioavailable dual inhibitors of EGFR and human epidermal growth factor receptor 2 (HER2).…”

“…Neratinib is undergoing a Phase I/II trial in combination with the mTOR inhibitor, temsirolimus in patients with metastatic HER2-amplified or TNBC (NCT01111825). The results from a Phase I trial showed the combination was well tolerated with a response rate (RR) of 67% [60].…”

Current Approaches and Emerging Directions in HER2-resistant Breast Cancer

“…In an ongoing phase 1/2 study of neratinib in combination with temsirolimus in patients who previously received trastuzumab therapy, six patients treated at the MTD (8 mg intravenous) were evaluable for response, four achieved partial response, and one had stable disease (ClinialTrials.gov identifier NCT01111825). 82 Phase 2 study results in 117 patients with advanced breast cancer who received no more than two prior trastuzumab regimens and who were randomly assigned to receive neratinib or lapatinib plus capecitabine have been reported. 83 For neratinib and combination therapy, median PFS was 4.5 and 6.8 months (HR 1.3, 95% CI 1.0-1.8, P = 0.091) and median OS was 19.4 and 19.0 months, respectively (P = 0.180; and ORR was 29% and 41%, P = 0.067), indicating that neratinib monotherapy was not as effective as lapatinib plus capecitabine (ClinicalTrials.gov identifier NCT00777101).…”