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A phase 2 study of everolimus combined with trastuzumab and paclitaxel in patients with HER2-overexpressing advanced breast cancer that progressed during prior trastuzumab and taxane therapy.

Hurvitz SA, Dalenc F, Campone M, O'Regan RM, Tjan-Heijnen VC, Gligorov J, Llombart A, Jhangiani H, Mirshahidi HR, Tan-Chiu E, Miao S, El-Hashimy M, Lincy J, Taran T, Soria JC, Sahmoud T, André F - Breast Cancer Res. Treat. (2013)

Bottom Line: Endpoints included overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety.The ORR was 21.8 %, the clinical benefit rate was 36.4 %, the median PFS estimate was 5.5 months (95 % confidence interval [CI]: 4.99-7.69 months), and the median OS estimate was 18.1 months (95 % CI: 12.85-24.11 months).Hematologic grade 3/4 adverse events (AEs) included neutropenia (25.5 % grade 3, 3.6 % grade 4), anemia (7.3 % grade 3), and thrombocytopenia (5.5 % grade 3, 1.8 % grade 4).

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Hematology/Oncology, UCLA Jonsson Comprehensive Cancer Center, 10945 Le Conte Avenue, PVUB Suite 3360, Los Angeles, CA, 90095, USA, shurvitz@mednet.ucla.edu.

ABSTRACT
Increased activation of the PI3K/Akt/mTOR pathway is a common factor in putative mechanisms of trastuzumab resistance, resulting in dysregulation of cell migration, growth, proliferation, and survival. Data from preclinical and phase 1/2 clinical studies suggest that adding everolimus (an oral mTOR inhibitor) to trastuzumab plus chemotherapy may enhance the efficacy of, and restore sensitivity to, trastuzumab-based therapy. In this phase 2 multicenter study, adult patients with HER2-positive advanced breast cancer resistant to trastuzumab and pretreated with a taxane received everolimus 10 mg/day in combination with paclitaxel (80 mg/m(2) days 1, 8, and 15 every 4 weeks) and trastuzumab (4 mg/kg loading dose followed by 2 mg/kg weekly), administered in 28-day cycles. Endpoints included overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety. Fifty-five patients were enrolled; one remained on study treatment at the time of data cutoff. The median number of prior chemotherapy lines for advanced disease was 3.5 (range 1-11). The ORR was 21.8 %, the clinical benefit rate was 36.4 %, the median PFS estimate was 5.5 months (95 % confidence interval [CI]: 4.99-7.69 months), and the median OS estimate was 18.1 months (95 % CI: 12.85-24.11 months). Hematologic grade 3/4 adverse events (AEs) included neutropenia (25.5 % grade 3, 3.6 % grade 4), anemia (7.3 % grade 3), and thrombocytopenia (5.5 % grade 3, 1.8 % grade 4). Nonhematologic grade 3/4 AEs included stomatitis (20.0 %), diarrhea (5.5 %), vomiting (5.5 %), fatigue (5.5 %), and pneumonia (5.5 %), all grade 3. These findings suggest that the combination of everolimus plus trastuzumab and paclitaxel is feasible, with promising activity in patients with highly resistant HER2-positive advanced breast cancer. This combination is currently under investigation in the BOLERO-1 phase 3 trial.

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Related in: MedlinePlus

Kaplan–Meier analyses of overall survival in patients with human epidermal growth factor receptor-2-positive advanced breast cancer treated with everolimus (EVE), trastuzumab (TRAS), and paclitaxel (T). CI confidence interval
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Fig2: Kaplan–Meier analyses of overall survival in patients with human epidermal growth factor receptor-2-positive advanced breast cancer treated with everolimus (EVE), trastuzumab (TRAS), and paclitaxel (T). CI confidence interval

Mentions: The trial met its primary endpoint with 12 partial responses, resulting in an ORR of 21.8 % (Table 4). Disease stabilization was achieved in 26 (47.3 %) patients, whereas eight (14.5 %) patients had progressive disease. The disease control rate (defined as ORR plus stable disease) was 69.1 % and the CBR (defined as ORR plus stable disease lasting 24 weeks or longer) was 36.4 %. Overall, at the time of data cutoff, there were 36 PFS events (34 progressive disease and two deaths) based on local radiology review, and the median PFS estimate was 5.5 months (95 % CI: 4.99–7.69 months; Fig. 1). The median OS estimate since start of the study was 18.1 months (95 % CI: 12.85–24.11 months; Fig. 2).Table 4


A phase 2 study of everolimus combined with trastuzumab and paclitaxel in patients with HER2-overexpressing advanced breast cancer that progressed during prior trastuzumab and taxane therapy.

Hurvitz SA, Dalenc F, Campone M, O'Regan RM, Tjan-Heijnen VC, Gligorov J, Llombart A, Jhangiani H, Mirshahidi HR, Tan-Chiu E, Miao S, El-Hashimy M, Lincy J, Taran T, Soria JC, Sahmoud T, André F - Breast Cancer Res. Treat. (2013)

Kaplan–Meier analyses of overall survival in patients with human epidermal growth factor receptor-2-positive advanced breast cancer treated with everolimus (EVE), trastuzumab (TRAS), and paclitaxel (T). CI confidence interval
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3824346&req=5

Fig2: Kaplan–Meier analyses of overall survival in patients with human epidermal growth factor receptor-2-positive advanced breast cancer treated with everolimus (EVE), trastuzumab (TRAS), and paclitaxel (T). CI confidence interval
Mentions: The trial met its primary endpoint with 12 partial responses, resulting in an ORR of 21.8 % (Table 4). Disease stabilization was achieved in 26 (47.3 %) patients, whereas eight (14.5 %) patients had progressive disease. The disease control rate (defined as ORR plus stable disease) was 69.1 % and the CBR (defined as ORR plus stable disease lasting 24 weeks or longer) was 36.4 %. Overall, at the time of data cutoff, there were 36 PFS events (34 progressive disease and two deaths) based on local radiology review, and the median PFS estimate was 5.5 months (95 % CI: 4.99–7.69 months; Fig. 1). The median OS estimate since start of the study was 18.1 months (95 % CI: 12.85–24.11 months; Fig. 2).Table 4

Bottom Line: Endpoints included overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety.The ORR was 21.8 %, the clinical benefit rate was 36.4 %, the median PFS estimate was 5.5 months (95 % confidence interval [CI]: 4.99-7.69 months), and the median OS estimate was 18.1 months (95 % CI: 12.85-24.11 months).Hematologic grade 3/4 adverse events (AEs) included neutropenia (25.5 % grade 3, 3.6 % grade 4), anemia (7.3 % grade 3), and thrombocytopenia (5.5 % grade 3, 1.8 % grade 4).

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Hematology/Oncology, UCLA Jonsson Comprehensive Cancer Center, 10945 Le Conte Avenue, PVUB Suite 3360, Los Angeles, CA, 90095, USA, shurvitz@mednet.ucla.edu.

ABSTRACT
Increased activation of the PI3K/Akt/mTOR pathway is a common factor in putative mechanisms of trastuzumab resistance, resulting in dysregulation of cell migration, growth, proliferation, and survival. Data from preclinical and phase 1/2 clinical studies suggest that adding everolimus (an oral mTOR inhibitor) to trastuzumab plus chemotherapy may enhance the efficacy of, and restore sensitivity to, trastuzumab-based therapy. In this phase 2 multicenter study, adult patients with HER2-positive advanced breast cancer resistant to trastuzumab and pretreated with a taxane received everolimus 10 mg/day in combination with paclitaxel (80 mg/m(2) days 1, 8, and 15 every 4 weeks) and trastuzumab (4 mg/kg loading dose followed by 2 mg/kg weekly), administered in 28-day cycles. Endpoints included overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety. Fifty-five patients were enrolled; one remained on study treatment at the time of data cutoff. The median number of prior chemotherapy lines for advanced disease was 3.5 (range 1-11). The ORR was 21.8 %, the clinical benefit rate was 36.4 %, the median PFS estimate was 5.5 months (95 % confidence interval [CI]: 4.99-7.69 months), and the median OS estimate was 18.1 months (95 % CI: 12.85-24.11 months). Hematologic grade 3/4 adverse events (AEs) included neutropenia (25.5 % grade 3, 3.6 % grade 4), anemia (7.3 % grade 3), and thrombocytopenia (5.5 % grade 3, 1.8 % grade 4). Nonhematologic grade 3/4 AEs included stomatitis (20.0 %), diarrhea (5.5 %), vomiting (5.5 %), fatigue (5.5 %), and pneumonia (5.5 %), all grade 3. These findings suggest that the combination of everolimus plus trastuzumab and paclitaxel is feasible, with promising activity in patients with highly resistant HER2-positive advanced breast cancer. This combination is currently under investigation in the BOLERO-1 phase 3 trial.

Show MeSH
Related in: MedlinePlus