Buparlisib plus fulvestrant versus placebo plus fulvestrant in postmenopausal, hormone receptor-positive, HER2-negative, advanced breast cancer (BELLE-2): a randomised, double-blind, placebo-controlled, phase 3 trial
Summary Background Phosphatidylinositol 3-kinase (PI3K) pathway activation is a hallmark of endocrine therapy-resistant, hormone receptor-positive breast cancer. This phase 3 study assessed the efficacy of the pan-PI3K inhibitor buparlisib plus fulvestrant in patients with advanced breast cancer, in...
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| creator | Baselga, José, Prof Im, Seock-Ah, Prof Iwata, Hiroji, MD Cortés, Javier, MD De Laurentiis, Michele, MD Jiang, Zefei, Prof Arteaga, Carlos L, Prof Jonat, Walter, Prof Clemons, Mark, Prof Ito, Yoshinori, MD Awada, Ahmad, Prof Chia, Stephen, MD Jagiełło-Gruszfeld, Agnieszka, MD Pistilli, Barbara, MD Tseng, Ling-Ming, MD Hurvitz, Sara, MD Masuda, Norikazu, MD Takahashi, Masato, MD Vuylsteke, Peter, MD Hachemi, Soulef, PhD Dharan, Bharani, MS Di Tomaso, Emmanuelle, PhD Urban, Patrick, MD Massacesi, Cristian, MD Campone, Mario, Prof |
| description | Summary Background Phosphatidylinositol 3-kinase (PI3K) pathway activation is a hallmark of endocrine therapy-resistant, hormone receptor-positive breast cancer. This phase 3 study assessed the efficacy of the pan-PI3K inhibitor buparlisib plus fulvestrant in patients with advanced breast cancer, including an evaluation of the PI3K pathway activation status as a biomarker for clinical benefit. Methods The BELLE-2 trial was a randomised, double-blind, placebo-controlled, multicentre study. Postmenopausal women aged 18 years or older with histologically confirmed, hormone receptor-positive and human epidermal growth factor (HER2)-negative inoperable locally advanced or metastatic breast cancer whose disease had progressed on or after aromatase inhibitor treatment and had received up to one previous line of chemotherapy for advanced disease were included. Eligible patients were randomly assigned (1:1) using interactive voice response technology (block size of 6) on day 15 of cycle 1 to receive oral buparlisib (100 mg/day) or matching placebo, starting on day 15 of cycle 1, plus intramuscular fulvestrant (500 mg) on days 1 and 15 of cycle 1, and on day 1 of subsequent 28-day cycles. Patients were assigned randomisation numbers with a validated interactive response technology; these numbers were linked to different treatment groups which in turn were linked to treatment numbers. PI3K status in tumour tissue was determined via central laboratory during a 14-day run-in phase. Randomisation was stratified by PI3K pathway activation status (activated vs non-activated vs and unknown) and visceral disease status (present vs absent). Patients, investigators, local radiologists, study team, and anyone involved in the study were masked to the identity of the treatment until unblinding. The primary endpoints were progression-free survival by local investigator assessment per Response Evaluation Criteria In Solid Tumors (version 1.1) in the total population, in patients with known (activated or non-activated) PI3K pathway status, and in PI3K pathway-activated patients. Efficacy analyses were done in the intention-to-treat population. Safety was analysed in all patients who received at least one dose of study drug and had at least one post-baseline safety assessment according to the treatment they received. This trial is registered with ClinicalTrials.gov , number NCT01610284 , and is currently ongoing but not recruiting participants. Findings Between Sept 7, 2012, and Sep |
| doi_str_mv | 10.1016/S1470-2045(17)30376-5 |
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| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_5549667</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>S1470204517303765</els_id><sourcerecordid>1905740052</sourcerecordid><originalsourceid>FETCH-LOGICAL-c602t-437e9af9c1ba3cbaa2e6bc2fefbd2ffd6b13bfdf328374aa36d0fac2cfecbc323</originalsourceid><addsrcrecordid>eNqFks9u1DAQxiMEoqXwCCBLXLbSBmwnjnd7KKLVQpFWQuLP2Ro7k66LNw52slLflMfB2SwFyoGTPfbP38x4vix7zugrRln1-jMrJc05LcWMydOCFrLKxYPsOB2XuSgXi4f7_YQcZU9ivKGUSUbF4-yIL4SsKimOsx8XQwfB2Wg16dwQSTO4HcY-QNuTHYaYjjoHBrX_9962pPOx32LrOxgiuDnZ-LD1LZKABrvehzwBtrc7nJOr1Seet3gNUwj1DlqDNdEBIfbEjFEgs4vVer3K-ekZAZKy1H5rI9ZzUvtBO8y1s22KDjXlxrd98M6NRLeBiKQgfbDgnmaPGnARnx3Wk-zru9WXy6t8_fH9h8u369xUlPd5WUhcQrM0TENhNADHShveYKNr3jR1pVmhm7op-KKQJUBR1bQBw02DRpuCFyfZ-aTbDXqLtcFUDzjVBbuFcKs8WPX3TWs36trvlBDlMs0gCcwOAsF_H9LXqtSwQeegRT9ExZZUyJJSMeZ6eQ-98UNoU3uJYuVCcslEosREmeBjDNjcFcOoGr2j9t5RozEUk2rvHTW-e_FnJ3evfpklAW8mANN_7iwGFY3FcYY2jbtXtbf_TXF-T8GkcVoD7hveYvzdjYpc0Ulk1GByryCKn9tb74w</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1914872715</pqid></control><display><type>article</type><title>Buparlisib plus fulvestrant versus placebo plus fulvestrant in postmenopausal, hormone receptor-positive, HER2-negative, advanced breast cancer (BELLE-2): a randomised, double-blind, placebo-controlled, phase 3 trial</title><source>MEDLINE</source><source>Elsevier ScienceDirect Journals</source><creator>Baselga, José, Prof ; Im, Seock-Ah, Prof ; Iwata, Hiroji, MD ; Cortés, Javier, MD ; De Laurentiis, Michele, MD ; Jiang, Zefei, Prof ; Arteaga, Carlos L, Prof ; Jonat, Walter, Prof ; Clemons, Mark, Prof ; Ito, Yoshinori, MD ; Awada, Ahmad, Prof ; Chia, Stephen, MD ; Jagiełło-Gruszfeld, Agnieszka, MD ; Pistilli, Barbara, MD ; Tseng, Ling-Ming, MD ; Hurvitz, Sara, MD ; Masuda, Norikazu, MD ; Takahashi, Masato, MD ; Vuylsteke, Peter, MD ; Hachemi, Soulef, PhD ; Dharan, Bharani, MS ; Di Tomaso, Emmanuelle, PhD ; Urban, Patrick, MD ; Massacesi, Cristian, MD ; Campone, Mario, Prof</creator><creatorcontrib>Baselga, José, Prof ; Im, Seock-Ah, Prof ; Iwata, Hiroji, MD ; Cortés, Javier, MD ; De Laurentiis, Michele, MD ; Jiang, Zefei, Prof ; Arteaga, Carlos L, Prof ; Jonat, Walter, Prof ; Clemons, Mark, Prof ; Ito, Yoshinori, MD ; Awada, Ahmad, Prof ; Chia, Stephen, MD ; Jagiełło-Gruszfeld, Agnieszka, MD ; Pistilli, Barbara, MD ; Tseng, Ling-Ming, MD ; Hurvitz, Sara, MD ; Masuda, Norikazu, MD ; Takahashi, Masato, MD ; Vuylsteke, Peter, MD ; Hachemi, Soulef, PhD ; Dharan, Bharani, MS ; Di Tomaso, Emmanuelle, PhD ; Urban, Patrick, MD ; Massacesi, Cristian, MD ; Campone, Mario, Prof</creatorcontrib><description>Summary Background Phosphatidylinositol 3-kinase (PI3K) pathway activation is a hallmark of endocrine therapy-resistant, hormone receptor-positive breast cancer. This phase 3 study assessed the efficacy of the pan-PI3K inhibitor buparlisib plus fulvestrant in patients with advanced breast cancer, including an evaluation of the PI3K pathway activation status as a biomarker for clinical benefit. Methods The BELLE-2 trial was a randomised, double-blind, placebo-controlled, multicentre study. Postmenopausal women aged 18 years or older with histologically confirmed, hormone receptor-positive and human epidermal growth factor (HER2)-negative inoperable locally advanced or metastatic breast cancer whose disease had progressed on or after aromatase inhibitor treatment and had received up to one previous line of chemotherapy for advanced disease were included. Eligible patients were randomly assigned (1:1) using interactive voice response technology (block size of 6) on day 15 of cycle 1 to receive oral buparlisib (100 mg/day) or matching placebo, starting on day 15 of cycle 1, plus intramuscular fulvestrant (500 mg) on days 1 and 15 of cycle 1, and on day 1 of subsequent 28-day cycles. Patients were assigned randomisation numbers with a validated interactive response technology; these numbers were linked to different treatment groups which in turn were linked to treatment numbers. PI3K status in tumour tissue was determined via central laboratory during a 14-day run-in phase. Randomisation was stratified by PI3K pathway activation status (activated vs non-activated vs and unknown) and visceral disease status (present vs absent). Patients, investigators, local radiologists, study team, and anyone involved in the study were masked to the identity of the treatment until unblinding. The primary endpoints were progression-free survival by local investigator assessment per Response Evaluation Criteria In Solid Tumors (version 1.1) in the total population, in patients with known (activated or non-activated) PI3K pathway status, and in PI3K pathway-activated patients. Efficacy analyses were done in the intention-to-treat population. Safety was analysed in all patients who received at least one dose of study drug and had at least one post-baseline safety assessment according to the treatment they received. This trial is registered with ClinicalTrials.gov , number NCT01610284 , and is currently ongoing but not recruiting participants. Findings Between Sept 7, 2012, and Sept 10, 2014, 1147 patients from 267 centres in 29 countries were randomly assigned to receive buparlisib (n=576) or placebo plus fulvestrant (n=571). In the total patient population (n=1147), median progression-free survival was 6·9 months (95% CI 6·8–7·8) in the buparlisib group versus 5·0 months (4·0–5·2) in the placebo group (hazard ratio [HR] 0·78 [95% CI 0·67–0·89]; one-sided p=0·00021). In patients with known PI3K status (n=851), median progression-free survival was 6·8 months (95% CI 5·0–7·0) in the buparlisib group vs 4·5 months (3·3–5·0) in the placebo group (HR 0·80 [95% CI 0·68–0·94]; one-sided p=0·0033). In PI3K pathway-activated patients (n=372), median progression-free survival was 6·8 months (95% CI 4·9–7·1) in the buparlisib group versus 4·0 months (3·1–5·2) in the placebo group (HR 0·76 [0·60–0·97], one-sided p=0·014). The most common grade 3–4 adverse events in the buparlisib group versus the placebo group were increased alanine aminotransferase (146 [25%] of 573 patients vs six [1%] of 570), increased aspartate aminotransferase (103 [18%] vs 16 [3%]), hyperglycaemia (88 [15%] vs one [<1%]), and rash (45 [8%] vs none). Serious adverse events were reported in 134 (23%) of 573 patients in the buparlisib group compared with 90 [16%] of 570 patients in the placebo group; the most common serious adverse events (affecting ≥2% of patients) were increased alanine aminotransferase (17 [3%] of 573 vs one [<1%] of 570) and increased aspartate aminotransferase (14 [2%] vs one [<1%]). No treatment-related deaths occurred. Interpretation The results from this study show that PI3K inhibition combined with endocrine therapy is effective in postmenopausal women with endocrine-resistant, hormone receptor-positive and HER2-negative advanced breast cancer. Use of more selective PI3K inhibitors, such as α-specific PI3K inhibitor, is warranted to further improve safety and benefit in this setting. No further studies are being pursued because of the toxicity associated with this combination. Funding Novartis Pharmaceuticals Corporation.</description><identifier>ISSN: 1470-2045</identifier><identifier>EISSN: 1474-5488</identifier><identifier>DOI: 10.1016/S1470-2045(17)30376-5</identifier><identifier>PMID: 28576675</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>1-Phosphatidylinositol 3-kinase ; Aged ; Alanine ; Alanine transaminase ; Alanine Transaminase - blood ; Aminopyridines - administration & dosage ; Aminopyridines - adverse effects ; Anticoagulants ; Antineoplastic Combined Chemotherapy Protocols - adverse effects ; Antineoplastic Combined Chemotherapy Protocols - therapeutic use ; Aromatase ; Aspartate aminotransferase ; Aspartate Aminotransferases - blood ; Biomarkers, Tumor - genetics ; Breast cancer ; Breast Neoplasms - chemistry ; Breast Neoplasms - drug therapy ; Breast Neoplasms - genetics ; Breast Neoplasms - pathology ; Cancer therapies ; Chemotherapy ; Class I Phosphatidylinositol 3-Kinases ; Clinical trials ; Disease-Free Survival ; DNA Mutational Analysis ; DNA, Neoplasm - blood ; Double-Blind Method ; Double-blind studies ; Drug Eruptions - etiology ; Endocrine therapy ; Epidermal growth factor ; ErbB-2 protein ; Estradiol - administration & dosage ; Estradiol - analogs & derivatives ; Estrogens ; Exanthema ; Exanthema - chemically induced ; Female ; Fulvestrant ; Hematology, Oncology and Palliative Medicine ; Humans ; Hyperglycemia - chemically induced ; Metastases ; Metastasis ; Middle Aged ; Morpholines - administration & dosage ; Morpholines - adverse effects ; Motivation ; Mutation ; Neoplasm Metastasis ; Phosphatidylinositol 3-Kinases - genetics ; Post-menopause ; Postmenopause ; Receptor, ErbB-2 - analysis ; Receptors, Estrogen - analysis ; Receptors, Progesterone - analysis ; Response Evaluation Criteria in Solid Tumors ; Retreatment ; Signal Transduction - genetics ; Solid tumors ; Survival ; Survival Rate ; Toxicity ; Tumors ; Womens health</subject><ispartof>The lancet oncology, 2017-07, Vol.18 (7), p.904-916</ispartof><rights>Elsevier Ltd</rights><rights>2017 Elsevier Ltd</rights><rights>Copyright © 2017 Elsevier Ltd. All rights reserved.</rights><rights>Copyright Elsevier Limited Jul 1, 2017</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c602t-437e9af9c1ba3cbaa2e6bc2fefbd2ffd6b13bfdf328374aa36d0fac2cfecbc323</citedby><cites>FETCH-LOGICAL-c602t-437e9af9c1ba3cbaa2e6bc2fefbd2ffd6b13bfdf328374aa36d0fac2cfecbc323</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S1470204517303765$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>230,314,776,780,881,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28576675$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Baselga, José, Prof</creatorcontrib><creatorcontrib>Im, Seock-Ah, Prof</creatorcontrib><creatorcontrib>Iwata, Hiroji, MD</creatorcontrib><creatorcontrib>Cortés, Javier, MD</creatorcontrib><creatorcontrib>De Laurentiis, Michele, MD</creatorcontrib><creatorcontrib>Jiang, Zefei, Prof</creatorcontrib><creatorcontrib>Arteaga, Carlos L, Prof</creatorcontrib><creatorcontrib>Jonat, Walter, Prof</creatorcontrib><creatorcontrib>Clemons, Mark, Prof</creatorcontrib><creatorcontrib>Ito, Yoshinori, MD</creatorcontrib><creatorcontrib>Awada, Ahmad, Prof</creatorcontrib><creatorcontrib>Chia, Stephen, MD</creatorcontrib><creatorcontrib>Jagiełło-Gruszfeld, Agnieszka, MD</creatorcontrib><creatorcontrib>Pistilli, Barbara, MD</creatorcontrib><creatorcontrib>Tseng, Ling-Ming, MD</creatorcontrib><creatorcontrib>Hurvitz, Sara, MD</creatorcontrib><creatorcontrib>Masuda, Norikazu, MD</creatorcontrib><creatorcontrib>Takahashi, Masato, MD</creatorcontrib><creatorcontrib>Vuylsteke, Peter, MD</creatorcontrib><creatorcontrib>Hachemi, Soulef, PhD</creatorcontrib><creatorcontrib>Dharan, Bharani, MS</creatorcontrib><creatorcontrib>Di Tomaso, Emmanuelle, PhD</creatorcontrib><creatorcontrib>Urban, Patrick, MD</creatorcontrib><creatorcontrib>Massacesi, Cristian, MD</creatorcontrib><creatorcontrib>Campone, Mario, Prof</creatorcontrib><title>Buparlisib plus fulvestrant versus placebo plus fulvestrant in postmenopausal, hormone receptor-positive, HER2-negative, advanced breast cancer (BELLE-2): a randomised, double-blind, placebo-controlled, phase 3 trial</title><title>The lancet oncology</title><addtitle>Lancet Oncol</addtitle><description>Summary Background Phosphatidylinositol 3-kinase (PI3K) pathway activation is a hallmark of endocrine therapy-resistant, hormone receptor-positive breast cancer. This phase 3 study assessed the efficacy of the pan-PI3K inhibitor buparlisib plus fulvestrant in patients with advanced breast cancer, including an evaluation of the PI3K pathway activation status as a biomarker for clinical benefit. Methods The BELLE-2 trial was a randomised, double-blind, placebo-controlled, multicentre study. Postmenopausal women aged 18 years or older with histologically confirmed, hormone receptor-positive and human epidermal growth factor (HER2)-negative inoperable locally advanced or metastatic breast cancer whose disease had progressed on or after aromatase inhibitor treatment and had received up to one previous line of chemotherapy for advanced disease were included. Eligible patients were randomly assigned (1:1) using interactive voice response technology (block size of 6) on day 15 of cycle 1 to receive oral buparlisib (100 mg/day) or matching placebo, starting on day 15 of cycle 1, plus intramuscular fulvestrant (500 mg) on days 1 and 15 of cycle 1, and on day 1 of subsequent 28-day cycles. Patients were assigned randomisation numbers with a validated interactive response technology; these numbers were linked to different treatment groups which in turn were linked to treatment numbers. PI3K status in tumour tissue was determined via central laboratory during a 14-day run-in phase. Randomisation was stratified by PI3K pathway activation status (activated vs non-activated vs and unknown) and visceral disease status (present vs absent). Patients, investigators, local radiologists, study team, and anyone involved in the study were masked to the identity of the treatment until unblinding. The primary endpoints were progression-free survival by local investigator assessment per Response Evaluation Criteria In Solid Tumors (version 1.1) in the total population, in patients with known (activated or non-activated) PI3K pathway status, and in PI3K pathway-activated patients. Efficacy analyses were done in the intention-to-treat population. Safety was analysed in all patients who received at least one dose of study drug and had at least one post-baseline safety assessment according to the treatment they received. This trial is registered with ClinicalTrials.gov , number NCT01610284 , and is currently ongoing but not recruiting participants. Findings Between Sept 7, 2012, and Sept 10, 2014, 1147 patients from 267 centres in 29 countries were randomly assigned to receive buparlisib (n=576) or placebo plus fulvestrant (n=571). In the total patient population (n=1147), median progression-free survival was 6·9 months (95% CI 6·8–7·8) in the buparlisib group versus 5·0 months (4·0–5·2) in the placebo group (hazard ratio [HR] 0·78 [95% CI 0·67–0·89]; one-sided p=0·00021). In patients with known PI3K status (n=851), median progression-free survival was 6·8 months (95% CI 5·0–7·0) in the buparlisib group vs 4·5 months (3·3–5·0) in the placebo group (HR 0·80 [95% CI 0·68–0·94]; one-sided p=0·0033). In PI3K pathway-activated patients (n=372), median progression-free survival was 6·8 months (95% CI 4·9–7·1) in the buparlisib group versus 4·0 months (3·1–5·2) in the placebo group (HR 0·76 [0·60–0·97], one-sided p=0·014). The most common grade 3–4 adverse events in the buparlisib group versus the placebo group were increased alanine aminotransferase (146 [25%] of 573 patients vs six [1%] of 570), increased aspartate aminotransferase (103 [18%] vs 16 [3%]), hyperglycaemia (88 [15%] vs one [<1%]), and rash (45 [8%] vs none). Serious adverse events were reported in 134 (23%) of 573 patients in the buparlisib group compared with 90 [16%] of 570 patients in the placebo group; the most common serious adverse events (affecting ≥2% of patients) were increased alanine aminotransferase (17 [3%] of 573 vs one [<1%] of 570) and increased aspartate aminotransferase (14 [2%] vs one [<1%]). No treatment-related deaths occurred. Interpretation The results from this study show that PI3K inhibition combined with endocrine therapy is effective in postmenopausal women with endocrine-resistant, hormone receptor-positive and HER2-negative advanced breast cancer. Use of more selective PI3K inhibitors, such as α-specific PI3K inhibitor, is warranted to further improve safety and benefit in this setting. No further studies are being pursued because of the toxicity associated with this combination. Funding Novartis Pharmaceuticals Corporation.</description><subject>1-Phosphatidylinositol 3-kinase</subject><subject>Aged</subject><subject>Alanine</subject><subject>Alanine transaminase</subject><subject>Alanine Transaminase - blood</subject><subject>Aminopyridines - administration & dosage</subject><subject>Aminopyridines - adverse effects</subject><subject>Anticoagulants</subject><subject>Antineoplastic Combined Chemotherapy Protocols - adverse effects</subject><subject>Antineoplastic Combined Chemotherapy Protocols - therapeutic use</subject><subject>Aromatase</subject><subject>Aspartate aminotransferase</subject><subject>Aspartate Aminotransferases - blood</subject><subject>Biomarkers, Tumor - genetics</subject><subject>Breast cancer</subject><subject>Breast Neoplasms - chemistry</subject><subject>Breast Neoplasms - drug therapy</subject><subject>Breast Neoplasms - genetics</subject><subject>Breast Neoplasms - pathology</subject><subject>Cancer therapies</subject><subject>Chemotherapy</subject><subject>Class I Phosphatidylinositol 3-Kinases</subject><subject>Clinical trials</subject><subject>Disease-Free Survival</subject><subject>DNA Mutational Analysis</subject><subject>DNA, Neoplasm - blood</subject><subject>Double-Blind Method</subject><subject>Double-blind studies</subject><subject>Drug Eruptions - etiology</subject><subject>Endocrine therapy</subject><subject>Epidermal growth factor</subject><subject>ErbB-2 protein</subject><subject>Estradiol - administration & dosage</subject><subject>Estradiol - analogs & derivatives</subject><subject>Estrogens</subject><subject>Exanthema</subject><subject>Exanthema - chemically induced</subject><subject>Female</subject><subject>Fulvestrant</subject><subject>Hematology, Oncology and Palliative Medicine</subject><subject>Humans</subject><subject>Hyperglycemia - chemically induced</subject><subject>Metastases</subject><subject>Metastasis</subject><subject>Middle Aged</subject><subject>Morpholines - administration & dosage</subject><subject>Morpholines - adverse effects</subject><subject>Motivation</subject><subject>Mutation</subject><subject>Neoplasm Metastasis</subject><subject>Phosphatidylinositol 3-Kinases - genetics</subject><subject>Post-menopause</subject><subject>Postmenopause</subject><subject>Receptor, ErbB-2 - analysis</subject><subject>Receptors, Estrogen - analysis</subject><subject>Receptors, Progesterone - analysis</subject><subject>Response Evaluation Criteria in Solid Tumors</subject><subject>Retreatment</subject><subject>Signal Transduction - genetics</subject><subject>Solid tumors</subject><subject>Survival</subject><subject>Survival Rate</subject><subject>Toxicity</subject><subject>Tumors</subject><subject>Womens health</subject><issn>1470-2045</issn><issn>1474-5488</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNqFks9u1DAQxiMEoqXwCCBLXLbSBmwnjnd7KKLVQpFWQuLP2Ro7k66LNw52slLflMfB2SwFyoGTPfbP38x4vix7zugrRln1-jMrJc05LcWMydOCFrLKxYPsOB2XuSgXi4f7_YQcZU9ivKGUSUbF4-yIL4SsKimOsx8XQwfB2Wg16dwQSTO4HcY-QNuTHYaYjjoHBrX_9962pPOx32LrOxgiuDnZ-LD1LZKABrvehzwBtrc7nJOr1Seet3gNUwj1DlqDNdEBIfbEjFEgs4vVer3K-ekZAZKy1H5rI9ZzUvtBO8y1s22KDjXlxrd98M6NRLeBiKQgfbDgnmaPGnARnx3Wk-zru9WXy6t8_fH9h8u369xUlPd5WUhcQrM0TENhNADHShveYKNr3jR1pVmhm7op-KKQJUBR1bQBw02DRpuCFyfZ-aTbDXqLtcFUDzjVBbuFcKs8WPX3TWs36trvlBDlMs0gCcwOAsF_H9LXqtSwQeegRT9ExZZUyJJSMeZ6eQ-98UNoU3uJYuVCcslEosREmeBjDNjcFcOoGr2j9t5RozEUk2rvHTW-e_FnJ3evfpklAW8mANN_7iwGFY3FcYY2jbtXtbf_TXF-T8GkcVoD7hveYvzdjYpc0Ulk1GByryCKn9tb74w</recordid><startdate>20170701</startdate><enddate>20170701</enddate><creator>Baselga, José, Prof</creator><creator>Im, Seock-Ah, Prof</creator><creator>Iwata, Hiroji, MD</creator><creator>Cortés, Javier, MD</creator><creator>De Laurentiis, Michele, MD</creator><creator>Jiang, Zefei, Prof</creator><creator>Arteaga, Carlos L, Prof</creator><creator>Jonat, Walter, Prof</creator><creator>Clemons, Mark, Prof</creator><creator>Ito, Yoshinori, MD</creator><creator>Awada, Ahmad, Prof</creator><creator>Chia, Stephen, MD</creator><creator>Jagiełło-Gruszfeld, Agnieszka, MD</creator><creator>Pistilli, Barbara, MD</creator><creator>Tseng, Ling-Ming, MD</creator><creator>Hurvitz, Sara, MD</creator><creator>Masuda, Norikazu, MD</creator><creator>Takahashi, Masato, MD</creator><creator>Vuylsteke, Peter, MD</creator><creator>Hachemi, Soulef, PhD</creator><creator>Dharan, Bharani, MS</creator><creator>Di Tomaso, Emmanuelle, PhD</creator><creator>Urban, Patrick, MD</creator><creator>Massacesi, Cristian, MD</creator><creator>Campone, Mario, Prof</creator><general>Elsevier Ltd</general><general>Elsevier Limited</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>0TZ</scope><scope>3V.</scope><scope>7RV</scope><scope>7TO</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8C2</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>H94</scope><scope>K9.</scope><scope>KB0</scope><scope>M0S</scope><scope>M1P</scope><scope>NAPCQ</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20170701</creationdate><title>Buparlisib plus fulvestrant versus placebo plus fulvestrant in postmenopausal, hormone receptor-positive, HER2-negative, advanced breast cancer (BELLE-2): a randomised, double-blind, placebo-controlled, phase 3 trial</title><author>Baselga, José, Prof ; Im, Seock-Ah, Prof ; Iwata, Hiroji, MD ; Cortés, Javier, MD ; De Laurentiis, Michele, MD ; Jiang, Zefei, Prof ; Arteaga, Carlos L, Prof ; Jonat, Walter, Prof ; Clemons, Mark, Prof ; Ito, Yoshinori, MD ; Awada, Ahmad, Prof ; Chia, Stephen, MD ; Jagiełło-Gruszfeld, Agnieszka, MD ; Pistilli, Barbara, MD ; Tseng, Ling-Ming, MD ; Hurvitz, Sara, MD ; Masuda, Norikazu, MD ; Takahashi, Masato, MD ; Vuylsteke, Peter, MD ; Hachemi, Soulef, PhD ; Dharan, Bharani, MS ; Di Tomaso, Emmanuelle, PhD ; Urban, Patrick, MD ; Massacesi, Cristian, MD ; Campone, Mario, Prof</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c602t-437e9af9c1ba3cbaa2e6bc2fefbd2ffd6b13bfdf328374aa36d0fac2cfecbc323</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>1-Phosphatidylinositol 3-kinase</topic><topic>Aged</topic><topic>Alanine</topic><topic>Alanine transaminase</topic><topic>Alanine Transaminase - blood</topic><topic>Aminopyridines - administration & dosage</topic><topic>Aminopyridines - adverse effects</topic><topic>Anticoagulants</topic><topic>Antineoplastic Combined Chemotherapy Protocols - adverse effects</topic><topic>Antineoplastic Combined Chemotherapy Protocols - therapeutic use</topic><topic>Aromatase</topic><topic>Aspartate aminotransferase</topic><topic>Aspartate Aminotransferases - blood</topic><topic>Biomarkers, Tumor - genetics</topic><topic>Breast cancer</topic><topic>Breast Neoplasms - chemistry</topic><topic>Breast Neoplasms - drug therapy</topic><topic>Breast Neoplasms - genetics</topic><topic>Breast Neoplasms - pathology</topic><topic>Cancer therapies</topic><topic>Chemotherapy</topic><topic>Class I Phosphatidylinositol 3-Kinases</topic><topic>Clinical trials</topic><topic>Disease-Free Survival</topic><topic>DNA Mutational Analysis</topic><topic>DNA, Neoplasm - blood</topic><topic>Double-Blind Method</topic><topic>Double-blind studies</topic><topic>Drug Eruptions - etiology</topic><topic>Endocrine therapy</topic><topic>Epidermal growth factor</topic><topic>ErbB-2 protein</topic><topic>Estradiol - administration & dosage</topic><topic>Estradiol - analogs & derivatives</topic><topic>Estrogens</topic><topic>Exanthema</topic><topic>Exanthema - chemically induced</topic><topic>Female</topic><topic>Fulvestrant</topic><topic>Hematology, Oncology and Palliative Medicine</topic><topic>Humans</topic><topic>Hyperglycemia - chemically induced</topic><topic>Metastases</topic><topic>Metastasis</topic><topic>Middle Aged</topic><topic>Morpholines - administration & dosage</topic><topic>Morpholines - adverse effects</topic><topic>Motivation</topic><topic>Mutation</topic><topic>Neoplasm Metastasis</topic><topic>Phosphatidylinositol 3-Kinases - genetics</topic><topic>Post-menopause</topic><topic>Postmenopause</topic><topic>Receptor, ErbB-2 - analysis</topic><topic>Receptors, Estrogen - analysis</topic><topic>Receptors, Progesterone - analysis</topic><topic>Response Evaluation Criteria in Solid Tumors</topic><topic>Retreatment</topic><topic>Signal Transduction - genetics</topic><topic>Solid tumors</topic><topic>Survival</topic><topic>Survival Rate</topic><topic>Toxicity</topic><topic>Tumors</topic><topic>Womens health</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Baselga, José, Prof</creatorcontrib><creatorcontrib>Im, Seock-Ah, Prof</creatorcontrib><creatorcontrib>Iwata, Hiroji, MD</creatorcontrib><creatorcontrib>Cortés, Javier, MD</creatorcontrib><creatorcontrib>De Laurentiis, Michele, MD</creatorcontrib><creatorcontrib>Jiang, Zefei, Prof</creatorcontrib><creatorcontrib>Arteaga, Carlos L, Prof</creatorcontrib><creatorcontrib>Jonat, Walter, Prof</creatorcontrib><creatorcontrib>Clemons, Mark, Prof</creatorcontrib><creatorcontrib>Ito, Yoshinori, MD</creatorcontrib><creatorcontrib>Awada, Ahmad, Prof</creatorcontrib><creatorcontrib>Chia, Stephen, MD</creatorcontrib><creatorcontrib>Jagiełło-Gruszfeld, Agnieszka, MD</creatorcontrib><creatorcontrib>Pistilli, Barbara, MD</creatorcontrib><creatorcontrib>Tseng, Ling-Ming, MD</creatorcontrib><creatorcontrib>Hurvitz, Sara, MD</creatorcontrib><creatorcontrib>Masuda, Norikazu, MD</creatorcontrib><creatorcontrib>Takahashi, Masato, MD</creatorcontrib><creatorcontrib>Vuylsteke, Peter, MD</creatorcontrib><creatorcontrib>Hachemi, Soulef, PhD</creatorcontrib><creatorcontrib>Dharan, Bharani, MS</creatorcontrib><creatorcontrib>Di Tomaso, Emmanuelle, PhD</creatorcontrib><creatorcontrib>Urban, Patrick, MD</creatorcontrib><creatorcontrib>Massacesi, Cristian, MD</creatorcontrib><creatorcontrib>Campone, Mario, Prof</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Pharma and Biotech Premium PRO</collection><collection>ProQuest Central (Corporate)</collection><collection>Nursing & Allied Health Database</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Lancet Titles</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Nursing & Allied Health Premium</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The lancet oncology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Baselga, José, Prof</au><au>Im, Seock-Ah, Prof</au><au>Iwata, Hiroji, MD</au><au>Cortés, Javier, MD</au><au>De Laurentiis, Michele, MD</au><au>Jiang, Zefei, Prof</au><au>Arteaga, Carlos L, Prof</au><au>Jonat, Walter, Prof</au><au>Clemons, Mark, Prof</au><au>Ito, Yoshinori, MD</au><au>Awada, Ahmad, Prof</au><au>Chia, Stephen, MD</au><au>Jagiełło-Gruszfeld, Agnieszka, MD</au><au>Pistilli, Barbara, MD</au><au>Tseng, Ling-Ming, MD</au><au>Hurvitz, Sara, MD</au><au>Masuda, Norikazu, MD</au><au>Takahashi, Masato, MD</au><au>Vuylsteke, Peter, MD</au><au>Hachemi, Soulef, PhD</au><au>Dharan, Bharani, MS</au><au>Di Tomaso, Emmanuelle, PhD</au><au>Urban, Patrick, MD</au><au>Massacesi, Cristian, MD</au><au>Campone, Mario, Prof</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Buparlisib plus fulvestrant versus placebo plus fulvestrant in postmenopausal, hormone receptor-positive, HER2-negative, advanced breast cancer (BELLE-2): a randomised, double-blind, placebo-controlled, phase 3 trial</atitle><jtitle>The lancet oncology</jtitle><addtitle>Lancet Oncol</addtitle><date>2017-07-01</date><risdate>2017</risdate><volume>18</volume><issue>7</issue><spage>904</spage><epage>916</epage><pages>904-916</pages><issn>1470-2045</issn><eissn>1474-5488</eissn><abstract>Summary Background Phosphatidylinositol 3-kinase (PI3K) pathway activation is a hallmark of endocrine therapy-resistant, hormone receptor-positive breast cancer. This phase 3 study assessed the efficacy of the pan-PI3K inhibitor buparlisib plus fulvestrant in patients with advanced breast cancer, including an evaluation of the PI3K pathway activation status as a biomarker for clinical benefit. Methods The BELLE-2 trial was a randomised, double-blind, placebo-controlled, multicentre study. Postmenopausal women aged 18 years or older with histologically confirmed, hormone receptor-positive and human epidermal growth factor (HER2)-negative inoperable locally advanced or metastatic breast cancer whose disease had progressed on or after aromatase inhibitor treatment and had received up to one previous line of chemotherapy for advanced disease were included. Eligible patients were randomly assigned (1:1) using interactive voice response technology (block size of 6) on day 15 of cycle 1 to receive oral buparlisib (100 mg/day) or matching placebo, starting on day 15 of cycle 1, plus intramuscular fulvestrant (500 mg) on days 1 and 15 of cycle 1, and on day 1 of subsequent 28-day cycles. Patients were assigned randomisation numbers with a validated interactive response technology; these numbers were linked to different treatment groups which in turn were linked to treatment numbers. PI3K status in tumour tissue was determined via central laboratory during a 14-day run-in phase. Randomisation was stratified by PI3K pathway activation status (activated vs non-activated vs and unknown) and visceral disease status (present vs absent). Patients, investigators, local radiologists, study team, and anyone involved in the study were masked to the identity of the treatment until unblinding. The primary endpoints were progression-free survival by local investigator assessment per Response Evaluation Criteria In Solid Tumors (version 1.1) in the total population, in patients with known (activated or non-activated) PI3K pathway status, and in PI3K pathway-activated patients. Efficacy analyses were done in the intention-to-treat population. Safety was analysed in all patients who received at least one dose of study drug and had at least one post-baseline safety assessment according to the treatment they received. This trial is registered with ClinicalTrials.gov , number NCT01610284 , and is currently ongoing but not recruiting participants. Findings Between Sept 7, 2012, and Sept 10, 2014, 1147 patients from 267 centres in 29 countries were randomly assigned to receive buparlisib (n=576) or placebo plus fulvestrant (n=571). In the total patient population (n=1147), median progression-free survival was 6·9 months (95% CI 6·8–7·8) in the buparlisib group versus 5·0 months (4·0–5·2) in the placebo group (hazard ratio [HR] 0·78 [95% CI 0·67–0·89]; one-sided p=0·00021). In patients with known PI3K status (n=851), median progression-free survival was 6·8 months (95% CI 5·0–7·0) in the buparlisib group vs 4·5 months (3·3–5·0) in the placebo group (HR 0·80 [95% CI 0·68–0·94]; one-sided p=0·0033). In PI3K pathway-activated patients (n=372), median progression-free survival was 6·8 months (95% CI 4·9–7·1) in the buparlisib group versus 4·0 months (3·1–5·2) in the placebo group (HR 0·76 [0·60–0·97], one-sided p=0·014). The most common grade 3–4 adverse events in the buparlisib group versus the placebo group were increased alanine aminotransferase (146 [25%] of 573 patients vs six [1%] of 570), increased aspartate aminotransferase (103 [18%] vs 16 [3%]), hyperglycaemia (88 [15%] vs one [<1%]), and rash (45 [8%] vs none). Serious adverse events were reported in 134 (23%) of 573 patients in the buparlisib group compared with 90 [16%] of 570 patients in the placebo group; the most common serious adverse events (affecting ≥2% of patients) were increased alanine aminotransferase (17 [3%] of 573 vs one [<1%] of 570) and increased aspartate aminotransferase (14 [2%] vs one [<1%]). No treatment-related deaths occurred. Interpretation The results from this study show that PI3K inhibition combined with endocrine therapy is effective in postmenopausal women with endocrine-resistant, hormone receptor-positive and HER2-negative advanced breast cancer. Use of more selective PI3K inhibitors, such as α-specific PI3K inhibitor, is warranted to further improve safety and benefit in this setting. No further studies are being pursued because of the toxicity associated with this combination. Funding Novartis Pharmaceuticals Corporation.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>28576675</pmid><doi>10.1016/S1470-2045(17)30376-5</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1470-2045 |
| ispartof | The lancet oncology, 2017-07, Vol.18 (7), p.904-916 |
| issn | 1470-2045 1474-5488 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_5549667 |
| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | 1-Phosphatidylinositol 3-kinase Aged Alanine Alanine transaminase Alanine Transaminase - blood Aminopyridines - administration & dosage Aminopyridines - adverse effects Anticoagulants Antineoplastic Combined Chemotherapy Protocols - adverse effects Antineoplastic Combined Chemotherapy Protocols - therapeutic use Aromatase Aspartate aminotransferase Aspartate Aminotransferases - blood Biomarkers, Tumor - genetics Breast cancer Breast Neoplasms - chemistry Breast Neoplasms - drug therapy Breast Neoplasms - genetics Breast Neoplasms - pathology Cancer therapies Chemotherapy Class I Phosphatidylinositol 3-Kinases Clinical trials Disease-Free Survival DNA Mutational Analysis DNA, Neoplasm - blood Double-Blind Method Double-blind studies Drug Eruptions - etiology Endocrine therapy Epidermal growth factor ErbB-2 protein Estradiol - administration & dosage Estradiol - analogs & derivatives Estrogens Exanthema Exanthema - chemically induced Female Fulvestrant Hematology, Oncology and Palliative Medicine Humans Hyperglycemia - chemically induced Metastases Metastasis Middle Aged Morpholines - administration & dosage Morpholines - adverse effects Motivation Mutation Neoplasm Metastasis Phosphatidylinositol 3-Kinases - genetics Post-menopause Postmenopause Receptor, ErbB-2 - analysis Receptors, Estrogen - analysis Receptors, Progesterone - analysis Response Evaluation Criteria in Solid Tumors Retreatment Signal Transduction - genetics Solid tumors Survival Survival Rate Toxicity Tumors Womens health |
| title | Buparlisib plus fulvestrant versus placebo plus fulvestrant in postmenopausal, hormone receptor-positive, HER2-negative, advanced breast cancer (BELLE-2): a randomised, double-blind, placebo-controlled, phase 3 trial |
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