Elena López-Miranda, Jose Manuel Pérez-García, María Gión, Nuria Ribelles, Patricia Cortez-Castedo, José Luis Alonso-Romero, María Martínez García, Santiago González-Santiago, Begoña Bermejo, Serafín Morales, Vicente Carañana, Laia Garrigós, Melissa Fernández-Pinto, Silvia García-Vicente, Alicia Garcia-Sanz, Arnau Mena-Molina, Olga Boix, Daniel Alcalá-López, Antonio Llombart-Cussac, Javier Cortés
{"title":"Ipatasertib联合非紫杉烷化疗治疗先前治疗过的晚期三阴性乳腺癌患者：PATHFINDER IIa期试验","authors":"Elena López-Miranda, Jose Manuel Pérez-García, María Gión, Nuria Ribelles, Patricia Cortez-Castedo, José Luis Alonso-Romero, María Martínez García, Santiago González-Santiago, Begoña Bermejo, Serafín Morales, Vicente Carañana, Laia Garrigós, Melissa Fernández-Pinto, Silvia García-Vicente, Alicia Garcia-Sanz, Arnau Mena-Molina, Olga Boix, Daniel Alcalá-López, Antonio Llombart-Cussac, Javier Cortés","doi":"10.1186/s13058-025-02089-4","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>The PI3K/AKT pathway is frequently altered in advanced triple-negative breast cancer (aTNBC), representing a promising target. Ipatasertib, a pan-AKT inhibitor, has shown activity with taxane-based chemotherapy and acceptable safety. This study evaluated the safety and efficacy of ipatasertib with non-taxane chemotherapy for aTNBC.</p><p><strong>Methods: </strong>The PATHFINDER trial was a multicenter, open-label, non-comparative, phase IIa study with a safety run-in phase. Eligible patients had TNBC pretreated in the advanced setting with one or two chemotherapy regimens, including a taxane, and no prior exposure to PI3K/mTOR/AKT inhibitors. Patients received 21-day cycles of ipatasertib combined with capecitabine (arm A), eribulin (arm B), or carboplatin plus gemcitabine (arm C). The safety run-in phase determined feasibility and phase IIa doses. The primary endpoint was the incidence of treatment-emergent adverse events (TEAEs). Key secondary endpoints included progression-free survival (PFS), overall survival (OS), and objective response rate (ORR). The analysis was exploratory without formal hypothesis testing.</p><p><strong>Results: </strong>A total of 54 patients were assigned to arms A (N = 22), B (N = 25), and C (N = 7). Arm C was discontinued due to toxicity during the safety run-in phase. At data cut-off (November 2023), the overall median follow-up was 12.1 (range: 0.2-35.6) months. Common TEAEs in arm A were diarrhea (59.1%, 0.0% G ≥ 3), fatigue (36.4%, 0.0% G ≥ 3), and nausea (36.4%, 0.0% G ≥ 3); in arm B neutropenia (52.0%; 32.0% G ≥ 3), diarrhea (52.0%, 4.0% G3) and stomatitis (44.0%; 8.0% G3); and in arm C thrombocytopenia (85.7%, 85.7%G ≥ 3), anemia (85.7%, 57.1% G ≥ 3), neutropenia (71.4%, 71.4% G ≥ 3). No treatment-related deaths occurred. Median PFS was 2.7 (95%CI, 1.5-4.1) and 3.8 (95%CI, 1.5-9.6) months; median OS was 15.5 (95%CI, 11.8-19.3) and 11.5 (95%CI, 8.8-25.1) months; and ORR was 9.1% and 36.0% for arms A and B, respectively. No significant differences in efficacy were observed by PIK3CA mutational status.</p><p><strong>Conclusions: </strong>Ipatasertib combined with capecitabine or eribulin showed acceptable safety but was not tolerable with carboplatin plus gemcitabine. The addition of ipatasertib to capecitabine or eribulin shows a potential efficacy signal in this patient population, compared to historical monotherapy data of these treatments. Identifying biomarkers to predict response to AKT inhibitors in TNBC is crucial.</p><p><strong>Trial registration: </strong>www.</p><p><strong>Clinicaltrials: </strong>gov , NCT04464174. Registered 09 July 2020.</p>","PeriodicalId":49227,"journal":{"name":"Breast Cancer Research","volume":"27 1","pages":"141"},"PeriodicalIF":5.6000,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12326808/pdf/","citationCount":"0","resultStr":"{\"title\":\"Ipatasertib combined with non-taxane chemotherapy for patients with previously treated advanced triple-negative breast cancer: the PATHFINDER phase IIa trial.\",\"authors\":\"Elena López-Miranda, Jose Manuel Pérez-García, María Gión, Nuria Ribelles, Patricia Cortez-Castedo, José Luis Alonso-Romero, María Martínez García, Santiago González-Santiago, Begoña Bermejo, Serafín Morales, Vicente Carañana, Laia Garrigós, Melissa Fernández-Pinto, Silvia García-Vicente, Alicia Garcia-Sanz, Arnau Mena-Molina, Olga Boix, Daniel Alcalá-López, Antonio Llombart-Cussac, Javier Cortés\",\"doi\":\"10.1186/s13058-025-02089-4\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>The PI3K/AKT pathway is frequently altered in advanced triple-negative breast cancer (aTNBC), representing a promising target. 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The analysis was exploratory without formal hypothesis testing.</p><p><strong>Results: </strong>A total of 54 patients were assigned to arms A (N = 22), B (N = 25), and C (N = 7). Arm C was discontinued due to toxicity during the safety run-in phase. At data cut-off (November 2023), the overall median follow-up was 12.1 (range: 0.2-35.6) months. Common TEAEs in arm A were diarrhea (59.1%, 0.0% G ≥ 3), fatigue (36.4%, 0.0% G ≥ 3), and nausea (36.4%, 0.0% G ≥ 3); in arm B neutropenia (52.0%; 32.0% G ≥ 3), diarrhea (52.0%, 4.0% G3) and stomatitis (44.0%; 8.0% G3); and in arm C thrombocytopenia (85.7%, 85.7%G ≥ 3), anemia (85.7%, 57.1% G ≥ 3), neutropenia (71.4%, 71.4% G ≥ 3). No treatment-related deaths occurred. Median PFS was 2.7 (95%CI, 1.5-4.1) and 3.8 (95%CI, 1.5-9.6) months; median OS was 15.5 (95%CI, 11.8-19.3) and 11.5 (95%CI, 8.8-25.1) months; and ORR was 9.1% and 36.0% for arms A and B, respectively. 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Registered 09 July 2020.</p>\",\"PeriodicalId\":49227,\"journal\":{\"name\":\"Breast Cancer Research\",\"volume\":\"27 1\",\"pages\":\"141\"},\"PeriodicalIF\":5.6000,\"publicationDate\":\"2025-08-06\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12326808/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Breast Cancer Research\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1186/s13058-025-02089-4\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"Medicine\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Breast Cancer Research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1186/s13058-025-02089-4","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"Medicine","Score":null,"Total":0}
Ipatasertib combined with non-taxane chemotherapy for patients with previously treated advanced triple-negative breast cancer: the PATHFINDER phase IIa trial.
Background: The PI3K/AKT pathway is frequently altered in advanced triple-negative breast cancer (aTNBC), representing a promising target. Ipatasertib, a pan-AKT inhibitor, has shown activity with taxane-based chemotherapy and acceptable safety. This study evaluated the safety and efficacy of ipatasertib with non-taxane chemotherapy for aTNBC.
Methods: The PATHFINDER trial was a multicenter, open-label, non-comparative, phase IIa study with a safety run-in phase. Eligible patients had TNBC pretreated in the advanced setting with one or two chemotherapy regimens, including a taxane, and no prior exposure to PI3K/mTOR/AKT inhibitors. Patients received 21-day cycles of ipatasertib combined with capecitabine (arm A), eribulin (arm B), or carboplatin plus gemcitabine (arm C). The safety run-in phase determined feasibility and phase IIa doses. The primary endpoint was the incidence of treatment-emergent adverse events (TEAEs). Key secondary endpoints included progression-free survival (PFS), overall survival (OS), and objective response rate (ORR). The analysis was exploratory without formal hypothesis testing.
Results: A total of 54 patients were assigned to arms A (N = 22), B (N = 25), and C (N = 7). Arm C was discontinued due to toxicity during the safety run-in phase. At data cut-off (November 2023), the overall median follow-up was 12.1 (range: 0.2-35.6) months. Common TEAEs in arm A were diarrhea (59.1%, 0.0% G ≥ 3), fatigue (36.4%, 0.0% G ≥ 3), and nausea (36.4%, 0.0% G ≥ 3); in arm B neutropenia (52.0%; 32.0% G ≥ 3), diarrhea (52.0%, 4.0% G3) and stomatitis (44.0%; 8.0% G3); and in arm C thrombocytopenia (85.7%, 85.7%G ≥ 3), anemia (85.7%, 57.1% G ≥ 3), neutropenia (71.4%, 71.4% G ≥ 3). No treatment-related deaths occurred. Median PFS was 2.7 (95%CI, 1.5-4.1) and 3.8 (95%CI, 1.5-9.6) months; median OS was 15.5 (95%CI, 11.8-19.3) and 11.5 (95%CI, 8.8-25.1) months; and ORR was 9.1% and 36.0% for arms A and B, respectively. No significant differences in efficacy were observed by PIK3CA mutational status.
Conclusions: Ipatasertib combined with capecitabine or eribulin showed acceptable safety but was not tolerable with carboplatin plus gemcitabine. The addition of ipatasertib to capecitabine or eribulin shows a potential efficacy signal in this patient population, compared to historical monotherapy data of these treatments. Identifying biomarkers to predict response to AKT inhibitors in TNBC is crucial.
Trial registration: www.
Clinicaltrials: gov , NCT04464174. Registered 09 July 2020.
期刊介绍：
Breast Cancer Research, an international, peer-reviewed online journal, publishes original research, reviews, editorials, and reports. It features open-access research articles of exceptional interest across all areas of biology and medicine relevant to breast cancer. This includes normal mammary gland biology, with a special emphasis on the genetic, biochemical, and cellular basis of breast cancer. In addition to basic research, the journal covers preclinical, translational, and clinical studies with a biological basis, including Phase I and Phase II trials.
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