Komal L Jhaveri, Melissa K Accordino, Philippe L Bedard, Andrés Cervantes, Valentina Gambardella, Erika Hamilton, Antoine Italiano, Kevin Kalinsky, Ian E Krop, Mafalda Oliveira, Peter Schmid, Cristina Saura, Nicholas C Turner, Andrea Varga, Sravanthi Cheeti, Stephanie Hilz, Katherine E Hutchinson, Yanling Jin, Stephanie Royer-Joo, Ubong Peters, Noopur Shankar, Jennifer L Schutzman, Dejan Juric
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The primary objective was to evaluate safety or tolerability.</p><p><strong>Results: </strong>Fifty-three patients were included, 33 in the Inavo + Palbo + Letro arm and 20 in the Inavo + Palbo + Fulv arm. Median duration of inavolisib treatment was 15.7 and 20.8 months (cutoff: March 27, 2023), respectively. Treatment-related adverse events (TRAEs) occurred in all patients; the most frequent were stomatitis, hyperglycemia, and diarrhea; grade ≥3 any TRAE rates were 87.9% and 85.0%; 6.1% and 10.0% discontinued any treatment due to TRAEs in the Inavo + Palbo + Letro and Inavo + Palbo + Fulv arms, respectively. No PK drug-drug interactions (DDIs) were observed among the study treatments when administered. Confirmed objective response rates were 52.0% and 40.0% in patients with measurable disease, and median progression-free survival was 23.3 and 35.0 months in the Inavo + Palbo + Letro and Inavo + Palbo + Fulv arms, respectively. Available paired pre- and on-treatment tumor tissue and circulating tumor DNA analyses confirmed the effects of study treatment on pharmacodynamic and pathophysiologic biomarkers of response.</p><p><strong>Conclusion: </strong>Inavolisib plus palbociclib and ET demonstrated a manageable safety profile, lack of DDIs, and promising preliminary antitumor activity.</p>","PeriodicalId":15384,"journal":{"name":"Journal of Clinical Oncology","volume":" ","pages":"3947-3956"},"PeriodicalIF":42.1000,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Phase I/Ib Trial of Inavolisib Plus Palbociclib and Endocrine Therapy for <i>PIK3CA</i>-Mutated, Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced or Metastatic Breast Cancer.\",\"authors\":\"Komal L Jhaveri, Melissa K Accordino, Philippe L Bedard, Andrés Cervantes, Valentina Gambardella, Erika Hamilton, Antoine Italiano, Kevin Kalinsky, Ian E Krop, Mafalda Oliveira, Peter Schmid, Cristina Saura, Nicholas C Turner, Andrea Varga, Sravanthi Cheeti, Stephanie Hilz, Katherine E Hutchinson, Yanling Jin, Stephanie Royer-Joo, Ubong Peters, Noopur Shankar, Jennifer L Schutzman, Dejan Juric\",\"doi\":\"10.1200/JCO.24.00110\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Purpose: </strong>To investigate the safety, tolerability, pharmacokinetics (PK), and preliminary antitumor activity of inavolisib, a potent and selective small-molecule inhibitor of p110α that promotes the degradation of mutated p110α, in combination with palbociclib and endocrine therapy (ET), in a phase I/Ib study in patients with <i>PIK3CA</i>-mutated, hormone receptor-positive/human epidermal growth factor receptor 2-negative locally advanced/metastatic breast cancer (ClinicalTrials.gov identifier: NCT03006172).</p><p><strong>Methods: </strong>Women ≥18 years of age received inavolisib, palbociclib, and letrozole (Inavo + Palbo + Letro arm) or fulvestrant (Inavo + Palbo + Fulv arm) until unacceptable toxicity or disease progression. The primary objective was to evaluate safety or tolerability.</p><p><strong>Results: </strong>Fifty-three patients were included, 33 in the Inavo + Palbo + Letro arm and 20 in the Inavo + Palbo + Fulv arm. Median duration of inavolisib treatment was 15.7 and 20.8 months (cutoff: March 27, 2023), respectively. Treatment-related adverse events (TRAEs) occurred in all patients; the most frequent were stomatitis, hyperglycemia, and diarrhea; grade ≥3 any TRAE rates were 87.9% and 85.0%; 6.1% and 10.0% discontinued any treatment due to TRAEs in the Inavo + Palbo + Letro and Inavo + Palbo + Fulv arms, respectively. No PK drug-drug interactions (DDIs) were observed among the study treatments when administered. Confirmed objective response rates were 52.0% and 40.0% in patients with measurable disease, and median progression-free survival was 23.3 and 35.0 months in the Inavo + Palbo + Letro and Inavo + Palbo + Fulv arms, respectively. Available paired pre- and on-treatment tumor tissue and circulating tumor DNA analyses confirmed the effects of study treatment on pharmacodynamic and pathophysiologic biomarkers of response.</p><p><strong>Conclusion: </strong>Inavolisib plus palbociclib and ET demonstrated a manageable safety profile, lack of DDIs, and promising preliminary antitumor activity.</p>\",\"PeriodicalId\":15384,\"journal\":{\"name\":\"Journal of Clinical Oncology\",\"volume\":\" \",\"pages\":\"3947-3956\"},\"PeriodicalIF\":42.1000,\"publicationDate\":\"2024-11-20\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Clinical Oncology\",\"FirstCategoryId\":\"1\",\"ListUrlMain\":\"https://doi.org/10.1200/JCO.24.00110\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/9/5 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"ONCOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Clinical Oncology","FirstCategoryId":"1","ListUrlMain":"https://doi.org/10.1200/JCO.24.00110","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/9/5 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}
引用次数: 0
摘要
研究目的目的：在PIK3CA突变、激素受体阳性/内分泌治疗（ET）患者的I/Ib期研究中，研究inavolisib（一种强效、选择性的p110α小分子抑制剂，可促进突变p110α的降解）的安全性、耐受性、药代动力学（PK）和初步抗肿瘤活性、在一项针对PIK3CA突变、激素受体阳性/人表皮生长因子受体2阴性的局部晚期/转移性乳腺癌患者的I/Ib期研究中，与palbociclib和内分泌治疗（ET）联合使用（ClinicalTrials.gov标识符：NCT03006172）：年龄≥18岁的女性接受依那西普、帕博西利和来曲唑（依那西普+帕博+来曲臂）或氟维司群（依那西普+帕博+氟维司群臂）治疗，直至出现不可接受的毒性或疾病进展。主要目的是评估安全性或耐受性：共纳入53例患者，其中33例在伊纳沃+帕博+来曲治疗组，20例在伊纳沃+帕博+氟维司群治疗组。依那韦利西治疗的中位持续时间分别为15.7个月和20.8个月（截止日期：2023年3月27日）。所有患者均发生了治疗相关不良事件（TRAEs）；最常见的不良事件是口腔炎、高血糖和腹泻；≥3级的任何TRAE发生率分别为87.9%和85.0%；因TRAEs而中断任何治疗的患者在伊那沃+帕博+乐妥和伊那沃+帕博+Fulv两组分别占6.1%和10.0%。在用药过程中，未观察到研究治疗药物之间的 PK 药物相互作用 (DDI)。可测量疾病患者的确诊客观反应率分别为52.0%和40.0%，Inavo + Palbo + Letro治疗组和Inavo + Palbo + Fulv治疗组的中位无进展生存期分别为23.3个月和35.0个月。现有的治疗前和治疗中肿瘤组织和循环肿瘤DNA配对分析证实了研究治疗对反应的药效学和病理生理学生物标志物的影响：Inavolisib plus palbociclib and ET表现出了可控的安全性、无DDIs和良好的初步抗肿瘤活性。
Phase I/Ib Trial of Inavolisib Plus Palbociclib and Endocrine Therapy for PIK3CA-Mutated, Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced or Metastatic Breast Cancer.
Purpose: To investigate the safety, tolerability, pharmacokinetics (PK), and preliminary antitumor activity of inavolisib, a potent and selective small-molecule inhibitor of p110α that promotes the degradation of mutated p110α, in combination with palbociclib and endocrine therapy (ET), in a phase I/Ib study in patients with PIK3CA-mutated, hormone receptor-positive/human epidermal growth factor receptor 2-negative locally advanced/metastatic breast cancer (ClinicalTrials.gov identifier: NCT03006172).
Methods: Women ≥18 years of age received inavolisib, palbociclib, and letrozole (Inavo + Palbo + Letro arm) or fulvestrant (Inavo + Palbo + Fulv arm) until unacceptable toxicity or disease progression. The primary objective was to evaluate safety or tolerability.
Results: Fifty-three patients were included, 33 in the Inavo + Palbo + Letro arm and 20 in the Inavo + Palbo + Fulv arm. Median duration of inavolisib treatment was 15.7 and 20.8 months (cutoff: March 27, 2023), respectively. Treatment-related adverse events (TRAEs) occurred in all patients; the most frequent were stomatitis, hyperglycemia, and diarrhea; grade ≥3 any TRAE rates were 87.9% and 85.0%; 6.1% and 10.0% discontinued any treatment due to TRAEs in the Inavo + Palbo + Letro and Inavo + Palbo + Fulv arms, respectively. No PK drug-drug interactions (DDIs) were observed among the study treatments when administered. Confirmed objective response rates were 52.0% and 40.0% in patients with measurable disease, and median progression-free survival was 23.3 and 35.0 months in the Inavo + Palbo + Letro and Inavo + Palbo + Fulv arms, respectively. Available paired pre- and on-treatment tumor tissue and circulating tumor DNA analyses confirmed the effects of study treatment on pharmacodynamic and pathophysiologic biomarkers of response.
Conclusion: Inavolisib plus palbociclib and ET demonstrated a manageable safety profile, lack of DDIs, and promising preliminary antitumor activity.
期刊介绍：
The Journal of Clinical Oncology serves its readers as the single most credible, authoritative resource for disseminating significant clinical oncology research. In print and in electronic format, JCO strives to publish the highest quality articles dedicated to clinical research. Original Reports remain the focus of JCO, but this scientific communication is enhanced by appropriately selected Editorials, Commentaries, Reviews, and other work that relate to the care of patients with cancer.
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