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Abstract：
Sapanisertib (CB-228/TAK-228) is a potent, selective ATP-competitive, dual inhibitor of mTORC1/2. Metformin is thought to inhibit the mTOR pathway through upstream activation of 5\'-AMP-activated protein kinase (AMPK) suggesting combination therapy may enhance antitumor activity of sapanisertib. We report preliminary safety, tolerability, and efficacy from the dose-escalation study of sapanisertib in combination with metformin in patients with advanced solid tumors.
Patients with advanced metastatic solid tumors resistant or refractory to standard treatment, with and without mTOR/AKT/PI3K pathway alterations, received sapanisertib 3 or 4 mg daily together with metformin once to three times daily (500-1,500 mg). All patients underwent 14-day titration period for metformin in cycle 1. Tumor measurements were performed following cycle 2 and subsequently every 8 weeks.
A total of 30 patients were enrolled across four cohorts (3 mg/500 mg; 3 mg/1,000 mg, 4 mg/1,000 mg; 4 mg/1,500 mg). 19 were female (63%), median age was 57 (range: 30-77), all were Eastern Cooperative Oncology Group performance status 1. Tumor types included sarcoma (6), breast (4), ovarian (4), head and neck (3), colorectal (2), lung (2), renal cell (2), endometrial (2), gastroesophageal junction (1), prostate (1), stomach (1), urachus (1), and cervical cancer (1). Median number of prior lines of therapy was 4. Most common genomic alterations included PIK3CA (27%), PTEN (17%), AKT1/2 (10%), mTOR (10%). Of 30 patients evaluable for response, 4 patients achieved partial response (PR); 15 patients achieved stable disease (SD) as best response. Disease control rate (PR+SD) was 63%. Of the responders in PR, 3 of 4 patients had documented PTEN mutations (3/5 patients enrolled with PTEN mutations had PR); 2 of 4 of patients in PR had comutations (patient with leiomyosarcoma had both PTEN and TSC; patient with breast cancer had both PTEN and STK11); 1 of 4 patients in PR had AKT and mTOR mutation; tumor types included leiomyosarcoma (n = 2), breast (n = 1), and endometrial cancer (n = 1). Most common treatment-emergent adverse events included nausea, anorexia, diarrhea, and rash. Grade (G) 3-5 treatment-related adverse events included hyperglycemia (4/30; 13%), fatigue (2/30; 7%), hypertriglyceridemia (1/30; 3%), rash (2/20; 7%), diarrhea (2/30; 7%), creatinine increase (1/30; 3%), acidosis (1/30; 3%). No dose-limiting toxicities (DLT) were reported in the 3 mg/500 mg cohort. One of 6 patient had DLT in the 3 mg/1,000 mg cohort (G3 diarrhea) and 2 of 11 patients had DLTs in the 4 mg/1,500 mg cohort (G3 fatigue, G3 rash). 4 mg/1,000 mg was defined as the MTD.
The safety profile of mTORC1/2 inhibitor sapanisertib in combination with metformin was generally tolerable, with antitumor activity observed in patients with advanced malignancies harboring PTEN mutations and AKT/mTOR pathway alterations.
Sapanisertib (CB-228/TAK-228) is a potent, selective ATP-competitive, next-generation dual inhibitor of mTORC1/2. Metformin is thought to inhibit the mTOR pathway through upstream activation of AMPK suggesting combination therapy may enhance antitumor activity of sapanisertib. This dose-escalation study of sapanisertib and metformin in advanced solid tumors and mTOR/AKT/PI3K pathway alterations, demonstrates safety, tolerability, and early clinical activity in advanced malignancies harboring PTEN mutations and AKT/mTOR pathway alterations.Clinical trial information: NCT03017833.
Patients with advanced metastatic solid tumors resistant or refractory to standard treatment, with and without mTOR/AKT/PI3K pathway alterations, received sapanisertib 3 or 4 mg daily together with metformin once to three times daily (500-1,500 mg). All patients underwent 14-day titration period for metformin in cycle 1. Tumor measurements were performed following cycle 2 and subsequently every 8 weeks.
A total of 30 patients were enrolled across four cohorts (3 mg/500 mg; 3 mg/1,000 mg, 4 mg/1,000 mg; 4 mg/1,500 mg). 19 were female (63%), median age was 57 (range: 30-77), all were Eastern Cooperative Oncology Group performance status 1. Tumor types included sarcoma (6), breast (4), ovarian (4), head and neck (3), colorectal (2), lung (2), renal cell (2), endometrial (2), gastroesophageal junction (1), prostate (1), stomach (1), urachus (1), and cervical cancer (1). Median number of prior lines of therapy was 4. Most common genomic alterations included PIK3CA (27%), PTEN (17%), AKT1/2 (10%), mTOR (10%). Of 30 patients evaluable for response, 4 patients achieved partial response (PR); 15 patients achieved stable disease (SD) as best response. Disease control rate (PR+SD) was 63%. Of the responders in PR, 3 of 4 patients had documented PTEN mutations (3/5 patients enrolled with PTEN mutations had PR); 2 of 4 of patients in PR had comutations (patient with leiomyosarcoma had both PTEN and TSC; patient with breast cancer had both PTEN and STK11); 1 of 4 patients in PR had AKT and mTOR mutation; tumor types included leiomyosarcoma (n = 2), breast (n = 1), and endometrial cancer (n = 1). Most common treatment-emergent adverse events included nausea, anorexia, diarrhea, and rash. Grade (G) 3-5 treatment-related adverse events included hyperglycemia (4/30; 13%), fatigue (2/30; 7%), hypertriglyceridemia (1/30; 3%), rash (2/20; 7%), diarrhea (2/30; 7%), creatinine increase (1/30; 3%), acidosis (1/30; 3%). No dose-limiting toxicities (DLT) were reported in the 3 mg/500 mg cohort. One of 6 patient had DLT in the 3 mg/1,000 mg cohort (G3 diarrhea) and 2 of 11 patients had DLTs in the 4 mg/1,500 mg cohort (G3 fatigue, G3 rash). 4 mg/1,000 mg was defined as the MTD.
The safety profile of mTORC1/2 inhibitor sapanisertib in combination with metformin was generally tolerable, with antitumor activity observed in patients with advanced malignancies harboring PTEN mutations and AKT/mTOR pathway alterations.
Sapanisertib (CB-228/TAK-228) is a potent, selective ATP-competitive, next-generation dual inhibitor of mTORC1/2. Metformin is thought to inhibit the mTOR pathway through upstream activation of AMPK suggesting combination therapy may enhance antitumor activity of sapanisertib. This dose-escalation study of sapanisertib and metformin in advanced solid tumors and mTOR/AKT/PI3K pathway alterations, demonstrates safety, tolerability, and early clinical activity in advanced malignancies harboring PTEN mutations and AKT/mTOR pathway alterations.Clinical trial information: NCT03017833.
摘要：
背景：Sapanisertib（CB-228/TAK-228）是一种有效的，选择性ATP竞争，mTORC1/2的双重抑制剂。我们报告初步安全性，与二甲双胍联用的效果。
方法：标准治疗难以治疗的晚期转移性实体瘤患者，有/无mTOR/AKT/PI3K通路改变，每天服用sapanisertib3mg或4mg，并服用二甲双胍1至3次（500mg-1500mg）。
结果：在4个队列中招募了30名患者（3mg/500mg；3mg/1000mg，4mg/1000mg；4mg/1500mg）。19人是女性（63%），中位年龄为57岁(范围:30-77岁).肿瘤类型包括肉瘤（6），乳房(4),卵巢（4）。最常见的基因组改变包括PIK3CA（27％），PTEN（17%），AKT1/2（10%），mTOR（10%）。在可评估反应的30名患者中，4名患者获得部分反应（PR）；15名患者获得稳定的疾病（SD）作为最佳反应。疾病控制率(PR+SD)为63%。公关的响应者中，3/4pts有PTEN突变（3/5pts入组PTEN突变有PR）；2/4pts有共同突变（pt有平滑肌肉瘤有PTEN和TSC；pt有乳腺癌有PTEN和STK11）；1/4pts有AKT和mTOR突变。（G）3-5级治疗相关不良事件包括高血糖（4/30;13%）疲劳（2/30;7%）高甘油三酯血症（1/30;3%）皮疹（2/20;7%），腹泻（2/30;7%），肌酐增加（1/30；3%），酸中毒（1/30；3%）。4mg/1000mg被定义为最年夜耐受剂量。
结论：mTORC1/2抑制剂sapanisertib联合二甲双胍的安全性总体上是可以耐受的，在具有PTEN/AKT/mTOR通路改变的晚期恶性肿瘤患者中观察到抗肿瘤活性。
方法：标准治疗难以治疗的晚期转移性实体瘤患者，有/无mTOR/AKT/PI3K通路改变，每天服用sapanisertib3mg或4mg，并服用二甲双胍1至3次（500mg-1500mg）。
结果：在4个队列中招募了30名患者（3mg/500mg；3mg/1000mg，4mg/1000mg；4mg/1500mg）。19人是女性（63%），中位年龄为57岁(范围:30-77岁).肿瘤类型包括肉瘤（6），乳房(4),卵巢（4）。最常见的基因组改变包括PIK3CA（27％），PTEN（17%），AKT1/2（10%），mTOR（10%）。在可评估反应的30名患者中，4名患者获得部分反应（PR）；15名患者获得稳定的疾病（SD）作为最佳反应。疾病控制率(PR+SD)为63%。公关的响应者中，3/4pts有PTEN突变（3/5pts入组PTEN突变有PR）；2/4pts有共同突变（pt有平滑肌肉瘤有PTEN和TSC；pt有乳腺癌有PTEN和STK11）；1/4pts有AKT和mTOR突变。（G）3-5级治疗相关不良事件包括高血糖（4/30;13%）疲劳（2/30;7%）高甘油三酯血症（1/30;3%）皮疹（2/20;7%），腹泻（2/30;7%），肌酐增加（1/30；3%），酸中毒（1/30；3%）。4mg/1000mg被定义为最年夜耐受剂量。
结论：mTORC1/2抑制剂sapanisertib联合二甲双胍的安全性总体上是可以耐受的，在具有PTEN/AKT/mTOR通路改变的晚期恶性肿瘤患者中观察到抗肿瘤活性。
