A phase I/IB study of ipatasertib in combination with carboplatin or carboplatin/paclitaxel or capecitabine and atezolizumab in patients with metastatic triple-negative breast cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 1078-1078
Author(s):  
Yuan Yuan ◽  
Susan Elaine Yost ◽  
Paul Henry Frankel ◽  
Christopher Ruel ◽  
Mireya Murga ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Akt Inhibitor ◽  
Combination Methods ◽  
Stomach Pain ◽  
Clinically Significant ◽  
Recommended Phase Ii Dose ◽  
Best Responses ◽  
Continuous Dosing

1078 Background: Ipatasertib (ipat) is an AKT inhibitor which has shown efficacy in combination with paclitaxel and atezolizumab in patients with triple negative breast cancer (TNBC). In previous trials, ipat was given 21 days on 7 days off due to gastrointestinal toxicities. The current trial was designed to test the safety and efficacy of ipat continuous dosing in combination with carboplatin (carbo) or carboplatin/paclitaxel (carbo/taxol). The trial was later amended to include an additional arm using ipat 21 days on 7 days off with capecitabine/atezolizumab (cape/atezo) to explore the safety of the combination. Methods: Patients with metastatic TNBC and up to 2 lines of prior chemotherapy were enrolled to receive the following: Arm A, ipat 400 mg daily, carbo AUC 2 and taxol 80 mg/m2 IV days 1, 8, 15, every 28 days; Arm B, ipat 400 mg daily, carbo AUC 2 IV days 1, 8, 15, every 28 days; Arm C, ipat 300 mg daily 21 days on 7 days off, cape 750 mg/m2 7 days on 7 days off, atezo 840 mg IV every 28 days. Ipat continuous dosing was used for Arms A and B. Ipat 21 days on 7 days off dosing was used for Arm C. The primary endpoint is safety and recommended phase II dose (RP2D). Secondary endpoints are response rate (RR) and overall survival (OS). Results: Twenty-three patients with median age 49 (29-75) were enrolled from 04/2019 to 12/2020, with 9 in Arm A, 10 in Arm B, and 4 in Arm C. A total of 15/23 (65%) had dose delay and 10/23 (43%) had dose modification. 3/4 (75%) of patients in Arm A had dose limiting toxicities (DLT) including diarrhea and gastric pain, which led to de-escalation to dose -1 with ipat (300 mg daily). 5 more patients were treated at dose -1 of Arm A with only 1 DLT (maculo-papular rash). No DLTs were observed in Arm B. Of the 4 patients treated in Arm C, 1 had DLT (maculo-papular rash). The RP2D for Arms A and B are: ipat 300 mg/carbo AUC2/taxol 80 mg/m2; ipat 400 mg/carbo AUC2. RP2D for Arm C has not been determined and accrual is ongoing. There were no clinically significant G4 toxicities in Arm A; G3 toxicities included 4/9 (44%) diarrhea, 1/9 (11%) hypertension, 1/9 (11%) stomach pain, and 1/9 (11%) neutropenia. For Arm B, G3 toxicities included 2/10 (20%) diarrhea, 1/10 (10%) anemia, 1/10 (10%) maculo-papular rash, and 1/10 (10%) hyperglycemia. For Arm C, there was 1/4 (25%) G3 maculo-papular rash. Best overall responses for Arm A were: 2/9 (22%) PR, 4/9 (44%) SD, and 3/9 (33%) PD. Best responses for Arm B were 2/10 (20%) PR, 6/10 (60%) SD, and 2/10 (20%) PD. For Arm C, best responses were 3/4 (75%) SD, and 1 not evaluable (repeat biopsy showed HER2+ disease). With a median follow up of 8.1 months, the median PFS was 4.0 months (95% CI [2.6, 5.3]). Conclusions: Continuous dosing of ipatasertib in combination with carbo or carbo/taxol is well-tolerated with modest efficacy. Clinical trial information: NCT03853707 .

scholarly journals Dual Inhibition of AKT and MEK Pathways Potentiates the Anti-Cancer Effect of Gefitinib in Triple-Negative Breast Cancer Cells

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1205
Author(s):  
Kyu Sic You ◽  
Yong Weon Yi ◽  
Jeonghee Cho ◽  
Yeon-Sun Seong
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Kinase Inhibitors ◽  
Triple Negative ◽  
Protein Kinase Inhibitors ◽  
Akt Inhibitor ◽  
Term Survival ◽  
Viral Oncogene ◽  
Dual Inhibition ◽  
Viral Oncogene Homolog

There is an unmet medical need for the development of new targeted therapeutic strategies for triple-negative breast cancer (TNBC). With drug combination screenings, we found that the triple combination of the protein kinase inhibitors (PKIs) of the epidermal growth factor receptor (EGFR), v-akt murine thymoma viral oncogene homolog (AKT), and MAPK/ERK kinase (MEK) is effective in inducing apoptosis in TNBC cells. A set of PKIs were first screened in combination with gefitinib in the TNBC cell line, MDA-MB-231. The AKT inhibitor, AT7867, was identified and further analyzed in two mesenchymal stem-like (MSL) subtype TNBC cells, MDA-MB-231 and HS578T. A combination of gefitinib and AT7867 reduced the proliferation and long-term survival of MSL TNBC cells. However, gefitinib and AT7867 induced the activation of the rat sarcoma (RAS)/ v-raf-1 murine leukemia viral oncogene homolog (RAF)/MEK/ extracellular signal-regulated kinase (ERK) pathway. To inhibit this pathway, MEK/ERK inhibitors were further screened in MDA-MB-231 cells in the presence of gefitinib and AT7867. As a result, we identified that the MEK inhibitor, PD-0325901, further enhanced the anti-proliferative and anti-clonogenic effects of gefitinib and AT7867 by inducing apoptosis. Our results suggest that the dual inhibition of the AKT and MEK pathways is a novel potential therapeutic strategy for targeting EGFR in TNBC cells.

scholarly journals Efficacy and safety of camrelizumab combined with apatinib in advanced triple-negative breast cancer: an open-label phase II trial

2020 ◽  
Vol 8 (1) ◽  
pp. e000696
Author(s):  
Jieqiong Liu ◽  
Qiang Liu ◽  
Ying Li ◽  
Qian Li ◽  
Fengxi Su ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Phase Ii ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Phase Ii Trial ◽  
Objective Response ◽  
Therapeutic Effects ◽  
Open Label ◽  
Programmed Death ◽  
Continuous Dosing

BackgroundPrevious trials showed that antiangiogenesis or anti-programmed death protein 1/programmed death ligand 1 (PD-1/PD-L1) monotherapy only showed marginal effect in triple-negative breast cancer (TNBC). Preclinical studies demonstrated that antiangiogenic therapy could sensitize breast cancer to PD-1/PD-L1 blockade via reprogramming tumor microenvironment. Combinational treatment of checkpoint blockade and antiangiogenesis for TNBC has not been reported.MethodsPatients with advanced TNBC with less than three lines of systemic therapy were enrolled in an open-label, non-comparative, two-arm, phase II trial at Sun Yat-sen Memorial Hospital. Camrelizumab (intravenously every 2 weeks) with apatinib orally at either continuous dosing (d1–d14) or intermittent dosing (d1–d7) was given until disease progression or unacceptable toxicities. Primary endpoint was objective response rate (ORR).ResultsFrom January 2018 to April 2019, 40 patients were enrolled, including 10 in the apatinib intermittent dosing cohort and 30 in the apatinib continuous dosing cohort. The ORR was 43.3% (13 of 30) in the continuous dosing cohort, while no objective response was observed in the intermittent dosing cohort. The disease control rate was 63.3% (19 of 30) in the apatinib continuous dosing cohort, and 40.0% (4 of 10) in the apatinib intermittent dosing cohort, respectively. The median progression-free survival (PFS) was 3.7 (95% CI 2.0 to 6.4) months and 1.9 (95% CI 1.8 to 3.7) months in the continuous dosing and intermittent dosing cohort, respectively. In the continuous dosing cohort, the median PFS of patients with partial response (8.3 months, 95% CI 5.9 to not reached) was significantly longer than that of patients with stable disease/progressive disease/not evaluable (2.0 months, 95% CI 1.7 to 3.0). The most common adverse events (AEs) included elevated aspartate aminotransferase/alanine aminotransferase and hand-foot syndrome. Overall, 26.7% and 20.0% of patients experienced grade ≥3 AEs in the continuous dosing and intermittent dosing cohort, respectively. In the continuous dosing cohort, a high percentage of baseline tumor-infiltrating lymphocytes (>10%) was associated with higher ORR and favorable PFS (p=0.029, 0.054, respectively).ConclusionsThe ORR by this chemo-free regimen was dramatically higher than previously reported ORR by anti-PD-1/PD-L1 antibody or apatinib monotherapy. Camrelizumab combined with apatinib demonstrated favorable therapeutic effects and a manageable safety profile in patients with advanced TNBC.Trial registration numberNCT03394287.

scholarly journals Prognostic Significance of Tumor–infiltrating Lymphocytes and Androgen Receptors in Patients with Early Triple-negative Breast Cancer

2021 ◽  
Author(s):  
Ana Tečić Vuger ◽  
Robert Šeparović ◽  
Sanda Šitić ◽  
Ljubica Vazdar ◽  
Mirjana Pavlović ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Androgen Receptors ◽  
Prognostic Significance ◽  
Tumor Infiltrating Lymphocytes ◽  
Tissue Samples ◽  
Formalin Fixed Paraffin Embedded ◽  
Clinically Significant ◽  
Infiltrating Lymphocytes

Abstract Aims This study aimed to investigate the association between tumor-infiltrating lymphocytes (TIL) and androgen receptors (AR) and to assess their impact on early triple-negative breast cancer (TNBC) prognosis. Previous studies analyzed only stromal TIL (sTIL) and intratumoral (ITIL), while this study includes an additional spatial analysis for TIL in central tumor (CT) and invasive margin (IM) compartments and correlation with AR expression and overall survival (OS). Methods A retrospective cohort study encompassing 152 early TNBC tissue samples from patients treated at a tertiary oncologic center between 2009 and 2012. TIL and AR were assessed using formalin-fixed paraffin-embedded samples, using hematoxylin-eosin staining and immunohistochemistry. AR-positive tumors were considered those with ≥ 1% nuclear-stained cells. Results High TIL indicators were found to be positive prognostic factors. Although AR was not an independent prognostic factor, its interactions with sTIL and ITIL at IM impacted OS. Positive AR along with high sTIL and ITIL in IM were associated with favorable OS (HR for sTIL 0.22; 95%CI 0.05–0.97; p = 0.045 and HR for ITIL 0.10; 95%CI 0.01–0.78; p = 0.028). Conclusion Spatial morphological analysis of TIL reveals an additional prognostic value when combined with AR status, and shows a clinically significant impact on OS in early TNBC.

Efficacy and safety of anti-PD-1 antibody SHR-1210 combined with apatinib in patients with advanced triple-negative breast cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 1066-1066 ◽  
Author(s):  
Jieqiong Liu ◽  
Zefei Jiang ◽  
Qian Li ◽  
Ying Li ◽  
Qiang Liu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Systemic Therapy ◽  
Triple Negative ◽  
Antiangiogenic Therapy ◽  
Objective Response ◽  
Clinical Activity ◽  
Open Label ◽  
Metastatic Setting ◽  
Continuous Dosing

1066 Background: PD-1/PD-L1 blockade monotherapy delivered positive outcomes in early-phase trials in advanced triple-negative breast cancer (TNBC). However, t he highest objective response rate (ORR) is 18.5%. IMPassion130 trial has demonstrated that only PD-L1+ TNBC had overall survival benefit from anti-PD-L1 antibody combined with chemotherapy. Preclinical studies found that antiangiogenic therapy could sensitize anti-PD-1 treatment via inducing PD-L1 expression and increasing CTLs infiltration in tumor microenvironment. Thus, we designed a phase II, open-label trial (NCT03394287) of SHR-1210 (anti-PD-1 antibody) in combination with apatinib (VEGFR2 inhibitor) in patients with advanced TNBC. Methods: 20-58 advanced TNBC patients whose systemic therapy lines in the metastatic setting was less than 3, will be randomly (1:1) enrolled from Sun Yat-sen Memorial Hospital to receive either SHR-1210 200mg Q2W plus apatinib 250mg, continuous dosing (d1-d14), or SHR-1210 200mg Q2W plus apatinib 250mg, intermittent dosing (d1-d7), until progression or unacceptable toxicities. Primary endpoint was ORR. Secondary end points included PFS, DCR, TTR, DoR, CBR, one year-OS and toxicity. Results: Until Jan 30, 2019, 34 patients were enrolled, 10 in the intermittent dosing arm, and 24 in the continuous dosing arm. 26 (76.5%) patients had prior systemic therapy in the metastatic setting. At the cutoff date (Jan 30, 2019), 28 patients were evaluable for ORR as per RECIST. The ORR was 47.4% (9 of 19) in the continuous dosing cohort, and no confirmed objective response was found in the intermittent dosing arm. The DCR was 68.4% in the continuous dosing arm, whereas it was 44.4% in the other arm. The median PFS was 2 months in the intermittent dosing cohort, while it was not reached in the continuous dosing cohort. The most common adverse events (AEs) was fatigue (65.0%), hand-foot syndrome (63.3%), and elevated aspartate aminotransferase and/or alanine aminotransferase (73.3%). There were no treatment-related deaths. Another 5 patients will be enrolled into the continuous dosing arm because of its favorable response. Conclusions: Anti-PD-1 antibody SHR-1210 combined with apatinib demonstrates favorable clinical activity and a manageable safety profile in patients with advanced TNBC. Clinical trial information: NCT03394287.

scholarly journals An increased cell cycle gene network determines MEK and Akt inhibitor double resistance in triple-negative breast cancer

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Vera E. van der Noord ◽  
Ronan P. McLaughlin ◽  
Marcel Smid ◽  
John A. Foekens ◽  
John W. M. Martens ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Cell Lines ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Treatment Strategies ◽  
Mek Inhibitor ◽  
Akt Inhibitor ◽  
Molecular Features ◽  
Tnbc Cell

Abstract Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with poor clinical prognosis and limited targeted treatment strategies. Kinase inhibitor screening of a panel of 20 TNBC cell lines uncovered three critical TNBC subgroups: 1) sensitive to only MEK inhibitors; 2) sensitive to only Akt inhibitors; 3) resistant to both MEK/Akt inhibitors. Using genomic, transcriptomic and proteomic datasets of these TNBC cell lines we unravelled molecular features associated with the MEK and Akt drug resistance. MEK inhibitor-resistant TNBC cell lines were discriminated from Akt inhibitor-resistant lines by the presence of PIK3CA/PIK3R1/PTEN mutations, high p-Akt and low p-MEK levels, yet these features could not distinguish double-resistant cells. Gene set enrichment analyses of transcriptomic and proteomic data of the MEK and Akt inhibitor response groups revealed a set of cell cycle-related genes associated with the double-resistant phenotype; these genes were overexpressed in a subset of breast cancer patients. CDK inhibitors targeting the cell cycle programme could overcome the Akt and MEK inhibitor double-resistance. In conclusion, we uncovered molecular features and alternative treatment strategies for TNBC that are double-resistant to Akt and MEK inhibitors.

scholarly journals Capivasertib Plus Paclitaxel Versus Placebo Plus Paclitaxel As First-Line Therapy for Metastatic Triple-Negative Breast Cancer: The PAKT Trial

2020 ◽  
Vol 38 (5) ◽  
pp. 423-433 ◽  
Author(s):  
Peter Schmid ◽  
Jacinta Abraham ◽  
Stephen Chan ◽  
Duncan Wheatley ◽  
Adrian Murray Brunt ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Progression Free Survival ◽  
Akt Inhibitor ◽  
First Line ◽  
Double Blind ◽  
Significance Level ◽  
First Line Therapy ◽  
Line Therapy

PURPOSE The phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway is frequently activated in triple-negative breast cancer (TNBC). The AKT inhibitor capivasertib has shown preclinical activity in TNBC models, and drug sensitivity has been associated with activation of PI3K or AKT and/or deletions of PTEN. The PAKT trial was designed to evaluate the safety and efficacy of adding capivasertib to paclitaxel as first-line therapy for TNBC. PATIENTS AND METHODS This double-blind, placebo-controlled, randomized phase II trial recruited women with untreated metastatic TNBC. A total of 140 patients were randomly assigned (1:1) to paclitaxel 90 mg/m2 (days 1, 8, 15) with either capivasertib (400 mg twice daily) or placebo (days 2-5, 9-12, 16-19) every 28 days until disease progression or unacceptable toxicity. The primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS), PFS and OS in the subgroup with PIK3CA/ AKT1/ PTEN alterations, tumor response, and safety. RESULTS Median PFS was 5.9 months with capivasertib plus paclitaxel and 4.2 months with placebo plus paclitaxel (hazard ratio [HR], 0.74; 95% CI, 0.50 to 1.08; 1-sided P = .06 [predefined significance level, 1-sided P = .10]). Median OS was 19.1 months with capivasertib plus paclitaxel and 12.6 months with placebo plus paclitaxel (HR, 0.61; 95% CI, 0.37 to 0.99; 2-sided P = .04). In patients with PIK3CA/ AKT1/ PTEN-altered tumors (n = 28), median PFS was 9.3 months with capivasertib plus paclitaxel and 3.7 months with placebo plus paclitaxel (HR, 0.30; 95% CI, 0.11 to 0.79; 2-sided P = .01). The most common grade ≥ 3 adverse events in those treated with capivasertib plus paclitaxel versus placebo plus paclitaxel, respectively, were diarrhea (13% v 1%), infection (4% v 1%), neutropenia (3% v 3%), rash (4% v 0%), and fatigue (4% v 0%). CONCLUSION Addition of the AKT inhibitor capivasertib to first-line paclitaxel therapy for TNBC resulted in significantly longer PFS and OS. Benefits were more pronounced in patients with PIK3CA/ AKT1/ PTEN-altered tumors. Capivasertib warrants further investigation for treatment of TNBC.

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