L. Voorwerk (Amsterdam, Netherlands)
Netherlands Cancer InstituteAuthor Of 1 Presentation
LBA3 - Atezolizumab with carboplatin as immune induction in metastatic lobular breast cancer: first results of the GELATO-trial (ID 320)
Abstract
Background
Invasive lobular breast cancer (ILC) is a special histological breast cancer subtype for which endocrine treatment is effective, but options thereafter are limited. ILC appears to be a different disease entity than invasive breast cancer of no special type. Translational data suggested that a subgroup of ILC has high expression of immune-related genes. Preclinical data revealed that this subtype may be responsive to combined platinum and immune checkpoint blockade. Here we present the first results of a single-arm phase II trial of atezolizumab (atezo) after immune induction with carboplatin in metastatic (m)ILC.
Methods
In the single-arm, multicenter GELATO-trial (NCT03147040), patients with mILC were treated with 12 cycles of carboplatin q1w (AUC 1.5 mg/mL·min) and atezo (1200 mg) q3w starting from the third cycle of carboplatin and continuing until progression or intolerability. Patients had received a maximum of 2 lines of palliative chemotherapy and were endocrine refractory in case of ER-positive tumors. The primary endpoint was progression-free survival at 24 weeks according to RECIST1.1. Following a Simon’s two-stage design, 22 patients, receiving at least 1 cycle of atezo, needed to be included in the first stage, of whom at least 3 patients had to be free of progression after 24 weeks to warrant further investigation in the second stage.
Results
Among 23 included evaluable patients, 4 patients were free of progression at 24 weeks, meeting the primary endpoint of the first stage of the trial. 1 patient has an ongoing response and 2 patients have started treatment but have not yet reached an endpoint. 4 out of these 21 patients had a partial response resulting in an objective response rate of 19% and 2 patients had stable disease, resulting in a clinical benefit rate of 29%. 4 of the patients with clinical benefit had triple negative (TN)-ILC, whereas in total 5 out of 23 patients had TN-ILC. Stromal tumor-infiltrating lymphocytes were not associated with clinical benefit. PD-L1 and CD8 will be presented at the meeting.
Conclusions
This is the first clinical immunotherapy trial executed exclusively in mILC. We show a clear efficacy signal of PDL1-blockade in combination with carboplatin in mILC, mainly in patients with TN-ILC.
Clinical trial identification
NCT03147040.
Legal entity responsible for the study
Netherlands Cancer Institute.
Funding
Roche.
Disclosure
H. Horlings: Advisory/Consultancy: SlideScore.com; Advisory/Consultancy: Ellogen.ai. R.F. Salgado: Research grant/Funding (institution): Breast Cancer Research Foundation. G.S. Sonke: Research grant/Funding (institution): AstraZeneca; Research grant/Funding (institution): Merck; Research grant/Funding (institution): Novartis; Research grant/Funding (institution): Roche. K. de Visser: Research grant/Funding (institution): Roche; Advisory/Consultancy: Third Rock Ventures. T.N. Schumacher: Advisory/Consultancy: Adaptive Biotechnologies; Advisory/Consultancy, Shareholder/Stockholder/Stock options: AIMM Therapeutics; Advisory/Consultancy, Shareholder/Stockholder/Stock options: Allogene Therapeutics; Advisory/Consultancy: Amgen; Advisory/Consultancy: Merus; Advisory/Consultancy, Shareholder/Stockholder/Stock options: Neon Therapeutics; Advisory/Consultancy: Scenic Biotech; Research grant/Funding (institution): Merck; Research grant/Funding (institution): Bristol-Myers-Squibb; Research grant/Funding (institution): Merck KGaA. C.U. Blank: Advisory/Consultancy, Research grant/Funding (institution): Bristol-Myers-Squibb; Advisory/Consultancy: MSD; Advisory/Consultancy, Research grant/Funding (institution): Novartis; Advisory/Consultancy: Lilly; Advisory/Consultancy: Pfizer; Advisory/Consultancy: GSK; Advisory/Consultancy: GenMab; Advisory/Consultancy: Pierre Fabre; Advisory/Consultancy: Third Rock Venture; Research grant/Funding (institution): NanoString Technologies; Shareholder/Stockholder/Stock options: Immagene B.V. C.P. Schroder: Research grant/Funding (institution): Pfizer; Research grant/Funding (institution): Roche/Genentech; Research grant/Funding (institution): SNS Oncology; Research grant/Funding (institution): G1 Therapeutics; Research grant/Funding (institution): AbbVie; Research grant/Funding (institution): Synthon; Research grant/Funding (institution): CytoMx Therapeutics. V. Tjan-Heijnen: Research grant/Funding (institution): AstraZeneca; Honoraria (institution), Research grant/Funding (institution): Novartis; Research grant/Funding (institution): Pfizer; Honoraria (institution), Research grant/Funding (institution): Roche; Research grant/Funding (institution): Eisai; Honoraria (institution), Research grant/Funding (institution): E. Lilly. S.C. Linn: Advisory/Consultancy, Research grant/Funding (institution): AstraZeneca; Research grant/Funding (institution): Eurocept- Pharmaceuticals; Advisory/Consultancy: Cergentis; Advisory/Consultancy: IBM; Advisory/Consultancy, Research grant/Funding (institution): Pfizer; Advisory/Consultancy, Research grant/Funding (institution): Roche/Genentech; Research grant/Funding (institution): Novartis; Research grant/Funding (institution): Tesaro; Research grant/Funding (institution): Immunomedics. M. Kok: Advisory/Consultancy, Research grant/Funding (institution): Bristol-Myers-Squib; Advisory/Consultancy, Research grant/Funding (institution): Roche; Advisory/Consultancy: MSD; Advisory/Consultancy: Daiichi Sankyo; Research grant/Funding (institution): AstraZeneca.
Presenter Of 1 Presentation
LBA3 - Atezolizumab with carboplatin as immune induction in metastatic lobular breast cancer: first results of the GELATO-trial (ID 320)
Abstract
Background
Invasive lobular breast cancer (ILC) is a special histological breast cancer subtype for which endocrine treatment is effective, but options thereafter are limited. ILC appears to be a different disease entity than invasive breast cancer of no special type. Translational data suggested that a subgroup of ILC has high expression of immune-related genes. Preclinical data revealed that this subtype may be responsive to combined platinum and immune checkpoint blockade. Here we present the first results of a single-arm phase II trial of atezolizumab (atezo) after immune induction with carboplatin in metastatic (m)ILC.
Methods
In the single-arm, multicenter GELATO-trial (NCT03147040), patients with mILC were treated with 12 cycles of carboplatin q1w (AUC 1.5 mg/mL·min) and atezo (1200 mg) q3w starting from the third cycle of carboplatin and continuing until progression or intolerability. Patients had received a maximum of 2 lines of palliative chemotherapy and were endocrine refractory in case of ER-positive tumors. The primary endpoint was progression-free survival at 24 weeks according to RECIST1.1. Following a Simon’s two-stage design, 22 patients, receiving at least 1 cycle of atezo, needed to be included in the first stage, of whom at least 3 patients had to be free of progression after 24 weeks to warrant further investigation in the second stage.
Results
Among 23 included evaluable patients, 4 patients were free of progression at 24 weeks, meeting the primary endpoint of the first stage of the trial. 1 patient has an ongoing response and 2 patients have started treatment but have not yet reached an endpoint. 4 out of these 21 patients had a partial response resulting in an objective response rate of 19% and 2 patients had stable disease, resulting in a clinical benefit rate of 29%. 4 of the patients with clinical benefit had triple negative (TN)-ILC, whereas in total 5 out of 23 patients had TN-ILC. Stromal tumor-infiltrating lymphocytes were not associated with clinical benefit. PD-L1 and CD8 will be presented at the meeting.
Conclusions
This is the first clinical immunotherapy trial executed exclusively in mILC. We show a clear efficacy signal of PDL1-blockade in combination with carboplatin in mILC, mainly in patients with TN-ILC.
Clinical trial identification
NCT03147040.
Legal entity responsible for the study
Netherlands Cancer Institute.
Funding
Roche.
Disclosure
H. Horlings: Advisory/Consultancy: SlideScore.com; Advisory/Consultancy: Ellogen.ai. R.F. Salgado: Research grant/Funding (institution): Breast Cancer Research Foundation. G.S. Sonke: Research grant/Funding (institution): AstraZeneca; Research grant/Funding (institution): Merck; Research grant/Funding (institution): Novartis; Research grant/Funding (institution): Roche. K. de Visser: Research grant/Funding (institution): Roche; Advisory/Consultancy: Third Rock Ventures. T.N. Schumacher: Advisory/Consultancy: Adaptive Biotechnologies; Advisory/Consultancy, Shareholder/Stockholder/Stock options: AIMM Therapeutics; Advisory/Consultancy, Shareholder/Stockholder/Stock options: Allogene Therapeutics; Advisory/Consultancy: Amgen; Advisory/Consultancy: Merus; Advisory/Consultancy, Shareholder/Stockholder/Stock options: Neon Therapeutics; Advisory/Consultancy: Scenic Biotech; Research grant/Funding (institution): Merck; Research grant/Funding (institution): Bristol-Myers-Squibb; Research grant/Funding (institution): Merck KGaA. C.U. Blank: Advisory/Consultancy, Research grant/Funding (institution): Bristol-Myers-Squibb; Advisory/Consultancy: MSD; Advisory/Consultancy, Research grant/Funding (institution): Novartis; Advisory/Consultancy: Lilly; Advisory/Consultancy: Pfizer; Advisory/Consultancy: GSK; Advisory/Consultancy: GenMab; Advisory/Consultancy: Pierre Fabre; Advisory/Consultancy: Third Rock Venture; Research grant/Funding (institution): NanoString Technologies; Shareholder/Stockholder/Stock options: Immagene B.V. C.P. Schroder: Research grant/Funding (institution): Pfizer; Research grant/Funding (institution): Roche/Genentech; Research grant/Funding (institution): SNS Oncology; Research grant/Funding (institution): G1 Therapeutics; Research grant/Funding (institution): AbbVie; Research grant/Funding (institution): Synthon; Research grant/Funding (institution): CytoMx Therapeutics. V. Tjan-Heijnen: Research grant/Funding (institution): AstraZeneca; Honoraria (institution), Research grant/Funding (institution): Novartis; Research grant/Funding (institution): Pfizer; Honoraria (institution), Research grant/Funding (institution): Roche; Research grant/Funding (institution): Eisai; Honoraria (institution), Research grant/Funding (institution): E. Lilly. S.C. Linn: Advisory/Consultancy, Research grant/Funding (institution): AstraZeneca; Research grant/Funding (institution): Eurocept- Pharmaceuticals; Advisory/Consultancy: Cergentis; Advisory/Consultancy: IBM; Advisory/Consultancy, Research grant/Funding (institution): Pfizer; Advisory/Consultancy, Research grant/Funding (institution): Roche/Genentech; Research grant/Funding (institution): Novartis; Research grant/Funding (institution): Tesaro; Research grant/Funding (institution): Immunomedics. M. Kok: Advisory/Consultancy, Research grant/Funding (institution): Bristol-Myers-Squib; Advisory/Consultancy, Research grant/Funding (institution): Roche; Advisory/Consultancy: MSD; Advisory/Consultancy: Daiichi Sankyo; Research grant/Funding (institution): AstraZeneca.
Author Of 1 Presentation
- V. Geurts (Amsterdam, Netherlands)
- L. Voorwerk (Amsterdam, Netherlands)
- K. Sikorska (Amsterdam, Netherlands)
- M. Van Dongen (Amsterdam, Netherlands)
- I. Kemper (Amsterdam, Netherlands)
- I. Mandjes (Amsterdam, Netherlands)
- J. Haanen (Amsterdam, Netherlands)
- G. Sonke (Amsterdam, Netherlands)
- M. Kok (Amsterdam, Netherlands)
90TiP - Monalizumab and trastuzumab in metastatic HER2-positive breast cancer: MIMOSA-trial
Abstract
Background
Targeting the human epidermal growth factor receptor-2 (HER2) is the cornerstone of the treatment of HER2+ breast cancer patients. The mechanism of action of trastuzumab is partly based on lysis of tumor cells via antibody dependent cellular cytotoxicity (ADCC), which among others involves NK cells. However, NK cell and CD8+ T-cell activity is inhibited by binding of the inhibitory receptor NKG2A to HLA-E. HLA-E expression is upregulated upon tumor cells and preserved throughout disease progression. Monalizumab is an antibody targeting the NKG2A receptor, thereby blocking NKG2A-HLA-E interaction. Monalizumab has shown clinical activity in head and neck cancer when combined with cetuximab (anti-EGFR). We hypothesize that monalizumab improves trastuzumab-mediated ADCC and thereby helps to overcome trastuzumab-resistance and can promote anti-tumor immunity by unleashing NK cells and CD8+ T cells in HER2+ breast cancer.
Trial design
The MIMOSA-trial (NCT04307329) is an explorative phase II trial in which patients will be treated biweekly with trastuzumab and monalizumab. Clinical efficacy will be assessed separately in patients with high stromal tumor-infiltrating lymphocytes (sTILs) (≥ 5%) and in patients with low sTILs (< 5%) using a Simon’s-two stage design. In stage I, eleven patients will be accrued per cohort. If two or more responders are observed, another eight patients will be accrued. Inclusion criteria comprise histologically confirmed HER2+ breast cancer on a metastatic lesion, progression during previous trastuzumab or TDM-1 therapy, administration of at least one and maximum of three lines of palliative chemotherapy, a metastatic lesion accessible for biopsy and LDH <500 U/l. Primary endpoint is the objective response rate according to RECIST1.1. Secondary endpoints include to evaluate clinical benefit and progression-free survival according to RECIST1.1, overall survival and safety. Before and on-treatment blood and biopsies will be used for translational research to explore treatment-induced intra-tumoral and systemic changes with a focus on NK-cells and CD8+ T-cells. The MIMOSA-trial is currently open for enrollment at the Netherlands Cancer Institute.
Clinical trial identification
NCT04307329.
Legal entity responsible for the study
Netherlands Cancer Institute.
Funding
AstraZeneca.
Disclosure
J.B.A.G. Haanen: Advisory/Consultancy, Research grant/Funding (institution): BMS; Advisory/Consultancy, Research grant/Funding (institution): Merck; Advisory/Consultancy: Roche; Advisory/Consultancy, Research grant/Funding (institution): Neon Therapeutics; Advisory/Consultancy: Pfizer; Advisory/Consultancy: Ipsen; Advisory/Consultancy, Research grant/Funding (institution): Novartis; Advisory/Consultancy: Aimm; Advisory/Consultancy: Achilles Therapeutics; Advisory/Consultancy: Amgen; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Bayer; Advisory/Consultancy: Celsius Therapeutics; Advisory/Consultancy: GSK; Advisory/Consultancy: Immunocore; Advisory/Consultancy: MSD; Advisory/Consultancy: Neogene Therapeutics; Advisory/Consultancy: Sanofi; Advisory/Consultancy: Seattle Genetics. G.S. Sonke: Research grant/Funding (institution): AstraZeneca; Research grant/Funding (institution): Merck; Research grant/Funding (institution): Novartis; Research grant/Funding (institution): Roche. M. Kok: Advisory/Consultancy, Research grant/Funding (institution): BMS; Research grant/Funding (institution): Roche; Research grant/Funding (institution): AstraZeneca; Advisory/Consultancy: Daiichi Sankyo. All other authors have declared no conflicts of interest.