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Antitumor activity of the WEE1 inhibitor AZD1775 as a monotherapy and in combination with the PARP inhibitor olaparib in patient-derived explant (PDX) models
S142 Poster abstracts
Poster Session – Molecular targeted agents II, Thursday 1 December 2016
patients with measurable disease (n = 14) but was not detected in 1 patient who was disease-free following surgical resection 2 years prior. Changes in the mutant AF from baseline correlated with radiographic response to chemotherapy. Conclusions: Serial analysis of plasma-derived cfDNA for the detection of IDH1 mutations in patients with metastatic cholangiocarcinoma by ddPCR is feasible. Further evaluation as a potential predictive biomarker of response to chemotherapy and targeted therapy directed towards IDH1 mutations in cholangiocarcinoma is warranted. We gratefully acknowledge the support of the Integrated Genomics Operation and Bioinformatics Core (P30 CA008748), and the Marie-Josee ´ and Henry R. Kravis Center for Molecular Oncology, MSKCC. Conflict of interest: Advisory Board: Agios. 435 Poster (Board P114) Landscape of RAF1 fusions in solid tumors and therapeutic utility of sorafenib J. Mehnert1 , S. Ali2 , A. Kulkarni3 , D. Pavlick2 , J. Goydos4 , S. Chen5 , A. Shrock2 , K. Hirshfield3 , L. Rodriguez6 , M. Stein3 , E. White4 , J. Ross2 , V. Miller2 , P. Stephens2 , S. Ganesan3 . 1 Cancer Institute of New Jersey, Medicine, New Brunswick, USA; 2 Foundation Medicine, Foundation Medicine, Cambridge, USA; 3 Rutgers Cancer Institute of New Jersey, Medicine, New Brunswick, USA; 4 Rutgers Cancer Institute of New Jersey, Surgery, New Brunswick, USA; 5 Rutgers University, Pharmcay, New Brunswick, USA; 6 Rutgers Cancer Institute of New Jersey, obstetrics and gynecology, New Brunswick, USA Background: Fusions involving the RAF1 (cRAF) kinase have been reported in several solid tumors as likely driver mutations. We now present the landscape of RAF1 fusions identified through clinical grade comprehensive genomic profiling of 79,209 solid tumors. A clinical response to sorafenib in a patient with pancreatic acinar carcinoma harboring a RAF1 fusion demonsrates the potential clinical utility of the RAF inhibitor sorafenib. Methods: Data from clinical grade comprehensive genomic profiling performed on 79,209 solid tumor samples using the FoundationOne assay was reviewed to identify cases harboring RAF1 fusions. A patient with refractory pancreatic acinar cancer was referred for treatment as part of a phase I trial of sorafenib combined with a glutatmate antagonist, based on the presence of a KANK4-RAF1 fusion identified by FoundationOne assay. A cDNA encoding KANK4-RAF1 fusion was synthesized and used to express fusion gene in NIH3T3 cells; cell growth and survival was measured using colony formation. Results: 59 in-frame RAF1 fusion events were seen in 79,209 solid tumors. The most common tumor types included lung non-small cell (8 cases or which 7 were adenocarcinoma, 0.05% of all lung cancers), melanoma (9 cases, 0.5% of melanoma), skin (10 cases) pancreatic cancer (9 cases, of which 3 were pancreatic acinar carcinomas and 3 were neuroendocrine cancers), brain (8 cases), and prostate (4 cases). These fusions result from 8 unique breakpoints, almost all occurring in intron 7 of RAF1, and involved 44 unique fusion partners. An index patient with metastatic pancreatic acinar cancer refractory to standard therapy, that harbored a KANK4-RAF1 fusion, experienced dramatic clinical improvement with RECIST partial response and more than 40 per cent tumor shrinkage in target lesions when treated with sorafenib and the glutamate antagonist riluzole on an investigational trial. In vitro characterization of the KANK4-RAF1 fusion, including sensitivity to RAF kinase inhibitors will be presented. Conclusions: In this large dataset, RAF1 fusions are present in multiple solid tumor types including lung adenocarcinomas, melanomas, pancreatic acinar carcinomas and prostate cancer. Cancers harboring RAF1 fusions may be exceptionally sensitive to treatment with RAF inhibitors. We propose further clinical investigation of RAF inhibitors such as sorafenib in pancreatic acinar and other cancers with RAF1 fusions. Conflict of interest: Ownership: Siraj Ali, Alexa Schrock, Jeffrey Ross, Dean Pavlick, Philips Stephens and Vincent Miller are employees of Foundation Medicine.
436 Poster (Board P115) Antitumor activity of the WEE1 inhibitor AZD1775 as a monotherapy and in combination with the PARP inhibitor olaparib in patient-derived explant (PDX) models M.J. O’Connor1 , R. Odedra2 , S. Palakurthi3 , A. Hughes1 , Z. Lai4 , P. Kirschmeier5 , Q. Zeng3 , S. Zhou3 , S. Dharma3 , E. Ivanova3 , A. Wang1 , A.J. Pierce1 , J. Yates1 , S. Powell1 , B. Dougherty4 , J.C. Barrett4 , J. English6 , P. Jewsbury2 , U.A. Matulonis7 , J.F. Liu7 . 1 AstraZeneca, Innovative Medicines and Early Development, Cambridge, United Kingdom; 2 AstraZeneca, Innovative Medicines and Early Development, Macclesfield, United Kingdom; 3 Belfer Center for Applied Cancer Science and Dana-Farber Cancer Institute, Medical Oncology, Boston, MA, USA; 4 AstraZeneca, Innovative Medicines and Early Development, Waltham, MA, USA; 5 Belfer Center for Applied Cancer Science and Dana-Farber Cancer Institute, Cancer Therapeutics, Boston, MA, USA; 6 Belfer Center for Applied Cancer Science and Dana-Farber Cancer Institute, Discovery Research, Boston, MA, USA; 7 Dana-Farber Cancer Institute, Medical Oncology, Boston, MA, USA Background: Cancers are associated with G1/S checkpoint deficiencies, higher levels of endogenous DNA damage and replication stress. This can lead to a dependency on the WEE1 kinase that during S phase deals with replication stress and provides a G2/M checkpoint to repair DNA damage before mitosis and cell division. AZD1775 is a highly selective small-molecule inhibitor of WEE1 being developed to treat patients (pts) with advanced solid tumors. In an AZD1775 monotherapy study in 25 pts with refractory solid tumors (Do et al 2015), partial responses were seen in two pts with a BRCA1/2 mutation (BRCAm). We assessed AZD1775 in triple-negative breast cancer (TNBC) and ovarian cancer (OC) PDX models with and without a BRCAm. Materials and Methods: TNBC models with varying sensitivities to platinum and olaparib (Lynparza™) were tested for response to different AZD1775 monotherapy doses and schedules. OC models were tested for response to olaparib and AZD1775 as monotherapy. Target engagement was assessed by PK/PD analyses. The efficacy of AZD1775 in combination with olaparib was assessed in all models. Results: Of three TNBC models, two had a BRCA2m: HBCx-10 was sensitive to olaparib but insensitive to AZD1775; HBCx-17 was relatively resistant to olaparib but very sensitive to AZD1775. The third model was resistant to olaparib and partially sensitive to AZD1775. In all models, AZD1775 plus olaparib led to enhanced effects on tumor regression and/or duration of response. All five OC models (whether BRCAm or BRCA wild type [wt]) were resistant to olaparib but responded to AZD1775; olaparib plus AZD1775 led to improved responses versus AZD1775 alone. Further genetic characterization of these models is ongoing. Conclusions: AZD1775 showed a greater-than-expected level of singleagent antitumor activity, with 7/8 PDX models having significant sensitivity. Responses to AZD1775 were not seen in the remaining model (HBCx-10), which was the most sensitive to olaparib. In all models, AZD1775 plus olaparib led to improved responses versus the single agents alone. These data support the clinical assessment of AZD1775 as monotherapy, and combined with olaparib, in TNBC and OC in both BRCAm and BRCAwt pts. Conflict of interest: Ownership: MJO’C, RO, AH, ZL, AJP, JY, SP, BD, JCB, and PJ own stock in AstraZeneca. Corporate-sponsored Research: JE has received research funding from AstraZeneca, Janssen, Merck, Array and Verstem; UAM has received research funding from AstraZeneca and Tesaro; JFL is the site principal investigator of clinical trials sponsored by Genentech/Roche, AstraZeneca, Merrimack Pharmaceuticals and Atara Biotherapeutics. Other Substantive Relationships: MJO’C, RO, AH, ZL, AW, AJP, JY, SP, BD, JCB, and PJ are employees of AstraZeneca; AJP holds patents/royalties/other intellectual property with AstraZeneca. JE is currently an employee of EMD Serono.
Poster Session – Molecular targeted agents II, Thursday 1 December 2016
patients with measurable disease (n = 14) but was not detected in 1 patient who was disease-free following surgical resection 2 years prior. Changes in the mutant AF from baseline correlated with radiographic response to chemotherapy. Conclusions: Serial analysis of plasma-derived cfDNA for the detection of IDH1 mutations in patients with metastatic cholangiocarcinoma by ddPCR is feasible. Further evaluation as a potential predictive biomarker of response to chemotherapy and targeted therapy directed towards IDH1 mutations in cholangiocarcinoma is warranted. We gratefully acknowledge the support of the Integrated Genomics Operation and Bioinformatics Core (P30 CA008748), and the Marie-Josee ´ and Henry R. Kravis Center for Molecular Oncology, MSKCC. Conflict of interest: Advisory Board: Agios. 435 Poster (Board P114) Landscape of RAF1 fusions in solid tumors and therapeutic utility of sorafenib J. Mehnert1 , S. Ali2 , A. Kulkarni3 , D. Pavlick2 , J. Goydos4 , S. Chen5 , A. Shrock2 , K. Hirshfield3 , L. Rodriguez6 , M. Stein3 , E. White4 , J. Ross2 , V. Miller2 , P. Stephens2 , S. Ganesan3 . 1 Cancer Institute of New Jersey, Medicine, New Brunswick, USA; 2 Foundation Medicine, Foundation Medicine, Cambridge, USA; 3 Rutgers Cancer Institute of New Jersey, Medicine, New Brunswick, USA; 4 Rutgers Cancer Institute of New Jersey, Surgery, New Brunswick, USA; 5 Rutgers University, Pharmcay, New Brunswick, USA; 6 Rutgers Cancer Institute of New Jersey, obstetrics and gynecology, New Brunswick, USA Background: Fusions involving the RAF1 (cRAF) kinase have been reported in several solid tumors as likely driver mutations. We now present the landscape of RAF1 fusions identified through clinical grade comprehensive genomic profiling of 79,209 solid tumors. A clinical response to sorafenib in a patient with pancreatic acinar carcinoma harboring a RAF1 fusion demonsrates the potential clinical utility of the RAF inhibitor sorafenib. Methods: Data from clinical grade comprehensive genomic profiling performed on 79,209 solid tumor samples using the FoundationOne assay was reviewed to identify cases harboring RAF1 fusions. A patient with refractory pancreatic acinar cancer was referred for treatment as part of a phase I trial of sorafenib combined with a glutatmate antagonist, based on the presence of a KANK4-RAF1 fusion identified by FoundationOne assay. A cDNA encoding KANK4-RAF1 fusion was synthesized and used to express fusion gene in NIH3T3 cells; cell growth and survival was measured using colony formation. Results: 59 in-frame RAF1 fusion events were seen in 79,209 solid tumors. The most common tumor types included lung non-small cell (8 cases or which 7 were adenocarcinoma, 0.05% of all lung cancers), melanoma (9 cases, 0.5% of melanoma), skin (10 cases) pancreatic cancer (9 cases, of which 3 were pancreatic acinar carcinomas and 3 were neuroendocrine cancers), brain (8 cases), and prostate (4 cases). These fusions result from 8 unique breakpoints, almost all occurring in intron 7 of RAF1, and involved 44 unique fusion partners. An index patient with metastatic pancreatic acinar cancer refractory to standard therapy, that harbored a KANK4-RAF1 fusion, experienced dramatic clinical improvement with RECIST partial response and more than 40 per cent tumor shrinkage in target lesions when treated with sorafenib and the glutamate antagonist riluzole on an investigational trial. In vitro characterization of the KANK4-RAF1 fusion, including sensitivity to RAF kinase inhibitors will be presented. Conclusions: In this large dataset, RAF1 fusions are present in multiple solid tumor types including lung adenocarcinomas, melanomas, pancreatic acinar carcinomas and prostate cancer. Cancers harboring RAF1 fusions may be exceptionally sensitive to treatment with RAF inhibitors. We propose further clinical investigation of RAF inhibitors such as sorafenib in pancreatic acinar and other cancers with RAF1 fusions. Conflict of interest: Ownership: Siraj Ali, Alexa Schrock, Jeffrey Ross, Dean Pavlick, Philips Stephens and Vincent Miller are employees of Foundation Medicine.
436 Poster (Board P115) Antitumor activity of the WEE1 inhibitor AZD1775 as a monotherapy and in combination with the PARP inhibitor olaparib in patient-derived explant (PDX) models M.J. O’Connor1 , R. Odedra2 , S. Palakurthi3 , A. Hughes1 , Z. Lai4 , P. Kirschmeier5 , Q. Zeng3 , S. Zhou3 , S. Dharma3 , E. Ivanova3 , A. Wang1 , A.J. Pierce1 , J. Yates1 , S. Powell1 , B. Dougherty4 , J.C. Barrett4 , J. English6 , P. Jewsbury2 , U.A. Matulonis7 , J.F. Liu7 . 1 AstraZeneca, Innovative Medicines and Early Development, Cambridge, United Kingdom; 2 AstraZeneca, Innovative Medicines and Early Development, Macclesfield, United Kingdom; 3 Belfer Center for Applied Cancer Science and Dana-Farber Cancer Institute, Medical Oncology, Boston, MA, USA; 4 AstraZeneca, Innovative Medicines and Early Development, Waltham, MA, USA; 5 Belfer Center for Applied Cancer Science and Dana-Farber Cancer Institute, Cancer Therapeutics, Boston, MA, USA; 6 Belfer Center for Applied Cancer Science and Dana-Farber Cancer Institute, Discovery Research, Boston, MA, USA; 7 Dana-Farber Cancer Institute, Medical Oncology, Boston, MA, USA Background: Cancers are associated with G1/S checkpoint deficiencies, higher levels of endogenous DNA damage and replication stress. This can lead to a dependency on the WEE1 kinase that during S phase deals with replication stress and provides a G2/M checkpoint to repair DNA damage before mitosis and cell division. AZD1775 is a highly selective small-molecule inhibitor of WEE1 being developed to treat patients (pts) with advanced solid tumors. In an AZD1775 monotherapy study in 25 pts with refractory solid tumors (Do et al 2015), partial responses were seen in two pts with a BRCA1/2 mutation (BRCAm). We assessed AZD1775 in triple-negative breast cancer (TNBC) and ovarian cancer (OC) PDX models with and without a BRCAm. Materials and Methods: TNBC models with varying sensitivities to platinum and olaparib (Lynparza™) were tested for response to different AZD1775 monotherapy doses and schedules. OC models were tested for response to olaparib and AZD1775 as monotherapy. Target engagement was assessed by PK/PD analyses. The efficacy of AZD1775 in combination with olaparib was assessed in all models. Results: Of three TNBC models, two had a BRCA2m: HBCx-10 was sensitive to olaparib but insensitive to AZD1775; HBCx-17 was relatively resistant to olaparib but very sensitive to AZD1775. The third model was resistant to olaparib and partially sensitive to AZD1775. In all models, AZD1775 plus olaparib led to enhanced effects on tumor regression and/or duration of response. All five OC models (whether BRCAm or BRCA wild type [wt]) were resistant to olaparib but responded to AZD1775; olaparib plus AZD1775 led to improved responses versus AZD1775 alone. Further genetic characterization of these models is ongoing. Conclusions: AZD1775 showed a greater-than-expected level of singleagent antitumor activity, with 7/8 PDX models having significant sensitivity. Responses to AZD1775 were not seen in the remaining model (HBCx-10), which was the most sensitive to olaparib. In all models, AZD1775 plus olaparib led to improved responses versus the single agents alone. These data support the clinical assessment of AZD1775 as monotherapy, and combined with olaparib, in TNBC and OC in both BRCAm and BRCAwt pts. Conflict of interest: Ownership: MJO’C, RO, AH, ZL, AJP, JY, SP, BD, JCB, and PJ own stock in AstraZeneca. Corporate-sponsored Research: JE has received research funding from AstraZeneca, Janssen, Merck, Array and Verstem; UAM has received research funding from AstraZeneca and Tesaro; JFL is the site principal investigator of clinical trials sponsored by Genentech/Roche, AstraZeneca, Merrimack Pharmaceuticals and Atara Biotherapeutics. Other Substantive Relationships: MJO’C, RO, AH, ZL, AW, AJP, JY, SP, BD, JCB, and PJ are employees of AstraZeneca; AJP holds patents/royalties/other intellectual property with AstraZeneca. JE is currently an employee of EMD Serono.