3/7/2018 18 th Multidisciplinary Management of Cancers: A Case‐based Approach 18 th Multidisciplinary Management of Cancers: A Case‐based Approach Case 1: A 45 year old woman with metastatic lung adenocarcinoma and polyarthralgias 2018 Developmental Therapeutics Panel Shivaani Kummar MD Stanford Shortness * Establish care at Stanford of breath Diane Tseng MD PhD Stanford fellow PD PD Rahul Aggarwal MD UC San Francisco v Pamela Munster MD UC San Francisco 2012 2013 2014 2015 2016 2017 Karen Kelly MD UC Davis Tianhong (Tina) Li MD PhD UC Davis Carbo/pem x 8 cycles Declines tx, herbal supplements Akshiv Malhotra MD Epic Care Ming‐Gui Pan MD Kaiser Permanente Develops joint pain 18 th Multidisciplinary Management of Cancers: A Case‐based Approach 18 th Multidisciplinary Management of Cancers: A Case‐based Approach Case 1: A 45 year old woman with metastatic lung adenocarcinoma and polyarthralgias Case 1: A 45 year old woman with metastatic lung adenocarcinoma and polyarthralgias Biopsy of LLL: SQSTM1‐NTRK1 translocation detected Shortness Shortness * Establish care at Stanford * Establish care at Stanford of breath of breath PD PD SD PD PD SD v v v v 2012 2013 2014 2015 2016 2017 2012 2013 2014 2015 2016 2017 Carbo/pem x 8 cycles Declines tx, herbal supplements Carbo/pem x 8 cycles Declines tx, herbal supplements Platinum/pem x 6 cycles Platinum/pem x 6 cycles Develops joint pain Develops joint pain 1
3/7/2018 18 th Multidisciplinary Management of Cancers: A Case‐based Approach 18 th Multidisciplinary Management of Cancers: A Case‐based Approach LOXO‐TRK‐15002: A Phase II Basket Study of the Oral TRK Inhibitor Larotrectinib in LOXO‐TRK‐15002: A Phase II Basket Study of the Oral TRK Inhibitor Larotrectinib in Subjects with NTRK Fusion‐Positive Tumors Subjects with NTRK Fusion‐Positive Tumors Pre-treatment Pre-treatment After 2 cycles After 6 cycles Larotrectinib Larotrectinib 100 mg PO BID 100 mg PO BID 18 th Multidisciplinary Management of Cancers: A Case‐based Approach 18 th Multidisciplinary Management of Cancers: A Case‐based Approach LOXO‐TRK‐15002: A Phase II Basket Study of the Oral TRK Inhibitor Larotrectinib in Subjects with NTRK Fusion‐Positive Tumors Pre-treatment After 2 cycles After 6 cycles After 12 cycles After 16 cycles Larotrectinib 100 mg PO BID RECIST ‐59% PR Presented By David Hyman at 2017 ASCO Annual Meeting 2
3/7/2018 18 th Multidisciplinary Management of Cancers: A Case‐based Approach 18 th Multidisciplinary Management of Cancers: A Case‐based Approach Presented By David Hyman at 2017 ASCO Annual Meeting Presented By David Hyman at 2017 ASCO Annual Meeting 18 th Multidisciplinary Management of Cancers: A Case‐based Approach 18 th Multidisciplinary Management of Cancers: A Case‐based Approach How are NTREK fusions detected? How are NTREK fusions detected? A) Next Generation Sequences (NGS) A) Next Generation Sequences (NGS) B) Fluorescence in situ hybridization (FISH) B) Fluorescence in situ hybridization (FISH) C) Real‐time polymerase chain reaction (RT‐PCR) C) Real‐time polymerase chain reaction (RT‐PCR) D) Immunohistochemistry (IHC) D) Immunohistochemistry (IHC) E) A, B, and C E) A, B, and C 3
3/7/2018 18 th Multidisciplinary Management of Cancers: A Case‐based Approach 18 th Multidisciplinary Management of Cancers: A Case‐based Approach Larotrectinib is effective against which of the following NTREK fusion genes? Larotrectinib is effective against which of the following NTREK fusion genes? A) NTREK1 A) NTREK1 B) NTREK2 B) NTREK2 C) NTREK3 C) NTREK3 D) A, B, and C D) A, B, and C 18 th Multidisciplinary Management of Cancers: A Case‐based Approach 18 th Multidisciplinary Management of Cancers: A Case‐based Approach NTRK fusions have been found in which tumors? A) Highly prevalent tumors (lung, colorectal, thyroid) B) Moderately prevalent tumors (AML, glioblastoma, soft tissue sarcoma, GI stromal tumors) C) Rare pediatric and adult cancer types: juvenile secretory breast cancer, infantile fibrosarcoma, conenital mesoblastic nephroma) D) All of the above Presented By David Hyman at 2017 ASCO Annual Meeting 4
3/7/2018 18 th Multidisciplinary Management of Cancers: A Case‐based Approach 18 th Multidisciplinary Management of Cancers: A Case‐based Approach NTRK fusions have been found in which tumors? A) Highly prevalent tumors (lung, colorectal, thyroid) B) Moderately prevalent tumors (AML, glioblastoma, soft tissue sarcoma, GI stromal tumors) C) Rare pediatric and adult cancer types: juvenile secretory breast cancer, infantile fibrosarcoma, conenital mesoblastic nephroma) D) All of the above Presented By David Hyman at 2017 ASCO Annual Meeting 18 th Multidisciplinary Management of Cancers: A Case‐based Approach 18 th Multidisciplinary Management of Cancers: A Case‐based Approach How would you manage patients who have developed resistance to larotrectinib? A) Consider switching to another first‐generation TRK inhibitor B) Refer to palliative care C) Consider clinical trial with next‐generation TRK inhibitors D) Standard of care chemotherapy Presented By David Hyman at 2017 ASCO Annual Meeting 5
3/7/2018 18 th Multidisciplinary Management of Cancers: A Case‐based Approach 18 th Multidisciplinary Management of Cancers: A Case‐based Approach Solvent front mutations in TRKA and TRKC lead to steric hindrance for larotrectinib binding How would you manage patients who have developed resistance to larotrectinib? A) Consider switching to another first‐generation TRK inhibitor B) Refer to palliative care C) Consider clinical trial with next‐generation TRK inhibitors D) Standard of care chemotherapy * Trial open at Stanford Drilon et al. Cancer Discov 2017. 18 th Multidisciplinary Management of Cancers: A Case‐based Approach 18 th Multidisciplinary Management of Cancers: A Case‐based Approach History Immuno‐Oncology • Phase 1/2 Multicenter Trial of ICOS Agonist Monoclonal Antibody (mAb) JTX‐2011 Alone or in Combination with Nivolumab in Adult Subjects with Advanced Refractory Solid Tumor Malignancies • A Phase 1/1b, Open‐Label, Multicenter, Repeat‐Dose, Dose‐Selection Study of CPI‐444 as Single Agent and in Combination with Atezolizumab in Patients with Selected Incurable Cancers Case 2: A 63 y/o M, diagnosed in 2014, presented with Gleason 5+4 prostate • A Phase 1b/2, Open‐Label, Multicenter, Dose‐Escalation and Expansion Trial of Intratumoral of SD‐101 in Combination with adenocarcinoma Pembrolizumab in Patients with Metastatic Melanoma or Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma Antibody‐Drug conjugate • An open‐label Phase I dose‐escalation study to evaluate the safety, tolerability, maximum tolerated dose, pharmacokinetics, and • Bone and lymph node metastases at diagnosis pharmacodynamics of the anti‐C4.4a antibody drug conjugate BAY 1129980 in subjects with advanced solid tumors known to express C4.4a • A Phase 1, Open‐Label, Dose‐Escalation Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Antitumor Activity of ADCT‐502 in Patients with Advanced Solid Tumors with HER2 Expression • Treated with systemic therapy with Lupron + docetaxel x 6 cycles Small Molecules • A Phase 1/2a Study to Assess the Safety, Pharmacokinetics, and Pharmacodynamics of PLX8394 in Patients with Advanced, Unresectable Solid Tumors • A Phase III Study of AL3818 (Anlotinib) Hydrochloride Monotherapy in Subjects with Metastatic or Advanced Alveolar Soft Part • Initial response then recurrence after 12 months on Lupron Sarcoma, Leiomyosarcoma and Synovial Sarcoma • Phase I clinical trial of VX‐970 in combination with the topoisomerase I inhibitor irinotecan in patients with advanced solid tumors 6
3/7/2018 18 th Multidisciplinary Management of Cancers: A Case‐based Approach 18 th Multidisciplinary Management of Cancers: A Case‐based Approach • Restaging scans with significant interval progression of disease What is the reason to consider with bulky nodal metastases metastatic tumor biopsy? • No visceral metastases • PSA 142 A) To evaluate for targetable molecular alterations in his tumor B) To evaluate for evidence of neuroendocrine differentiation C) To evaluate for PD‐L1 expression in the tumor D) A and B E) A, B, and C 18 th Multidisciplinary Management of Cancers: A Case‐based Approach 18 th Multidisciplinary Management of Cancers: A Case‐based Approach What is the reason to consider Biopsy of Supraclavicular Node Demonstrates Small Cell Neuroendocrine Histology metastatic tumor biopsy? A) To evaluate for targetable molecular alterations in his tumor Adenocarcinoma Small Cell B) To evaluate for evidence of neuroendocrine differentiation C) To evaluate for PD‐L1 expression in the tumor D) A and B E) A, B, and C 7
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