Karel A. Dicke M.D., Ph.D.

Transcription

1 Karel A. Dicke M.D., Ph.D. 1

2 Genomic Medicine Chemotherapy selected on the basis of biomarkers, i.e. proteins in the tumor. Chemotherapy is cytotoxic and kills tumor cells. Targeted Therapy (i.e. Precision Medicine) are drugs against single gene mutations that silence proliferation, cell division, metabolism, angiogenesis. Targeting drugs do not necessarily kill tumor cells but silence specific functions of the cell. Chemotherapy based on biomarker selection + Drugs targeting single gene mutations = Genomic Medicine 2

3 Randomized studies Evaluation of efficacy of Genomic Medicine Comparison with carefully matched historical controls Comparison outcomes with similar cohorts of patients published in the literature, including tumor registry Observational studies, single or multiple patients 3

4 Update of 2013 results OS BRCA from 2 nd Met Caris Comparison: Genomic versus Physician selected treatment Metastatic Breast Cancer after 2 nd recurrence 4

5 Case Report 1 HISTORY 57-year-old female diagnosed 2002 with left-sided breast cancer at the 10 o clock position Triple negative (ER -, PR -, Her2/neu - ) T2 N1 MO with lumpectomies, Cytoxan/Taxotere/5FU (TAC) x6 courses, 5FU, Mitomycin, Cisplatin, VP-16(FUMEP) x2 course and radiation to the left breast and axilla. Recurrence August 2014 Site: Left Breast 1:30 position, Triple negative (ER -, PR -, Her2/neu - ) T2N0 M0 unilateral mastectomy Clinical Testing: CT: Negative for metastatic disease PET: Four (4) small left subpectoral muscle lymph nodes SUV 9 Genomic Profiling: Genomic testing for chemotherapy (Caris Life Sciences) Single mutation gene analysis (Foundation Medicine) 5

6 Case Report 1 (cont.) Genomic Profile Caris Life Sciences Chemotherapy Biomarkers Drugs RRM1 ( - ) SPARC ( + ) TS ( - ) gemcitabine (Gemzar) nab-paclitaxel (Abraxane) 5FU Foundation Medicine Targeted Therapy Single Gene Mutations MCL 1 amplification FGFR1 amplification Drugs sorafenib(nexavar), everolimus,(afinitor) pazopanib (Votrient) LYN amplification Dasatinib (Sprycel) *Eight (8) additional mutations identified, no drugs available. 6

7 Case Report 1 (cont.) Rationale of the Targeted Treatment Program 1 MCL 1 amplification MCL-1 regulates apoptosis. Amplification inhibits apoptosis. Sorafenib down regulates MCL-1 and synergizes with mtor inhibitors such as everolimus to induce cell death. 7

8 Case Report 1 (cont) Program 1 / Course 1: 10/29 11/15/2014 Treatment nab-paclitaxel day 3, 7, 10, 13, 17 to reduce number of tumor cells sorafenib + Everolimus day 1 to day 17 to open apoptosis pathway Duration 17 days on and 13 days off Radiology 11/15/2014: Pet scan before treatment: 4 lymph nodes: SUV 9 PET scan after treatment: 2 of 4 lymph nodes: SUV ( - ) 1 node: SUV node: SUV 2.3 Toxicity: G.I. toxicity, grade 1 hematopoietic toxicity grade 1 2 Generalized weakness grade 1 Quality of Life (QoL): FACT-G score = 99 of 108 Pt able to work a full time job. Conclusion: Program 1 was effective 8

9 Case Report 1 (cont) Program 1 / Course 2: 11/28 12/19/2014 w/ Radiation Treatment: nab-paclitaxel day 3,7,10, 13,17 to reduce number of tumor cells sorafenib + Everolimus day 1 to day 17 to open apoptosis pathway Radiation Therapy: 22 treatments M F Duration: 17 days on and 13 days off Radiology 12/18/2014: Pet scan negative Toxicity: G.I. toxicity, grade 1 hematopoietic toxicity, grade 1 2 Generalized weakness, grade 1 Radiation induced toxicity Quality of Life (QoL): FACT-G score = 99 of 108 Pt able to work a full time job. Conclusion: Program 1 / Course 2 with radiation was effective 9

10 Case Report 1 (cont) Program 1 / Course 3: 1/2-1/16/2015 Treatment: nab-paclitaxel day 3, 7, 10, 13, 17 to reduce number of tumor cells sorafenib + Everolimus day 1 to day 17 to open apoptosis pathway Duration: 17 days on and 14 days off Toxicity: G.I.toxicity, grade1hematopoietic toxicity, grade 1-2 Generalized weakness, grade1 Quality of Life (QoL): FACT-G score = 99 of 108 Pt able to work a full time job. Radiology 1/15/2015: Pet/CT - Negative Conclusion: Program 1 / Course 3 was effective 10

11 Case Report 1 (cont) Post 14 days off after Program 1 / Course 3 PET/CT: 2/2/2015 (+) Positive T6 vertebra SUV = 6.5 Conclusion: Program 1: chemo + unblocking apoptosis pathway is effective, but duration is short. 11

12 Case Report 1 (cont) Treatment Program 2 (expansion of program 1) Marker SPARC Chemotherapy Nab-paclitaxel (Abraxane) Target MCL - 1 FGFR1 LYN RANK L Targeted Therapy Sorafenib (Nexavar), Everolimus (Affinitor) Pazopanib (Votrient) Dasatinib (Sprycel) Denosumab (Xgeva) New Drugs 12

13 Case Report 1 (cont.) Rationale of the Targeted Treatment Program 2 FGFR amplification FGFR encodes the protein fibroblast factor receptor 1 and regulates the RAS, MAPK and AKT signaling pathways. Amplification of FGFR, activates RAS leading to inappropriate cell proliferation. Tumors with FGFR1 amplification are sensitive to FGFR inhibitors such as pazopanib (voltrient). 13

14 Case Report 1 (cont.) Rationale of the Targeted Treatment Program 2 LYN amplification LYN transducts signals from the membrane receptors to the nucleus and regulates cell migration and proliferation Amplification leads to inappropriate cell migration and proliferation. LYN, encodes the tyrosine protein kinase Lyn belonging to the Src family kinases. Dasatinib, a kinase inhibitor targets Bcr-Abl fusion protein and also targets Src family kinases including Lyn. 14

15 Case Report 1 (cont.) Rationale of the Targeted Treatment Program 2 RANK L RANK is a soluble protein produced by osteoblasts Binds to the RANK receptor on the osteoclast and induces differentiation of immature osteoclasts. Differentiated osteoclasts produce factors stimulating tumor growth in the marrow. Denosumab (Xgeva) binds to the RANK protein and inhibits osteoclast differentiation and therefore prevents production of factors stimulating tumor growth. 15

16 Case Report 1 (cont) Program 2 / Course 1: 2/3 3/3/2015 Treatment: Nab-paclitaxel Sorafenib+Everolimus Pazopanib Dasatinib Denosumab Duration: 28 days on and 14 days off Radiology: 2/2, PET SUV 6.5 3/15, PET SUV 3.5 Toxicity: GI toxicity, grade 1 Hematopietic toxicity, grade 2 Generalized weakness, grade 1 Quality of life: Fact G score = 99 of 108 Pt able to work a full time job Conclusion: Program 2, course 1 is effective Course 1 is followed by radiation to the T6 vertebra 16

17 Location: Radiation to T6 vertebra Duration: (3/13 to 3/24) Mon Friday total of 10 treatments Toxicity: Grade I fatigue Radiology: 3/31 PET/CT (-) Negative Conclusion: Case Report 1 (cont) Radiation Therapy Radiation is effective and treatment is continued with Program 2, course 2. 17

18 Case Report 1 (cont) Program 2 / Course 2: 3/30 to 4/14/2015 Treatment nab-paclitaxel 5FU sorafenib + Everolimus Pazopanib Dasatinib Denosumab Duration 16 days Toxicity: GI toxicity, grade 1 hematopoietic toxicity, grade 2 Generalized weakness, grade 1 Quality of Life (QoL): Pt able to work a full time job. Radiology 4/20/2015: PET ( + ) L5 Vertebra, SUV 4.5 Right Ilium SUV4.7 CT scans Neg ( - ) Conclusion: Response to P2/C2 is short. Potential explanations: Time interval between P2/C1 to P2/C2too long Treatment plan not active enough. 18

19 Case Report 1 (cont) Treatment Program 3 (expansion of program 2) Marker SPARC Chemotherapy Nab-paclitaxel (Abraxane) Target MCL - 1 FGFR1 LYN RANK L Targeted Therapy Sorafenib,Everolimus, Vorinostat ( Zolinza) Pazopanib (Votrient) Dasatinib (Sprycel) Denosumab (Xgeva) 19

20 Case Report 1 (cont.) Rationale of the Targeted Treatment Program 1 MCL 1 amplification MCL-1 regulates apoptosis. Amplification inhibits apoptosis. Sorafenib down regulates MCL-1 and synergizes with mtor inhibitors such as everolimus to induce cell death. Down regulation of MCL1 by Sorafenib is synergized by Vorinostat. We postulate that MCL1 amplification is the strongest inhibitory factor of cell death in this genomic pattern. 20

21 Case Report 1 (cont) Program 3 / Course 1: 4/20 to Treatment nab-paclitaxel 5FU sorafenib + Everolimus Pazopanib Dasatinib Denosumab Vorinostat Toxicity: Quality of Life (QoL): Radiology : Conclusion: Duration 16 21

22 HISTORY Original Diagnosis 8/21/2007: Case Report 2 39-year-old female diagnosed 8/21/2007 with left sided breast cancer. Pt had lumpectomy pathology showed ER-, PR- HER-2/neu-, Ki-67 was 90%. BRCA1 and BRACA2 negative treated with adjuvant chemotherapy, Adriamycin / Cyclophosphamide x 4 courses and paclitaxel 4 courses. NED x 5 years. Recurrence November 2013: November 2013 right mammogram suspected lesion, biopsy 12/3/2013 ductal cell carcinoma, ER-, PR-, HER-2/neu- and Ki-67 90%. Treated with docetacel (Taxotere) and Carboplatin and docetacel and cyclophosphamide. Bilateral mastectomy 1/17/2014. Genomic Profiling: Genomic testing for chemotherapy (Caris Life Sciences) Single mutation gene analysis (Foundation Medicine) 22

23 Case Report 2 (cont.) Genomic Profile Caris Life Sciences - Chemotherapy Biomarker RRM1 ( - ) SPARC ( - ) Drug gemcitabine (Gemzar) nab-paclitaxel (Abraxane) TS ( - ) 5FU Foundation Medicine - Targeted Therapy Single Gene Mutations MCL 1 amplification PIK3R1 T369fs*6 BAP1 K626fs*11 LYN amplification Drug sorafenib (Nexavar) everolimus (Afinitor) vorinostat(zolinza) dasatinib (Sprycel) *two (2) additional mutations identified, no drugs available. 23

24 Case Report 2 (cont.) Rationale of the Targeted Treatment Program 1 MCL 1 amplification MCL-1 regulates apoptosis. Amplification inhibits apoptosis. Sorafenib downregulates MCL-1 and synergizes with mtor inhibitors such as everolimus to induce cell death. PIK3R1 (T3bgfs*6) PIK3R1 encodes the p85 protein which stabilizes and inhibits PI3K. The mutation of PIK3R1 activates PI3K pathway signaling and subsequently BAP-1 K626fs*11 Is a tumor suppressor and interacts with protein Brca1 Mutation truncates protein Bap1 and results in loss of BAP1 function. Deregulates BRCA1 maintenance of genomic stability. Vorinostat is being used for potential treatment. the downstream AKT/mTOR pathway. Stimulates cell proliferation. Everolimus is a mtor inhibitor. 24

25 Case Report 2 (cont.) Treatment schedule : Drug and Dose Duration Arm 1 Nab-paclitaxel 50mg/kg Day 3, 7, 10, 14 5FU 800mg bolus Day 3 & 10 Sorafenib 200mg bid Days 1 15 Vorinostat 200 mg daily Days 1-15 Everolimus 5mg daily Days 1-15 Arm 2 Gemcitabine 500mg/m2 Day 3 5FU 1000mg/m2 CI 48hours Days 10 & 11 Sorafenib 200mg bid Days 1-15 Vorinostat 200mg dialy Days 1-15 Everolimus 5mg daily Days 1-15 *Duration of treatments 15 days with time intervals of 15 days 25

26 Case Report 2 (cont.) Treatment Results Evaluation results: 16 + months NED per PET scan and blood tumor marker Toxicity: Minimal G.I. toxicity grade 1 2 hemotoxicity minimal weakness QoL: excellent, patient works a full time job Conclusion: NED not interrupted by recurrence Longer follow up necessary to asses the real benefit 26

27 Case Report 3 HISTORY: In 2011, female age 36 from the Netherlands noticed increasing pain in her groin while biking. Physical examination, xrays and CT scans followed by biopsy of the symphysis in September 2011 revealed metastatic adenocarcinoma. Whole body scanning showed primary of the lung, right upper lobe. Patient was treated with palliative radiotherapy to the pelvis and started erlotinib (Tarveca) in October She still took erlotinib when she came to ACC in April Genetics 2011 NL: EGFR overexpression EGFR mutation exon 19 K-ras wild type At ACC April 2012: PET/CT ( + ) upper lobe of right lung only 70% reduction and decrease in activity May 2012: Removal of primary lesion. Genomic testing (Caris) SPARC EGFR overexpressed EGFR mutation Exon 19 27

28 Rationale of Program 1 Case Report 3 SPARC Overexpression improves tumor response to nab-paclitaxel. EGFR Encodes the protein Egfr which belongs to the receptor tyrosine kinase family Extracellular signals activate the protein Egfr and stimulates growth. Overexpression of EGFR stimulates growth without extra cellular signals Erlotinib, inhibits Egfr activity and cell growth Treatment Program #1 Erlotinib daily Nab-paclitaxol 2x s wkly x1mo q 3 mo Conclusion of Program 1 Progression free for 17 months 9/2011 3/

29 Case Report 3 (cont.) March 2013: ACC, PET / CT ( + ) positive Left pelvic lymph node Subcarinal lymph node Right hilum Peritracheal node Plan of action after progression 1 Removal of subcarinal node for genomic testing Radiation to all positive sites excluding pretracheal node Pretracheal node used for monitoring response to the next genomic program Genomic Results Caris: EGFR mutation Exon19 cmet amplification PIK3CA E726K 29

30 Rationale & Program #2 EGFR overexpressed Exon 19 EGFR overexpression without inhibitory mutations for activation of erlotinib (Tarceva) therefore, the use of eroltinib was continued. cmet overexpressed Overexpression of cmet triggers downstream signaling pathways leading to activation of cellular programs without extracellular stimulation. Associated with resistance to EGFR inhibition. Tivantinib inhibits MEK activity. PIK3CA mutated Encodes the protein p110-alpha, a subunit of 3-kinase (PI3K) Pathway is involved in cell signaling and regulates cell growth Activates and increases PI3K signaling and increases activation of AKT. Predicts sensitivity to inhibitors of the PI3k-AKT-mTOR pathway such as everolimus Treatment Program #2 Erlotinib Tivantinib Everolimus 30

31 Results: Case Report 3 (cont.) Program #2 June 2013: PET/CT: pretracheal node Negative Conclusion: Initially Erlotinib was effective. Resistance to Erlotinib by PIK3CA mutation and by overexpression of cmet. The addition of everolimus and Tivantinib initiated tumor reduction and decreased tumor activity (PET scan negative). The combination of erlotinib, everolimus and Tivantinib induced minor toxicity. 31

32 Radiology: MRI Case Report 3 (cont.) CNS relapse 7small weakly enhancing lesions. PET Negative Treatment : Radiation therapy: Whole-brain irradiation 3000 cgy /10 fractions Treatment: Continuation of Erlotinib, everolimus, Tivantinib July 2013 Recurrence #2: CNS Conclusion: In the CNS, 4 of 7 lesions disappeared and 2 reduced by 50%, 1 lesion stable and was cyberknifed. PET / CT remained negative until April months stable disease 32

33 Case Report 3 (cont.) April 2014 Recurrence #3: Meningeal disease Radiology: MRI 4/7/2014 Meningeal recurrence PET 4/22/2014 lesion left adrenal gland SUV4.2 Results: Slow disease progression in meninges and adrenal gland. Conclusion: Progression of disease most likely due to additional mutation(s). Initial Treatment: Temodar + intrathecal MTX Continue Erlotinib, everolimus, Tivantinib 33

34 Case Report 3 Plan of action after disease progression Removal of adrenal gland Debulking Genomic testing Genomic results: EGFR amplification + 790M Exon 20 cmet overexpressed PIK3CA E726K Treatment Program #3 Afatinib replacing erlotinib Tivantinib cmet Everolimus PIK3CA Results Major improvement of CNS disease including meningeal disease Rationale : Afatinib overrides the EGFR T790 mutation Afatinib crosses the blood brain barrier Tivantinib is active against C-MET overexpression Everolimus inhibits the mtor pathway Temodar and intratheacal MTX were deleted due to toxicity and disease progression 34

35 Case Report 3 (cont.) Conclusion Afatinib (Gilotrif) is effective despite 790M in EGFR Afatinib (Gilotrif) is passing the blood brain barrier Treatment longer than 14 days caused severe weakness, GI symptoms, and marrow toxicity Toxicity reversible by interruption of treatment Quality of life was meaningful Patient opted to stop treatment in July 2014 and expired , 3 ½ years after diagnosis. 35

36 Case Report (4) Age: 38 Diagnosis: Status: Treatment: Nonseminoma, yolk sac tumor After 4 th recurrence Fifth-line chemo plus high-dose chemo plus autologous stem cells, achieved CR, followed with involved-field radiation and maintenance with irinotecan (CPT-11), Doxorubicin (Adriamycin) followed by Gemcitabine (Gemzar) + Carboplatin with the addition of Sunitinib(Sutent) according to Caris for the last 48+ months. Conclusion: NED 48+ months; AFP <10 Data in literature: OS <10% 12 mo after high-dose 36

37 Case Report 5 - Update from 2013 History 69 year-old male from the Netherlands diagnosed August 2011 with metastatic adenocarcinoma of the cecum with metastasis to peritoneum and right lung. Pt had surgery in October 2011 to attempt to remove the primary tumor. ACC treatment begins: November 2011 Removal of primary tumor Removal right upper lung lobe metastasis Genomic testing (Caris Life Science) 37

38 Case Report 5 (cont.) Genomic Profile by Caris Life Science Primary Tumor Biomarker Effective Drug Peritoneal Met Biomarker Effective Drug TS SPARC TOP1A PDGRRB HIFIA - 5 FU TS - Abraxane ERCC1 - Anthracycline SPARC + Sutent TOP2A Sutent * Not effective for Erbitux, Platinol, CPT-11 Lung Met Biomarker TS SPARC TOP FU Platinol Abraxane anthracycline *Not effective for Erbitux and CPT- 11 Effective Drug 5FU Abraxane irinotecan * Not effective for Erbitux and Platinol

39 Case Report 5 (cont.) Treatment at ACC : 12/ /2013 (24 months): Avastin, CPT-11, 5FU bolus, Abraxane, 5FU C.I. Avastin, CPT-11, 5FU bolus, Abraxane, Oxaliplatin, 5FU C.I. 3 4 weeks between courses Results: PET/CT stayed negative with normal CEA and became weakly positive on 11/27/2013: Two small lesions in the right lung, 1 small lesion in the left lung, CEA 7 39

40 Case Report 5 (cont.) Transferred treatment to the Netherlands: 1/2014 Current Oxaliplatin, Xeloda, Avastin Oxaliplatin, 5 FU bolus C.I., Avastin Interruptions of treatment at the request of the patient. Results: CT scan 3/17/2015; 4 pulmonary lesions, stable since 1/14/2015 CEA 24 Quality of Life is excellent 45 months after onset of disease!! 40

41 2002 HERO: Jop Rappange 21 months old, inoperable anaplastic astrocytoma; c- Kit+++Treated with radiation, Temodar, Thalidomide, Gleevec. 41

42 2013 In action - CR 11+ years. 42

43 2015 CR 13 + years, A Dream Come True! 43

44 A Special Thank You to The patients and family of our case study patients. Foundation Medicine team Caris Life Sciences team Dr. Alden Kielhorn Jerome Madison Dr. Reinhardt von Daiichi Cankyo ACC staff Sylvia Hanks Ashley Davis Jessica Watson Angela Vadrasko Lee Knox, Regulatory Spec. THR FDA Staff Bethesda, MD IRB, THR 44