Case studies of the development of targeted therapies for cancer: - PDF document

As Presented at the NCCS Cancer Policy Roundtable October 18-19, 2011 Case studies of the development of targeted therapies for cancer: 1. BRAF inhibitors in melanoma 2. Autophagy Inhibitors Ravi Amaravadi, MD Assistant Professor of Medicine Division of Hematology-Oncology Department of Medicine Abramson Cancer Center Perelman School of Medicine University of Pennsylvania Disclosures Laboratory Grant Funding NCI Abramson Cancer Center Penn-Pfizer Alliance Millenium Pharmaceuticals Tetralogics Pharmaceuticals Industry Support for clinical trials Advisory Board/Speakers Fee Pfizer Tetralogics Millenium Novartis Roche Roche Merck Bayer Millenium (Takeda) Genentech Patent Pending US 61/177,697 Combination antineoplastic therapy with mTOR and autophagy inhibitors US 61/486,641 Novel autophagy inhibitors for cancer therapy 1

As Presented at the NCCS Cancer Policy Roundtable October 18-19, 2011 Case 1: BRAF inhibitors for metastatic melanoma Treatment of Metastatic Melanoma: No standard 1 st Line therapy identified Interferon Interleukin-2 Cisplatin, Vincristine, Dacarbazine v. Dacarbazine Temozolomide High dose temozolomide Tamoxifen Median Survival: 8 months Median Survival Brain Metastases: 3 months 2

As Presented at the NCCS Cancer Policy Roundtable October 18-19, 2011 2010 NCCN guidelines for first line treatment of Stage IV melanoma Clinical trial preferred Or Interleukin 2 Or Dacarbazine Or Temozolomide ± cisplatin and vinblastine 3

As Presented at the NCCS Cancer Policy Roundtable October 18-19, 2011 Ibrahim and Haluska Ann rev. pathology mech. Disease 2009 Suppression of BRAF induces cell death in BRAF mutant cell lines Karasarides et al. Oncogene (2004) 23, 6292–6298 4

As Presented at the NCCS Cancer Policy Roundtable October 18-19, 2011 CF 3 O O Cl O N Sorafenib H N N N H H Kinase assays IC 50 C-Raf 2 nM mVEGFR2, 6-10 nM VEGFR3 wt B-Raf, V599E B- 20–40 nM Raf p38, PDGFr � 28–38 nM FLT-3, c-KIT 40–80 nM EGFR, PKC, MEK, Inactive at ERK 10 mM Wan PT et al. Cell. 2004 Mar 19;116(6):855-67 Sorafenib in Melanoma 2002: phase II trial of sorafenib 2002: phase II trial of sorafenib in melanoma: 2% response rate. in melanoma: 2% response rate. 2002: phase I/II trial of 2002: phase I/II trial of sorafenib sorafenib + + carboplatin carboplatin and and paclitaxel paclitaxel 105 patients: 27% response rate/8 month PFS 105 patients: 27% response rate/8 month PFS 2005: 2005: Sorafenib Sorafenib approved for renal cell ca approved for renal cell ca 2007 Sorafenib 2007 Sorafenib approved for HCC approved for HCC 2007 2007-2009: 2 large randomized phase III trials (n=>1000 patients) 2009: 2 large randomized phase III trials (n=>1000 patients) of of sorafenib sorafenib + + carbo carbo/taxol taxol versus versus carbo carbo/taxol taxol found absolutely no found absolutely no difference in response rate, or survival with the addition of difference in response rate, or survival with the addition of sorafenib to chemotherapy sorafenib to chemotherapy 5

As Presented at the NCCS Cancer Policy Roundtable October 18-19, 2011 Could targeting BRAF be too simplistic or even misguided? 33,345 mutations were found in the Nature 463 , 191-196 (14 January 2010) | doi:10.1038/nature08658; Received 30 July melanoma genome compared to 2009; Accepted 4 November 2009; Published online 16 December 2009; Corrected 14 the normal genome from the same January 2010 patient. A comprehensive catalogue of somatic mutations from a human cancer genome Erin D. Pleasance 1,8 et al. 187 mutations were predicted to alter the known function of specific proteins. 6

As Presented at the NCCS Cancer Policy Roundtable October 18-19, 2011 Pharmacodynamics: Does the drug hit its target in patient tumors? Pre-treatment Post-treatment Sorafenib: No PLX4032: Yes 7

As Presented at the NCCS Cancer Policy Roundtable October 18-19, 2011 Phase I Results of PLX4032 in patients with BRAF mutant melanoma Dose and schedule 960 mg bid maximal tolerated dose and phase II dose Safety Common side effects include a rash, squamous cell carcinoma, and fatigue. Response Definition No % Complete response No evidence of disease 1 4 Partial Response >30% tumor shrinkage 18 67 from baseline Stable Disease <30% shrinkage and 6 22 <20% growth from (all had baseline shrinkage) Progressive Disease >20% growth from 2 7 baseline or new tumors Total 27 100 V600E+ melanoma patient PET scan at baseline and day +15 after PLX4032 treatment at 720 mg BID Day 0 Day 15 Flaherty, ASCO 2009 8

As Presented at the NCCS Cancer Policy Roundtable October 18-19, 2011 1st interim analysis found that Vemurafenib reduces the risk of progression by 74% and the risk of dying by 63% compared to chemotherapy Chapman et al NEJM 2011 The rapid success and approval of vemurafenib in BRAF mutant melanoma depended on the following: 1) The molecular target was identified and validated in preclinical models 2) The target is present in a large fraction of patients 3) Lessons learned from the failure of the first generation Raf inhibitor sorafenib were used by persistent investigators 4) A more potent and specific second generation inhibitor was found 5) Phase I testing with PK and PD analysis was performed with rigor 6) The phase I dose was increased to the maximal tolerated dose 7) The drug was tested in a biomarker-restricted population (BRAF mutant melanoma) 8) An OPEN collaboration between multiple academic investigators, Pharma teams, and the FDA 9) LUCK 9

As Presented at the NCCS Cancer Policy Roundtable October 18-19, 2011 Case 2: Autophagy a new therapeutic target in cancer Autophagy, the cell’s garbage disposal and built in recycling plant gets rid of waste and feeds the cancer cell when it is faced with stresses. Damaged cell component Autophagic Vesicle Recycled building blocks Lysosome 10

As Presented at the NCCS Cancer Policy Roundtable October 18-19, 2011 Chloroquine derivatives impair the lysosome, blocking the last step of autophagy Autophagy Inhibition augments cancer cell death in the context of… Nutrient Limitation Lum et al. Cell 2005 Growth Factor Limitation Lum et al. Cell 2005 P53 activation or Amaravadi et al. JCI 2007 Alkylating chemotherapy Tumorigenesis McLean et al. JCI 2008 HDAC inhibitor Carew et al. Blood 2007 Dormant tumor cells Luo et al. JCI 2008 Akt inhibitor Degtyarev M J Cell Bio 2008 (Genentech) Imatinib Bellodi JCI 2009 Velcade Ding et al. MBC 2009 11

As Presented at the NCCS Cancer Policy Roundtable October 18-19, 2011 Could chloroquine (CQ) or hydroxychloroquine (HCQ) be used to treat cancer? • Chloroquine derivatives used in humans since 1940’s • Used for decades for malaria, rheumatoid arthritis • Extensive preclinical testing, hundreds of thousands of patients worth of safety data • Hydroxychloroquine is a safer drug than chloroquine at high doses • Generic drug with no pharmaceutical company interested in marketing for cancer indications Excellent brain penetration Drug Monthly Cost Erbitux $ 9600 Avastin $ 4400-8800 Sorafenib $ 5614 Gleevec $ 3816 Herceptin $ 3195 Tarceva $ 2697 Hydroxychloroquine $ 50-200 12

As Presented at the NCCS Cancer Policy Roundtable October 18-19, 2011 Other investigators have already tested chloroquine for cancer Randomized phase III trial of RT/carmustine +/- low dose CQ in newly diagnosed Glioma (Brain Tumors) Sotelo, et al. Ann Int. Med. 2006. Kaplan Meier Analysis of Overall Survival in GBM patients treated on the phase III trial of CQ/carmustine/RT v. placebo/carmustine/RT ( p>0.05) HCQ Trial #1: ABTC 0603: A phase I/II trial of hydroxychloroquine with radiation therapy and concomitant and adjuvant temozolomide in patients with newly diagnosed GBM Initiation Cycle Initiation Cycle PI: Myrna Rosenfeld, MD, PhD WK WK 1 1 2 2 3 3 4 4 5 5 6 6 7 7 8 8 9 9 10 10 Sample Size: Phase I: 6-18 Phase II: 76 Radiation 59.4 Gy/33 fractions Radiation 59.4 Gy/33 fractions RT RT 80% power to detect a 40% v. 26% 2-year overall survival rate. Temozolomide 75 mg/m2 po qd Temozolomide 75 mg/m2 po qd TMZ TMZ HCQ HCQ Hydroxychloroquine 200 mg po qd…MTD Hydroxychloroquine 200 mg po qd…MTD Setting ABTC (15 centers) Maintenance Cycle: Maintenance Cycle: 1-5 1-5 6-28 6-28 DAY DAY TMZ 150 mg/m 2 TMZ 150 mg/m 2 TMZ TMZ po d1-5 po d1-5 HCQ HCQ HCQ 200 mg po qd…MTD HCQ 200 mg po qd…MTD 13