TARGETED CANCER THERAPY IN 2016: WHAT THE PRACTICING PATHOLOGIST OR ONCOLOGIST NEEDS TO KNOW (SUPPLEMENTARY SLIDES) Steven J. Kussick, MD, PhD Associate Medical Director PhenoPath Laboratories May 2016

Other Hematolymphoid Disorders, FDA-Approved IL-6 inhibition (siltuximab/Sylvant): For multicentric Castleman disease in HIV- / HHV-8-negative patients, 2014IL-6 inhibition (siltuximab/Sylvant): For multicentric Castleman disease in HIV- / HHV-8-negative patients, 2014

BCR-ABL Mutations Described After Imatinib Hughes T, et al. Blood. 2006;108:28-37

Therapeutic Target Assessment by IHC: BTK Therapeutic Target Assessment by IHC: BTK Normal tonsil Follicular lymphoma

P P P P GRBSOSMEKBRAFKRASERKPI3-KAKTmTORSTAT EGFR Signaling Pathway NUCLEUS EGFR Ligand Proliferation Anti-Apoptosis * * * * * Mutated In Tumors

Breast Carcinoma: FDA-Approved Tx Anti-ER:Anti-ER: Tamoxifen (selective estrogen receptor modulation, first approved in 1990; approved for CA risk reduction in 1998)Tamoxifen (selective estrogen receptor modulation, first approved in 1990; approved for CA risk reduction in 1998) Palbociclib (Ibrance, CDK4/6 inhibitor) for use with letrozole for the treatment of postmenopausal women with ER-positive, HER2-negative advanced breast cancer as initial endocrine therapy (2014), or after endocrine therapy (2016)Palbociclib (Ibrance, CDK4/6 inhibitor) for use with letrozole for the treatment of postmenopausal women with ER-positive, HER2-negative advanced breast cancer as initial endocrine therapy (2014), or after endocrine therapy (2016) Anti-HER2:Anti-HER2: Trastuzumab (Herceptin) - first FDA approval in 1998, plus later additionsTrastuzumab (Herceptin) - first FDA approval in 1998, plus later additions Pertuzumab (Perjeta) - targets extracellular dimerization domain of HER2, and blocks ligand-dependent hetero-dimerization of HER2 with other HER family members (2013)Pertuzumab (Perjeta) - targets extracellular dimerization domain of HER2, and blocks ligand-dependent hetero-dimerization of HER2 with other HER family members (2013) Anti-VEGF-A (bevacizumab/Avastin): Approved for metastatic breast CA in 2008, revoked in 2011 for lack of survival benefitAnti-VEGF-A (bevacizumab/Avastin): Approved for metastatic breast CA in 2008, revoked in 2011 for lack of survival benefit

Thyroid Carcinoma: FDA-Approved Tx Anti-RAF/MEK/ERK pathway (sorafenib/Nexavar): For locally recurrent or metastatic thyroid carcinoma refractory to radioiodineAnti-RAF/MEK/ERK pathway (sorafenib/Nexavar): For locally recurrent or metastatic thyroid carcinoma refractory to radioiodine Anti-RET/MET/VEGFR-2 (cabozantinib/Cometriq): For metastatic medullary thyroid CA (2012)Anti-RET/MET/VEGFR-2 (cabozantinib/Cometriq): For metastatic medullary thyroid CA (2012) Anti-pan-VEGFR (lenvatinib/Lenvima): For locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated (follicular or papillary) thyroid cancer (2015)Anti-pan-VEGFR (lenvatinib/Lenvima): For locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated (follicular or papillary) thyroid cancer (2015)

Melanoma: FDA-Approved Therapies Anti-BRAF: For metastatic melanoma with V600E muta.Anti-BRAF: For metastatic melanoma with V600E muta. Vemurafinib/Zelboraf (2011)Vemurafinib/Zelboraf (2011) Dabrafenib/Tafinlar (2013)Dabrafenib/Tafinlar (2013) Trametinib/Mekinist (2013; also for V600K)Trametinib/Mekinist (2013; also for V600K) Cobimetinib/Cotellic (2015; for combination with Vemurafinib, also for V600K)Cobimetinib/Cotellic (2015; for combination with Vemurafinib, also for V600K)

Melanoma: FDA-Approved (cont.) Anti-CTLA-4 (ipilimumab/Yervoy) for unresectable/late-stage melanoma (2013), or regional >1 mm (2015)Anti-CTLA-4 (ipilimumab/Yervoy) for unresectable/late-stage melanoma (2013), or regional >1 mm (2015) Anti-PD-1 (pembrolizumab/Keytruda):Anti-PD-1 (pembrolizumab/Keytruda): Unresectable or metastatic disease with progression after ipilimumab and, if BRAF+, after BRAF inhibitor (2014)Unresectable or metastatic disease with progression after ipilimumab and, if BRAF+, after BRAF inhibitor (2014) Initial treatment of patients with unresectable or metastatic melanoma (2015)Initial treatment of patients with unresectable or metastatic melanoma (2015) Anti-PD-1 (Nivolumab/Opdivo):Anti-PD-1 (Nivolumab/Opdivo): With ipilimumab for BRAF-WT unresectable or metastatic melanoma (2015)With ipilimumab for BRAF-WT unresectable or metastatic melanoma (2015)

NUCLEUS RTK BRAFKRASERKMEK Proliferation Anti-Apoptosis Constitutive RTK Signaling Due to Mutant BRAF in the Absence of Ligand * Mutated BRAF

Melanoma: Chapmen et al., NEJM, 2011, 364:2507 Vemurafenib treatment resulted in improved overall survival and progression free survival compared to dacarbazineVemurafenib treatment resulted in improved overall survival and progression free survival compared to dacarbazine Response rates were 48% for vemurafenib and 5% for dacarbazineResponse rates were 48% for vemurafenib and 5% for dacarbazine Vemurafenib (Zelboraf) is FDA approved for metastatic melanoma patients with a BRAF V600E mutationVemurafenib (Zelboraf) is FDA approved for metastatic melanoma patients with a BRAF V600E mutation

Renal Cell Carcinoma: FDA-Approved Tx Anti-RAF/MEK/ERK pathway (sorafenib/Nexavar): For advanced renal cancer, 2005Anti-RAF/MEK/ERK pathway (sorafenib/Nexavar): For advanced renal cancer, 2005 Anti-VEGF-A (bevacizumab/Avastin): Metastatic renal cell CA, 2009Anti-VEGF-A (bevacizumab/Avastin): Metastatic renal cell CA, 2009 Cabozantinib (Cabometyx): For advanced renal cell CA in patients who have received prior anti-angiogenic therapy, 2016Cabozantinib (Cabometyx): For advanced renal cell CA in patients who have received prior anti-angiogenic therapy, 2016

Other Solid Tumors: FDA-Approved Anti-c-KIT (imatinib): For metastatic/unresectable GISTs (2002)Anti-c-KIT (imatinib): For metastatic/unresectable GISTs (2002) Anti-RAF/MEK/ERK pathway (sorafenib/Nexavar): For advanced hepatocellular carcinoma (2007)Anti-RAF/MEK/ERK pathway (sorafenib/Nexavar): For advanced hepatocellular carcinoma (2007) Anti-EGFR (cetuximab/Erbitux): For advanced squamous CA of head and neck (2006)Anti-EGFR (cetuximab/Erbitux): For advanced squamous CA of head and neck (2006) Anti-HER2 (trastuzumab): For HER2+ metastatic gastric CA by IHC (2010)Anti-HER2 (trastuzumab): For HER2+ metastatic gastric CA by IHC (2010) Anti-VEGF-A (bevacizumab/Avastin): For recurrent glioblastoma (2009); Recurrent/metastatic cervical CA, with paclitaxel and cisplatin/topotecan (2014)Anti-VEGF-A (bevacizumab/Avastin): For recurrent glioblastoma (2009); Recurrent/metastatic cervical CA, with paclitaxel and cisplatin/topotecan (2014) Anti-VEGFR (ramucirumab/Cyramza): For advanced/metastatic gastric/gastroesophageal adenocarcinoma with progression on or after prior treatment with chemotherapyAnti-VEGFR (ramucirumab/Cyramza): For advanced/metastatic gastric/gastroesophageal adenocarcinoma with progression on or after prior treatment with chemotherapy (2015)

Other Solid Tumors: FDA-Approved (cont.) Anti-GDS (dinutuximab/Unituxin): High risk peds. neuroblastoma with at least partial response to 1st-line multiagent therapy (2015)Anti-GDS (dinutuximab/Unituxin): High risk peds. neuroblastoma with at least partial response to 1st-line multiagent therapy (2015) Anti-FUS/CHOP DNA binding (trabectedin/Yondelis): Unresectable or metastatic liposarcoma or leiomyosarcoma, in patients who have received a prior anthracycline (2015)Anti-FUS/CHOP DNA binding (trabectedin/Yondelis): Unresectable or metastatic liposarcoma or leiomyosarcoma, in patients who have received a prior anthracycline (2015) Anti-smoothened (sonidegib/Odomzo): Locally advanced basal cell carcinoma that has recurred after surgery or radiation (2015)Anti-smoothened (sonidegib/Odomzo): Locally advanced basal cell carcinoma that has recurred after surgery or radiation (2015) Anti-mTOR (everolimus/Afinitor): For subependymal giant cell astrocytoma in tuberous scleroisis patients, 2010; For non- functional/ non-sectory neuroendocrine tumors of GI or lung origin & unresectable, locally advanced or metastatic disease, 2016Anti-mTOR (everolimus/Afinitor): For subependymal giant cell astrocytoma in tuberous scleroisis patients, 2010; For non- functional/ non-sectory neuroendocrine tumors of GI or lung origin & unresectable, locally advanced or metastatic disease, 2016 Anti-tubulin (eribulin/Halaven): For unresectable or metastatic liposarcoma and prior anthracycline, 2016Anti-tubulin (eribulin/Halaven): For unresectable or metastatic liposarcoma and prior anthracycline, 2016 Anti-PD-L1 (atezolizumab/Tecentriq): For locally advanced or metastatic urothelial CA worsening after platinum-based tx, 2016Anti-PD-L1 (atezolizumab/Tecentriq): For locally advanced or metastatic urothelial CA worsening after platinum-based tx, 2016