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This presentation provides an overview of FDA-approved targeted therapy options for various types of cancer, including breast carcinoma, thyroid carcinoma, melanoma, renal cell carcinoma, and other solid tumors. The slides cover the mechanism of action and clinical indications for each therapy.
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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, 2014
BCR-ABL Mutations Described After Imatinib Hughes T, et al. Blood. 2006;108:28-37
Therapeutic Target Assessment by IHC: BTK Normal tonsil Follicular lymphoma
Ligand EGFR Signaling Pathway EGFR * * * * * Mutated InTumors GRB SOS BRAF KRAS P P P P Proliferation mTOR STAT AKT PI3-K ERK MEK Anti-Apoptosis NUCLEUS
Breast Carcinoma: FDA-Approved Tx • Anti-ER: • 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) • Anti-HER2: • Trastuzumab (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) • Anti-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 radioiodine • 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)
Melanoma: FDA-Approved Therapies • Anti-BRAF: For metastatic melanoma with V600E muta. • Vemurafinib/Zelboraf (2011) • Dabrafenib/Tafinlar (2013) • Trametinib/Mekinist (2013; 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 node-positive @ >1 mm (2015) • Anti-PD-1 (pembrolizumab/Keytruda): • 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) • Anti-PD-1 (Nivolumab/Opdivo): • With ipilimumab for BRAF-WT unresectable or metastatic melanoma (2015)
RTK * Constitutive RTK Signaling Due to Mutant BRAF in the Absence of Ligand Mutated BRAF BRAF KRAS ERK MEK Proliferation Anti-Apoptosis NUCLEUS
Melanoma: Chapmen et al., NEJM, 2011, 364:2507 • Vemurafenib treatment resulted in improved overall survival and progression free survival compared to dacarbazine • Response rates were 48% for vemurafenib and 5% for dacarbazine • Vemurafenib (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, 2005 • Anti-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, 2016
Other Solid Tumors: FDA-Approved • Anti-c-KIT (imatinib): For metastatic/unresectable GISTs (2002) • 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-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-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-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-mTOR (everolimus/Afinitor): For subependymal giant cell astrocytoma in tuberous scleroisis patients, 2010; For non-functional/ non-sectoryneuroendocrine 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, 2016 • Anti-PD-L1 (atezolizumab/Tecentriq): For locally advanced or metastatic urothelial CA worsening after platinum-based tx, 2016
