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 ID: 784900
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Slide1
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
Slide2Other Hematolymphoid Disorders,
FDA-Approved
IL-6 inhibition (siltuximab/Sylvant): For multicentric Castleman disease in HIV- / HHV-8-negative patients, 2014
Slide3BCR-ABL Mutations Described After
Imatinib
Hughes T, et al.
Blood
. 2006;108:28-37
Slide4Therapeutic Target Assessment by IHC: BTK
Normal tonsil
Follicular lymphoma
Slide5P
P
P
P
GRB
SOS
MEK
BRAF
KRAS
ERK
PI3-K
AKT
mTOR
STAT
EGFR Signaling
Pathway
NUCLEUS
EGFR
Ligand
Proliferation
Anti-Apoptosis
*
*
*
*
*
Mutated
In
Tumors
Slide6Breast 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
Slide7Thyroid 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)
Slide8Melanoma: 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)
Slide9Melanoma: 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)
Slide10NUCLEUS
RTK
BRAF
KRAS
ERK
MEK
Proliferation
Anti-Apoptosis
Constitutive RTK Signaling Due to Mutant BRAF in the Absence of Ligand
*
Mutated
BRAF
Slide11Melanoma: 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
Slide12Renal 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
Slide13Other 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)
Slide14Other 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-sectory neuroendocrine tumors of GI or lung origin & unresectable, locally advanced or metastatic disease, 2016Anti-tubulin (eribulin/
Halaven
): For
unresectable or metastatic liposarcoma and prior anthracycline, 2016Anti-PD-L1 (atezolizumab/Tecentriq): For locally advanced or metastatic urothelial CA worsening after platinum-based tx
, 2016