Page 283 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

262 PART III Therapeutic Modalities for the Cancer Patient

of B-cell malignancies 145,146 and cetuximab (Erbitux), which tar- are typical in this subset of patients, with many more of patients
gets ErbB1/HER1/EGFR known to be overexpressed in several experiencing long-term disease stabilization. 165,166
Vemurafenib (Zelboraf) is a small molecule inhibitor of B-raf
76,140,147
carcinomas.
VetBooks.ir ATP binding site of kinases, essentially acting as either reversible that has significant activity against cutaneous malignant melano-
Small molecule inhibitors work primarily by blocking the
mas that possess activating mutations in the BRAF gene. Response
or irreversible competitive inhibitors; a smaller number of these rates in the setting of BRAF mutant melanoma exceed 50%, com-
inhibitors work by preventing necessary protein–protein interac- pared with less than 5% for patients treated with dacarbazine. 167
tions (allosteric inhibition). 148 In the absence of ATP, the kinase Inhibition of mTOR has become of interest in several cancers,
is unable to phosphorylate itself or downstream signaling ele- given the activation of the PI3K pathway and the critical role of
ments, thereby interrupting a survival/growth signal essential to mTOR in mediating its effects. Rapamycin (Rapamune), a drug
the tumor cell, ultimately resulting in cell death. As the molecular used for many years as an immunosuppressive agent, is the pro-
characterization of tumors has improved, the development and totypic mTOR inhibitor. 168,169 Temisorlimus (Torisel) and evoro-
application of small molecule inhibitors has rapidly expanded in limus (Zortress), two rapamycin analogs, have been approved for
human oncology, and their use is markedly altering how cancers use in patients with metastatic renal carcinoma, and other mTOR
are managed. Such inhibitors are often easy to synthesize in large inhibitors are currently under investigation for their potential util-
quantities, frequently orally bioavailable, and can readily enter ity in treating soft tissue and bone sarcomas. 168,169
cells to bind the intended target. Several new kinase inhibitors target signal transduction path-
The first small molecule inhibitor to be approved for human ways in hematologic malignancies. Ibrutinib (Imbruvica) blocks
use was imatinib (Gleevec), an orally administered drug that binds signaling through the BTK cytoplasmic kinase that is critical for
the ATP pocket of ABL and the RTKs KIT and PDGFR-α. 149 B cell receptor activity. 170 It is approved for use in several B-cell
As previously discussed, BCR-ABL fusion proteins are present in malignancies including CLL, follicular lymphoma, and Walden-
90% of human patients with CML, making ABL a good target ström’s macroglobulinemia; response rates in these diseases
for therapeutic intervention. The application of imatinib to CML typically exceed 70% to 80% and are often durable in nature.
has been transformative, with significant biologic activity demon- With respect to T-cell malignancies, small molecule inhibitors
strated in several clinical trials resulting in the approval of ima- of PI3Kγδ (tenalisib, duvelisib) have shown significant activity
tinib for first-line care of affected individuals. 150–155 In the chronic against peripheral and cutaneous T-cell lymphomas, with response
phase of the CML, imatinib induces a remission rate of close to rates ranging from 40% to 50%. 171
95%, and most patients remain in remission for longer than 1 Whereas the inhibitors discussed earlier tend to inhibit a
year. Unfortunately, the remission rate is much lower for patients restricted set of kinases, there are other inhibitors that exhibit more
in blast crisis (20%–50%), often lasting less than 10 months. broadly targeted inhibition. Sunitinib (Sutent) is a small molecule
Resistance to imatinib has been well characterized and is primar- inhibitor of several RTKs including VEGFR1/2, PDGFR-α/β,
ily a result of the development of mutations in ABL that prevent KIT, FLT3, CSFR1, and RET. 172 The multitargeted nature of this
drug binding, although gene amplification has also been docu- inhibitor may be responsible for its observed activity in several
mented. 156,157 Imatinib also has clinical activity against human types of cancer including GIST, renal cell carcinoma, thyroid car-
GIST, in which 50% to 60% of the tumors have point mutations cinoma, and insulinoma, among others. 172 Although such agents
or deletions in the juxtamembrane domain of KIT resulting in often have significant clinical activity, they are typically associated
constitutive activation. 158,159 Imatinib therapy for GIST patients with a broader range of toxicities that may limit their use.
results in response rates of 50% to 70%, far better than the 5%
response rate observed with standard chemotherapy. 160,161 A small Kinase Inhibitors in Veterinary Medicine
number of GISTs have activating mutations in PDGFR-α instead
of KIT mutations; these patients also respond to imatinib. 162 There are now two small molecule inhibitors approved for use in
There are now more than 30 FDA-approved protein kinase dogs in veterinary oncology. Toceranib (TOC) phosphate (Palladia)
inhibitors for the treatment of human cancers, ranging from is a multitargeted inhibitor closely related to sunitinib that exhibits
those that target specific mutations in a single kinase to those a similar target profile including VEGFR, PDGFR, KIT, FLT3, and
that are multitargeted in nature, affecting both tumor cells CSF1R. TOC has demonstrated activity against MCT and sarcomas
and the microenvironment. For example, a subset of people and carcinomas. In the original phase I study, 28% of dogs expe-
with NSCLC have tumors with activating mutations in EGFR rienced objective responses to treatment, with an additional 26%
(in exons 19 or 21) that respond to erlotinib (Tarceva) or gefi- experiencing stable disease for an overall clinical benefit of 54%.
173
tinib (Iressa), small molecule inhibitors of EGFR. 163 Response A pivotal study of TOC was subsequently conducted in dogs with
rates in patients with EGFR mutations can be as high as 80% recurrent or metastatic intermediate or high-grade MCTs, resulting in
compared with less than 10% to 20% for those without, dem- an objective response rate of 42.8% (21 complete responses (CR), 42
onstrating that the efficacy of targeted therapies is often depen- partial responses (PR)), with an additional 16 dogs experiencing sta-
dent on the presence of a known activated signaling element. ble disease for an overall clinical benefit of 60%. Dogs whose MCT
174
Resistance to erlotinib/gefitinib is often mediated by a second harbored activating mutations in KIT were roughly twice as likely to
mutation at codon 790 (T790M), and a protein kinase inhibi- respond to TOC than those without mutations (69% vs 37%). After
tor osimertinib (Tagrisso), which targets this specific resistance approval of TOC in 2009, it has been used to treat a number of differ-
175
mutation, has been approved. 164 A small number of patients ent solid tumors. Biologic activity has been reported in dogs with
with NSCLC also exhibit activation of the RTK ALK through anal sac adenocarcinoma, thyroid carcinoma, head and neck carci-
its fusion to EML4. 165 A small molecule inhibitor of ALK, crizo- noma, and nasal carcinoma. Work is ongoing to more clearly define
tinib (Xalkori) has demonstrated significant activity against lung the role of TOC in the treatment of canine and feline cancer.
cancer patients whose tumors express the EML4–ALK transloca- Mastinib (MAS, Kinavet, Masivet) is a small molecule inhibi-
tion. Objective response rates of greater than 50% to crizotinib tor of KIT, PDGFR-α/β and Lyn that has been evaluated in both