Targeted therapy for cancer in cats and dogs.

Targeted Therapy for Cats and Dogs with Cancer

What are targeted cancer therapies?
Targeted cancer therapies refer to drugs or other agents that block the growth and/or spread of cancer by interfering with
specific molecules in the tumor cells known to be important for cancer progression. Scientists often call these molecules
“molecular targets” so targeted cancer therapies are sometimes referred to as “molecularly targeted drugs,” “molecularly
targeted therapies,” or other similar names. Since targeted therapies act on molecules specific to cancer cells, they hold
the promise to be more effective than other types of treatment, including chemotherapy and radiation therapy, with
potentially less toxicities. In some cases, targeted therapies can be combined with existing treatments in order to improve
the efficacy.

How do targeted cancer therapies work?
Targeted cancer therapies interfere with cancer cell division (multiplication) and spread to other organs (metastasis) in
different ways. Many of targeted therapies focus on proteins involved in signaling pathways, which form a complex
communication system that cells use to control basic cellular functions such as cell division, cell movement or how a cell
responds to specific external stimuli. Since targeted therapies are designed to block signals that tell cancer cells to grow
and multiply, these therapies help stop cancer progression and may cause killing of cancer cells through a process
known as apoptosis. Other targeted therapies can cause cancer cell death directly, by specifically inducing the process of
apoptosis, or indirectly, by stimulating the immune system to recognize and destroy cancer cells and/or by delivering toxic
substances to them.

Once a molecular target has been identified by scientists, a therapy must be developed. Most targeted therapies are
either small molecule drugs or monoclonal antibodies. Small molecule drugs are typically able to diffuse into cells and can
act on targets that are found inside the cell. Most monoclonal antibodies usually cannot diffuse into the cells and are
directed against targets located on the outside cell surface. Candidates for small-molecule drugs are usually identified in
studies known as drug screens - laboratory tests that look at the effects of thousands of test compounds on a specific
molecular target. The best candidates are then chemically modified to produce numerous versions, each of which is
tested to identify the most effective and specific drug(s) - called lead compound(s). The lead compound is then tested in
laboratory animals for safety and any signs of efficacy, and once these tests are satisfactorily completed, the lead
compound becomes available for a clinical trial in client-owned pets with the disease of interest. If the drug shows efficacy
in these client-owned pets and has an acceptable safety profile, the drug's safety and efficacy data is submitted for a
review by government regulatory agencies that oversee the development of drugs for veterinary medicine. Once
approved, the drug becomes commercially available.

What targeted therapies are currently approved in cats and dogs with cancer?
In the United States, two targeted cancer therapies are currently approved for mast cell tumors in dogs. Palladia
(toceranib, Pfizer Animal Health) is currently approved for Grade II/III cutaneous (skin) mast cell tumors in dogs; and
Kinavet (masitinib, AB Science) has been recently approved as treatment for recurrent or non-resectable (tumors that
cannot be surgically removed) Grade II and Grade III cutaneous mast cell tumors in dogs that have not previously
received radiotherapy and/or chemotherapy except corticosteroids.

In Europe, masitinib (sold under the name Masivet) was approved in November 2008 for dogs with non-resectable Grade
II/III mast cell tumors that have a confirmed mutation in a c-KIT tyrosine kinase receptor (the molecular target of both
Palladia and masitinib). Palladia is also approved in Europe.

Palladia (toceranib phosphage, Pfizer Animal Health)
Palladia specifically inhibits several molecular targets: proteins called c-KIT, vascular endothelial growth factor receptor-2
(VEGFR-2), and platelet-derived growth factor receptor (PDGFR-beta), which are known to play a role in cancer. Palladia
was evaluated in a multi-center, randomized, placebo-controlled clinical trial in 153 dogs with mast cell tumors that
recurred (came back) after surgery. In this study, dogs were randomized to either receive Palladia (given orally at 3.25
mg/kg dose) or placebo (inactive substance serving as a control) every other day for six weeks. During this time, neither
the veterinary oncologist nor the owner knew which pill was administered (Palladia or placebo) - a term known as blinded
study - to ensure that no bias is introduced and the study is well controlled. The results showed that 32 of 86 dogs
(37.2%) who received Palladia responded to treatment, with seven dogs achieving complete response and 25 dogs
achieving partial response. In contrast, only five of 63 dogs (7.9%) treated with placebo achieved partial responses. This
difference in response between Palladia and placebo was statistically significant. The median time to progression was
longer for dogs treated with Palladia compared to those treated with placebo (>6 weeks versus 3 weeks, respectively);
and more dogs progressed on placebo versus Palladia during the 6-week blinded phase of the study (66.7% vs. 34.9%,
respectively). Dogs with c-Kit mutations were more likely to respond to Palladia compared to dogs with no c-Kit mutation
(60% vs. 31.3%, respectively). Dogs who were in the placebo group could receive Palladia after the blinded phase of the
study ended, making the total number of dogs treated with Palladia 145. Of these 145 Palladia-treated dogs, 42.8%
responded to treatment (21 dogs achieved complete response and 41 dogs achieved partial response). Among the 62
dogs who responded to therapy, median duration of response was 12 weeks and time to tumor progression was 18.1
weeks. Side effects (any severity) that occurred more frequently in dogs receiving Palladia compared to placebo included
diarrhea (46% vs 26.6%), bloody stool (12.6% vs. 3.1%), weight loss (14.9% vs. 3.1%), and neutrophil toxicity (46% vs.
6.3%). The full clinical trial results were published in a research journal (London, Clin Cancer Res, 2009), and can be
accessed by clicking on the link.

Client information sheet about Palladia's safety and efficacy can be found here.

Masitinib (AB Science)
Masitinib is currently available in Europe under the name Masivet and in the United States under the name Kinavet.
Masitinib specifically inhibits several molecular targets: c-Kit, PDGFR alpha and beta, and Lyn. In a clinical trial with 202
dogs of different breeds, dogs with mast cell tumors were randomized to either receive the drug (12.5 mg/kg) or placebo
(inactive control). The results of the study showed that masitinib was safe and effective in dogs with Grade II/III skin mast
cell tumors. In dogs whose mast cell tumors could not be removed by surgery, masitinib was better than placebo in
delaying the time it took for the tumor to progress. Median time to tumor progression for masitinib was 173 days compared
to 75 days for dogs treated with placebo. This result was statistically significant (p=0.001). Masitinib also showed a trend
toward improving overall survival (617 days for dogs treated with masitinib versus 322 days for dogs treated with placebo;
p=0.078), but this result did not reach statistical significance (a statistical significance is usually considered at p value of
<0.05). For dogs with tumors harboring a mutation in c-KIT tyrosine kinase receptor, the efficacy of masitinib was even
greater compared to placebo in terms of prolonging time to tumor progression (230 days for masitinib versus 42 days for
placebo, p=0.006), and median overall survival time (160 days for masitinib versus 62 days for placebo, p=0.025).

The most common side effects of masitinib are gastrointestinal reactions (diarrhea and vomiting), which are usually mild to
moderate and temporary, although a few may last for up to four weeks. Dogs who receive masitinib should be monitored
for side effects by their veterinarian at least once monthly, and if side effects do occur, the veterinarian may either lower
the dose or decide to discontinue the treatment. Masitinib cannot be used in dogs with certain liver and kidney conditions,
or anemia (low red blood cel count) or neutropenia (low white blood cell count). Additionally, masatinib cannot be used in
dogs <6 months old or less than 4kg in weight, or pregnant or nursing female dogs.

For more information about masitinib from AB Science, please visit www.masivet.com

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