Newly approved oncology drugs fill a niche for 2 common canine cancers

Stelfonta^®–A new localized therapy for canine mast cell tumors

Stelfonta® (Tigilanol tiglate) is a novel anti-cancer protein kinase C activator that is fully FDA-approved for the treatment of certain canine mast cell tumors. Tigilanol tiglate was originally isolated from the seed of Fontainea picrosperma and is now formulated for intratumoral injection.

Photo courtesy of BluPearl.

Stelfonta^®–Label at a glance

• Approved for dogs with
• • All grades of non-metastatic MCTs
• Any cutaneous MCT
• Subcutaneous MCTs located at or distal to the elbow or the hock
• Tumors must be less than or equal to 10 cm³ in volume and must be accessible for intratumoral injection

How it Works

Tigilanol tiglate (1 mg/ml) is injected via a single puncture site into the tumor, then the dose is distributed by fanning the needle throughout the tumor mass. The dose is calculated based upon tumor volume (Modified Ellipsoid Method, in cm³). Once injected, Stelfonta^® induces a rapid and localized inflammatory response and destruction of local blood supply to the tumor; ischemic necrosis is thought to be the main mechanism of action of tumor cell death. Interestingly, Stelfonta® promotes healing of the affected area with minimal scar formation. Bandaging and Elizabethan collars are not recommended, as the dog’s licking helps remove necrotic tumor tissue from the site. The treatment site is considered a “clean” wound, so antibiotics are likewise not commonly needed.^1,2,3

Stelfonta® in action

Photo courtesy of BluePearl.

Efficacy data

In the most recent prospective study², a single Stelfonta^® treatment resulted in 75% complete response (CR) by 28 days, with that CR maintained in 94% of dogs by 84 days and 89% of dogs by 12 months. Dogs not achieving a complete response with the first treatment can receive a second treatment, which results in an improved overall CR rate of 88%.

Side effects

Adverse effects of TT are typically low grade, transient, and directly associated with the mode of action.¹ These include:

• Wound formation (possibly extensive) following tumor necrosis and slough
• Localized pain, swelling, erythema, and bruising at the tumor site
• Lameness in a treated limb
• Regional lymph node enlargement

*Specific concomitant medications (prednisone, famotidine, and diphenhydramine) must be used to minimize potential for MCT degranulation.

Tidbits and tricks of the trade

• Candidate patients to consider for Stelfonta^®:
  • Dogs with multiple MCT
  • Dog whose owner who elects against surgery
  • Dogs with a tumor in a challenging location to obtain a complete surgical removal
• Prior to TT, need to assess regional lymph node to confirm non-metastatic
• Prior to TT, submit slides for cytologic grading since histopathology will not be obtained
  • If cytologically high grade, systemic therapy is warranted following Stelfonta^®
  • No margin analysis, however, 89% of dogs had no local recurrence
• • Wound formation after tumor slough and wound size relative to tumor volume is associated with efficacy⁴
  • In 98.2% of cases, full healing was observed within 3 months
• Suggested follow up visit schedule:
  • Day 0 - injection
  • Day 2 or 3 – check the site to confirm necrosis occurring
  • Day 7 – assess wound
  • Day 28 – reassess wound
  • Further visits will be variable and dependent upon patient response and wound healing

Client communications

• Virbac has photos of wounds with associated time frames to help with owner expectations
• https://vet-us.virbac.com/stelfonta

Human safety

• Wear personal protective equipment including gloves, protective eyewear, and a lab coat or gown when handling and administering this product
• Caution is required during treatment to avoid accidental self-injection, which may cause severe wound formation
  • General anesthesia not needed, but consider pre-treatment anti-anxiety +/- analgesic drugs and/or injectable sedation for treatment of very active or agitated patients

Laverdia™-CA1–A novel oral drug for dogs with lymphoma

Laverdia™-CA1 (verdinexor tablets) is the first oral drug for dogs with lymphoma (LSA) and has been conditionally approved (CA) by the FDA pending a full demonstration of effectiveness. Conditional approval allows veterinarians to access Laverdia™-CA1 as the company continues clinical trials to support full approval.Laverdia™-CA1 is commercially available in three tablets sizes – 2.5 mg, 10 mg, and 50 mg.

Photo courtesy of BluePearl.

How it works

Verdinexor is a small molecule inhibitor, specifically a Selective Inhibitor of Nuclear Transport (SINE) drug. Verdinexor targets Exportin-1 (XPO1) – a transport protein that is overexpressed in certain types of cancer including lymphoma. XPO1 exports tumor suppressor proteins (TSPs) from the nuclei of cells, thus leaving the cell vulnerable to uncontrolled cell growth and proliferation. Verdinexor binds to XPO1, trapping TSPs inside the nucleus, and thus triggering programmed cell death of lymphoma cells while sparing normal cells.⁵

Dosing

• The package insert includes a helpful chart that lists the number of each tablet size that is needed to provide the dose for the different ranges of canine body weights
• N.B.Laverdia™-CA1 should be given to dogs immediately after eating, as this increases the amount of drug absorbed into the bloodstream

Efficacy data

From the Phase II study:⁶

• Objective response rate (partial or complete response) was 34.5% (20/58 dogs).
  • B-cell (naïve): 57% overall response rate
  • B-cell (relapse): 43% overall response rate
  • T-cell (naïve & relapse): 71% overall response rate
• The median time to progression (duration of response) was 36.5 days (range 7-244) for naïve patients and 22 days (range 7-194) for relapse patients.

Side effects

Most adverse effects are mild but may include lethargy, anorexia, weight loss, vomiting, diarrhea, polyuria, polydipsia, elevated liver enzymes, and thrombocytopenia.^5,6

Tidbits and tricks of the trade

• Can be used for any type of canine LSA (the label is broad)
• This is not a silver bullet, but could have a role for certain patients, such as those with:
  • Relapsed lymphoma, especially if the owner is reluctant to pursue more traditional or intensive protocols
  • Unique forms of T-cell LSA
    • cutaneous/epitheliotrophic
    • indolent T-zone
  • Can be considered as maintenance therapy if the complete response is not achieved with first-line protocol
  • Naïve lymphoma if an owner does not intend to pursue chemotherapy or has a prolonged wait prior to referral
• Verdinexor does not appear to induce P-glycoprotein, which has been implicated in chemotherapy resistance and notoriously develops as a result of prednisone administration.
  • Could serve as a substitute palliative care option for dogs whose disease is prednisone-resistant or for those that cannot receive prednisone

Photo courtesy of BluePearl

Human safety

• Approved chemotherapy gloves should be worn when handling Laverdia™-CA1 and cleaning up excrement of a dog undergoing treatment and for three days following the last treatment.
• Pregnant women, women who may become pregnant, and nursing women, should not handle or administer the drug or touch the feces, urine, vomit, or saliva of treated dogs.
• Children also should not touch Laverdia™-CA1 or the feces, urine, vomit, or saliva of treated dogs.

References

1. De Ridder TR, Campbell JE, Burke-Schwarz C, et al. Randomized controlled clinical study evaluating the efficacy and safety of intratumoral treatment of canine mast cell tumors with tigilanol tiglate (EBC-46). J Vet Intern Med 2020;1-15. https://doi.org/10.1111/jvim.15806
2. Jones PD, Campbell JE, Brown G, Johannes CM, Reddell P. Recurrence-free interval 12 months after local treatment of mast cell tumors in dogs using intratumoral injection of tigilanol tiglate. J Vet Intern Med 2020;1–5. https://doi.org/10.1111/jvim.16018
3. Miller J, et al. Dose Characterization of the Investigational Anticancer Drug Tigilanol Tiglate (EBC-46) in the Local Treatment of Canine Mast Cell Tumors. Frontiers in Veterinary Science 2019;6:106. https://doi.org/10.3389/fvets.2019.00106
4. Reddell P, De Ridder TR, Morton JM, et al. Wound formation, wound size, and progression of wound healing after intratumoral treatment of mast cell tumors in dogs with tigilanol tiglate. J Vet Intern Med 2021;1–12. https://doi.org/10.1111/jvim.16009
5. London CA, Bernabe LF, Barnard S, et al. Preclinical Evaluation of the Novel, Orally Bioavailable Selective Inhibitor of Nuclear Export (SINE) KPT-335 in Spontaneous Canine Cancer: Results of a Phase I Study.PLos One 2014;9(2):e87585. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0087585
6. Sadowski AR, Gardner HL, Borgatti A, et al. Phase II study of the oral selective inhibitor of nuclear export (SINE) KPT-335 (verdinexor) in dogs with lymphoma. BMC Vet Res 2018;14:250. https://bmcvetres.biomedcentral.com/articles/10.1186/s12917-018-1587-9