KIMMTRAK

Antineoplastic Bispecific Fusion Proteins Targeting gp100 and CD3

Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

Tebentafusp is available as a single-dose 100 mcg/0.5 mL vial; further dilution is necessary prior to IV infusion.
Add albumin to prevent adsorption of tebentafusp to the infusion bag and other components of the drug delivery system.
Preparation:
Using a 1-mL syringe with a sterile needle, withdraw 0.5 mL of albumin 5% (50 g/L), 0.13 mL of albumin 20% (200 g/L), or 0.1 mL of albumin 25% (250 g/L) and add to a 100-mL 0.9% Sodium Chloride injection bag made of polyolefins (PO), such as polyethylene (PE) and polypropylene (PP), or polyvinyl chloride (PVC) for a final albumin concentration of 250 mcg/mL.
Gently mix by inverting the infusion bag so that the bag is upside down with the entry port positioned on top and tap the side of the port tubing to ensure that any residual solution is released into the bulk solution.
Continue mixing by gently rotating the bag lengthwise 360 degrees from the inverted position at least 5 times; do not shake the infusion bag.
Repeat the inversion and rotation steps 3 additional times.
Drug Dilution:
Do not shake the tebentafusp vial.
Using a 1-mL syringe with a sterile needle, withdraw the appropriate volume from the tebentafusp 100 mcg/0.5 mL vial and add to the prepared infusion bag containing 0.9% Sodium Chloride injection and albumin.
20-mcg dose: Add 0.1 mL30-mcg dose: Add 0.15 mL68-mcg dose: Add 0.34 mL
Repeat the inversion and rotation steps as specified in the Preparation section above; discard any unused portion of the vial.
Storage of diluted admixture: Use immediately if possible. May be stored for up to 4 hours at room temperature or up to 24 hours in the refrigerator (2 to 8 degrees C; 36 to 46 degrees F); storage time includes from the time of preparation through the duration of the infusion.
Once removed from the refrigerator, do not refrigerate the admixture again; do not freeze.
Intravenous (IV) Infusion:
Allow the admixture solution to warm to room temperature if stored in the refrigerator.
Administer the admixture solution as an IV infusion over 15 to 20 minutes using a dedicated IV line and a sterile, non-pyrogenic, low protein binding 0.2-micron in-line filter infusion set.
After the infusion, flush the line with an adequate volume of sterile 0.9% Sodium Chloride injection to ensure that the entire contents of the infusion bag are given.
Do not mix tebentafusp with other drugs or administer other drugs through the same IV line.
Monitor patients during the infusion and for at least 16 hours after the infusion is complete for the first 3 doses. In patients who do not experience grade 2 or worse hypotension (requiring medical intervention) during or after the third infusion, continue subsequent infusions in an ambulatory setting and monitor for at least 30 minutes after each dose.

lymphopenia / Delayed / 56.0-56.0
rash / Early / 18.0-18.0
elevated hepatic enzymes / Delayed / 9.0-13.0
hypophosphatemia / Delayed / 11.0-11.0
fatigue / Early / 6.0-6.0
pruritus / Rapid / 4.5-4.5
hyperamylasemia / Delayed / 4.1-4.1
hyperbilirubinemia / Delayed / 4.1-4.1
fever / Early / 3.7-3.7
hyperglycemia / Delayed / 3.3-3.3
hypotension / Rapid / 3.3-3.3
abdominal pain / Early / 2.9-2.9
hyponatremia / Delayed / 2.9-2.9
hypoalbuminemia / Delayed / 2.1-2.1
neutropenia / Delayed / 2.0-2.0
nausea / Early / 2.0-2.0
hyperkalemia / Delayed / 1.6-1.6
hypocalcemia / Delayed / 1.6-1.6
diarrhea / Early / 1.2-1.2
vomiting / Early / 1.2-1.2
pulmonary embolism / Delayed / 0-1.0
cerebral edema / Early / 0-1.0
anaphylactoid reactions / Rapid / 0-1.0
anemia / Delayed / 0.8-0.8
hypokalemia / Delayed / 0.8-0.8
arthralgia / Delayed / 0.8-0.8
cytokine release syndrome / Rapid / 0.8-0.8
nephrotoxicity / Delayed / 0.4-0.4
hypoglycemia / Early / 0.4-0.4
chills / Rapid / 0.4-0.4
headache / Early / 0.4-0.4

edema / Delayed / 45.0-45.0
hypomagnesemia / Delayed / 34.0-34.0
antibody formation / Delayed / 29.0-33.0
erythema / Early / 25.0-25.0
constipation / Delayed / 0-20.0
dyspnea / Early / 0-20.0
hypertension / Early / 0-20.0
sinus tachycardia / Rapid / 0-20.0
thrombocytopenia / Delayed / 16.0-16.0
hypercalcemia / Delayed / 13.0-13.0
hypoxia / Early / Incidence not known

xerosis / Delayed / 31.0-31.0
skin hypopigmentation / Delayed / 28.0-28.0
alopecia / Delayed / 0-20.0
flushing / Rapid / 0-20.0
hair discoloration / Delayed / 0-20.0
skin hyperpigmentation / Delayed / 0-20.0
anorexia / Delayed / 0-20.0
night sweats / Early / 0-20.0
paresthesias / Delayed / 0-20.0
dizziness / Early / 0-20.0
back pain / Delayed / 0-20.0
muscle cramps / Delayed / 0-20.0
myalgia / Early / 0-20.0
influenza / Delayed / 0-20.0

Cytokine release syndrome (CRS) has been reported in patients who received tebentafusp; some cases were serious or life-threatening. Symptoms may include fever, hypotension, hypoxia, chills, nausea, vomiting, rash, elevated transaminase levels, fatigue, and headache. Tebentafusp administration requires a specialized care setting where health care providers have immediate access to emergency medications and resuscitative equipment to manage CRS. Screen patients for dehydration prior to starting therapy. Closely monitor patients (e.g., fluid status, vital signs, and oxygenation level) for signs or symptoms of CRS for 16 hours after the completion of the infusion; initiate appropriate therapy as required. In patients who do not experience grade 2 or greater hypotension (requiring medical intervention) during or after the third infusion, subsequent infusions may be given in an ambulatory setting; monitor patients for at least 30 minutes after the end of each infusion. Therapy interruption or discontinuation may be necessary in patients who develop CRS. In patients who develop 2 to 3 hours of moderate CRS or severe CRS, premedicate with dexamethasone (4 mg or equivalent) at least 30 minutes prior to the next dose. Administer IV corticosteroids (e.g., 2 mg/kg per day methylprednisolone or equivalent) in patients who develop severe or life-threatening CRS.

KIMMTRAK

Rx

Bispecific gp100-directed CD3 T-cell engager fusion protein
Used in adults with HLA-A*02:01-positive unresectable or metastatic uveal melanoma
Black box warning for cytokine release syndrome

20 micrograms (mcg) IV on day 1, 30 mcg IV on day 8, 68 mcg IV on day 15, and then 68 mcg IV once weekly until disease progression. Therapy interruption or permanent discontinuation may be necessary in patients who develop severe toxicity. At a median follow-up time of 14.1 months, the median overall survival ([OS] primary endpoint; 21.7 months vs. 16 months; hazard ratio (HR) = 0.51; 95% CI, 0.37 to 0.71; p less than 0.001) and progression-free survival ([PFS] 3.3 months vs. 2.9 months; HR = 0.73; 95% CI, 0.59 to 0.94) times were significantly improved with tebentafusp compared with investigator choice therapy (21.7 months vs. 16 months; hazard ratio (HR) = 0.51; 95% CI, 0.37 to 0.71; p less than 0.001) in adult patients with previously untreated HLA-A*02:01-positive metastatic uveal melanoma in a randomized (2:1), phase 3 trial (n =378; IMCgp100-202 trial). The estimated 1-year OS rates were 73% and 59% in the tebentafusp and investigator choice arms, respectively; the estimated 6-month PFS rates were 31% and 19%, respectively. In this study, investigator choice therapy consisted of single-agent pembrolizumab (n = 103), ipilimumab (n = 16), or dacarbazine (n = 7). After the first interim analysis, patients in the investigator choice arm were able to cross over to the tebentafusp arm.

Baseline hepatic impairment: Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Treatment-related grade 3 or 4 elevated hepatic enzymes: Hold therapy until toxicity resolves to grade 1 or less or baseline. Administer an IV corticosteroid if there is no improvement within 24 hours. If the toxicity occurred concurrently with grade 3 cytokine release syndrome (CRS), resume tebentafusp at the same dose level and resume dose escalation if the next administration is tolerated. If the toxicity occurred without grade 3 CRS, resume dose escalation if the dose is less than 68 mcg or resume at the same dose level if dose escalation has completed.

Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.

Tebentafusp Intravenous Inj Sol: 0.5mL, 100mcg

68 mcg IV.

68 mcg IV.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

Tebentafusp is a bispecific T-cell engager (BiTE) fusion protein that binds the gp100 peptide presented by human leukocyte antigen-A*02:01 (HLAA*02:01) on the cell surface of uveal melanoma tumor cells to CD3 expressed on the surface of T cells. Tebentafusp is a cancer immunotherapy that utilizes an immune-mobilizing monoclonal T-cell receptors against cancer (ImmTAC) platform. ImmTAC molecules work by binding to cells that present a peptide derived from a target antigen and then recruiting T cells to lyse the target. Tebentafusp binding enables polyclonal activation of native T cells to release inflammatory cytokines and cytolytic proteins resulting in direct lysis of uveal melanoma tumor cells. ImmTAC molecules may have an advantage over antibody-based therapeutics that target only highly expressed, cell surface proteins and immune checkpoint inhibitors which require preexisting cancer-specific T-cells to lyse cancer cells.

Tebentafusp is administered intravenously. It has a geometric mean steady-state volume of distribution of 7.56 L (coefficient of variation (CV), 24%), geometric mean clearance of 16.4 L/day (CV, 24.5%), and median terminal half-life of 7.5 hours (range, 6.8 to 7.5 hours). It is metabolized into small peptides and amino acids via catabolism.
Affected cytochrome P450 isoenzymes: CYP450 substrates
Although no drug interaction studies have been performed with tebentafusp, CYP450 enzyme activity may be suppressed due to an elevation of certain proinflammatory cytokines during therapy.

The steady-state geometric mean Cmax and AUC(0-7d) values are 13 nanograms (ng)/mL (coefficient of variation (CV), 34.6%) and 4.6 ng X day/mL (CV, 23%), respectively, with no accumulation following the administration of the approved recommended tebentafusp dosage in patients with metastatic uveal melanoma. After a single dose of tebentafusp, the Cmax and AUC(0-7d) values increased in an approximate dose proportional manner over a dose range of 20 to 68 mg.

Tebentafusp may cause fetal harm if administered during pregnancy, based on its mechanism of action. Patients of reproductive potential should avoid pregnancy and use effective contraction during and after tebentafusp therapy. Advise pregnant patients of the potential risk to the fetus with tebentafusp use. It has not been studied in pregnant woman and no animal reproductive or developmental toxicity studies have been conducted. However, other drugs with similar molecular weight are known to cross the placenta resulting in fetal exposure.

It is not known if tebentafusp is secreted in human milk or if it has effects on the breast-fed child or on milk production. Due to the potential for serious adverse reactions in a breastfed child, patients should avoid breast-feeding during therapy and for 1 week after the last tebentafusp dose.