LARTRUVO

LARTRUVO — olaratumab injection, solution
Eli Lilly and Company

1 INDICATIONS AND USAGE

LARTRUVO™ is indicated, in combination with doxorubicin, for the treatment of adult patients with soft tissue sarcoma (STS) with a histologic subtype for which an anthracycline-containing regimen is appropriate and which is not amenable to curative treatment with radiotherapy or surgery.

This indication is approved under accelerated approval [see Clinical Studies (14)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trial.

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosage

The recommended dose of LARTRUVO is 15 mg/kg administered as an intravenous infusion over 60 minutes on Days 1 and 8 of each 21-day cycle until disease progression or unacceptable toxicity. For the first 8 cycles, LARTRUVO is administered with doxorubicin, [see Clinical Studies (14)].

Refer to doxorubicin prescribing information for dosing, and dose modifications.

2.2 Premedication

  • Premedicate with diphenhydramine (25 to 50 mg intravenously) and dexamethasone (10 to 20 mg intravenously) prior to LARTRUVO on Day 1 of cycle 1.

2.3 Dosing Modifications

Infusion-Related Reactions

  • Permanently discontinue LARTRUVO for Grade 3 or 4 infusion-related reactions [see Dosage and Administration (2.2) and Warnings and Precautions (5.1)].
  • Interrupt infusion of LARTRUVO for Grade 1 or 2 infusion-related reactions (IRR). After resolution, resume LARTRUVO infusion at 50% of the initial infusion rate. [see Warnings and Precautions (5.1)]

Neutropenia

  • For neutropenic fever/infection or Grade 4 neutropenia lasting longer than 1 week, discontinue administration of LARTRUVO until the absolute neutrophil count is 1,000 /microliter or greater and then permanently reduce the dose to 12 mg/kg.

2.4 Preparation and Administration

Preparation

  • Inspect vial contents for particulate matter and discoloration prior to dilution [see Description (11)]. Discard the vial if particulate matter or discolorations are identified.
  • Withdraw calculated dose and further dilute with 0.9% Sodium Chloride Injection, USP to a final volume of 250 mL for intravenous infusion. Do not use dextrose-containing or other solutions.
  • Gently invert but do not shake.
  • DO NOT FREEZE the diluted solution.
  • Store the diluted solution for up to 24 hours under refrigeration at 2°C to 8°C (36°F to 46°F) and for up to an additional 8 hours at room temperature (below 25°C [77°F]). Storage times include the duration of infusion. If refrigerated, allow the diluted solution to come to room temperature prior to administration.
  • Discard vial with any unused portion of LARTRUVO.

Administration

  • Do not administer LARTRUVO as an intravenous push or bolus. Do not co-infuse with electrolytes or other medications through the same intravenous line.
  • Visually inspect the diluted solution for particulate matter and discoloration prior to administration. If particulate matter or discolorations are identified, discard the solution.
  • Administer diluted solution as an intravenous infusion over 60 minutes. Flush the line with 0.9% Sodium Chloride Injection, USP at end of infusion.

3 DOSAGE FORMS AND STRENGTHS

Injection: 500 mg/50 mL (10 mg/mL) or 190 mg/19 mL (10 mg/mL) clear to slightly opalescent, colorless to slightly yellow solution in a single-dose vial.

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

5.1 Infusion-Related Reactions

Infusion-related reactions (IRR) occurred in 70 (14%) of 485 patients who received at least one dose of LARTRUVO across clinical trials. For 68 of these 70 patients (97%), the first occurrence of IRR was in the first or second cycle. Grade ≥3 IRR occurred in 11 (2.3%) of 485 patients, with one (0.2%) fatality. Symptoms of IRR included flushing, shortness of breath, bronchospasm, or fever/chills, and in severe cases symptoms manifested as severe hypotension, anaphylactic shock, or cardiac arrest.

Infusion-related reactions required permanent discontinuation in 2.3% of patients and interruption of infusion in 10% of patients. All 59 patients with Grade 1 or 2 IRR resumed LARTRUVO; 12 (20%) of these patients had a Grade 1 or 2 IRR with rechallenge. The incidence of IRR in the overall safety database (N = 485) was similar (18% versus 12%) between those who did (56%) and those who did not (44%) receive premedication.

Monitor patients during and following LARTRUVO infusion for signs and symptoms of IRR in a setting with available resuscitation equipment. Immediately and permanently discontinue LARTRUVO for Grade 3 or 4 IRR [see Dosage and Administration (2.2, 2.3) and Adverse Reactions (6.1)].

5.2 Embryo-Fetal Toxicity

Based on animal data and its mechanism of action, LARTRUVO can cause fetal harm when administered to a pregnant woman. Animal knockout models link disruption of platelet-derived growth factor receptor alpha (PDGFR-α) signaling to adverse effects on embryo-fetal development. Administration of an anti-murine PDGFR-α antibody to pregnant mice during organogenesis caused malformations and skeletal variations. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with LARTRUVO and for 3 months after the last dose [see Use in Specific Populations (8.1, 8.3)].

6 ADVERSE REACTIONS

The following adverse drug reactions are described elsewhere in the labeling:

  • Infusion-Related Reactions [see Warnings and Precautions (5.1)].

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data in the Warnings and Precautions section reflect exposure to LARTRUVO in 485 patients from three randomized, open-label, active-controlled clinical trials, which enrolled 256 patients with various tumors who received LARTRUVO in combination with chemotherapy (191 patients) or LARTRUVO as a single agent (65 patients); four open-label single-arm trials which enrolled 96 patients with various tumors who received LARTRUVO as a single agent at doses of 10 to 20 mg/kg; and two trials, including Trial 1, which enrolled 133 patients with soft tissue sarcoma who received LARTRUVO at doses of 15 to 20 mg/kg in combination with doxorubicin (103 patients) or LARTRUVO as a single agent (30 patients). Among the 485 patients, 25% were exposed to LARTRUVO for ≥6 months and 6% were exposed for ≥12 months.

The data described below reflect exposure to LARTRUVO in 64 patients with metastatic soft tissue sarcoma enrolled in Trial 1, a multicenter, randomized (1:1), open-label, active-controlled trial comparing LARTRUVO plus doxorubicin with doxorubicin as a single agent. LARTRUVO was administered at 15 mg/kg as an intravenous infusion on Days 1 and 8 of each 21-day cycle until disease progression or unacceptable toxicity [see Clinical Studies (14)]. All patients received doxorubicin 75 mg/m2 as an intravenous infusion on Day 1 of each 21-day cycle for a maximum of eight cycles and received dexrazoxane, prior to doxorubicin in cycles 5 to 8. In Trial 1, no patients had received a prior anthracycline-containing regimen. The trial excluded patients with an ECOG performance status >2; left ventricular ejection fraction <50%; or unstable angina pectoris, angioplasty, cardiac stenting, or myocardial infarction within 6 months.

Baseline demographics and disease characteristics were: median age 58 years (range 22 to 86); 45% male; 87% White, 8% Black, 3% Asian, 2% Other; 57% ECOG PS 0, 39% ECOG PS 1, and 5% ECOG PS 2. The median duration of exposure to LARTRUVO was 6 months (range: 21 days to 29.4 months) with 36 (56%) patients receiving LARTRUVO for ≥6 months and 10 (16%) patients receiving LARTRUVO for ≥12 months. The median cumulative doxorubicin dose was 488 mg/m2 in the LARTRUVO plus doxorubicin arm and 300 mg/m2 in the doxorubicin arm.

In Trial 1, adverse reactions resulting in permanent discontinuation of LARTRUVO occurred in 8% (5/64) of patients. The most common adverse reaction leading to LARTRUVO discontinuation was infusion-related reaction (3%). Dose reductions of LARTRUVO for adverse reactions occurred in 25% (16/64) of patients; the most common adverse reaction leading to dose reduction was Grade 3 or 4 neutropenia (20%). Dose delays of LARTRUVO for adverse reactions occurred in 52% (33/64) of patients; the most common adverse reactions resulting in dose delays were neutropenia (33%), thrombocytopenia (8%), and anemia (5%).

Table 1 summarizes adverse reactions that occurred in at least 10% of patients receiving LARTRUVO in the randomized portion of the study. The most common adverse reactions reported in at least 20% of patients receiving LARTRUVO plus doxorubicin were nausea, fatigue, musculoskeletal pain, mucositis, alopecia, vomiting, diarrhea, decreased appetite, abdominal pain, neuropathy, and headache.

Table 1: Adverse Reactions Occurring in ≥10% (All Grades) of Patients in the LARTRUVO plus Doxorubicin Arm and at a Higher Incidence than in the Doxorubicin Arm (Between Arm Difference of ≥5% for All Grades or ≥2% for Grades 3 and 4) (Trial 1)

a Abdominal pain includes: abdominal pain, lower abdominal pain, and upper abdominal pain.

b Fatigue includes: asthenia and fatigue.

c Musculoskeletal pain includes: arthralgia, back pain, bone pain, flank pain, groin pain, musculoskeletal chest pain, musculoskeletal pain, myalgia, muscle spasms, neck pain, and pain in extremity.

Adverse Reactions LARTRUVO plus Doxorubicin N=64 Doxorubicin N=65
All Grades (%) Grade 3-4 (%) All Grades (%) Grade 3-4 (%)
Gastrointestinal Disorders
Nausea 73 2 52 3
Mucositis 53 3 35 5
Vomiting 45 0 19 0
Diarrhea 34 3 23 0
Abdominal Paina 23 3 14 0
General Disorders and Administrative Site Conditions
Fatigueb 69 9 69 3
Infusion-Related Reactions 13 3 3 0
Musculoskeletal and Connective Tissue Disorders
Musculoskeletal Painc 64 8 25 2
Skin and Subcutaneous Tissue Disorders
Alopecia 52 0 40 0
Metabolic and Nutritional Disorders
Decreased Appetite 31 2 20 0
Nervous System Disorders
Neuropathy 22 0 11 0
Headache 20 0 9 0
Psychiatric Disorder
Anxiety 11 0 3 0
Eye Disorder
Dry Eyes 11 0 3 0

In Trial 1, the most common laboratory abnormalities (≥20%) were lymphopenia, neutropenia, thrombocytopenia, hyperglycemia, elevated aPTT, hypokalemia, and hypophosphatemia as shown in Table 2.

Table 2: Laboratory Abnormalities Worsening from Baseline in >10% (All Grades) of Patients in the LARTRUVO plus Doxorubicin Arm and Occurring at a Higher Incidence than in the Doxorubicin Arm (Between Arm Difference ≥5% for All Grades or ≥2% for Grades 3 and 4) (Trial 1)

a The incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement: LARTRUVO plus doxorubicin arm (range 60 to 63 patients) and doxorubicin arm (range 39 to 62 patients).

b aPTT = activated partial thromboplastin time

Laboratory Abnormality LARTRUVO plus Doxorubicin a Doxorubicin a
All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%)
Chemistry
Hyperglycemia 52 2 28 3
Increased aPTTb 33 5 13 0
Hypokalemia 21 8 15 3
Hypophosphatemia 21 5 7 3
Increased Alkaline Phosphatase 16 0 7 0
Hypomagnesemia 16 0 8 0
Hematology
Lymphopenia 77 44 73 37
Neutropenia 65 48 63 38
Thrombocytopenia 63 6 44 11
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