LARTRUVO SIDE EFFECTS

SIDE EFFECTS

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

• Infusion-Related Reactions

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 openlabel 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. 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)

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)

Immunogenicity

As with all therapeutic proteins, there is the potential for immunogenicity. In clinical trials, 13/370 (3.5%) of evaluable LARTRUVO-treated patients tested positive for treatment-emergent anti-olaratumab antibodies by an enzymelinked immunosorbent assay (ELISA). Neutralizing antibodies were detected in all patients who tested positive for treatment-emergent anti-olaratumab antibodies. The effects of anti-olaratumab antibodies on efficacy, safety, and exposure could not be assessed due to the limited number of patients with treatment-emergent anti-olaratumab antibodies.

The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to LARTRUVO with the incidences of antibodies to other products may be misleading.

SRC: NLM .