The following clinically significant adverse reactions are described elsewhere in the label: Injection-Site Reactions, including phlebitis and thrombophlebitis [ s ee Warnings and Precautions ( 5.1 )] Acute Drug Hypersensitivity Reactions [see Warnings and Precautions ( 5.2 )] ILD/Pneumonitis [see Warnings and Precautions ( 5.3 )] The most common adverse reactions (≥10% of patients with ≥2% difference in incidence compared to placebo) were fatigue, hypocalcemia, hypokalemia, hypophosphatemia, aspartate aminotransferase increased, headache, and pneumonia.
( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact G1 Therapeutics, Inc., at 1-800-790-4189 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.1Clinical 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 with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The safety of COSELA was evaluated in Studies 1, 2, and 3 [see Clinical Studies ( 14 )] . Patients received COSELA 240 mg/m 2 by 30-minute intravenous infusion prior to chemotherapy on each chemotherapy day.
The data described in this section reflect exposure to COSELA among 240 patients (122 patients in the trilaciclib group and 118 patients in the placebo group) being treated for extensive stage-small cell lung cancer (ES-SCLC) in 3 randomized, double-blind, placebo-controlled trials: 32 patients with treatment naïve ES-SCLC received carboplatin (AUC 5 Day 1) + etoposide (100 mg/m 2 Days 1-3) every 21 days; 58 received carboplatin (AUC 5 Day 1) + etoposide (100 mg/m 2 Days 1-3) every 21 days + atezolizumab (1200 mg on Day 1) every 21 days; 32 patients with previously treated ES-SCLC received topotecan (1.5 mg/m 2 Days 1-5) every 21 days.
Study 1: COSELA Prior to Etoposide, Carboplatin, and Atezolizumab (E/P/A) Patients with newly diagnosed ES-SCLC not previously treated with chemotherapy Study 1 (G1T28-05; NCT03041311) was an international, randomized (1:1), double-blind, placebo-controlled study of COSELA or placebo administered prior to treatment with etoposide, carboplatin, and atezolizumab (E/P/A) for patients with newly diagnosed ES-SCLC not previously treated with chemotherapy.
The data presented below are for the 105 patients who received study treatment. Eighty-five percent of patients receiving COSELA and 91% receiving placebo completed 4 cycles of induction therapy. Study 2: COSELA Prior to Etoposide and Carboplatin (E/P) Patients with newly diagnosed ES-SCLC not previously treated with chemotherapy Study 2 (G1T28-02; NCT02499770) was an international, randomized (1:1), double-blind, placebo-controlled study of COSELA or placebo administered prior to treatment with etoposide and carboplatin (E/P) for patients with newly diagnosed ES-SCLC not previously treated with chemotherapy.
The data presented below are for the 75 patients who received study treatment. Seventy-six percent of patients in the COSELA group and 87% of patients in the placebo group completed at least 4 cycles of therapy. The median duration of treatment was 6 cycles in each treatment group. Study 3: COSELA Prior to Topotecan Patients with ES-SCLC previously treated with chemotherapy Study 3 (G1T28-03; NCT02514447) was an international, randomized (2:1), double-blind, placebo-controlled study of COSELA or placebo administered prior to treatment with topotecan for patients with ES-SCLC previously treated with chemotherapy.
The data presented below are for the 60 patients who received study treatment with the 1.5 mg/m 2 dose of topotecan. Thirty-eight percent of patients receiving COSELA and 29% of patients receiving placebo completed 5 or more cycles of therapy. The median duration of treatment was 3 cycles in each treatment group. Integrated Safety Analysis The adverse reaction summary presented in Table 3 are pooled safety results from Studies 1, 2, and 3.
The patients included in the pooling are those randomized patients that received at least 1 dose of COSELA (122 patients) or placebo (118 patients). Seventy-one percent of patients receiving COSELA and 78% of patients receiving placebo completed at least 4 cycles of therapy. The median duration of treatment was the same (4 cycles) for patients receiving COSELA and placebo. Serious adverse reactions occurred in 30% of patients receiving COSELA.
Serious adverse reactions reported in >3% of patients who received COSELA included respiratory failure, hemorrhage, and thrombosis. Permanent discontinuation due to an adverse reaction occurred in 9% of patients who received COSELA. Adverse reactions leading to permanent discontinuation of any study treatment for patients receiving COSELA included pneumonia (2%), asthenia (2%), injection-site reaction, thrombocytopenia, cerebrovascular accident, ischemic stroke, infusion-related reaction, respiratory failure, and myositis (<1% each).
Fatal adverse reactions were observed in 5% of patients receiving COSELA. Fatal adverse reactions for patients receiving COSELA included pneumonia (2%), respiratory failure (2%), acute respiratory failure (<1%), hemoptysis (<1%), and cerebrovascular accident (<1%). Infusion interruptions due to an adverse reaction occurred in 4.1% of patients who received COSELA. The most common adverse reactions (≥10%) were fatigue, hypocalcemia, hypokalemia, hypophosphatemia, aspartate aminotransferase increased, headache, and pneumonia.
The most frequently reported Grade ≥3 adverse reaction (≥5%) in patients receiving COSELA occurring at the same or higher incidence than in patients receiving placebo was hypophosphatemia. The most common adverse reactions reported in at least 5% of patients receiving COSELA with a ≥2% higher incidence compared to patients receiving placebo are shown in Table 3 . Table 3: Adverse Reactions in ≥5% Patients with SCLC Receiving COSELA (with ≥2% Higher Incidence in COSELA Compared to Placebo) Adverse Reaction COSELA (N=122) Placebo (N=118) All Grades a (%) Grade ≥3 (%) All Grades a (%) Grade ≥3 (%) a Graded per NCI CTCAE v4.03 b Hypocalcemia=calcium decreased (lab) or treatment-emergent adverse event (TEAE) preferred term 'Hypocalcemia' c Hypokalemia=potassium decreased (lab) or TEAE preferred terms 'Hypokalemia,' 'Blood potassium decreased' d Hypophosphatemia=phosphate decreased (lab) or TEAE preferred terms 'Hypophosphatemia,' 'Blood phosphorus decreased' e Aspartate aminotransferase increased=aspartate aminotransferase increased (lab) or TEAE preferred term 'Blood aspartate aminotransferase increased' Fatigue 34 3 27 2 Hypocalcemia b 24 <1 21 <1 Hypokalemia c 22 6 18 3 Hypophosphatemia d 21 7 16 2 Aspartate aminotransferase increased e 17 <1 14 <1 Headache 13 0 9 0 Pneumonia 10 7 8 7 Rash 9 <1 6 0 Infusion-related reaction 8 0 2 0 Edema peripheral 7 0 4 <1 Abdominal pain upper 7 0 3 0 Thrombosis 7 3 2 2 Hyperglycemia 6 2 3 0 Grade 3/4 hematological adverse reactions occurring in patients treated with COSELA and placebo included neutropenia (32% and 69%), febrile neutropenia (3% and 9%), anemia (16% and 34%), thrombocytopenia (18% and 33%), leukopenia (4% and 17%), and lymphopenia (<1% and <1%), respectively.
