Because clinical trials are conducted under widely varying conditions, adverse reactions rates cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in clinical practice.

In clinical trials, the most common adverse reactions (incidence ≥ 20%) of PEMRYDI RTU, when administered as a single agent, are fatigue, nausea, and anorexia. The most common adverse reactions (incidence ≥ 20 %) of PEMRYDI RTU, when administered in combination with cisplatin are vomiting, neutropenia, anemia, stomatitis/pharyngitis, thrombocytopenia, and constipation. The most common adverse reactions (incidence ≥ 20%) of PEMRYDI RTU, when administered in combination with pembrolizumab and platinum chemotherapy, are fatigue/asthenia, nausea, constipation, diarrhea, decreased appetite, rash, vomiting, cough, dyspnea, and pyrexia.

The safety of PEMRYDI RTU, in combination with pembrolizumab and investigator’s choice of platinum (either carboplatin or cisplatin), was investigated in Study KEYNOTE-189, a multicenter, double-blind, randomized (2:1), active-controlled trial in patients with previously untreated, metastatic non-squamous NSCLC with no EGFR or ALK genomic tumor aberrations. A total of 607 patients received PEMRYDI RTU, pembrolizumab, and platinum every 3 weeks for 4 cycles followed by PEMRYDI RTU and pembrolizumab (n=405), or placebo, PEMRYDI RTU, and platinum every 3 weeks for 4 cycles followed by placebo and PEMRYDI RTU (n=202). Patients with autoimmune disease that required systemic therapy within 2 years of treatment; a medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible

The median duration of exposure to PEMRYDI RTU was 7.2 months (range: 1 day to 1.7 years). Seventy-two percent of patients received carboplatin. The study population characteristics were: median age of 64 years (range: 34 to 84), 49% age 65 years or older, 59% male, 94% White and 3% Asian, and 18% with history of brain metastases at baseline.

PEMRYDI RTU was discontinued for adverse reactions in 23% of patients in the PEMRYDI RTU, pembrolizumab, and platinum arm. The most common adverse reactions resulting in discontinuation of PEMRYDI RTU in this arm were acute kidney injury (3%) and pneumonitis (2%). Adverse reactions leading to interruption of PEMRYDI RTU occurred in 49% of patients in the PEMRYDI RTU, pembrolizumab, and platinum arm. The most common adverse reactions or laboratory abnormalities leading to interruption of PEMRYDI RTU in this arm (≥ 2%) were neutropenia (12%), anemia (7%), asthenia (4%), pneumonia (4%), thrombocytopenia (4%), increased blood creatinine (3%), diarrhea (3%), and fatigue (3%).

Table 2 summarizes the adverse reactions that occurred in ≥ 20% of patients treated with PEMRYDI RTU, pembrolizumab, and platinum.

Table 3 summarizes the laboratory abnormalities that worsened from baseline in at least 20% of patients treated with PEMRYDI RTU, pembrolizumab, and platinum.

The safety of PEMRYDI RTU was evaluated in Study JMDB, a randomized (1:1), open-label, multicenter trial conducted in chemotherapy-naive patients with locally advanced or metastatic NSCLC. Patients received either PEMRYDI RTU 500 mg/m

Study JMDB excluded patients with an Eastern Cooperative Oncology Group Performance Status (ECOG PS of 2 or greater), uncontrolled third-space fluid retention, inadequate bone marrow reserve and organ function, or a calculated creatinine clearance less than 45 mL/min. Patients unable to stop using aspirin or other non-steroidal anti-inflammatory drugs or unable to take folic acid, vitamin B

The data described below reflect exposure to PEMRYDI RTU plus cisplatin in 839 patients in Study JMDB. Median age was 61 years (range 26-83 years); 70% of patients were men; 78% were White, 16% were Asian, 2.9% were Hispanic or Latino, 2.1% were Black or African American, and <1% were other ethnicities; 36% had an ECOG PS 0. Patients received a median of 5 cycles of PEMRYDI RTU.

Table 4 provides the frequency and severity of adverse reactions that occurred in ≥ 5% of 839 patients receiving PEMRYDI RTU in combination with cisplatin in Study JMDB. Study JMDB was not designed to demonstrate a statistically significant reduction in adverse reaction rates for PEMRYDI RTU, as compared to the control arm, for any specified adverse reaction listed in Table 4.

The following additional adverse reactions were observed in patients assigned to receive PEMRYDI RTU.

In Study JMEN, the safety of PEMRYDI RTU was evaluated in a randomized (2:1), placebo-controlled, multicenter trial conducted in patients with non-progressive locally advanced or metastatic NSCLC following four cycles of a first-line, platinum-based chemotherapy regimen. Patients received either PEMRYDI RTU 500 mg/m

Study JMEN excluded patients with an ECOG PS of 2 or greater, uncontrolled third-space fluid retention, inadequate bone marrow reserve and organ function, or a calculated creatinine clearance less than 45 mL/min. Patients unable to stop using aspirin or other non-steroidal anti-inflammatory drugs or unable to take folic acid, vitamin B

The data described below reflect exposure to PEMRYDI RTU in 438 patients in Study JMEN. Median age was 61 years (range 26-83 years), 73% of patients were men; 65% were White, 31% were Asian, 2.9% were Hispanic or Latino, and < 2% were other ethnicities; 39% had an ECOG PS 0. Patients received a median of 5 cycles of PEMRYDI RTU and a relative dose intensity of PEMRYDI RTU of 96%. Approximately half the patients (48%) completed at least six, 21-day cycles and 23% completed ten or more 21-day cycles of PEMRYDI RTU.

Table 5 provides the frequency and severity of adverse reactions reported in ≥ 5% of the 438 PEMRYDI RTU-treated patients in Study JMEN.

The requirement for transfusions (9.5% versus 3.2%), primarily red blood cell transfusions, and for erythropoiesis stimulating agents (5.9% versus 1.8%) were higher in the PEMRYDI RTU arm compared to the placebo arm.

The following additional adverse reactions were observed in patients who received PEMRYDI RTU.

The safety of PEMRYDI RTU was evaluated in PARAMOUNT, a randomized (2:1), placebo-controlled study conducted in patients with non-squamous NSCLC with non-progressive (stable or responding disease) locally advanced or metastatic NSCLC following four cycles of PEMRYDI RTU in combination with cisplatin as first-line therapy for NSCLC. Patients were randomized to receive PEMRYDI RTU 500 mg/m

PARAMOUNT excluded patients with an ECOG PS of 2 or greater, uncontrolled third-space fluid retention, inadequate bone marrow reserve and organ function, or a calculated creatinine clearance less than 45 mL/min. Patients unable to stop using aspirin or other non-steroidal anti-inflammatory drugs or unable to take folic acid, vitamin B

The data described below reflect exposure to PEMRYDI RTU in 333 patients in PARAMOUNT. Median age was 61 years (range 32 to 83 years); 58% of patients were men; 94% were White, 4.8% were Asian, and < 1% were Black or African American; 36% had an ECOG PS 0. The median number of maintenance cycles was 4 for PEMRYDI RTU and placebo arms. Dose reductions for adverse reactions occurred in 3.3% of patients in the PEMRYDI RTU arm and 0.6% in the placebo arm. Dose delays for adverse reactions occurred in 22% of patients in the PEMRYDI RTU arm and 16% in the placebo arm.

Table 6 provides the frequency and severity of adverse reactions reported in ≥ 5% of the 333 PEMRYDI RTU-treated patients in PARAMOUNT.

The requirement for red blood cell (13% versus 4.8%) and platelet (1.5% versus 0.6%) transfusions, erythropoiesis stimulating agents (12% versus 7%), and granulocyte colony stimulating factors (6% versus 0%) were higher in the PEMRYDI RTU arm compared to the placebo arm.

The following additional Grade 3 or 4 adverse reactions were observed more frequently in the PEMRYDI RTU arm.

The safety of PEMRYDI RTU was evaluated in Study JMEI, a randomized (1:1), open-label, active-controlled trial conducted in patients who had progressed following platinum-based chemotherapy. Patients received PEMRYDI RTU 500 mg/m

Study JMEI excluded patients with an ECOG PS of 3 or greater, uncontrolled third-space fluid retention, inadequate bone marrow reserve and organ function, or a calculated creatinine clearance less than 45 mL/min. Patients unable to discontinue aspirin or other non-steroidal anti-inflammatory drugs or unable to take folic acid, vitamin B

The data described below reflect exposure to PEMRYDI RTU in 265 patients in Study JMEI. Median age was 58 years (range 22 to 87 years); 73% of patients were men; 70% were White, 24% were Asian, 2.6% were Black or African American, 1.8% were Hispanic or Latino, and < 2% were other ethnicities; 19% had an ECOG PS 0.

Table 7 provides the frequency and severity of adverse reactions reported in ≥ 5% of the 265 PEMRYDI RTU-treated patients in Study JMEI. Study JMEI is not designed to demonstrate a statistically significant reduction in adverse reaction rates for PEMRYDI RTU, as compared to the control arm, for any specified adverse reaction listed in the Table 7 below.

The following additional adverse reactions were observed in patients assigned to receive PEMRYDI RTU.

The safety of PEMRYDI RTU was evaluated in Study JMCH, a randomized (1:1), single-blind study conducted in patients with MPM who had received no prior chemotherapy for MPM. Patients received PEMRYDI RTU 500 mg/m

Study JMCH excluded patients with Karnofsky Performance Scale (KPS) of less than 70, inadequate bone marrow reserve and organ function, or a calculated creatinine clearance less than 45 mL/min. Patients unable to stop using aspirin or other non-steroidal anti-inflammatory drugs were also excluded from the study.

The data described below reflect exposure to PEMRYDI RTU in 168 patients that were fully supplemented with folic acid and vitamin B

Table 8 provides the frequency and severity of adverse reactions ≥ 5% in the subgroup of PEMRYDI RTU-treated patients who were fully vitamin supplemented in Study JMCH. Study JMCH was not designed to demonstrate a statistically significant reduction in adverse reaction rates for PEMRYDI RTU, as compared to the control arm, for any specified adverse reaction listed in the table below.

The following additional adverse reactions were observed in patients receiving PEMRYDI RTU plus cisplatin:

Table 9 provides the results of exploratory analyses of the frequency and severity of NCI CTCAE Grade 3 or 4 adverse reactions reported in more PEMRYDI RTU-treated patients who did not receive vitamin supplementation (never supplemented) as compared with those who received vitamin supplementation with daily folic acid and vitamin B

The following adverse reactions occurred more frequently in patients who were fully vitamin supplemented than in patients who were never supplemented:

The following adverse reactions have been identified during post-approval use of PEMRYDI RTU. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.