6 ADVERSE REACTIONS

The following clinically significant adverse reactions are described elsewhere in the labeling:

•: Severe and fatal immune-mediated adverse reactions [see Warnings and Precautions (5.1)]
•: Infusion-related reactions [see Warnings and Precautions (5.2)]

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 with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety population described in the Warnings and Precautions for use of JEMPERLI in combination with carboplatin and paclitaxel was evaluated in 241 patients with primary advanced or recurrent EC in the randomized, double-blind, active-controlled RUBY trial.

Additionally, the pooled safety population described in Warnings and Precautions reflects exposure to JEMPERLI as a single agent in 605 patients with advanced or recurrent solid tumors in the non-randomized, open-label, multicohort GARNET trial that enrolled 314 patients with EC and 291 patients with other solid tumors. JEMPERLI was administered intravenously at doses of 500 mg every 3 weeks for 4 cycles followed by 1,000 mg every 6 weeks until disease progression or unacceptable toxicity. Among the 605 patients, 32% were exposed for >1 year and 19% were exposed for >2 years.

Primary Advanced or Recurrent Endometrial Cancer: JEMPERLI in Combination with Carboplatin and Paclitaxel

The safety of JEMPERLI in patients with primary advanced or recurrent EC was evaluated in RUBY [see Clinical Studies (14.1)]. Patients received JEMPERLI 500 mg (n = 241) or placebo (n = 246) in combination with carboplatin and paclitaxel every 3 weeks for 6 cycles followed by JEMPERLI 1,000 mg or placebo every 6 weeks until disease progression or unacceptable toxicity. Among the 241 patients, 38.6% were exposed for >1 year and 24.1% were exposed for >2 years.

Serious adverse reactions occurred in 39% of patients receiving JEMPERLI in combination with carboplatin and paclitaxel; the most common serious adverse reactions were sepsis, including urosepsis (3.7%), and pulmonary embolism (3.3%). Fatal adverse reactions occurred in 1.2% of patients receiving JEMPERLI including septic shock (0.8%) and myelosuppression (0.4%).

In patients receiving JEMPERLI in combination with carboplatin and paclitaxel, JEMPERLI was permanently discontinued due to adverse reactions in 46 patients (19%). Adverse reactions that required permanent discontinuation in ≥2 patients included 3 cases (1.2%) of rash maculo-papular, and 2 cases (0.8%) each of increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), diarrhea, pancreatitis, fatigue, pneumonitis, and arthralgia.

Dosage interruptions due to an adverse reaction occurred in 37% of patients who received JEMPERLI in combination with carboplatin and paclitaxel. Adverse reactions that required dosage interruption in ≥5% of patients who received JEMPERLI in combination with carboplatin and paclitaxel were anemia, thrombocytopenia, and peripheral neuropathy.

The most common adverse reactions, including laboratory abnormalities (≥20%), were decreased hemoglobin, increased creatinine, peripheral neuropathy, decreased white blood cell count, fatigue, nausea, alopecia, decreased platelets, increased glucose, decreased lymphocytes, decreased magnesium, decreased neutrophils, increased AST, arthralgia, rash, constipation, diarrhea, increased ALT, decreased potassium, decreased albumin, decreased sodium, increased alkaline phosphatase, abdominal pain, dyspnea, decreased appetite, increased amylase, decreased phosphate, urinary tract infection, and vomiting.

Table 3 summarizes the adverse reactions that occurred in ≥20% of patients with primary advanced or recurrent EC receiving JEMPERLI in combination with carboplatin and paclitaxel in RUBY.

Table 3. Adverse Reactions (≥20%) in Patients with Endometrial Cancer Who Received JEMPERLI with Carboplatin and Paclitaxel in RUBY
Graded per National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.03.
a Includes neuropathy peripheral and peripheral sensory neuropathy.
b Includes fatigue and asthenia.
c Includes abdominal pain, abdominal pain upper, abdominal pain lower, gastrointestinal pain, abdominal discomfort, epigastric discomfort, and abdominal tenderness.
d Includes rash, rash maculo-papular, palmar-plantar erythrodysesthesia syndrome, rash pustular, skin exfoliation, and vulvovaginal rash.
e Includes dyspnea and dyspnea exertional.
f Includes urinary tract infection, urinary tract infection bacterial, cystitis, and pyelonephritis.
Adverse Reaction	JEMPERLI with Carboplatin and Paclitaxel N = 241		Placebo withCarboplatin and Paclitaxel N = 246
Adverse Reaction	All Grades %	Grade 3 or 4 %	All Grades %	Grade 3 or 4 %
Nervous System Disorders
Peripheral neuropathya	64	4.1	61	2.0
General
Fatigueb	56	3.3	63	5
Gastrointestinal Disorders
Nausea	54	2.9	46	1.6
Constipation	35	0.4	36	0
Diarrhea	32	1.7	29	0.8
Abdominal painc	24	2.5	29	2
Vomiting	20	1.7	20	1.6
Skin and Subcutaneous Tissue
Alopecia	54	0	50	1.2
Rashd	37	7	18	1.2
Musculoskeletal and Connective Tissue
Arthralgia	37	1.2	35	0.4
Respiratory, Thoracic and Mediastinal Disorders
Dyspneae	23	1.7	26	0.8
Metabolism and Nutrition Disorders
Decreased appetite	22	2.1	18	0.4
Infections and Infestations
Urinary tract infectionf	21	3.3	18	1.6

Clinically relevant adverse reactions in <20% of patients with primary advanced or recurrent EC who received JEMPERLI in combination with carboplatin and paclitaxel included:

Endocrine Disorders: Hypothyroidism, hyperthyroidism, thyroiditis, adrenal insufficiency.

Eye Disorders: Keratitis, uveitis.

Gastrointestinal Disorders: Colitis, pancreatitis.

Metabolism and Nutrition Disorders: Type 1 diabetes mellitus.

Musculoskeletal and Connective Tissue Disorders: Immune-mediated arthritis.

Respiratory, Thoracic, and Mediastinal Disorders: Pneumonitis.

Cardiac Disorders: Myocarditis.

Nervous System Disorders: Encephalopathy.

Vascular Disorders: Hypertension, hemorrhage.

Table 4 summarizes the laboratory abnormalities in patients with primary advanced or recurrent EC receiving JEMPERLI in combination with carboplatin and paclitaxel in RUBY.

Table 4. Select Laboratory Abnormalities that Worsened from Baseline Occurring in ≥20% of Patients with Endometrial Cancer Receiving JEMPERLI with Carboplatin and Paclitaxel in RUBY
ALT = alanine aminotransferase; AST = aspartate aminotransferase.
a Consists of new onset of laboratory abnormality or worsening of baseline laboratory abnormality.
Laboratory Test	JEMPERLI with Carboplatin and Paclitaxel N = 241		Placebo with Carboplatin and Paclitaxel N = 246
Laboratory Test	All Gradesa %	Grade 3 or 4a %	All Gradesa %	Grade 3 or 4a %
Hematology
Decreased hemoglobin	79	14	83	16
Decreased white blood cell count	62	13	58	11
Decreased platelet count	48	4.1	48	7
Decreased lymphocytes	44	14	39	13
Decreased neutrophils	42	14	52	18
Chemistry
Increased creatinine	75	1.7	82	0.4
Increased glucose	47	10	44	10
Increased AST	38	3.3	23	1.6
Increased ALT	30	2.5	19	0.8
Decreased albumin	29	0.8	21	0
Increased alkaline phosphatase	28	1.7	22	0.4
Increased amylase	21	5	11	1.6
Electrolytes
Decreased magnesium	44	2.1	47	2
Decreased potassium	30	6	29	4.1
Decreased sodium	29	6	22	3.7
Decreased phosphate	21	1.2	18	3.7

Mismatch Repair Deficient Recurrent or Advanced Endometrial Cancer: JEMPERLI as a Single Agent

The safety of JEMPERLI was evaluated in GARNET in 150 patients with advanced or recurrent dMMR EC who received at least 1 dose of JEMPERLI [see Clinical Studies (14.1)]. Patients received JEMPERLI 500 mg every 3 weeks for 4 cycles followed by 1,000 mg every 6 weeks as an intravenous infusion until disease progression or unacceptable toxicity. Patients with autoimmune disease that required systemic therapy within 2 years of treatment or a medical condition that required immunosuppression were ineligible. Among patients receiving JEMPERLI, 41% were exposed for >1 year and 23% were exposed for >2 years.

A fatal adverse reaction occurred in one patient (0.7%) who received JEMPERLI, due to concurrent immune-mediated encephalitis and urinary tract infection.

Serious adverse reactions occurred in 38% of patients receiving JEMPERLI. Serious adverse reactions in >2% of patients included urinary tract infection (4%), sepsis (3.3%), acute kidney injury (2.7%), and abdominal pain (2.7%).

JEMPERLI was permanently discontinued due to adverse reactions in 15 (10%) patients, including increased transaminases, sepsis, bronchitis, pneumonitis, rash, pruritus, pancreatitis, encephalitis, and nephritis. Dosage interruptions due to an adverse reaction occurred in 28% of patients who received JEMPERLI. Adverse reactions that required dosage interruption in >1% of patients who received JEMPERLI were anemia, diarrhea, asthenia, colitis, sepsis, and pneumonitis.

The most common adverse reactions (≥20%) were fatigue/asthenia, anemia, nausea, diarrhea, constipation, vomiting, and rash.

Table 5 summarizes the adverse reactions that occurred in ≥10% of patients with dMMR EC on JEMPERLI in GARNET.

Table 5. Adverse Reactions (≥10%) in Patients with dMMR Endometrial Cancer Who Received JEMPERLI in GARNET
dMMR = Mismatch Repair Deficient.
Toxicity was graded per National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.03. a Includes fatigue and asthenia. b Includes anemia, decreased hemoglobin, iron deficiency, and iron deficiency anemia.
c Includes rash, rash maculo-papular, rash pruritic, erythema, and pemphigoid.
d Includes increased alanine aminotransferase, increased aspartate aminotransferase, increased transaminases, and hypertransaminasemia.
Adverse Reaction	JEMPERLI N = 150
Adverse Reaction	All Grades %	Grade 3 or 4 %
General and administration site
Fatiguea Pyrexia	49 13	3.3 0
Blood and lymphatic system Anemiab	35	18
Gastrointestinal
Nausea	32	0.7
Diarrhea	29	2.7
Constipation	23	0.7
Vomiting	23	0.7
Skin and subcutaneous tissue Rashc Pruritus	21 19	0 1.3
Infections Urinary tract infection	19	4
Metabolism and nutrition
Decreased appetite	15	0
Respiratory, thoracic, and mediastinal
Cough	15	0
Musculoskeletal and connective tissue
Myalgia	10	0
Investigations Increased transaminasesd	13	4
Endocrine Disorders Hypothyroidism	11	0

Clinically relevant adverse reactions in <10% of patients who received JEMPERLI included:

Endocrine Disorders: Hyperthyroidism, adrenal insufficiency, hypophysitis.

Eye Disorders: Iridocyclitis, uveitis.

Gastrointestinal Disorders: Colitis, pancreatitis, enterocolitis, gastritis.

General Disorders and Administration Site Conditions: Chills.

Musculoskeletal and Connective Tissue Disorders: Immune-mediated myositis, immune-mediated arthritis.

Nervous System Disorders: Encephalitis.

Renal and Urinary Disorders: Nephritis.

Respiratory, Thoracic, and Mediastinal Disorders: Pneumonitis, interstitial lung disease.

Table 6 summarizes laboratory abnormalities worsening from baseline to Grade 3 or 4 in ≥1% of patients with dMMR EC on JEMPERLI in GARNET.

Table 6. Laboratory Abnormalities that Worsened from Baseline to Grade 3 or 4 Occurring in ≥1% of Patients with dMMR Endometrial Cancer Receiving JEMPERLI in GARNET
dMMR = Mismatch Repair Deficient.
a Consists of new onset of laboratory abnormality or worsening of baseline laboratory abnormality.
Laboratory Test	JEMPERLI N = 150
Laboratory Test	All Gradesa %	Grade 3 or 4a %
Hematology
Decreased lymphocytes	46	15
Decreased leukocytes Decreased neutrophils	21 17	2 2.7
Chemistry
Decreased albumin	36	2.7
Increased creatinine	33	3.4
Increased alkaline phosphatase	31	2.7
Increased aspartate aminotransferase	31	2
Increased alanine aminotransferase	25	4.7
Electrolytes
Decreased sodium Decreased magnesium Decreased potassium	29 28 22	5 2 2
Increased calcium	8	2

Mismatch Repair Deficient Recurrent or Advanced Solid Tumors

The safety of JEMPERLI was investigated in 267 patients with recurrent or advanced dMMR solid tumors enrolled in GARNET [see Clinical Studies (14.2)]. Patients received JEMPERLI 500 mg every 3 weeks for 4 cycles followed by 1,000 mg every 6 weeks as an intravenous infusion until disease progression or unacceptable toxicity. Patients with autoimmune disease that required systemic therapy within 2 years of treatment or a medical condition that required immunosuppression were ineligible. The median duration of exposure to JEMPERLI was 25 weeks (range: 1 to 139 weeks).

Serious adverse reactions occurred in 34% of patients receiving JEMPERLI. Serious adverse reactions in >2% of patients included abdominal pain (3.7%), sepsis (2.6%), and acute kidney injury (2.2%). Fatal adverse reaction occurred in 1 patient who received JEMPERLI due to respiratory failure.

JEMPERLI was permanently discontinued due to adverse reactions in 9% patients; the most common adverse reaction (≥1%) leading to discontinuation was increased alanine aminotransferase (1.1%).

Dosage interruptions due to an adverse reaction occurred in 23% of patients who received JEMPERLI. Adverse reactions that required dosage interruption in ≥1% of patients who received JEMPERLI were anemia, pneumonitis, diarrhea, adrenal insufficiency, increased alanine aminotransferase, and increased aspartate aminotransferase.

The most common adverse reactions (≥20%) were fatigue/asthenia, anemia, diarrhea, and nausea.

Table 7 summarizes the adverse reactions that occurred in ≥10% of patients with dMMR recurrent or advanced solid tumors in GARNET.

Table 7. Adverse Reactions (≥10%) in Patients with dMMR Recurrent or Advanced Solid Tumors in GARNET
dMMR = Mismatch Repair Deficient.
Toxicity was graded per National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.03. a Includes fatigue and asthenia. b Includes anemia, decreased hemoglobin, iron deficiency, and iron deficiency anemia. c Includes rash, rash maculopapular, rash macular, rash erythematous, rash papular, erythema, toxic skin eruption, and pemphigoid.
d Includes increased alanine aminotransferase, increased aspartate aminotransferase, increased transaminases, and hypertransaminasemia.
Adverse Reaction	JEMPERLI N = 267
Adverse Reaction	All Grades %	Grade 3 or 4 %
General and administration site
Fatiguea	42	3.4
Pyrexia	12	0
Blood and lymphatic system
Anemiab	30	11
Gastrointestinal
Diarrhea	25	1.5
Nausea	22	0.4
Vomiting	17	1.5
Constipation	16	0.4
Skin and subcutaneous tissue
Pruritus	15	0.4
Rashc	14	0.4
Respiratory, thoracic, and mediastinal
Cough	13	0
Metabolism and nutrition
Decreased appetite	12	0.4
Investigations
Increased transaminasesd	12	3

Clinically relevant adverse reactions in <10% of patients who received JEMPERLI included:

Endocrine Disorders: Hypothyroidism, hyperthyroidism, adrenal insufficiency, hypophysitis, autoimmune thyroiditis.

Eye Disorders: Uveitis.

Gastrointestinal Disorders: Colitis, enterocolitis, enterocolitis hemorrhage, pancreatitis, acute pancreatitis.

General Disorders and Administration Site Conditions: Chills.

Injury, Poisoning, and Procedural Complications: Infusion related reaction.

Hepatobiliary Disorders: Hepatocellular injury.

Musculoskeletal and Connective Tissue Disorders: Myalgia.

Renal and Urinary Disorders: Nephritis, tubulointerstitial nephritis.

Respiratory, Thoracic, and Mediastinal Disorders: Pneumonitis, interstitial lung disease.

Table 8 summarizes laboratory abnormalities worsening from baseline to Grade 3 or 4 in ≥1% of patients with dMMR recurrent or advanced solid tumors in GARNET.

Table 8. Laboratory Abnormalities that Worsened from Baseline to Grade 3 or 4 Occurring in ≥1% of Patients with dMMR Recurrent or Advanced Solid Tumors in GARNET
dMMR = Mismatch Repair Deficient.
a Consists of new onset of laboratory abnormality or worsening of baseline laboratory abnormality.
Laboratory Test	JEMPERLI N = 267
Laboratory Test	All Gradesa %	Grade 3 or 4a %
Hematology
Decreased lymphocytes	33	7
Decreased leukocytes	18	1.1
Decreased neutrophils	12	1.5
Chemistry
Decreased albumin	26	2.2
Increased alkaline phosphatase	26	3.4
Increased aspartate aminotransferase	26	1.5
Increased alanine aminotransferase	22	1.9
Increased creatinine	21	1.1
Increased total bilirubin	7	1.5
Electrolytes
Decreased sodium	21	4.9
Decreased magnesium	16	1.1
Decreased potassium	14	1.1
Increased potassium	14	1.1
Increased calcium	6	1.1
Increased magnesium	4.1	1.5
Decreased calcium	2.6	1.5