6 ADVERSE REACTIONS

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

Severe Myelosuppression [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 described in the WARNINGS AND PRECAUTIONS section and below reflect exposure to LONSURF at the recommended dose in 533 patients with metastatic colorectal cancer in RECOURSE, 246 patients with metastatic colorectal cancer treated with LONSURF as monotherapy in SUNLIGHT and 335 patients with metastatic gastric cancer in TAGS. Among the 1114 patients who received LONSURF as a single agent, 12% were exposed for 6 months or longer and 1% were exposed for 12 months or longer. The most common adverse reactions or laboratory abnormalities (≥10%) were neutropenia, anemia, thrombocytopenia, fatigue, nausea, decreased appetite, diarrhea, vomiting, abdominal pain, and pyrexia.

Among the 246 patients with metastatic colorectal cancer treated with LONSURF in combination with bevacizumab in SUNLIGHT, 39% were exposed for 6 months or longer, and 14% were exposed for 12 months or longer. The most common adverse reactions or laboratory abnormalities (≥20%) were neutropenia, anemia, thrombocytopenia, fatigue, nausea, increased AST, increased ALT, increased alkaline phosphatase, decreased sodium, diarrhea, abdominal pain, and decreased appetite.

Metastatic Colorectal Cancer

LONSURF as a single agent

The safety of LONSURF was evaluated in RECOURSE, a randomized (2:1), double-blind, placebo-controlled trial in patients with previously treated metastatic colorectal cancer [see Clinical Studies (14.1)]. Patients received LONSURF 35 mg/m2/dose (n=533) or placebo (n=265) twice daily on Days 1 through 5 and Days 8 through 12 of each 28-day cycle. In RECOURSE, 12% of patients received LONSURF for more than 6 months and 1% of patients received LONSURF for more than 1 year.

The study population characteristics were: median age 63 years; 61% male; 57% White, 35% Asian, and 1% Black.

The most common adverse reactions or laboratory abnormalities (≥10% in incidence) in patients treated with LONSURF at a rate that exceeds the rate in patients receiving placebo were anemia, neutropenia, asthenia/fatigue, nausea, thrombocytopenia, decreased appetite, diarrhea, vomiting, abdominal pain, and pyrexia.

In RECOURSE, 3.6% of patients discontinued LONSURF for an adverse reaction and 14% of patients required a dose reduction. The most common adverse reactions or laboratory abnormalities leading to dose reduction were neutropenia, anemia, febrile neutropenia, fatigue, and diarrhea.

Table 3 and Table 4 list the adverse reactions and laboratory abnormalities (graded using CTCAE v4.03), respectively, observed in RECOURSE.

Table 3: Adverse Reactions (≥5%) in Patients Receiving LONSURF and at a Higher Incidence (>2%) than in Patients Receiving Placebo in RECOURSE
* No Grade 4 definition for nausea, abdominal pain, or fatigue in National Cancer Institute Common Terminology † Incidence reflects 64 preferred terms in the Infections and Infestations system organ class.
Adverse Reactions	LONSURF (N=533)		Placebo (N=265)
Adverse Reactions	All Grades (%)	Grades 3-4* (%)	All Grades (%)	Grades 3-4* (%)
General
Asthenia/fatigue	52	7	35	9
Pyrexia	19	1.3	14	0.4
Gastrointestinal
Nausea	48	1.9	24	1.1
Diarrhea	32	3	12	0.4
Vomiting	28	2.1	14	0.4
Abdominal pain	21	2.4	19	3.8
Stomatitis	8	0.4	6	0
Metabolism and nutrition
Decreased appetite	39	3.6	29	4.9
Infections†	27	7	16	4.9
Nervous system
Dysgeusia	7	0	2.3	0
Skin and subcutaneous tissue
Alopecia	7	0	1.1	0

Table 4: Select Laboratory Abnormalities in RECOURSE
* Worst Grade at least one grade higher than baseline, with percentages based on number of patients with post-baseline samples, which may be <533 (LONSURF) or 265 (placebo) † One Grade 4 anemia adverse reaction based on clinical criteria was reported
Laboratory Parameter*	LONSURF		Placebo
Laboratory Parameter*	All Grades (%)	Grades 3-4 (%)	All Grades (%)	Grades 3-4 (%)
Hematologic
Anemia†	77	18	33	3
Neutropenia	67	38	0.8	0
Thrombocytopenia	42	5	8	0.4

In RECOURSE, pulmonary emboli occurred more frequently in LONSURF-treated patients (2%) compared to no patients on placebo.

LONSURF in combination with bevacizumab

The safety of LONSURF in combination with bevacizumab was evaluated in SUNLIGHT, an international, randomized, open label study in patients with previously treated metastatic colorectal cancer [see Clinical Studies (14.1)].

The study population characteristics were: median age 63 years (20 to 90 years); 52% male; 88% White, 1.4% Black, 0.2% Asian, 0.2% American Indian or Alaska Native, and 9.6% were unknown; and baseline ECOG performance status 0 (46%), 1 (54%), or 2 (0.2%).

Serious adverse reactions occurred in 25% of patients. The most frequent serious adverse reactions (≥2%) were intestinal obstruction (2.8%), and COVID-19 (2%). Fatal adverse reactions occurred in 1.2% of patients who received LONSURF in combination with bevacizumab, including rectal fistula (0.4%), bowel perforation (0.4%) and atrial fibrillation (0.4%).

Permanent treatment discontinuation due to an adverse reaction occurred in 13% of patients. The adverse reaction which resulted in permanent treatment discontinuation in ≥2% of patients was fatigue.

Dosage reductions due to an adverse reaction or laboratory abnormality occurred in 7% of patients. At least one dose reduction in 3.7% of patients was required for neutropenia.

Dosage interruptions due to an adverse reaction occurred in 11% of patients who received LONSURF in combination with bevacizumab. The adverse reaction that required dosage interruption in ≥2% of patients was nausea.

The most common adverse reactions or laboratory abnormalities (≥20% in incidence) in patients treated with LONSURF in combination with bevacizumab were neutropenia, anemia, thrombocytopenia, fatigue, nausea, increased aspartate aminotransferase, increased alanine aminotransferase, increased alkaline phosphatase, decreased sodium, diarrhea, abdominal pain, and decreased appetite. Table 5 and Table 6 list the adverse reactions and laboratory abnormalities, respectively, observed in SUNLIGHT.

Table 5: Adverse Reactions (≥5%) in SUNLIGHT
* Represents a composite of multiple related terms
Adverse Reactions	LONSURF + Bevacizumab (N=246) (%)		LONSURF (N=246) (%)
Adverse Reactions	All Grades	Grade 3 or 4	All Grades	Grade 3 or 4
Gastrointestinal disorders
Nausea	37	1.6	27	1.6
Diarrhea*	21	1.2	19	2.4
Abdominal pain*	20	2.8	18	3.7
Vomiting*	19	0.8	15	1.6
Stomatitis*	13	<0.4	4.1	0
Constipation	11	0	11	0.8
General disorders and administration site conditions
Fatigue*	45	5	37	8
Pyrexia	4.9	0	6	0.4
Infections and infestations*	31	8	24	8
Metabolism and nutrition disorders
Decreased appetite	20	<0.8	15	1.2
Musculoskeletal and connective tissue disorders
Musculoskeletal pain*	18	1.2	11	2
Nervous system disorder
Headache	8	0	3.7	0
Vascular disorders
Hypertension*	11	6	2	1.2
Hemorrhage*	10	1.2	3.7	0.8
Renal and urinary disorders
Proteinuria	6	0.8	1.2	0

Table 6: Select Laboratory Abnormalities (≥10%) in SUNLIGHT
* Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: LONSURF + bevacizumab group (n=242 patients) and LONSURF group (range: 240 to 242 patients).
Laboratory parameters	LONSURF + Bevacizumab*		LONSURF*
	All Grades (%)	Grade 3 or 4 (%)	All Grades (%)	Grade 3 or 4 (%)
Hematology
Neutrophils decreased	80	52	68	39
Hemoglobin decreased	68	5	73	11
Platelets decreased	54	4.1	29	0.8
Chemistry
Aspartate aminotransferase increased	34	2.1	28	1.2
Alanine aminotransferase increased	33	3.3	23	0.4
Alkaline phosphatase increased	31	0.8	36	1.2
Sodium decreased	25	2.1	20	3.3
Potassium increased	17	0	15	0
Potassium decreased	12	0.8	12	2.5
Creatinine increased	12	0.8	15	0

Metastatic Gastric Cancer

The safety of LONSURF was evaluated in TAGS, an international, randomized (2:1), double-blind, placebo-controlled trial in patients with metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma who were previously treated with at least 2 prior chemotherapy regimens for advanced disease [see Clinical Studies (14.2)]. Previous treatments must have included a fluoropyrimidine, a platinum, and either a taxane or irinotecan. Patients with HER2/neu-positive tumors must have received prior HER2/neu-targeted therapy, if available. Adjuvant chemotherapy could be counted as one prior regimen in patients who had recurrence during or within 6 months of completion of the adjuvant chemotherapy. Patients received LONSURF 35 mg/m2/dose (n=335) or placebo (n=168) twice daily on Days 1 through 5 and Days 8 through 12 of each 28-day cycle with best supportive care. In TAGS, 10% of patients received LONSURF for more than 6 months and 0.9% of patients received LONSURF for more than 1 year.

The study population characteristics were: median age 63 years (24 to 89 years); 73% male; 70% White, 16% Asian, and 1% Black.

The most common adverse reactions or laboratory abnormalities (≥10% in incidence) in patients treated with LONSURF at a rate that exceeds the rate in patients receiving placebo were neutropenia, anemia, nausea, decreased appetite, thrombocytopenia, vomiting, and diarrhea.

In TAGS, 13% of patients discontinued LONSURF for an adverse reaction and 11% of patients required a dose reduction. The most common adverse reactions or laboratory abnormalities leading to dose reduction were neutropenia, anemia, febrile neutropenia, and diarrhea.

Table 7 and Table 8 list the adverse reactions and laboratory abnormalities (graded using CTCAE v4.03), respectively, observed in TAGS.

Table 7: Adverse Reactions (≥5%) in Patients Receiving LONSURF and at a Higher Incidence (>2%) than in Patients Receiving Placebo in TAGS
* No Grade 4 definition for nausea or fatigue in NCI CTCAE, version 4.03. † Incidence reflects 46 preferred terms in the Infections and Infestations system organ class.
Adverse Reactions	LONSURF (N=335)		Placebo (N=168)
Adverse Reactions	All Grades (%)	Grades 3-4* (%)	All Grades (%)	Grades 3-4* (%)
Gastrointestinal
Nausea	37	3	32	3
Vomiting	25	4	20	2
Diarrhea	23	3	14	2
Metabolism and nutrition
Decreased appetite	34	9	31	7
Infections†	23	5	16	5

Table 8: Laboratory Abnormalities in TAGS
* Worst Grade at least one Grade higher than baseline, with percent based on number of patients with post-baseline samples which may be <335 (LONSURF) or 168 (placebo) † Anemia: No Grade 4 definition in CTCAE, v4.03
Laboratory Parameter*	LONSURF		Placebo
Laboratory Parameter*	All Grades (%)	Grades 3-4 (%)	All Grades (%)	Grades 3-4 (%)
Hematologic
Neutropenia	66	38	4	0
Anemia†	63	19	38	7
Thrombocytopenia	34	6	9	0

In TAGS, pulmonary emboli occurred more frequently in LONSURF-treated patients (3.1%) compared to 1.8% for patients on placebo.

Additional Clinical Experience

Interstitial lung disease was reported in 15 (0.2%) patients, 3 of which were fatal, among approximately 7,000 patients exposed to LONSURF in clinical studies and clinical practice settings in Asia.