First-Line Metastatic Colorectal Cancer (mCRC) Trial (N9741): Design & Efficacy
Study Objectives
- Compare the efficacy and safety between irinotecan + bolus 5-FU/LV (IFL) and...
- ELOXATIN + infusional 5-FU/LV q2w (FOLFOX4)
- ELOXATIN + irinotecan q3w (IROX)
-
...as first-line therapy in patients with previously untreated advanced colorectal cancer
Primary End Point
- Time to tumor progression (TTP): IFL vs. FOLFOX4 vs. IROX
Secondary End Points (IFL vs. FOLFOX4 vs. IROX)
- Overall survival
- Response rate
- Safety
Methods
A multicenter, open-label, randomized, controlled intergroup study (N9741) led by
the North Central Cancer Treatment Group (NCCTG)
Patient characteristics were well balanced between study arms.1
First-Line Trial—Patient Demographics
|
Sex (%)
|
|
|
|
|
Male
|
58.8%
|
65.2%
|
61.0%
|
|
Female
|
41.2%
|
34.8%
|
39.0%
|
|
Median Age (years)
|
61.0
|
61.0
|
61.0
|
|
<65 (%)
|
61.0%
|
62.0%
|
63.0%
|
|
>65 (%)
|
39.0%
|
38.0%
|
37.0%
|
|
ECOG (%)
|
|
|
|
|
0-1
|
94.4%
|
95.5%
|
94.7%
|
|
2
|
5.6%
|
4.5%
|
5.3%
|
|
Involved organs (%)
|
|
|
|
|
Colon only
|
0.7%
|
0.8%
|
0.4%
|
|
Liver only
|
39.3%
|
44.3%
|
39.0%
|
|
Liver + other
|
41.2%
|
38.6%
|
40.9%
|
|
Lung only
|
6.4%
|
3.8%
|
5.3%
|
Other
(including lymph nodes)
|
11.6%
|
11.0%
|
12.9%
|
|
Not reported
|
0.7%
|
1.5%
|
1.5%
|
|
Prior radiation (%)
|
3.0%
|
1.5%
|
3.0%
|
|
Prior surgery (%)
|
74.5%
|
79.2%
|
81.8%
|
|
Prior adjuvant (%)
|
15.7%
|
14.8%
|
15.2%
|
First-Line Trial—Cycles Administered
|
Length of treatment cycle (wk)
|
2
|
6
|
3
|
|
Median no. of cycles administered
|
10
|
4
|
7
|
For advanced disease, treatment is recommended until disease progression or unacceptable toxicity.
First-Line Trial—Post Study Chemotherapy
In patients previously untreated for advanced colorectal cancer in the randomized
clinical trial of ELOXATIN, 160 patients treated with ELOXCATIN and 5-fluorouracil/leucovorin
were < 65 years and 99 patients were (greater than or equal to) 65 years. The same
efficacy improvements in response rate, time to tumor progression, and overall survival
were observed in the (greater than or equal to) 65 year old patients as in the overall
study population.
Safety Information from the Metastatic Trial (N9741)
- 65% to 72% of patients received additional poststudy chemotherapy:
- 58% of FOLFOX4 patients received an irinotecan-containing regimen
- 23% of IFL patients received an ELOXATIN (oxaliplatin injection) containing regimen;
ELOXATIN (oxaliplatin injection) was not commercially available during the trial
First-Line Trial Results: Statistically Significant Advantage in Median Survival,
TTP, and Response Rate vs. IFL
Significantly Longer Median Survival vs. IFL (P<.0001)
*Hazard ratio (95% CI) = 0.65 (0.53-0.80)
- Significantly longer overall survival by 4.8 months vs. an irinotecan-based regimen
1
- Number of deaths N (%): 155 (58.1%) for ELOXATIN + infusional 5-FU/LV (N=267) vs. 192 (72.7%) for irinotecan + 5-FU/LV (N=264)
Significantly Longer TTP vs. IFL (Hazard ratio [HR] = 0.74; Confidence Interval
[95% CI], 0.61-0.89; P=.0014)
Significantly Greater Response Rate vs. IFL (Hazard ratio [HR] = 0.74; Confidence
Interval [95% CI], 0.53-0.80; P=.0080)
- The TTP and response rate analyses are based on unblinded investigator assessment
A descriptive subgroup analysis demonstrated that the improvement in survival for ELOXATIN plus 5-fluorouracil/leucovorin compared to irinotecan plus 5-fluorouracil/leucovorin appeared to be maintained across age groups, prior adjuvant therapy, and number of organs involved. An estimated survival advantage in ELOXATIN plus 5-fluorouracil/leucovorin versus irinotecan plus 5-fluorouracil/leucovorin was seen in both genders; however it was greater among women than men. Insufficient subgroup sizes prevented analysis by race.
In patients previously untreated for advanced colorectal cancer in the randomized
clinical trial of ELOXATIN, 160 patients treated with ELOXCATIN and 5-fluorouracil/leucovorin
were < 65 years and 99 patients were (greater than or equal to) 65 years. The
same efficacy improvements in response rate, time to tumor progression, and overall
survival were observed in the (greater than or equal to) 65 year old patients as
in the overall study population. The rate of overall adverse reactions, including
the more severe adverse reactions (Grade 3-4) were similar in older (≥65 years old)
and younger (<65 years old) patients.
The incidence of diarrhea, dehydration, hypokalemia, leukopenia, fatigue and syncope
were higher in patients ≥65 years old. No adjustment to starting dose was required
in patients ≥65 years old.
Safety Information from the Metastatic Trial (N9741)
- Most common (25% or more) adverse events (for all grade) for the arm receiving ELOXATIN
+ infusional 5FU/LV in this study (first line metastatic) were:
- Fatigue (70%), abdominal pain (29%), nausea (71%), diarrhea (56%), vomiting (41%),
stomatitis (38%), anorexia (35%), constipation (32%), overall neuropathy (82%),
paresthesias (77%), pharyngo-laryngeal dysthesias (38%), cough (35%), anemia (27%),
leucopenia (85%), neutropenia (81%), thrombocytopenia (71%)
- The most common grade 3/4 (greater than or equal to 5%) adverse events for the arm
receiving ELOXATIN + infusional 5FU/LV in this study (first line metastatic) were:
- Thrombosis (5%), Fatigue (7%), Abdominal Pain (8%), Nausea (6%), Diarrhea (12%),
Infection low ANC† (8%), Dehydration (5%), Overall Neuropathy
(19%), Paresthesias (19%), Dyspnea (7%)
Important Safety Information
ELOXATIN should not be administered to patients with a history of known allergy
to ELOXATIN or other platinum compounds. Hypersensitivity and anaphylactic/anaphylactoid
reactions to ELOXATIN have been reported and were similar in nature and severity
to those reported with other platinum compounds (i.e., rash, urticaria, erythema,
pruritus, and, rarely, bronchospasm and hypotension). These reactions occur within
minutes of administration and should be managed with appropriate supportive therapy.
Drug-related deaths from this reaction have been reported.
Safety in the Pivotal 1st-line mCRC trial, N9741
|
Overall Neuropathy
|
82%
|
19%
|
18%
|
2%
|
69%
|
7%
|
|
Paresthesias
|
77%
|
18%
|
16%
|
2%
|
62%
|
6%
|
|
Pharyngo-laryngeal dysesthesias
|
38%
|
2%
|
1%
|
0%
|
28%
|
1%
|
|
Neuro-sensory
|
12%
|
1%
|
2%
|
0%
|
9%
|
1%
|
|
Febrile neutropenia
|
4%
|
4%
|
15%
|
14%
|
12%
|
11%
|
|
Neutropenia
|
81%
|
53%
|
77%
|
44%
|
71%
|
36%
|
|
Infection—no ANC
|
10%
|
4%
|
5%
|
1%
|
7%
|
2%
|
|
Infection—ANC
|
8%
|
8%
|
12%
|
11%
|
9%
|
8%
|
|
Lymphopenia
|
6%
|
2%
|
4%
|
1%
|
5%
|
2%
|
|
Anemia
|
27%
|
3%
|
28%
|
4%
|
25%
|
3%
|
|
Leukopenia
|
85%
|
20%
|
84%
|
23%
|
76%
|
24%
|
|
Thrombocytopenia
|
71%
|
5%
|
26%
|
2%
|
44%
|
4%
|
|
Nausea
|
71%
|
6%
|
67%
|
15%
|
83%
|
19%
|
|
Diarrhea
|
56%
|
12%
|
65%
|
29%
|
76%
|
25%
|
|
Vomiting
|
41%
|
4%
|
43%
|
13%
|
64%
|
23%
|
|
Stomatitis
|
38%
|
0%
|
25%
|
1%
|
19%
|
1%
|
|
Anorexia
|
35%
|
2%
|
25%
|
4%
|
27%
|
5%
|
|
Constipation
|
32%
|
4%
|
27%
|
2%
|
21%
|
2%
|
|
Diarrhea—colostomy
|
13%
|
2%
|
16%
|
7%
|
16%
|
3%
|
|
Gastrointestinal NOS
|
5%
|
2%
|
4%
|
2%
|
3%
|
2%
|
* ≥1% NCI grade 3/4 adverse events.
ANC = absolute neutrophil count.
NOS = not otherwise specified.
Other adverse events reported with ELOXATIN in combination with infusional 5-FU/LV include:
|
Hypersensitivity
|
12%
|
2%
|
|
Thrombosis
|
6%
|
5%
|
|
Hypotension
|
5%
|
3%
|
|
Fatigue
|
70%
|
7%
|
|
Abdominal pain
|
29%
|
8%
|
|
Myalgia
|
14%
|
2%
|
|
Pain
|
7%
|
1%
|
|
Skin reaction (hand/foot)
|
7%
|
1%
|
|
Hyperglycemia
|
14%
|
2%
|
|
Hypokalemia
|
11%
|
3%
|
|
Dehydration
|
9%
|
5%
|
|
Hyponatremia
|
8%
|
2%
|
|
Urinary frequency
|
5%
|
1%
|
|
Cough
|
35%
|
1%
|
|
Dyspnea
|
18%
|
7%
|
|
Hiccups
|
5%
|
1%
|
- Among patients receiving FOLFOX4, the onset of grade 3 paresthesias occurred after
a median of 12 two-week treatment cycles2
- 60-day all-cause mortality was 2.3% with FOLFOX4, vs. 5.1% with IFL, and 3.1% with
IROX1
Important Safety Information
Anaphylactic-like reactions to ELOXATIN have been reported and may occur within
minutes of ELOXATIN administration. Epinephrine, corticosteroids, and antihistamines
have been employed to alleviate symptoms.
- ELOXATIN should not be administered to patients with a history of known allergy
to ELOXATIN or other platinum compounds. Hypersensitivity and anaphylactic/anaphylactoid
reactions to ELOXATIN have been reported and were similar in nature and severity
to those reported with other platinum compounds (ie, rash, urticaria, erythema,
pruritus, and, rarely, bronchospasm and hypotension). These reactions occur within
minutes of administration and should be managed with appropriate supportive therapy.
Drug-related deaths from this reaction have been reported.
- ELOXATIN may cause fetal harm when administered to a pregnant woman. Women of childbearing
potential should be advised not to become pregnant while receiving ELOXATIN. It
is not known whether ELOXATIN or its derivatives are excreted in human milk.
- ELOXATIN has been associated with pulmonary fibrosis (<1% of study patients),
which may be fatal. The combined incidence of cough and dyspnea was 7.4% (<1%
grade 3, no grade 4) in the ELOXATIN plus 5-FU/LV arm compared to 4.5% (no grade
3, 0.1% grade 4) in the 5-FU/LV alone arm in the adjuvant colon cancer study. In
this study, one patient died from eosinophilic pneumonia in the ELOXATIN combination
arm. The combined incidence of cough, dyspnea, and hypoxia was 43% (7% grade 3 and
4) in the ELOXATIN plus 5-FU/LV arm compared to 32% (5% grade 3 and 4) in the irinotecan
plus 5-FU/LV arm in patients with previously untreated colorectal cancer. In case
of unexplained respiratory symptoms, ELOXATIN should be discontinued until pulmonary
investigation excludes interstitial lung disease or pulmonary fibrosis.
- ELOXATIN is associated with two types of primarily peripheral sensory neuropathy:
an acute, reversible type of early onset and a persistent type (>14 days). In
patients with advanced colorectal cancer paresthesias occurred in 77% (all grades)
and 18% (grade 3/4) of previously untreated patients. In previously treated patients,
acute neuropathy occurred in 56% (all grades) and 2% (grade 3/4) of patients; persistent
neuropathy occurred in 48% (all grades) and 6% (grade 3/4) of patients. In patients
with stage II and III colon cancer, paresthesia was seen in 92% (all grades) and
13% (grade 3/4) of patients; 21% (all grades), 0.5% (grade 3/4) had residual paresthesia
at 18-month follow-up.
- Hepatotoxicity, as evidenced in the adjuvant study by increase in transaminases
and alkaline phosphatase was observed more commonly in the ELOXATIN combination
arm. The incidence of increased bilirubin was similar on both arms. Changes noted
on liver biopsies include: peliosis, nodular regenerative hyperplasia or sinusoidal
alterations, perisinusoidal fibrosis and veno-occlusive lesions. Hepatic vascular
disorders should be considered and, if appropriate, investigated in case of abnormal
liver function test results or portal hypertension not explained by liver metastases.
- Monitoring of white blood cell count with differential, hemoglobin, platelet count
and blood chemistries (including ALT, AST, bilirubin and creatinine) is recommended
before each ELOXATIN cycle.
- The safety and effectiveness of ELOXATIN plus 5-FU/LV in patients with renal impairment
have not been evaluated. Since the primary route of platinum elimination is renal,
this combination should be used with caution in patients with preexisting renal
impairment. Clearance of these products may be decreased by coadministration of
potentially nephrotoxic compounds, although this has not been specifically studied.
- The incidence of diarrhea, dehydration, hypokalemia, leukopenia, fatigue and syncope
were higher in patients ≥65 years old.
- Extravasation may result in local pain and inflammation that may be severe and lead
to complications, including necrosis. Injection site reaction, including redness,
swelling and pain, has been reported.
- There have been reports of prolonged prothrombin time and INR occasionally associated
with hemorrhage in patients receiving ELOXATIN plus 5-FU/LV while on anticoagulants.
Patients receiving ELOXATIN plus 5-FU/LV and requiring oral anticoagulants may require
closer monitoring.
- The most common adverse reactions in patients with stage II or III colon cancer
receiving adjuvant therapy were peripheral sensory neuropathy, neutropenia, thrombocytopenia,
anemia, nausea, increase in transaminases and alkaline phosphatase, diarrhea, emesis,
fatigue, and stomatitis. The most common adverse reactions in patients with advanced
colorectal cancer were peripheral sensory neuropathy, fatigue, neutropenia, nausea,
emesis, and diarrhea.
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