FDA Approves ERBITUX(R) (cetuximab) as First-Line Treatment in KRAS Mutation-Negative (Wild-Type) Epidermal Growth Factor Receptor (EGFR)-Expressing Metastatic Colorectal Cancer in Combination with FOLFIRI (Irinotecan, 5-Fluorouracil, Leucovorin)
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First and only
FDA -approved, biomarker-directed therapy for a specific subset of newly diagnosed EGFR-expressing metastatic colorectal cancer (mCRC) patients, targeting those with KRAS mutation-negative (wild-type) tumors - ERBITUX plus FOLFIRI is the first biologic treatment regimen approved in nearly a decade for newly diagnosed mCRC
"Cancer is a heterogeneous disease and we have learned that not all
patients with mCRC should be viewed as the same," said
The new indication is based on data from the CRYSTAL (Cetuximab
combined with iRinotecan in first-line therapY for metaSTatic
colorectAL cancer) trial, a Phase 3 open-label, randomized,
multicenter study conducted outside the U.S. that used
With today's approval, ERBITUX is now the first and only
The Full Prescribing Information for ERBITUX includes a Boxed WARNING regarding infusion reactions. Serious infusion reactions occurred with the administration of ERBITUX in approximately 3 percent of patients in clinical trials, with fatal outcome reported in less than 1 in 1000. Healthcare providers should immediately interrupt and permanently discontinue ERBITUX infusion for serious infusion reactions.
Please see Important Safety Information including Boxed WARNINGS on pages 6-10.
Among the all randomized patient population, a statistically significant improvement in PFS was observed for the EU-approved cetuximab plus FOLFIRI arm compared with the FOLFIRI-alone arm (median PFS 8.9 vs. 8.1 months, HR 0.85 [95% CI, 0.74-0.99], p-value=0.0358). Additionally, the median overall survival (OS) in each arm was 19.6 months (95% CI, 18-21) and 18.5 months (95% CI, 17-20), respectively (HR= 0.88; 95% CI, 0.78-1.0), which was not significantly different. The objective response rate (ORR) in each arm was 46% (95% CI, 42-50) and 38% (95% CI, 34-42), respectively.
In the post-hoc analysis of the KRAS subgroups, the median PFS of the KRAS mutation-negative (wild-type) patients treated with EU-approved cetuximab plus FOLFIRI (n=320) or FOLFIRI alone (n=356) was 9.5 months (95% CI, 8.9-11.1) and 8.1 months (95% CI, 7.4-9.2), respectively (HR= 0.70; 95% CI, 0.57-0.86). The median OS in each arm was 23.5 months (95% CI, 21-26) and 19.5 months (95% CI, 17-21), respectively (HR= 0.80; 95% CI, 0.67-0.94). The ORR in each arm was 57% (95% CI, 51-62) and 39% (95% CI, 34-44), respectively.
There is no evidence of effectiveness in the subgroup of patients with KRAS mutation-positive tumors. The median PFS of the KRAS mutation-positive patients treated with EU-approved cetuximab (n=216) or FOLFIRI alone (n=187) was 7.5 months (95% CI, 6.7-8.7) versus 8.2 months (95% CI, 7.4-9.2), respectively (HR= 1.13; 95% CI, 0.88-1.46). The median OS in each arm was 16.0 months (95% CI, 15-18) versus 16.7 months (95% CI, 15-19), respectively (HR=1.04; 95% CI, 0.84-1.29). The ORR in each arm was 31% (95% CI, 25-38) and 35% (95% CI, 28-43), respectively.
"Both response rates and overall survival in KRAS wild-type
patients treated with the CRYSTAL regimen are important when considering
the treatment options for patients with first-line mCRC," said
Selected adverse events of any grade from the CRYSTAL trial occurring in at least 10 percent of patients receiving EU-approved cetuximab in combination with FOLFIRI versus FOLFIRI alone were: acne-like rash (86% vs. 13%, respectively), diarrhea (66% vs. 60%), neutropenia (49% vs. 42%), rash (44% vs. 4%), stomatitis (31% vs. 19%), anorexia (30% vs. 23%), pyrexia (26% vs. 14%), dermatitis acneiform (26% vs. < 1%), dry skin (22% vs. 4%), acne (14% vs. 0), paronychia (20% vs. < 1%), palmar-plantar erythrodysesthesia syndrome (19% vs. 4%), skin fissures (19% vs. 1%), conjunctivitis (18% vs. 3%), dyspepsia (16% vs. 9%), weight decreased (15% vs. 9%), pruritis (14% vs. 3%), and infusion-related reaction (14% vs. < 1%). U.S.-licensed ERBITUX provides approximately 22 percent higher exposure relative to the EU-approved cetuximab. The data provided above are consistent in incidence and severity of adverse reactions with those seen for ERBITUX in this indication. The tolerability of the recommended dose is supported by safety data from additional studies of ERBITUX.
"The totality of the data from CRYSTAL, along with data from other
ERBITUX trials, provide compelling and consistent evidence of the
benefit of ERBITUX in the treatment of KRAS mutation negative
(wild-type) EGFR-expressing mCRC," said
KRAS: The Biomarker in mCRC to Help Identify Appropriate Patients for ERBITUX Therapy
Data from the landmark CRYSTAL study, along with other cetuximab studies, demonstrate the importance of testing for KRAS status at diagnosis of mCRC to identify appropriate patients for ERBITUX therapy.
Both the National Comprehensive Cancer Network® (NCCN)
Clinical Practice Guidelines in Oncology (NCCN Guidelines®,
Category 2A)* and the
"Research results have consistently demonstrated that KRAS is an
important biomarker in mCRC, underscoring the need for all patients with
this disease to undergo testing for KRAS status at initial
diagnosis," said
NCCN Guidelines recommend ERBITUX (cetuximab) for first-line as a treatment option in combination with FOLFIRI for patients with advanced or metastatic KRAS wild-type mCRC (Category 2A).*
Since its first approval in 2004, approximately 139,814 patients have received ERBITUX therapy in the U.S. alone.
About CRYSTAL
The approval is based on a Phase 3 randomized, open-label multicenter
study of patients with mCRC, which was sponsored by Merck KGaA,
Darmstadt,
Study treatment continued until disease progression or unacceptable toxicity occurred.Eighty-five percent of patients required no dose reduction (minimum cetuximab dose level greater than or equal to 225 mg/m2) and received the full treatment regimen.
About Metastatic Colorectal Cancer (mCRC)
In 2012, 143,460 new cases of colorectal cancer (CRC) are estimated to
occur, and an estimated 51,690 deaths from CRC are expected to occur,
accounting for 9 percent of all projected cancer deaths. Colorectal
cancer is a cancer that develops in the colon or the rectum, which are
both parts of the gastrointestinal system. Metastatic colorectal cancer
(mCRC) occurs when the disease has spread to at least one distant organ
and tissues, such as the liver, lungs, lining of the abdomen or ovaries.
One out of
"For colorectal cancer patients who are diagnosed at the late stage, it
is devastating," said
ERBITUX (cetuximab) is a monoclonal antibody (IgG1 Mab) designed to inhibit the function of a molecular structure expressed on the surface of normal and tumor cells called the epidermal growth factor receptor (EGFR, HER1, c-ErbB-1). In vitro assays and in vivo animal studies have shown that binding of cetuximab to the EGFR blocks phosphorylation and activation of receptor-associated kinases, resulting in inhibition of cell growth induction of apoptosis (cell death), and decreased matrix metalloproteinase and vascular endothelial growth factor production. Signal transduction through the EGFR results in activation of KRAS wild-type protein. However, in cells with activating KRAS somatic mutations, the mutant KRAS protein is continuously active and appears independent of EGFR regulation. In vitro, cetuximab can mediate antibody-dependent cellular cytotoxicity (ADCC) against certain human tumor types. In vitro assays and in vivo animal studies have shown that cetuximab inhibits the growth and survival of tumor cells that express the EGFR. No anti-tumor effects of cetuximab were observed in human tumor xenografts lacking EGFR expression.
INDICATIONS
Head and Neck Cancer
- ERBITUX® (cetuximab), in combination with radiation therapy, is indicated for the initial treatment of locally or regionally advanced squamous cell carcinoma of the head and neck
- ERBITUX is indicated in combination with platinum-based therapy with 5-FU for the first-line treatment of patients with recurrent locoregional disease or metastatic squamous cell carcinoma of the head and neck
- ERBITUX, as a single agent, is indicated for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck for whom prior platinum-based therapy has failed
Colorectal Cancer
ERBITUX is indicated for the treatment of KRAS mutation-negative
(wild-type) epidermal growth factor receptor (EGFR)-expressing
metastatic colorectal cancer (mCRC) as determined by
- in combination with FOLFIRI (irinotecan, 5-fluorouracil, leucovorin) for first-line treatment,
- in combination with irinotecan in patients who are refractory to irinotecan-based chemotherapy,
- as a single agent in patients who have failed oxaliplatin- and irinotecan-based chemotherapy or who are intolerant to irinotecan
Limitation of Use: ERBITUX is not indicated for treatment of KRAS mutation-positive colorectal cancer
IMPORTANT SAFETY INFORMATION INCLUDING BOXED WARNINGS
Infusion Reactions
-
Grade 3/4 infusion reactions occurred in approximately 3% of
patients receiving ERBITUX® (cetuximab) in
clinical trials, with fatal outcome reported in less than 1 in 1000
- Serious infusion reactions, requiring medical intervention and immediate, permanent discontinuation of ERBITUX, included rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), hypotension, shock, loss of consciousness, myocardial infarction, and/or cardiac arrest
- Immediately interrupt and permanently discontinue ERBITUX infusions for serious infusion reactions
-
Approximately 90% of the severe infusion reactions were associated
with the first infusion of ERBITUX despite premedication with
antihistamines
- Caution must be exercised with every ERBITUX infusion, as there were patients who experienced their first severe infusion reaction during later infusions
- Monitor patients for 1 hour following ERBITUX infusions in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis (eg, epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, and oxygen). Longer observation periods may be required in patients who require treatment for infusion reactions
Cardiopulmonary Arrest
-
Cardiopulmonary arrest and/or sudden death occurred in 4 (2%) of
208 patients with squamous cell carcinoma of the head and neck treated
with radiation therapy and ERBITUX, as compared to none of 212
patients treated with radiation therapy alone. In 3 patients with
prior history of coronary artery disease, death occurred 27, 32, and
43 days after the last dose of ERBITUX. One patient with no prior
history of coronary artery disease died one day after the last dose of
ERBITUX. Fatal cardiac disorders and/or sudden death occurred in 7
(3%) of the 219 patients with squamous cell carcinoma of the head and
neck treated with platinum-based therapy with 5-fluorouracil (FU) and
European Union (EU)-approved cetuximab as compared to 4 (2%) of the 215 patients treated with chemotherapy alone. Five of these 7 patients in the chemotherapy plus cetuximab arm received concomitant cisplatin and 2 patients received concomitant carboplatin. All 4 patients in the chemotherapy-alone arm received cisplatin- Carefully consider the use of ERBITUX in combination with radiation therapy or platinum-based therapy with 5-FU in head and neck cancer patients with a history of coronary artery disease, congestive heart failure or arrhythmias in light of these risks
- Closely monitor serum electrolytes including serum magnesium, potassium, and calcium during and after ERBITUX therapy
Pulmonary Toxicity
- Interstitial lung disease (ILD), which was fatal in one case, occurred in 4 of 1570 ( < 0.5%) patients receiving ERBITUX in Studies 1, 3, and 6, as well as other studies, in colorectal cancer and head and neck cancer. Interrupt ERBITUX for acute onset or worsening of pulmonary symptoms. Permanently discontinue ERBITUX for confirmed ILD
Dermatologic Toxicities
-
In clinical studies of ERBITUX, dermatologic toxicities, including
acneiform rash, skin drying and fissuring, paronychial inflammation,
infectious sequelae (eg, S. aureus sepsis, abscess formation,
cellulitis, blepharitis, conjunctivitis, keratitis/ulcerative
keratitis with decreased visual acuity, cheilitis), and
hypertrichosis, occurred in patients receiving ERBITUX therapy.
Acneiform rash occurred in 76-88% of 1373 patients receiving ERBITUX
in Studies 1, 3, 5, and 6. Severe acneiform rash occurred in 1-17% of
patients
- Acneiform rash usually developed within the first 2 weeks of therapy and resolved in a majority of the patients after cessation of treatment, although in nearly half, the event continued beyond 28 days
- Monitor patients receiving ERBITUX for dermatologic toxicities and infectious sequelae
- Sun exposure may exacerbate these effects
ERBITUX Plus Radiation Therapy and Cisplatin
-
The safety of ERBITUX in combination with radiation therapy and
cisplatin has not been established
- Death and serious cardiotoxicity were observed in a single-arm trial with ERBITUX, radiation therapy, and cisplatin (100 mg/m2) in patients with locally advanced squamous cell carcinoma of the head and neck
- Two of 21 patients died, one as a result of pneumonia and one of an unknown cause
- Four patients discontinued treatment due to adverse events. Two of these discontinuations were due to cardiac events
Electrolyte Depletion
-
Hypomagnesemia occurred in 55% of 365 patients receiving ERBITUX in
Study 5 and two other clinical trials in colorectal cancer and head
and neck cancer, respectively and was severe (NCI CTC grades 3 & 4) in
6-17%. In Study 2 the addition of EU-approved cetuximab to cisplatin
and 5-FU resulted in an increased incidence of hypomagnesemia (14% vs.
6%) and of Grade 3—4 hypomagnesemia (7% vs. 2%) compared to cisplatin
and 5-FU alone. In contrast, the incidence of hypomagnesemia was
similar for those who received cetuximab, carboplatin, and 5-FU
compared to carboplatin and 5-FU (4% vs. 4%). No patient experienced
Grade 3—4 hypomagnesemia in either arm in the carboplatin subgroup.
The onset of hypomagnesemia and accompanying electrolyte abnormalities
occurred days to months after initiation of ERBITUX therapy
- Monitor patients periodically for hypomagnesemia, hypocalcemia and hypokalemia, during, and for at least 8 weeks following the completion of ERBITUX therapy
- Replete electrolytes as necessary
Late Radiation Toxicities
-
The overall incidence of late radiation toxicities (any grade) was
higher with ERBITUX in combination with radiation therapy compared
with radiation therapy alone. The following sites were affected:
salivary glands (65%/56%), larynx (52%/36%), subcutaneous tissue
(49%/45%), mucous membranes (48%/39%), esophagus (44%/35%), and skin
(42%/33%) in the ERBITUX and radiation versus radiation alone arms,
respectively
- The incidence of grade 3 or 4 late radiation toxicities were similar between the radiation therapy alone and the ERBITUX plus radiation therapy arms
Pregnancy and Nursing
- In women of childbearing potential, appropriate contraceptive measures must be used during treatment with ERBITUX and for 6 months following the last dose of ERBITUX. ERBITUX may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. ERBITUX should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus
- It is not known whether ERBITUX is secreted in human milk. IgG antibodies, such as ERBITUX, can be excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from ERBITUX, a decision should be made whether to discontinue nursing or to discontinue ERBITUX, taking into account the importance of ERBITUX to the mother. If nursing is interrupted, based on the mean half-life of cetuximab, nursing should not be resumed earlier than 60 days following the last dose of ERBITUX
Adverse Events
- The most serious adverse reactions associated with ERBITUX across all studies were infusion reactions, cardiopulmonary arrest, dermatologic toxicity and radiation dermatitis, sepsis, renal failure, interstitial lung disease, and pulmonary embolus
- The most common adverse reactions associated with ERBITUX (incidence ≥25%) are cutaneous adverse reactions (including rash, pruritus, and nail changes), headache, diarrhea, and infection
- The most frequent adverse events seen in patients with carcinomas of the head and neck receiving ERBITUX in combination with radiation therapy (n=208) versus radiation alone (n=212) (incidence ≥50%) were acneiform rash (87%/10%), radiation dermatitis (86%/90%), weight loss (84%/72%), and asthenia (56%/49%). The most common grade 3/4 adverse events for ERBITUX in combination with radiation therapy (≥10%) versus radiation alone included: radiation dermatitis (23%/18%), acneiform rash (17%/1%), and weight loss (11%/7%)
- The most frequent adverse events for EU-approved cetuximab in combination with platinum-based therapy with 5-FU (CT) (n=219) versus CT alone (n=215) (incidence ≥40%) were acneiform rash (70%/2%), nausea (54%/47%), and infection (44%/27%). The most common grade 3/4 adverse events for cetuximab in combination with CT (≥10%) versus CT alone included: infection (11%/8%). Since U.S.-licensed ERBITUX provides approximately 22% higher exposure relative to the EU-approved cetuximab, the data provided above may underestimate the incidence and severity of adverse reactions anticipated with ERBITUX for this indication. However, the tolerability of the recommended dose is supported by safety data from additional studies of ERBITUX
- The most frequent events seen in patients with KRAS mutation-negative (wild-type) metastatic colorectal cancer treated with EU-approved cetuximab + FOLFIRI (n=317) versus FOLFIRI alone (n=350) (incidence ≥50%) were acne-like rash (86% vs 13%) and diarrhea (66% vs 60%). The most common grade 3/4 adverse events (≥10%) included: neutropenia (31% vs 24%), acne-like rash (18% vs < 1%), and diarrhea (16% vs 10%). Since U.S.-licensed ERBITUX provides approximately 22% higher exposure relative to the EU-approved cetuximab, the data provided above may underestimate the incidence and severity of adverse reactions anticipated with ERBITUX for this indication. However, the tolerability of the recommended dose is supported by safety data from additional studies of ERBITUX
- The most frequent events seen in patients with KRAS mutation-negative (wild-type) metastatic colorectal cancer treated with ERBITUX + best supportive care (BSC) (n=118) versus BSC alone (n=124) (incidence ≥50%) were rash/desquamation (95% vs 21%), fatigue (91% vs 79%), nausea (64% vs 50%), dry skin (57% vs 15%), pain-other (59% vs 37%), and constipation (53% vs 38%). The most common grade 3/4 adverse events (≥10%) included: fatigue (31% vs 29%), pain-other (18% vs 10%), rash/desquamation (16% vs 1%), dyspnea (16% vs 13%), other-gastrointestinal (12% vs 5%), and infection without neutropenia (11% vs 5%)
- The most frequent adverse events seen in patients with metastatic colorectal cancer (n=354) treated with ERBITUX plus irinotecan in clinical trials (incidence ≥50%) were acneiform rash (88%), asthenia/malaise (73%), diarrhea (72%), and nausea (55%). The most common grade 3/4 adverse events (≥ 10%) included: diarrhea (22%), leukopenia (17%), asthenia/malaise (16%), and acneiform rash (14%)
Please see Important Safety Information and U.S. Full Prescribing Information including Boxed WARNINGS.
About ERBITUX Patient Programs
In addition to Destination Access, The ERBITUX PATIENT SUPPORT PROGRAM has been developed to provide patients and healthcare providers with information and helpful resources on dermatological reactions associated with ERBITUX and guidance on how to manage them. For additional information, visit www.erbitux.com.
Lilly, a leading innovation-driven corporation, is developing a growing
portfolio of pharmaceutical products by applying the latest research
from its own worldwide laboratories and from collaborations with eminent
scientific organizations. Headquartered in
This press release contains "forward-looking statements" as that term
is defined in the Private Securities Litigation Reform Act of 1995
regarding product development. Such forward-looking statements are based
on current expectations and involve inherent risks and uncertainties,
including factors that could delay, divert or change any of them, and
could cause actual outcomes and results to differ materially from
current expectations. Among other risks, there can be no guarantee that
additional indications will be approved, or if approved, that they will
be commercially successful. Forward-looking statements in this press
release should be evaluated together with the many uncertainties that
affect
* Referenced with permission from the NCCN Clinical Practice Guidelines
in Oncology (NCCN Guidelines™) for Colon Cancer V3.2012. © 2012
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