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The K-ras Biomarker

The Role of K-ras

  • K-ras is a gene that codes for a protein that plays an important role downstream of the EGFR in the signaling pathway13
  • There are 2 different forms of the K-ras gene found in colorectal tumors: mutated and wild type (nonmutated)14

Approximate Incidence of K-ras Mutations Among Patients with Colorectal Cancer14,15

  • Mutations in codons 12 and 13 represent over 98% of all reported K-ras mutations in colorectal cancer16

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Impact of K-ras Predictive Biomarker on Anti-EGFR MAbs1

  • Retrospective analyses across 7 randomized clinical trials suggest that anti-EGFR MAbs are not effective for the treatment of patients with mCRC containing K-ras mutations1
  • In these trials, patients received standard of care (ie, best supportive care [BSC] or chemotherapy) and were randomized to receive an anti-EGFR antibody (ERBITUX® [cetuximab] or panitumumab) or no additional therapy1
  • In these analyses, investigational tests were used to detect K-ras mutations in codon 12 or 131
  • The percentage of study populations for which K-ras status was assessed ranged from 23-92%1
  • Currently, data linking tumor K-ras mutation status to the clinical efficacy of ERBITUX is limited to mCRC1

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The Effect of K-ras on EGFR Signaling in mCRC1

In Preclinical Studies

  • Signal transduction through the EGFR results in activation of wild-type K-ras protein. However, in cells with activating K-ras somatic mutations, the mutant K-ras protein is continuously active and appears independent of EGFR regulation1

EGFR Signaling in Wild-Type and Mutated K-ras mCRC Tumors1

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K-ras Testing Is Recommended in mCRC

  • American Society of Clinical Oncology (ASCO) provisional clinical opinion recommends K-ras testing for all patients with mCRC who are candidates for anti-EGFR antibody therapy, and that patients with K-ras mutations (in codon 12 or 13) should not receive anti-EGFR antibody therapy17
  • NCCN recommends K-ras gene testing for colorectal cancer patients at diagnosis of metastatic disease18
    • K-ras genotyping may be done on archived specimens of either the primary tumor or a metastasis
    • K-ras mutations occur early in the formation of colorectal cancer, and there is a strong correlation between mutation status in the primary tumor and the metastases

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Get more information about ERBITUX

Indications and Important Safety Information including
Boxed WARNINGS

Indications

Colorectal Cancer

  • ERBITUX® (cetuximab), as a single agent, is indicated for the treatment of EGFR-expressing metastatic colorectal cancer after failure of both irinotecan- and oxaliplatin-based regimens. ERBITUX, as a single agent, is also indicated for the treatment of EGFR-expressing metastatic colorectal cancer in patients who are intolerant to irinotecan-based regimens
  • ERBITUX, in combination with irinotecan, is indicated for the treatment of EGFR-expressing metastatic colorectal carcinoma in patients who are refractory to irinotecan-based chemotherapy. The effectiveness of ERBITUX in combination with irinotecan is based on objective response rates. Currently, no data are available that demonstrate an improvement in disease-related symptoms or increased survival with ERBITUX in combination with irinotecan for the treatment of EGFR-expressing metastatic colorectal carcinoma
  • Retrospective subset analyses of metastatic or advanced colorectal cancer trials have not shown a treatment benefit for ERBITUX in patients whose tumors had K-ras mutations in codon 12 or 13. Use of ERBITUX is not recommended for the treatment of colorectal cancer with these mutations

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
  • Most (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

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 5, 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 where ILD is confirmed

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, 4, and 5. Severe acneiform rash occurred in 1-17% of patients
    • Acneiform rash usually developed within the first two 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

Electrolyte Depletion

  • Hypomagnesemia occurred in 55% (199/365) of patients receiving ERBITUX in Study 4 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%. 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

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 metastatic colorectal cancer studies were infusion reactions, dermatologic toxicity, 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 metastatic colorectal cancer (n=288) treated with ERBITUX + best supportive care in a clinical trial (incidence ≥50%) were fatigue (89%), rash/desquamation (89%), abdominal pain (59%), and pain-other (51%). The most common grade 3/4 adverse events (≥10%) included: fatigue (33%), pain-other (16%), dyspnea (16%), abdominal pain (14%), infection without neutropenia (13%), rash/desquamation (12%), and other-gastrointestinal (10%)
  • 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.