FDA Approval for Cetuximab
Brand name(s): Erbitux®
- Approved for K-ras wild-type, EGFR-expressing metastatic colorectal cancer
- Approved for recurrent or metastatic head and neck cancer
- Approved for head and neck cancer
- Approved for colorectal cancer
Full prescribing information is available, including clinical trial information, safety, dosing, drug-drug interactions, and contraindications.
Approved for K-ras wild-type, EGFR-expressing Metastatic Colorectal Cancer
On July 6, 2012, the Food and Drug Administration (FDA) granted approval to cetuximab (Erbitux®, made by ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Co) for use in combination with FOLFIRI (irinotecan, 5-fluorouracil, and leucovorin) for first-line treatment of patients with K-ras mutation-negative (wild-type), EGFR-expressing metastatic colorectal cancer (mCRC) as determined by FDA-approved tests. FDA also approved the Therascreen® KRAS RGQ PCR Kit (QIAGEN Manchester, Ltd) concurrent with this cetuximab approval.
This approval was based on retrospective analyses of tumor samples from patients enrolled in the CRYSTAL trial and in two supportive studies, CA225025 and EMR 62 202-047 (OPUS), according to K-ras mutation status. The addition of cetuximab to chemotherapy or best supportive care (BSC) resulted in improved survival (OS), progression-free survival (PFS), and overall responses rate (ORR) in patients with K-ras wild-type tumors, whereas there was no benefit, or even potential harm, in patients with K-ras mutant tumors. The approval of the companion diagnostic, the QIAGEN Therascreen® KRAS RGQ PCR Kit, provides a reliable way to identify these subsets of patients. This QIAGEN test, a genetic assay, is a real-time polymerase chain reaction assay that detects seven different mutations of the K-ras gene in a tumor specimen. Tumors that are K-ras mutation-negative in this assay are commonly referred to as K-ras wild-type.
CRYSTAL was an open-label randomized controlled trial in patients with EGFR-expressing mCRC who had not received prior chemotherapy for metastatic disease. A total of 1217 patients were randomly assigned (1:1) to receive either cetuximab in combination with FOLFIRI or FOLFIRI alone, irrespective of K-ras mutation status. PFS was the primary efficacy endpoint.
In the overall population, a statistically significant improvement in PFS was observed in patients treated with cetuximab plus FOLFIRI compared with patients treated with FOLFIRI alone [median PFS 8.9 vs. 8.1 months, HR 0.85, (95 percent CI: 0.74, 0.99), p-value=0.036]. There was not a statistically significant improvement in OS, a secondary endpoint, in the planned analysis [HR 0.93, (95 percent CI: 0.82, 1.07), p-value 0.327, 838 events]. In an updated analysis with an additional 162 events, the median OS was 19.6 months for patients treated with cetuximab plus FOLFIRI compared with 18.5 months for patients treated with FOLFIRI alone [HR 0.88 (95 percent CI: 0.78, 1.00)].
Tumor tissue was evaluable for K-ras mutation status assessment in 89 percent of the patients (N=1079/1217); 676 patients (63 percent) had wild-type tumors and 403 patients (37 percent) had mutant tumors. Retrospective efficacy analyses demonstrated that the addition of cetuximab to FOLFIRI resulted in a favorable effect on OS, PFS, and ORR in in patients with K-ras wild-type tumors.
The median OS for the wild-type subgroup was 23.5 months for patients treated with cetuximab plus FOLFIRI, compared with 19.5 months for patients treated with FOLFIRI alone [HR 0.80 (95 percent CI: 0.67, 0.94)]. PFS and ORR findings in the K-ras wild-type subgroup supported the efficacy of cetuximab in combination with FOLFIRI. The median PFS for patients with wild-type K-ras treated with cetuximab plus FOLFIRI was 9.5 compared with 8.1 months for patients treated with FOLFIRI alone [HR 0.70 (95 percent CI: 0.57, 0.86)]. ORR was 57 percent in patients with wild-type K-ras treated with cetuximab plus FOLFIRI compared with 39 percent in patients treated with FOLFIRI alone. In the subgroup of patients with mutant K-ras, improvements in OS, PFS or ORR were not observed with the addition of cetuximab to FOLFIRI compared to FOLFIRI alone.
Retrospective analyses of two supportive studies, CA225025 and OPUS, by tumor K-ras mutation status supported cetuximab’s efficacy in the wild-type subgroup:
- CA225025 was an open-label randomized trial that compared cetuximab plus best supportive care (BSC) with BSC alone in patients with previously treated EGFR-expressing mCRC. CA225025 demonstrated a statistically significant improvement in OS in the cetuximab plus BSC arm compared to BSC alone. The planned efficacy results served as the basis for the full approval of cetuximab in October 2007 as a single agent for EGFR-expressing mCRC after failure of both irinotecan- and oxaliplatin-based regimens or in patients intolerant to irinotecan-based regimens.
Tumor tissue was evaluable for K-ras mutation status in 79 percent of patients (N=453/572). In the K-ras wild-type subgroup, cetuximab plus BSC resulted in an improvement in OS compared with BSC alone [HR 0.63 (95 percent CI: 0.47, 0.84)]. The median OS was 8.6 versus 5.0 months in the cetuximab plus BSC and BSC groups, respectively. The median PFS was 3.8 and 1.9 months in the cetuximab plus BSC and the BSC groups, respectively [HR 0.42 (95 percent CI: 0.32, 0.56)]. In the K-ras mutant subgroup, no improvements in OS, PFS or ORR were observed with the addition of cetuximab to BSC compared with BSC alone.
- OPUS was a randomized open-label phase II study that compared cetuximab in combination with 5-flourouracil, folinic acid, and oxaliplatin (FOLFOX-4) to FOLFOX-4 alone as first-line treatment of EGFR-expressing mCRC. Tumor tissue was evaluable for retrospective K-ras mutation status analysis in 93 percent of patients (N=315/337). ORR was the trial’s primary endpoint. In the wild-type subgroup (N=179/315, 57 percent), ORR was 57 percent (95 percent CI: 46, 68) in patients treated with cetuximab plus FOLFOX-4 compared with 34 percent (95 percent CI: 25, 44) in patients treated with FOLFOX-4. A numerical improvement in PFS was noted in the wild-type subgroup [HR 0.57 (95 percent CI: 0.38, 0.86)]. The median PFS was 8.3 in patients treated with cetuximab plus FOLFOX-4, compared with 7.2 months in patients treated with FOLFOX-4. A numerical OS improvement was also observed in the wild-type subgroup [HR 0.86 (95 percent CI: 0.60, 1.22)]. The median OS for patients treated with cetuximab plus FOLFOX-4 was 22.8 months, versus 18.5 months for patients treated with FOLFOX-4. In the K-ras mutant subgroup (N=136/315, 43 percent), no improvements in OS, PFS, or ORR were observed in patients treated with cetuximab plus FOLFOX-4 compared with patients treated with FOLFOX-4 alone.
Safety data were evaluated in 317 patients in the K-ras wild-type subgroup who received cetuximab in combination with FOLFIRI in the CRYSTAL study and in 118 patients with wild-type tumors who received cetuximab monotherapy in CA225025.
The frequency and nature of adverse events, including adverse events associated with cetuximab (acne-like rash, infusion reactions, cardiac events, and hypomagnesemia), observed in CRYSTAL, CA225025, and OPUS in the K-ras wild-type population were consistent with the known adverse drug reaction profiles of cetuximab, chemotherapy agents, and the underlying disease. No significant differences between the wild-type, mutant, and the overall safety populations have been noted.
The recommended dose and schedule for cetuximab is 400 mg/m2 administered intravenously as a 120-minute infusion as an initial dose, followed by 250 mg/m2 infused over 30 minutes weekly in combination with FOLFIRI. Cetuximab administration should be completed 1 hour prior to FOLFIRI.
Product labeling for cetuximab provides “Limitation of Use” information specifying that cetuximab is not indicated for treatment of K-ras mutation-positive colorectal cancer.
Approved for Recurrent or Metastatic Head and Neck Cancer
On November 7, 2011, the Food and Drug Administration (FDA) approved cetuximab (Erbitux®, made by ImClone LLC, a wholly-owned subsidiary of Eli-Lilly and Company) in combination with platinum-based therapy plus 5-florouracil (5-FU) for the first-line treatment of patients with recurrent locoregional disease and/or metastatic squamous cell carcinoma of the head and neck (SCCHN).
The approval was based primarily on the results of a multi-center clinical study conducted outside the United States in 442 patients with metastatic or locally recurrent head and neck cancer who were not suitable for potentially curative treatment with surgery or radiation. The study used a European Union (EU)-approved cetuximab rather than the US-approved cetuximab (Erbitux®). Erbitux provides approximately 22 percent higher exposure relative to the EU-approved cetuximab; these pharmacokinetic data, together with the results of the study conducted in Europe and other clinical trial data using Erbitux, establish the safety and efficacy of Erbitux at the recommended dose.
The trial enrolled 442 patients; 222 patients were randomly assigned to receive cetuximab plus cisplatin (or carboplatin) with 5-FU and 220 patients were randomly assigned to receive cisplatin (or carboplatin) with 5-FU. The selection of cisplatin or carboplatin was at the discretion of the treating health care provider.
Either cisplatin (100 mg/m2 intravenously day 1) or carboplatin (AUC 5 mg/mL/min intravenously day 1) with 5-FU (1000 mg/m2/day continuous intravenous infusion days 1–4) were administered every three weeks (one cycle). A maximum of six cycles was administered in the absence of disease progression or unacceptable toxicity. For patients randomly assigned to the Cetuximab group, cetuximab was administered as an initial dose of 400 mg/m2 intravenously, followed by a weekly dose of 250 mg/m2 intravenously. After completion of six planned courses, patients demonstrating at least stable disease on cetuximab in combination with chemotherapy continued cetuximab monotherapy (250 mg/m2 weekly) in the absence of disease progression or unacceptable toxicity.
Of the 442 patients, the median age was 57 years, 90 percent were male, 98 percent were Caucasian, and 88 percent had baseline Karnofsky performance score of at least 80. Thirty-four percent of patients had oropharyngeal tumors, 25 percent had laryngeal tumors, 20 percent had oral cavity tumors, and 14 percent had hypopharyngeal primary tumors. Fifty-three percent of patients had recurrent disease without metastases; the remaining 47 percent of patients had metastatic disease with or without recurrence.
Sixty-four percent of patients received cisplatin as initial therapy, while 34 percent of patients received carboplatin. Approximately 15 percent of patients changed from cisplatin to carboplatin during the treatment period.
The major efficacy outcome measure of the trial was overall survival (OS). Other outcome measures included progression-free survival (PFS) and objective response rate (ORR).
The median follow-up at the time of the OS analysis was 19.1 months for the patients treated with cetuximab plus chemotherapy and 18.2 months for the patients treated with chemotherapy alone. Overall survival was significantly improved in patients receiving cetuximab plus chemotherapy compared with those receiving chemotherapy alone (HR=0.80; 95 percent CI: 0.64, 0.98; p = 0.034, stratified log-rank test). The median survival for patients receiving cetuximab plus chemotherapy was 10.1 months, compared with 7.4 months for those receiving chemotherapy alone.
Progression-free survival was also significantly improved in patients receiving cetuximab plus chemotherapy (HR=0.57; 95 percent CI: 0.46, 0.72; p<0.0001, stratified log-rank test). The median PFS times were 5.5 months in the patients receiving cetuximab plus chemotherapy and 3.3 months in the patients receiving chemotherapy alone. The objective response rates were 35.6 percent in the patients receiving cetuximab plus chemotherapy and 19.5 percent in the patients receiving chemotherapy alone [Odds Ratio (OR) 2.33; 95 percent CI: 1.50, 3.60; p-value 0.0001, Cochran-Mantel-Haenszel test].
Exploratory subgroup analyses were conducted in subgroups by initial platinum therapy (cisplatin or carboplatin). For patients (N=284) receiving the EU-approved cetuximab plus cisplatin with 5-FU compared to cisplatin with 5-FU alone, the difference in median overall survival times was 3.3 months, with median OS times of 10.6 in patients receiving cetuximab and 7.3 months in patients receiving chemotherapy alone [HR 0.71 (95 percent CI: 0.54, 0.93)]. The difference in median progression-free survival was 2.1 months, with median PFS times of 5.6 in patients receiving cetuximab and 3.5 months in patients receiving chemotherapy alone [HR 0.55 (95 percent CI: 0.41, 0.73)]. The objective response rates were 39 percent in patients receiving cetuximab and 23 percent in patients receiving chemotherapy alone [OR 2.18 (95 percent CI: 1.29, 3.69)].
For patients (N=149) receiving cetuximab plus carboplatin with 5-FU compared with carboplatin with 5-FU alone, the difference in median overall survival was 1.4 months, with median survival of 9.7 months in patients receiving cetuximab and 8.3 months in patients receiving chemotherapy alone [HR 0.99 (95 percent CI: 0.69, 1.43)]. The difference in median progression-free survival was 1.7 months with median PFS times of 4.8 months in patients receiving cetuximab and 3.1 months in patients receiving chemotherapy alone [HR 0.61 (95 percent CI: 0.42, 0.89)]. The objective response rates were 30 percent in patients receiving cetuximab and 15 percent in patients receiving chemotherapy alone [OR 2.45 (95 percent CI: 1.10, 5.46)].
The most common adverse reactions (at least 25 percent) in patients treated with cetuximab were nausea, anemia, vomiting, neutropenia, rash, asthenia, diarrhea, and anorexia. Conjunctivitis occurred in 10 percent of the patients receiving cetuximab. Other adverse reactions, sometimes severe, caused by cetuximab included infusion reactions, hypomagnesemia, hypocalcemia and hypokalemia. Death attributed to cardiovascular event or sudden death was reported in 3.2 percent of the patients receiving cetuximab and in 1.9 percent of the patients receiving chemotherapy alone. Health care providers should closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after cetuximab administration.
The approved dose of Erbitux is 400 mg/m2 intravenously as an initial dose, followed by 250 mg/m2 intravenously weekly in combination with cisplatin or carboplatin plus continuous infusion 5-FU.
Head and Neck Cancer
On March 1, 2006, the FDA granted approval to cetuximab (Erbitux®, made by ImClone Systems, Inc.) for use in combination with radiation therapy (RT) for the treatment of locally or regionally advanced squamous cell carcinoma of the head and neck (SCCHN) or as a single agent for the treatment of patients with recurrent or metastatic SCCHN for whom prior platinum-based therapy has failed.
This approval is based on a statistically significant improvement in overall survival and duration of locoregional disease control for RT plus cetuximab when compared to RT alone. Evidence of cetuximab safety and efficacy is also supported by demonstration of durable objective tumor responses with cetuximab when administered as a single-agent in second- or third-line treatment of advanced SCCHN.
The safety and efficacy of cetuximab in combination with RT were demonstrated in a phase III randomized trial of 424 patients with stage III/IV SCC of the oropharynx, hypopharynx, or larynx who had no prior therapy. Patients were randomized to receive either cetuximab plus RT (211 patients) or RT alone (213 patients).
Cetuximab was administered as a 400 mg/m2 initial dose, followed by 250 mg/m2 weekly for the duration of RT (six to seven weeks), starting one week before RT. RT was administered for six to seven weeks as once daily, twice daily or concomitant boost.
The median survival time was 49 months on the cetuximab plus RT versus 29.3 months observed in patients receiving RT alone [p=0.03, stratified log-rank test; hazard ratio 0.74, (95 percent CI 90.56, 0.97)]. The median duration of locoregional control was 24.4 months in patients receiving cetuximab plus RT versus 14.9 months for those receiving RT alone [p=0.005, stratified log-rank test; hazard ratio 0.68, 95 percent CI (0.52, 0.89)]. The observed effect was primarily confined to patients enrolled in sites in the United States.
Additional data were derived from a single-arm trial of cetuximab monotherapy in103 patients with recurrent or metastatic SCCHN after failure of platinum-based therapy. Eighty percent had metastatic disease. Patients received cetuximab as a 400 mg/m2 loading dose, followed by 250 mg/m2 weekly. The objective response rate of cetuximab monotherapy was 12.6 percent (95 percent CI 7 percent to 21 percent). Median response duration was 5.8 months (95 percent CI 2.9; 5.8).
The most common adverse events reported for both treatment arms were mucositis and radiation dermatitis. The incidence of serious mucositis, radiation dermatitis and allergic/anaphylatoid reaction were > 2 percent higher in the RT + cetuximab arm when compared with RT alone. The following serious adverse reactions, some with fatal outcome were observed in the cetuximab plus RT arm: infusion reactions, cardiopulmonary arrest and/or sudden death and acneform rash.
The overall incidence of late radiation toxicity (any grade) was higher in the cetuximab plus RT arm compared with RT alone. However, the incidence of grade 3 or 4 late radiation toxicities were generally similar between the two treatment groups.
Death and serious cardiotoxicity were observed in a single arm trial combining cisplatin with cetuximab and RT conducted in patients with locally advanced squamous cell cancer of the head neck. The cetuximab, RT and cisplatin combination should be reserved for controlled clinical trials where toxicity can be clearly evaluated.
Adverse events associated with cetuximab monotherapy in patients with SCCHN were generally consistent with the adverse reactions previously described for cetuximab. The following serious adverse reactions, some with fatal outcomes, have been reported in the cetuximab safety data base: infusion reactions, interstitial lung disease, acneform rash and hypomagnesemia.
On February 12, 2004, the FDA approved cetuximab (Erbitux®, made by Imclone Systems, Inc.), a monoclonal antibody directed against the epidermal growth factor receptor (EGFR). Cetuximab is approved for use, in combination with irinotecan, for the treatment of EGFR-expressing, metastatic colorectal carcinoma in patients who are refractory to irinotecan-based chemotherapy.
Cetuximab is also approved for use as a single agent for the treatment of EGFR-expressing, recurrent metastatic colorectal carcinoma in patients who are intolerant to irinotecan-based chemotherapy.
Cetuximab is a recombinant, human/mouse chimeric IgG1 monoclonal antibody that binds specifically to the extracellular domain of the human epidermal growth factor receptor (EGFR). Cetuximab binds specifically to the epidermal growth factor receptor (EGFR, HER1, c-ErbB-1) on both normal and tumor cells, and competitively inhibits the binding of epidermal growth factor (EGF) and other ligands, such as transforming growth factor–alpha.
Binding of cetuximab to the EGFR blocks phosphorylation and activation of receptor-associated kinases, resulting in inhibition of cell growth, induction of apoptosis, and decreased matrix metalloproteinase and vascular endothelial growth factor production. The EGFR is constitutively expressed in many normal epithelial tissues, including the skin and hair follicle. Over-expression of EGFR is also detected in many human cancers including those of the colon and rectum.
The recommended dose of cetuximab, in combination with irinotecan or as monotherapy, is 400 mg/m2 as an initial loading dose (first infusion only) administered as a 120-minute IV infusion. The recommended weekly maintenance dose is 250 mg/m2 infused over 60 minutes.
Premedication with an H1 antagonist is recommended. Appropriate medical resources for the treatment of severe infusion reactions should be available during cetuximab infusions. The rate of cetuximab infusion should be reduced for mild or moderate infusion reactions; cetuximab should be discontinued for severe infusion reactions. Dose reductions are also recommended for moderate or severe skin toxicity.
The data establishing the efficacy and safety of cetuximab were derived mainly from the results of a multicenter, randomized, controlled clinical trial conducted in 329 patients; patients were randomized to receive either cetuximab plus irinotecan (218 patients) or cetuximab monotherapy (111 patients).
Supporting data were derived from an open-label, single-arm trial (138 patients) of cetuximab plus irinotecan and an open-label single-arm trial (57 patients) of cetuximab as a single agent. All studies enrolled patients with EGFR-expressing (75-82 percent of those screened were positive), recurrent, metastatic colorectal cancer. All patients had received prior irinotecan; two-thirds of the patients in the randomized study and half of those in the supportive study had progressed during or within 30 days of receiving an adequate course of irinotecan.
In the randomized trial, 38 percent had also received prior oxaliplatin. Determination of clinical benefit was based on evidence of durable responses without evidence of an effect on survival. In the randomized trial, the overall response rate was 23 percent with a median duration of response of 5.7 months in the cetuximab plus irinotecan arm. The overall response rate was 12 percent with a median duration of response of 4.1 months in the cetuximab monotherapy arm.
The median time to progression was significantly longer for patients receiving combination therapy (4.1 vs. 1.5 months). Comparable results were observed in the single arm studies of cetuximab plus irinotecan (15 percent ORR, 6.5 months median response duration) and cetuximab monotherapy (9 percent ORR, 1.4 months median response duration).
The most serious adverse reactions observed in clinical trials of cetuximab, alone or in combination with irinotecan, were infusion reactions (3 percent), dermatologic toxicity (1 percent), interstitial lung disease (0.5 percent), fever (5 percent), sepsis (3 percent); renal dysfunction (2 percent), pulmonary embolism (1 percent), dehydration (5 percent in patients receiving cetuximab plus irinotecan; 2 percent in patients receiving cetuximab monotherapy), and diarrhea (6 percent in patients receiving cetuximab plus irinotecan, 0 percent in patients receiving cetuximab monotherapy).
Thirty-seven (10 percent) patients receiving cetuximab plus irinotecan and 14 (5 percent) patients receiving cetuximab monotherapy discontinued treatment primarily because of adverse events.
The most common adverse events seen in 354 patients receiving cetuximab plus irinotecan were acneform rash (88 percent), asthenia/malaise (73 percent), diarrhea (72 percent), nausea (55 percent), abdominal pain (45 percent), and vomiting (41 percent).
The most common adverse events seen in 279 patients receiving cetuximab monotherapy were acneform rash (90 percent), asthenia/malaise (49 percent), fever (33 percent), nausea (29 percent), constipation (28 percent), and diarrhea (28 percent).
On October 2, 2007, the FDA expanded labeling and granted regular approval for single-agent cetuximab for the treatment of patients with EGFR-expressing metastatic colorectal cancer (mCRC) after failure of both irinotecan- and oxaliplatin-based chemotherapy regimens. Cetuximab was initially approved in 2004 under accelerated approval regulations and the study described below verifies the clinical benefit of single-agent cetuximab in this patient population.
The study supporting conversion to regular approval was an open-label, multinational study conducted by the NCI-Canada (NCIC) in patients with EGFR-expressing, progressive mCRC following both irinotecan- and oxaliplatin-containing regimens.
Five hundred seventy-two patients were randomized (1:1) to best supportive palliative care (BSC) or palliative care plus cetuximab administered as an intravenous infusion of 400 mg/m2 on the first dose, then 250 mg/m2 weekly until disease progression. Patients randomized to cetuximab demonstrated a statistically significant improvement in overall survival (OS) compared to those randomized to best supportive care (median OS: 6.1 vs. 4.6 months; hazard ratio 0.766, p=0.0048, stratified log-rank test). All documented tumor responses (evaluated centrally by NCIC) occurred in patients randomized to cetuximab (6.6 percent); the median response duration was 5.5 months and all were partial responses.
This summary was provided by Richard Pazdur, M.D., director of the FDA's Division of Oncology Drug Products.
The FDA is the division of the U.S. Department of Health and Human Services charged with ensuring the safety and effectiveness of new drugs and other products. (See "Learn How Drugs and Devices Get Approved.") The FDA's mission is to promote and protect the public health by helping safe and effective products to reach the market in a timely way, and monitoring products for continued safety after they are in use.