Cetuximab (Erbitux®) - (Head and Neck Cancers)
Posted: Thursday, May 31, 2018
Targeting a Key Molecular Driver
More than 90% of head and neck squamous cell cancers overexpress epidermal growth factor receptor (EGFR), a feature associated with aggressive behavior and poorer prognosis.1 Strategies for targeting this molecular driver therefore hold promise for improving outcomes for many patients.2
Cetuximab is a monoclonal antibody that inhibits EGFR. It was first approved by the U.S. Food and Drug Administration in 2006 for use in combination with radiation therapy to treat locally or regionally advanced squamous cell carcinoma of the head and neck or as a single agent to treat recurrent or metastatic disease after failure of platinum-based therapy.3 It was further approved in 2011 for use in combination with platinum-based therapy plus fluorouracil (5-FU) as first-line therapy for recurrent locoregional disease and/or metastatic squamous cell carcinoma of the head and neck.4 Cetuximab, an FDA-approved targeted therapy for head and neck cancers, is among recommended treatment options in national and international guidelines.5-7
There are a lot of different ways to integrate cetuximab into one’s practice.
One Agent, Many Uses
“There are a lot of different ways to integrate cetuximab into one’s practice,” commented Loren Scott Michel, MD, an associate attending physician and medical oncologist specializing in head and neck cancers at Memorial Sloan Kettering Cancer Center, New York.
Curative Therapy: When cetuximab was approved for use with radiation therapy in the curative (definitive) setting, the head and neck cancer community was looking to move away from platinum-based chemoradiation, Dr. Michel noted. Concurrent cetuximab and radiation therapy offered a new option, but real-world experience since then has tempered its use.
“Many oncologists refrain from using cetuximab with radiation therapy unless confronted with a patient who is not likely to tolerate chemotherapy well, because of retrospective studies showing its relative inferiority to chemotherapy protocols,” he said. “So in the definitive setting, patient selection for cetuximab therapy is critical.”
“For patients with curable disease, the standard is still cisplatin with radiation,” agreed Jason Glass, NP, a member of the Head and Neck Treatment Center Team at the Dana-Farber Cancer Institute, Boston. “We will consider cetuximab if someone is not a good candidate for cisplatin. A patient may have a lot of comorbidities or poor renal function and might not tolerate cisplatin’s side effects.”
Induction Therapy: Cetuximab also has a role in induction therapy to reduce bulky head and neck cancers before chemoradiation. “It’s highly useful as an upfront agent with a platinum and a taxane. I still use TPF induction (docetaxel, carboplatin, 5-FU), but in patients who might not tolerate that regimen, I use a paclitaxel and carboplatin doublet, and then add cetuximab to that,” Dr. Michel said, referring to the PCC regimen. [Editor’s Note: The PCC regimen is not currently included in the NCCN Guidelines recommendations.]
Historically, the Dana-Farber team has used the TPF regimen as induction therapy to reduce the tumor burden in patients with bulky disease, according to Mr. Glass. But the newer PCC regimen (paclitaxel, cetuximab, carboplatin) is gaining traction there as well because of its apparent better tolerability.
Therapy for Recurrent or Metastatic Disease: When used as first-line therapy for recurrent and metastatic disease, the combination of cetuximab with platinum-based chemotherapy and 5-FU (the EXTREME regimen) improves both progression-free and overall survival compared with platinum-based chemotherapy and 5-FU alone.8 “In the metastatic setting, I like to use cetuximab as a part of first-line therapy, which is where you get the most bang for the buck with this drug,” Dr. Michel commented to JNCCN 360.
In the metastatic setting, I like to use cetuximab as a part of first-line therapy, which is where you get the most bang for the buck with this drug.
“If we get a great response after 6 cycles or so of this triplet, we will sometimes give patients a chemotherapy holiday and just continue cetuximab alone or, depending on tolerability, cetuximab and a taxane, as maintenance therapy for another 8 to 12 weeks, and then rescan,” Dr. Michel stated. “I’ve had people on cetuximab and paclitaxel for many months with very good tolerability."
For recurrent or metastatic disease, Mr. Glass’ team usually uses the EXTREME regimen, followed by cetuximab monotherapy. “Typically, we would use that combination regimen for 6 cycles, and if the patient is doing well and responding, then the patient would go on to maintenance cetuximab alone given every week or every other week, for as long as it works, often several months,” he explained.
“In general, patients on cetuximab—even those on palliative treatment—tend to do very well, so they go through many lines of treatment,” he added. “Cetuximab should be fairly high on that list of therapies, maybe even first on the list, if a patient has a recurrence. Cetuximab plays a significant role in treatment of head and neck cancers.”
Lack of Predictive Factors
Beyond the indicated uses, determining which patients with head and neck cancers should or should not receive cetuximab enters “murky” territory, according to Dr. Michel. “There are no clear-cut contraindications or subpopulations where we would be able to predict that the patient is clearly not going to respond.”
Molecular predictors of benefit have thus far been elusive. “Unfortunately, there are no clearly established, validated biomarkers for cetuximab activity in head and neck cancer, unlike colon cancer, where KRAS mutation really does contraindicate its use,” he noted. Some data suggest that a small percentage of patients with RAS mutations in head and neck cancers may not respond to the drug, but definitive evidence is lacking.
Although cetuximab targets EGFR, neither tumor EGFR gene copy number nor tumor EGFR immunohistochemical expression predicts benefit from this agent in patients with head and neck cancers.9,10 Similarly, neither human papillomavirus (HPV) status nor p16 status has panned out as a reliable predictive biomarker.11 “Some evidence suggests patients with HPV-positive disease may not benefit as much from cetuximab, but the data are not compelling enough to apply to practice. I don’t use HPV to decide whether people should be put on this drug,” Dr. Michel told JNCCN 360.
Of note, initial trials of cetuximab in patients with head and neck cancers included all comers, with tumors of the oropharynx, hypopharynx, or larynx, according to Mr. Glass. “But when they broke it down, it was really the oropharynx folks—those with tumors of the tonsil or base of tongue—who actually had improved outcomes on cetuximab. Although cetuximab may not be the right drug for someone with a laryngeal cancer, for someone with a base of tongue tumor, it could be very effective.”
Optimizing Efficacy and Tolerability
Modifications of the EXTREME regimen8 are useful for tailoring care. “Many people who treat head and neck cancers are not enthused about 5-FU for this disease, and often, in the metastatic setting, we will modify that regimen and substitute paclitaxel for 5-FU and carboplatin for cisplatin,” Dr. Michel explained. “When we make some tweaks to that backbone regimen, the modified regimen is highly active and very well tolerated, even in people well into their 70s.”
“In some cases, we will withhold the platinum or the taxane if we don’t want to subject patients to greater multiagent toxicity. We would use cetuximab with just a taxane or just carboplatin,” he elaborated. “So there are modifications one can make depending on individual patients and their tolerability for different chemotherapies.”
“The key to optimizing the efficacy of cetuximab is keeping patients on it,” Mr. Glass maintained. It is important to make sure they are staying on schedule, especially for those who are receiving it concurrently with radiation, he added. “For a patient on curative treatment, when the radiation ends, the cetuximab ends, no matter what you have done. If a patient has gotten only four doses, that’s all he or she will get. So you want to work on managing the side effects that you can manage.”
“Nutrition is critical: People on cetuximab are prone to losing weight and to not having a great appetite. I watch my patients’ weight obsessively,” he adds. “If you are unable to maintain adequate nutrition in these patients, they are more likely to end up in the hospital, develop an infection, or need a break from the medication. All those things can conspire to decrease the efficacy of cetuximab.”
Better Tolerated but Not Without Risks
“I tell patients cetuximab is not chemotherapy, and it’s exceedingly safe and well tolerated,” Dr. Michel declared. “There is a black box warning on the label about the risk of cardiopulmonary arrest and sudden death, but I’ve never actually even come close to seeing anything like that. Of course, I’ve seen infusion reactions.”
“Cetuximab has a reputation of being a drug that is fairly easy to use, and that may be the case with some other cancers, when compared with alternatives. However, based on my experience in head and neck cancers, it’s not so much that it’s easier than standard chemotherapy, but that it’s different—the side-effect profile differs,” Mr. Glass told JNCCN 360. “It’s still an antineoplastic drug and has risks. Our patients on cetuximab can still struggle in a lot of ways, so clinicians shouldn’t get lulled into this idea that it’s an easy drug. It still requires a lot of work on the provider end to make sure that it is safe and tolerable.”
Treatment side effects overall are usually more severe when cetuximab is given with chemotherapy or radiation, he noted. “When you use cetuximab in an upfront regimen with radiation, it is a pretty potent radiosensitizer. We see an increase in the severity of radiation side effects: mucositis, radiation dermatitis, and other skin and mucosal toxicities (eg, dry mouth and fatigue).”
A dedicated patient education visit can go a long way toward ensuring smooth cetuximab therapy, according to Mr. Glass. “A couple years ago, we started a program to bring patients in on a day they are not being treated to have a dedicated chemotherapy teaching visit,” he explained. “If you try to review everything on the first treatment day, they are not paying attention; they are usually worked up about what’s going to happen. So we really try to set up this separate visit so they can really focus on what you are teaching them.”
He and his team incorporate printed materials covering various possible side effects. In addition, all patients are counseled about and given prescriptions and schedules for medications for prophylaxis against skin toxicity (discussed subsequently), as well as contact information for the treatment team.
One of the key take-aways for cetuximab is to be proactive and to anticipate the problems that may happen and try to prevent them as much as you can.
“One of the key take-aways for cetuximab is to be proactive and to anticipate the problems that may happen and try to prevent them as much as you can,” Mr. Glass said. “We stress to patients that small problems can become big problems, and big problems can lead to treatment breaks, hospitalizations, and delayed recovery after treatment. I tell my patients, if they have more than one episode of diarrhea in a day, if their skin is itchy despite putting on the cream, if their nails are splitting, or they are developing infections in their nail beds, I need to know about it. They always need to keep us in the loop about what’s going on.”
Preventing and Managing Common Adverse Effects
Skin Toxicity: At least three-quarters of patients given cetuximab develop an acneiform rash on their face, chest, and back, typically during the first few weeks of therapy. “I always tell patients the rash tends to be a good thing, because it’s always been considered a positive biomarker for activity of EGFR inhibitors,” Dr. Michel said. Other potential dermatologic adverse effects include dry skin, pruritus, fissuring, nail splitting, and hypertrichosis. In addition, when given with radiation, cetuximab is associated with more severe mucositis and radiation dermatitis.
Starting people on dermatology care prophylactically should be done on an individualized basis, noted Dr. Michel. Recommendations for preventive care using antibiotics and topicals are reviewed, and patients are engaged in the decision-making process. Each patient is treated as an individual. “When a patient experiences a particularly severe reaction, I send him or her to our dermatology colleagues, who typically add a steroid cream to help minimize the discomfort and cosmetic issues,” he told JNCCN 360.
The approach differs at Dana-Farber, according to Mr. Glass. “We work closely with our dermatology group for our patients receiving cetuximab. We anticipate the rash and try to prevent it,” he explained. Patients are put on a prophylactic regimen consisting of an oral antibiotic (minocycline or doxycycline) twice daily starting when cetuximab is initiated and continued for at least the first 6 weeks of treatment. They are also given prescriptions for a topical steroid for use on the truncal area as needed and a milder agent for use on their face. “Unless there is a reason not to, everyone starts on that regimen,” stated Mr. Glass. Patients are also advised to use a sunscreen with sun protection factor 30 at least once daily on all exposed skin, as sun exposure can worsen the rash.
Electrolyte Abnormalities: Patients can develop changes in electrolyte levels, most notably hypomagnesemia, days to months after starting cetuximab. “Watch their lab results, especially the magnesium and potassium, and address even small changes with replacement before they become big, symptomatic changes. Their potassium and magnesium can drop even when they are not having other side effects like diarrhea,” Mr. Glass noted. “We often need to replace magnesium, intravenously if it gets too low,” Dr. Michel concurred.
Diarrhea: Diarrhea is common when cetuximab is used to treat other cancers but typically not when it is used to treat head and neck cancers. “Our patients are usually on pain or antinausea medications, and those agents are all constipating. It can balance out,” Mr. Glass explained. “But if a patient is not on those medications, diarrhea can become an issue. In those cases, it is prudent to monitor bowel status.”
A less common but potentially life-threatening adverse effect is an allergic reaction at the time of cetuximab infusion, with most of the severe reactions occurring the first time the drug is given, despite premedication. These allergic reactions appear to be due largely to preexisting immunoglobulin E (IgE) antibodies that cross-react with the drug.12
“We usually treat that reaction as if it were a bee sting, with steroid, diphenhydramine, and only occasionally with epinephrine, if someone has a true anaphylactic reaction,” Dr. Michel reported.
On average, roughly 20% of patients across the United States have some type of allergic reaction to cetuximab. But there is a marked geographic variation, with both greater incidence and severity among patients treated in the mid-Southeast states.12 “It is believed that people in those regions are more likely to have IgE antibodies, possibly because of exposure to tick bites, and this could trigger a severe reaction,” Mr. Glass noted.
Dose Modifications and Treatment Discontinuations
“I haven’t used dose modifications as a strategy for dealing with the side effects of cetuximab,” Dr. Michel revealed. Most of his patients who have had a drug reaction at the full 400 mg/m2 loading dosage have been able to receive subsequent treatments at the recommended 250 mg/m2 dosage with appropriate premedication.
However, in patients being treated in the palliative setting who experience a bona fide anaphylactic reaction to cetuximab, he discontinues the drug. “That’s a situation where I don’t rechallenge because the potential benefit, in my view, is not sufficient to expose the patient to what could be a fatal reaction,” Dr. Michel told JNCCN 360.
“When it comes to the acneiform rash or hypomagnesemia, we want to give patients the full benefit of the drug. So rather than dose-modify, I tend to treat through the side effects and work to manage them with various interventions,” Dr. Michel reported. “It’s very rare to have such debilitating acne that people need to stop the drug.”
At Dana-Farber, cetuximab is often discontinued and replaced with another drug if an allergic reaction occurs in a patient who is receiving the drug with concurrent radiation, according to Mr. Glass. “Often, we go back and reconsider whether we might be able to use cisplatin or carboplatin.”
“I have had a few patients get through short-term treatment with cetuximab even after they’ve had a reaction,” Mr. Glass told JNCCN 360. “But the reactions are probably our biggest issue, aside from progression, in terms of having to stop treatment.”
On the other hand, even when the rash, hypomagnesemia, and diarrhea are more severe, they seldom require cetuximab dose delays or discontinuation, as long as providers are vigilant and manage these adverse effects, he said. “If we have to stop, patients can often restart treatment once the side effects decrease to grade 1 or resolve.”
Importance of Multidisciplinary Care
Most patients with head and neck cancers being treated with cetuximab receive care from a multidisciplinary team that includes, at minimum, medical, radiation, and surgical oncology specialties. Dermatology is likely the most important additional specialty, according to Mr. Glass. “I would even go so far as to say that if you are in a setting that doesn’t have a built-in dermatology group, or even if you do, it probably makes sense to work with just a few dermatologists so they can get experience with this drug and get comfortable managing these rashes,” he advised.
Social work also has a major role, given that the rash mainly affects the upper chest and face, meaning it is highly visible and embarrassing for patients. “It’s not bad enough they have cancer and are undergoing treatment, but now they don’t want to go out and be seen. It can be very isolating,” Mr. Glass explained. “We focus a lot on positive body image, and social work is very helpful with that.”
Loren Scott Michel, MD, disclosed no relevant relationships.
Jason Glass, NP, disclosed no relevant relationships.
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- Moreira J, Tobias A, O’Brien MP, et al. Targeted therapy in head and neck cancer: an update on current clinical developments in epidermal growth factor receptor-targeted therapy and immunotherapies. Drugs 2017;77:843–857.
- FDA approval for cetuximab. Head and neck cancer. Available at: https://www.cancer.gov/about-cancer/treatment/drugs/fda-cetuximab#Anchor-Hea-5647. Accessed May 21, 2018.
- FDA approval for cetuximab. Approved for recurrent or metastatic head and neck cancer. Available at: https://www.cancer.gov/about-cancer/treatment/drugs/fda-cetuximab#Anchor-Recur-11711. Accessed May 21, 2018.
- Pfister DG, Spencer S, Adelstein D, et al. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Head and Neck Cancers. Version 1.2018. Accessed May 21, 2018. To view the most recent version of these guidelines, visit NCCN.org.
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- Vermorken JB, Mesia R, Rivera F, et al. Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med 2008;359:1116–1127.
- Licitra L, Mesia R, Rivera F, et al. Evaluation of EGFR gene copy number as a predictive biomarker for the efficacy of cetuximab in combination with chemotherapy in the first-line treatment of recurrent and/or metastatic squamous cell carcinoma of the head and neck: EXTREME study. Ann Oncol 2011;22:1078–1087.
- Licitra L, Störkel S, Kerr KM, et al. Predictive value of epidermal growth factor receptor expression for first-line chemotherapy plus cetuximab in patients with head and neck and colorectal cancer: analysis of data from the EXTREME and CRYSTAL studies. Eur J Cancer 2013;49:1161–1168.
- Bonner JA, Mesia R, Giralt J, et al. p16, HPV, and cetuximab: what is the evidence? Oncologist 2017;22:811–822.
- Chung CH, Mirakhur B, Chan E, et al. Cetuximab-induced anaphylaxis and IgE specific for galactose-alpha-1,3-galactose. N Engl J Med 2008;358:1109–1017.