Cetuximab (Erbitux®) – (Non-Melanoma Skin Cancers)

NOTE: On September 28, 2018, the U.S. Food and Drug Administration (FDA) approved the first systemic agent, the immune checkpoint inhibitor cemiplimab-rwlc,¹ for patients with metastatic cutaneous squamous cell carcinoma or locally advanced cutaneous squamous cell carcinoma who are not candidates for curative surgery or curative radiation. Prior to this approval, a number of systemic agents and regimens, such as cetuximab, were used, with only modest (if any) benefit. [Editor's Note: A sentence here has been deleted from the original spotlight because it was not consistent with FDA labeling.] According to the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines),² cetuximab can be considered as an option.

Non-melanoma skin cancers, most of which are characterized histologically as basal cell or squamous cell carcinomas, are the most common cancers in the United States and usually are the least lethal: about 3,000 people die of basal cell carcinoma³ in the United States annually, and as many as 15,000 deaths may be attributable to squamous cell carcinoma.⁴ The vast majority (~90%) of cases of squamous cell carcinoma can be attributed to cumulative sun exposure.⁵ Patients who have undergone organ transplantation are roughly 100 times more likely to develop squamous cell carcinoma compared with the general population.⁶

Surgical Excision: The Gold Standard

Most basal and squamous cell cancers are best managed by surgical excision with histologically clear margins, as this approach has the highest cure rate.⁶ Referral to specialists (eg, surgeons familiar with Mohs surgery as well as head and neck cancer surgeons) may be appropriate, depending on the location of the lesion, the aggressiveness of the growth pattern, or the results of histology and the need for subsequent surgery(ies) to ensure clear margins, according to Chrysalyne D. Schmults, MD, MSCE, Associate Professor at Harvard Medical School, Boston, and a member of the NCCN Non-Melanoma Skin Cancers panel.

In rare cases, often when immune system function is compromised (perhaps because of organ or bone marrow transplant procedures), these tumors, particularly high-stage squamous cell carcinoma, can progress to unresectable local recurrence or metastasis.

Mohs surgery is used at most centers in the United States, even for larger tumors. “For larger tumors, especially multiply recurrent tumors, we believe Mohs surgery continues to be important to obtain total margin clearance with surgery,” Dr.  Schmults told JNCCN 360. This is also the goal stated by the NCCN Guidelines. “This means,” she explained, “that the entire peripheral margin and deep margin are evaluated under the microscope, unlike in traditional bread-loaf histology sections.” The NCCN Guidelines specify “CCPDMA” [complete circumferential peripheral and deep margin assessment], which is important for these high-risk and multiply recurrent squamous cell tumors. “They’ll often be highly infiltrative or have perineural invasion at the perimeter, which can be missed on ordinary bread-loaf sectioning.” Dr. Schmults, who is also Director of the Mohs and Dermatologic Surgery Center at the Dana-Farber/Brigham and Women’s Cancer Center, Boston, noted that dermatologic surgeons may work in conjunction with head and neck surgeons or surgical oncologists on these types of cases to ensure that total margin control is achieved if clear margins cannot be obtained in the outpatient surgery setting. Sometimes, when total margin control has not been achieved or is questionable, despite best efforts, radiation therapy may be added, Dr. Schmults said. “However, we don’t really have data that the addition of radiation reduces the risk of recurrence in these tumors at the locally advanced stage. For more advanced nodal disease, there is evidence that radiation provides benefit.”⁷

^{If we could predict which patients are likely to fail to respond to local treatments and treat more aggressively initially, we’d perhaps have fewer patients whose disease progresses to unresectable locally advanced disease.}

When attempts at surgery (with or without radiation) have failed, “we would consider systemic therapy,” Dr. Schmults observed. Based on findings from 3 large cohorts,^8–10 it has been reported that patients with squamous cell skin cancers do not often die of distant metastatic disease. Rather, the large majority of these patients die of local and regional disease. “They don’t often develop distant organ metastases,” Dr. Schmults told JNCCN 360. “That’s why achieving local control is so important. We have patients die of local extension; they never even develop a nodal metastasis. Now that there are systemic options available, we may want to look at using them earlier in the disease course. And, we anticipate the initiation of clinical trials in the adjuvant setting,” she continued. “If we could predict which patients are likely to fail to respond to local treatments and treat more aggressively initially, we’d perhaps have fewer patients whose disease progresses to unresectable locally advanced disease.”

Once it is established that a patient has unresectable disease because of extreme local advancement, distant metastases, or bulky nodal disease that cannot be cleared surgically, systemic treatment may be offered. In the United States, systemic therapy is usually provided by a medical oncologist. There are a few centers in the United States, Dr. Schmults said, where dermatologists have chemotherapy privileges and work collaboratively with medical oncologists to co-manage these patients. In contrast, in Europe (particularly Germany and France), she noted, dermatologists manage all of this care, including systemic therapies. The role of the medical oncologist with respect to these unresectable locally advanced squamous cell skin cancers has been relatively short-lived, because relapse is usually so rapid, occurring after just a few courses of epidermal growth factor receptor (EGFR)-antagonist treatment. “This may start to change if we can develop appropriate adjuvant regimens,” Dr. Schmults noted.

Discouraging Results With Systemic Therapy…Until Now

The small studies that have looked at systemic therapies, such as platinum-based regimens or cetuximab (and other EGFR antagonists), have not been encouraging.^11–15 “They have not produced impressive nor durable results,” Dr. Schmults told JNCCN 360. Response rates are about 20%, with rapid relapse being the norm. It is anticipated that the recent approval of cemiplimab may alter the dismal results historically seen with other systemic therapies. Although these systemic regimens may be administered by a medical oncologist, multidisciplinary team care remains important, because patients may need palliative surgery and/or radiation therapy. Not surprisingly, patients who present with unresectable skin cancers are often elderly and/or physiologically fragile. “In many cases,” Dr. Schmults explained, “they are not candidates for platinum-based treatment, and cetuximab was the best treatment option for them [prior to approval of cemiplimab-rwlc].” For more robust patients, some providers have combined platinum-based therapy with cetuximab or have used somewhat less toxic low-dose platinum regimens.

Critical State of the Immune System

Many patients with recurrent, unresectable cutaneous squamous cell cancers are immunocompromised. According to Dr. Schmults, “about one-third of patients whose disease progresses to unresectable skin cancer are immunocompromised, usually as a result of organ transplant or a hematologic disease such as chronic lymphocytic leukemia.” Dermatologists are experienced in working with organ transplant teams to determine whether immunosuppression can be modified, she pointed out. Those types of interventions may affect overall survival and “give patients a little more time.” There are even a few reports of spontaneous regression, without treatment, if the underlying immunosuppression can be reduced, she asserted. Likewise, “we work with hematology specialists when we have patients with leukemia or lymphoma to determine whether their immune systems can be bolstered. Some of these patients with leukemia or lymphoma have fairly well-controlled hematologic disease but still have immune dysfunction, which influences the aggressiveness of cutaneous squamous cell cancer. In these patients, cemiplimab-rwlc¹ may be a new option.” 

The Transplant Setting: Cetuximab Versus Cemiplimab-rwlc?

Until we better understand how to use immune checkpoint inhibitors in transplant patients, cetuximab will remain the first-line choice in these situations.

Of note, first-line cetuximab (or even a combination regimen with low-dose platinum)¹⁶ may be considered in transplant patients, whereas cemiplimab may be associated with more risk in most patients in that setting. “This is particularly true for patients with heart, lung, or liver transplants who don’t have dialysis as a backup option,” Dr. Schmults told JNCCN 360. Patients who have undergone organ transplants “have a 50-50 chance of rejection if they receive even a short-term treatment with an immune checkpoint inhibitor, such as cemiplimab. Moreover, that rejection can be a fulminant organ rejection, which is difficult to control and can rapidly be fatal. Those with kidney transplants may elect to receive cemiplimab, if they understand that a possible effect of treatment is that the organ will fail and they will have to go back on dialysis,” she cautioned. “Until we better understand how to use immune checkpoint inhibitors in transplant patients, cetuximab will remain the first-line choice in these situations,” she said.

Adverse Effects

According to Dr. Schmults, the dermatologic toxicity of EGFR inhibitors such as cetuximab is not a major concern. “It’s usually an acneiform rash, not something that progresses to a Stevens-Johnson type syndrome.¹⁷ And the development of rash has been correlated with better efficacy.¹⁸ Dermatologists can monitor and treat those rashes, so therapy can usually continue.”

“Until very recently, we haven’t had an FDA-approved systemic treatment for unresectable cutaneous squamous cell carcinoma [Editor’s Note: Dr. Schmults was referring to the approval for cemiplimab-rwlc, issued on September 28, 2018.¹], so everything we have used, including cetuximab, was off-label.” Dr. Schmults noted that obtaining insurance coverage for any of these systemic regimens involves some sort of approval process by the insurer. In some cases, patients have had to experience treatment failure of a platinum-based regimen before cetuximab would be approved. This is likely because chemotherapy is less expensive than biologic therapy.

Despite the recent approval of cemiplimab-rwlc for patients with unresectable cutaneous squamous cell carcinoma, cetuximab is likely to remain an option, with more data available for cetuximab^19–21 than for other drugs. Cetuximab may be considered as a first-line treatment in those who likely cannot tolerate cemiplimab-rwlc, specifically non-kidney organ transplant recipients, kidney transplant recipients who do not want to risk dialysis, and patients with severe autoimmune disease (eg, colitis) who may experience life-threatening flares with anti–programmed cell death protein 1 therapy. In fact, the NCCN Guidelines include cetuximab as an option in patients with squamous cell carcinoma, without specifying the line of therapy or patient group.²

Disclosures

Chrysalyne D. Schmults, MD, MSCE, has received a research grant from Genentech; is a steering committee member and site principal investigator for Regeneron; received speakers’ honoraria from Regeneron and Sanofi; and is on the steering committee for Castle Biosciences.

References

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