Cemiplimab-rwlc (Libtayo^®)

Before September 2018, there were no approved U.S. Food and Drug Administration (FDA) systemic therapies for metastatic or advanced, inoperable cutaneous squamous cell carcinoma. Although this type of skin cancer is generally curable with surgery and/or radiation therapy, a small number of patients cannot be adequately managed with local therapies alone. Cemiplimab-rwlc, a programmed cell death protein 1 (PD-1)–blocking antibody, is the first approved systemic agent for patients with metastatic or locally advanced cutaneous squamous cell carcinoma who are not candidates for curative surgery or curative radiation therapy.¹

Defining ‘Unresectable’ Disease

Metastatic squamous cell skin cancer is rare. Nevertheless, when metastases to the lungs are identified, for instance, the diagnosis of metastatic disease is unequivocal. There are situations, somewhat less rare, in which “we have to consider the morbidity associated with further surgery and the chances of surgery or radiation curing disease,” explained Ragini R. Kudchadkar, MD, Associate Professor of Hematology & Medical Oncology, Emory University School of Medicine, Atlanta. Most cases of cutaneous squamous cell carcinoma are curable with surgery and radiation therapy, but there are notable exceptions, especially in cases that start in the head and neck. For instance, in cases of head and neck squamous cell carcinoma, where optimal surgery would affect or destroy the patient’s vision, such surgery may not be acceptable to the patient. Likewise, certain surgeries may not be possible because of comorbidities.

“Sometimes, a surgeon will tell me, ‘I can operate, but we won’t be able to eradicate all disease due to its extent,’” Dr. Kudchadkar observed. “Or, the surgeon might say, ‘I can resect all disease, but the patient will be permanently blind or disfigured.’ In such cases, where it is clear that cure cannot be achieved with surgery or radiation therapy or that the result of surgery would be devastating for the patient, the option of a systemic approach may now be considered. Once the cancer is removed, the physician also must consider how best to put things back together.” Often, Dr. Kudchadkar explained, this is more difficult to achieve in certain populations, such as in active smokers or in those with previously radiated sites of disease. “Many advanced squamous cell cancers occur in smokers, and reconstruction with acceptable outcomes is not always feasible for these patients,” Dr. Kudchadkar told JNCCN 360.

Most non-melanoma skin cancers are usually resectable and do not usually progress to the point that a systemic therapy would be considered, agreed Christina Davis, PharmD, Oncology Clinical Pharmacy Specialist, University of Colorado Hospital, Melanoma & Cutaneous Oncology Section, Denver. However, cases that become advanced or are unresectable are likely to be referred to a regional cancer center.

“We may see older men, often from rural areas, for instance, who have not had convenient access to specialized medical care or have ignored their skin lesions until they become quite advanced. Other indications for considering systemic therapy arise when the lesion is invading a nerve or is unresectable for another reason,” she continued. Sometimes, the only potentially curable surgery is “extremely morbid, extensive, and/or disfiguring, in which case, having a systemic option is important.”

A multidisciplinary approach is optimal when it comes to management of these complicated cases, Dr. Kudchadkar asserted. Although historically patients with cutaneous squamous cell carcinoma have been treated by surgeons or radiation oncologists, medical oncologists may begin to play more of a role. Patients usually present to a skin cancer clinic and will see a skin or head and neck surgeon first. The surgeon will order staging to determine whether there is bone involvement, orbital involvement, or any local lymphadenopathies. “Ideally, we will all be involved and develop the best multidisciplinary approach for the patient.”

Challenging Patient Populations

The patient population for whom cemiplimab might be considered often has comorbidities, including serious health conditions such as organ or bone marrow transplants. Additionally, those who develop cutaneous squamous cell carcinoma from chronic sun exposure are often elderly and fragile. The median age of patients in the cemiplimab-rwlc pivotal trial,² for example, was in the 70s, “which is much older than what we usually see in cancer clinical trials,” Dr. Kudchadkar said.

The population at highest risk for cutaneous squamous cell carcinoma are transplant recipients, both those who have undergone organ transplants and those who have undergone bone marrow transplants. Nevertheless, these patients were not included in the pivotal trial and usually are not considered eligible for treatment with immunotherapy. 

“That said,” Dr. Kudchadkar continued, “patients who are off immunosuppressive regimens—especially those who had bone marrow transplants—would technically be eligible to receive an immune checkpoint inhibitor, such as cemiplimab-rwlc. Those who have had organ transplants may be at risk because use of this type of systemic therapy could result in organ failure,” she said. [Editor’s Note: The NCCN Guidelines for Management of Immunotherapy Related Toxicity³ allow for consideration of immunotherapy in transplant recipients who are on a stable maintenance immunosuppressive regimen, provided that they have a viable option for alternative therapy in the case of graft rejection.] According to Dr. Kudchadkar, the final decision probably is determined by the balance between risk from the cancer and risk from organ failure. “There is a risk associated with immunotherapy in a patient with an organ transplant, so any other available options should be explored first.” [Editor’s Note: See Spotlight on Cetuximab (Non-Melanoma Skin Cancers).] “A patient with a kidney transplant and advanced skin cancer might opt to take the risk, knowing he or she may require dialysis again.”

Considerations Before Treatment

Although there is a good deal of research interest in the value of PD-1/programmed cell death ligand 1 (PD-L1) expression testing or measurement of mutational burden in terms of selecting patients for treatment with immune checkpoint inhibitors,⁴ the response rate with cemiplimab-rwlc is high enough in the general population to move forward without such testing. “We are comfortable prescribing this therapy for eligible patients, regardless of PD-1/PD-L1 levels,” Dr. Kudchadkar said.

Many older patients are on multiple medications for comorbidities, so checking for drug interactions is important before a new drug is prescribed, Dr. Davis told JNCCN 360. With respect to cemiplimab-rwlc, “no formal pharmacokinetic studies have been conducted. However, I look for anything that may affect the immune system, such as corticosteroids prescribed by an outside provider. Corticosteroids are used for a variety of indications, so I always ask patients to check in with us before they start a new drug once they are on cemiplimab-rwlc,” she said. “This includes any herbal supplements and over-the-counter products.”

Prescribers and cancer care providers should ask patients about supplements, herbal tinctures, and “alternative therapies,” Dr. Davis noted. “A surprising number of patients are taking such products. Some of these products might interact with cemiplimab-rwlc, perhaps increasing the risk for adverse effects or decreasing efficacy.” She cautioned that unless specifically asked about such products, patients may be unlikely to include herbal supplements and other alternative therapies when reviewing current medications.

Cemiplimab-rwlc Administration

If the multidisciplinary team deems cemiplimab-rwlc a good choice for a particular patient and he or she is eligible, the medical oncologist will take over administration and management of the treatment. Although all patients do not need pretreatment for cemiplimab-rwlc administration, the most commonly used prophylactics are acetaminophen and diphenhydramine. “At Emory, our practice is also to give famotidine,” Dr. Kudchadkar said. In general, corticosteroids are not used in conjunction with immunotherapy for patients without immune-related adverse events, but “in case of a severe infusion reaction, they may be given. Again, premedication is not mandatory, but it may be indicated if the patient has a history of infusion reactions,” she explained.

Dr. Davis also noted that the risk of an infusion reaction with PD-1 inhibitors, including cemiplimab-rwlc, is low, “so we don’t typically give premedication unless the patient has already had a reaction. Likewise, we usually do not give patients any prescriptions to take home. We do intensive patient education before they start a regimen and review what to report, when to report, and to whom,” she said.

If there is an infusion reaction, it is typically similar to that observed with any of the other monoclonal antibodies—such as hypotension, rigors, fever, and low back pain. The most severe reaction, Dr. Kudchadkar observed, “would look like an anaphylactic episode.” Oncology nurses in the infusion clinic are well equipped to manage these reactions. Once the symptoms have been reduced with acetaminophen and diphenhydramine, for instance, “the infusion rate can be slowed and treatment may continue. And, once a patient has experienced an infusion reaction, we would order premedication for future treatments,” she said. [Editor’s Note: The NCCN Guidelines for Management of Immunotherapy Related Toxicity³ recommend premedication and continued therapy after a mild/moderate infusion reaction, but permanent discontinuation of the particular agent is recommended if severe reactions (grade 3­–4) occur.]

Any time you rev up the immune system to attack cancer, it can also attack other organs in the body.

Talking About Immune-Related Adverse Effects

“When I talk with a patient about an immune checkpoint inhibitor, I explain, ‘Any time you rev up the immune system to attack cancer, it can also attack other organs in the body. In the gut, for instance, treatment might cause diarrhea; in the skin, treatment might cause rash or itchiness,’” Dr. Kudchadkar said. Patients need to understand the variety of organs and systems that can be affected, she continued. “I also talk about the endocrine system and the fact that if patients develop something like hypothyroidism or hypophysitis, they will have to take medication to replace those hormones permanently.”

According to Dr. Kudchadkar, most patients do well on cemiplimab-rwlc. “If there’s a symptom that is bothersome, we want patients to call the team. We don’t want patients to try to ‘tough it out’ on their own.”

Dr. Davis pointed out that sometimes it is difficult to distinguish drug-related side effects from disease-related symptoms. “One of the things we talk about is that an immune-related adverse effect may occur anywhere in the body. And we ask patients to report everything, even occurrences they think are probably unrelated, underlining the importance of frequent, ongoing communication.

Furthermore, Dr. Davis’ team makes sure to explain and emphasize that “immunotherapy [ie, cemiplimab-rwlc] is not chemotherapy.” Patients may expect to be nauseous and to lose their hair, so the team focuses their education about immunotherapy and how it differs from chemotherapy. For example, “we reiterate that diarrhea caused by immunotherapy is treated differently than diarrhea caused by chemotherapy and should be reported promptly.” Early intervention is key to reducing the severity and duration of any immune-related adverse effect. 

Another critical point to make during patient education, according to Dr. Davis, is that immune-related adverse effects can happen at any time: after a first dose, after many months of treatment, and even after treatment has been discontinued. It is important for patients and caregivers to continue to be vigilant about these types of immune-related adverse effects throughout active treatment and beyond.

Immune-related adverse effects can happen at any time: after a first dose, after many months of treatment, and even after treatment has been discontinued.

In the Melanoma & Cutaneous Oncology Section at the University of Colorado Hospital, patient education is handled by either Dr. Davis or the clinic nurse who is assigned to the patient’s physician. “In our clinic, patients will call their own nurse or me with any questions or concerns.” And there is also an on-call number for patients to access after hours. “We get to know all of our patients quite well, and when we answer their calls, we know their background and situation.”

Durability of Response

Long-term data are not yet available, Dr. Kudchadkar noted, “but we are still following some of the first patients from the early trials and durability looks promising. Specifically, patients who received cemiplimab-rwlc in the phase I trial⁵ are still benefiting more than 2 years later,” she reported. She also pointed out that although 2 years of cemiplimab-rwlc treatment may be given in clinical trials, “we actually don’t know whether that’s necessary. Outside of a trial, 1 year of treatment in patients who have a good response may be sufficient.”

Clinical Trials and Expanding Use of Cemiplimab-rwlc

Most cancer drugs are first explored in the metastatic setting, where few or no options are available. Once proof of principle is established, additional clinical trials are conducted to determine whether the drug may be of value to treat earlier-stage disease, either preventing or delaying disease progression. 

It is not surprising, therefore, that a study of cemiplimab-rwlc in the adjuvant setting will be enrolling soon for patients at high risk. “It is the logical next step, given the high response rates we’ve seen,” Dr. Kudchadkar said. [Editor’s Note: Roughly half of patients who participated in the EMPOWER-CSCC-1 (ClinicalTrials.gov identifier NCT02760498; Study 1540) and advanced cutaneous squamous cell carcinoma expansion cohorts from the phase I trial (Study 1423) demonstrated responses.²]

Nevertheless, both Drs. Kudchadkar and Davis are keenly interested in the potential for cemiplimab-rwlc in the neoadjuvant setting, and Dr. Kudchadkar has proposed a clinical trial. “Although cemiplimab-rwlc is not approved in the neoadjuvant setting, some practitioners might want to consider it when surgery is not an option,” she told JNCCN 360.   

“We look forward to additional trials, particularly in the neoadjuvant setting,” Dr. Davis said. As the University of Colorado is an academic cancer center that is a regional resource, “we see patients for whom surgery may not be the best treatment option. We’d like to know whether neoadjuvant use of systemic treatment with an agent like cemiplimab-rwlc would be helpful, perhaps downsizing the tumor and allowing for less-extensive resection.”

A Seat at the Table for Medical Oncology

The approval of cemiplimab-rwlc, the first systemic therapy approved for cutaneous squamous cell carcinoma, means “the medical oncologist will finally have a seat at the table,” Dr. Kudchadkar reiterated. “We saw a similar situation in basal cell carcinoma when the hedgehog inhibitors emerged.⁶ There just weren’t any systemic therapies for these patients, so local therapies were the only options offered. Now, we can join the conversation. Patients at high risk deserve to be managed by a multidisciplinary team that includes medical oncology. Systemic treatment is not always going to be an appropriate choice, but it can never be a choice if no one brings it up.” Observing that surgeons may be less aware of the cemiplimab-rwlc data, Dr. Kudchadkar underscored the importance of involving medical oncologists in decision-making early in the process.  

In a cancer center setting such as the one at Emory, “I have a dermatologist, surgeon, and radiation oncologist on the same hallway, so it is easy to consult together,” shared Dr. Kudchadkar. “In the community, it is more challenging because everyone is separated, at least geographically. And in some rural communities, being able to see several related specialists may be particularly difficult.”

Dr. Davis remarked that although skin cancers are primarily managed with local therapies, “our unit specializes in melanoma, which means we are experienced with the use of systemic regimens,” she said. Cutaneous squamous cell carcinoma is different, of course, because “until recently, there hasn’t been an approved systemic therapy. We have occasionally used cetuximab, chemotherapy,^7,8 or another PD-1 inhibitor off-label, but we are pleased to finally have an FDA-approved agent for patients with advanced, unresectable cutaneous squamous cell carcinoma.”

Disclosures

Ragini R. Kudchadkar, MD, has received research funding from Merck and Bristol-Myers Squibb and has served on the advisory board of Bristol-Myers Squibb, Array, and Novartis.

Christina Davis, PharmD, is on the speakers bureau for Array BioPharma.

References

1. U.S. Food & Drug Administration. U.S. Department of Health and Human Services. FDA approves cemiplimab-rwlc for metastatic or locally advanced cutaneous squamous cell carcinoma. Available at: https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm622251.htm. Accessed December 11, 2018.
2. Migden MR, Rischin D, Schmults CD, et al. PD-1 blockade with cemiplimab in advanced cutaneous squamous-cell carcinoma. N Engl J Med 2018;379:341–351.
3. Thompson JA, Schneider BJ, Brahmer J, et al. NCCN Clinical Practice Guidelines in Oncology: Management of Immunotheray-Related Toxicities. Version 1.2019. Accessed January 18, 2019. To view the most recent version of these guidelines, visit NCCN.org.
4. Goodman AM, Kato S, Bazhenova L, et al. Tumor mutational burden as an independent predictor of response to immunotherapy in diverse cancers. Mol Cancer Ther 2017;16:2598–2608.
5. Papadopoulos KP, Owonikoko TK, Johnson ML, et al. REGN2810: A fully anti-PD-1 monoclonal antibody, for patients with unresectable locally advanced or metastatic cutaneous squamous cell carcinoma—initial safety and efficacy from expansion cohorts of phase I study. J Clin Oncol 2017;35(suppl):9503.
6. Fecher LA, Sharfman WH. Advanced basal cell carcinoma, the hedgehog pathway, and treatment options—role of smoothened inhibitors. Biologics 2015;9:129–140.
7. Suen JK, Bressler L, Shord SS, et al. Cutaneous squamous cell carcinoma responding serially to single-agent cetuximab. Anticancer Drugs 2007;18:827–829.
8. Bauman JE, Eaton KD, Martins RG. Treatment of recurrent squamous cell carcinoma of the skin with cetuximab. Arch Dermatol 2007;143:889–892.