(NEW) Cemiplimab-rwlc in Cutaneous Squamous Cell Carcinoma

Since 2018, the PD-1–blocking antibody cemiplimab-rwlc (Libtayo) has been used as systemic therapy for patients with metastatic or advanced cutaneous squamous cell carcinoma who are not candidates for surgery or radiation therapy.¹ Given the success of cemiplimab as a therapeutic strategy in locally advanced and metastatic disease, efforts have been dedicated to determine its efficacy as a neoadjuvant immunotherapy. Thus far, neoadjuvant cemiplimab has demonstrated promising potential as a means of reducing the extent of disease in this patient population.

Defining ‘Unresectable’ Disease

Most cutaneous squamous cell carcinomas present at as early stage, and the risk of metastatic squamous cell carcinoma is low.² Nevertheless, when metastases do occur, in the head and neck, they are typically identified in the parotid or cervical lymph nodes.³ Although these locally advanced and regionally metastatic tumors are often curable with surgery and radiation therapy, there are circumstances where surgical resection may not be feasible.

“In the head and neck region, surgery can be really challenging, because the tumors can be near critical structures like the ear or the nose or around the eye,” explained Theresa Guo, MD, Otolaryngologist–Head and Neck Surgeon, University of California San Diego Health. “So, removing them requires the removal of a large amount of skin and soft tissue, major reconstruction, and can result in cosmetic deformities.” These risks may not be acceptable to patients, and therefore, they may be interested in alternative management. Additionally, medical comorbidities may limit surgical interventions.

Sometimes, complete surgical resection is unobtainable because of the extent of disease. “If we do not think a resection will achieve negative margins, then we would not recommend surgery, because there is an increased likelihood of recurrence,” Dr. Guo told JNCCN 360. “The patient would undergo a large operation without a significant clinical benefit.” Under these circumstances, where patients are not considered surgical candidates for curative surgery or curative radiation, i Based on the improved clinical outcomes associated with cemiplimab in this patient population, the option of neoadjuvant cemiplimab may now be considered.⁴

Where patients are not considered surgical candidates for curative surgery or curative radiation, immunotherapy, such as cemiplimab, may represent one of the best therapeutic approaches.

“Generally, two doses of neoadjuvant cemiplimab have been sufficient to achieve dramatic improvements in these patients and increase their chances of obtaining a pathologic complete response after surgical resection,” explained Krista M. Rubin, CNP, of the Center for Melanoma/Cutaneous Oncology, Mass General Cancer Center, Boston. However, some cases may require additional neoadjuvant doses to achieve similar results that would improve surgical outcomes. These decisions are based on clinical examination and radiologic findings and should be approached from a multidisciplinary perspective with the tumor board.

Precautions should be taken in borderline-resectable cases, where neoadjuvant immunotherapy and surgical intervention are both suitable therapeutic options. Delaying definitive operative resection to reduce the extent of disease with neoadjuvant chemotherapy may not always result in the desired clinical outcome. “If the immunotherapy is ineffective, then a patient who could have been taken to surgery may no longer have that option,” stated Dr. Guo. The therapeutic benefits of cemiplimab may be hindered by a plethora of factors, including previous use of immunosuppressive therapies, which could limit its clinical efficacy.

Challenging Patient Populations

The patient population for whom neoadjuvant cemiplimab might be considered includes those with locally advanced or borderline-resectable disease. Typically, these patients are older males who may have multiple medical comorbidities. However, cutaneous squamous cell carcinoma has also been observed in younger patients.⁵ Moreover, the immunosuppressed population, such as those on chronic immunosuppression, transplant recipients, patients with human immunodeficiency virus, or patients with chronic lymphocytic leukemia, has an increased risk of developing cutaneous squamous cell carcinoma.

Transplant recipients represent the population at the highest risk for the development of cutaneous squamous cell carcinoma. Typically, these patients are on established immunosuppression and are in a stable, immunosuppressed state.

“Sometimes, we may need to alter the patient’s immunosuppressive regimen to improve healing and reduce the chance of recurrence or new onset of malignancy,” Dr. Guo noted. Co-management of these patients by all relevant members of the care team is critical.  

Considerations Before Treatment

To reduce the risk of complications associated with neoadjuvant cemiplimab, comprehensive patient assessment should be implemented. “An in-depth review of the patient’s medical records should be performed to determine whether there are any underlying immune conditions present that would increase the risk of treatment-related toxicities, such as colitis or rheumatoid arthritis,” suggested Ms. Rubin. “We try to get a sense of what is going on at home, what medications the patient is taking including herbal supplements, and identify any barriers to treatment that may need to be addressed before commencing neoadjuvant chemotherapy,” she told JNCCN 360. The increased number of comorbid health conditions managed with various medications in older adults increases the risk of drug interactions with cemiplimab therapy. Although no specific pharmacotherapeutic interactions have been identified, the use of cemiplimab in patients with severe hepatic impairment has not been studied and may represent a population susceptible to toxicities related to drug interactions.

“A thorough pretreatment lab analysis including a complete blood cell count, chemistries, and troponin levels is recommended. Similarly, a viral hepatitis panel and tuberculosis testing should be performed to reduce the risk of disease reactivation secondary to treatment with immunosuppression,” explained Ms. Rubin. The primary goal is to establish a baseline profile for patients, so any toxicities associated with neoadjuvant cemiplimab can be documented and managed accordingly.

Neoadjuvant Cemiplimab Administration

The administration and management of neoadjuvant cemiplimab are typically handled by the medical oncology team. Pretreatment is not required before beginning neoadjuvant cemiplimab. An intravenous infusion of cemiplimab at 350 mg is administered over 30 minutes every 3 weeks. “Most patients handle administration well without any evidence of an infusion reaction, as hypersensitivity reactions to cemiplimab are rare,” stated Ms. Rubin.

Most patients handle administration well without any evidence of an infusion reaction, as hypersensitivity reactions to cemiplimab are rare.

In the event that infusion reaction occurs, clinical signs are generally typical and include fever, hypotension, and shortness of breath.⁶ The severity of clinical symptoms varies; therefore, close monitoring is critical for effective management. Hypersensitivity reactions are generally managed by interrupting or slowing the rate of infusion and supportive care as per institutional guidelines.

“At our institution, we premedicate such patients for subsequent dosing with second-generation antihistamines such as fexofenadine the night before and day of the infusion,” explained Ms. Rubin. Following the completion of the infusion, patients should be monitored for an additional 30 to 60 minutes for a delayed reaction to treatment.

Immune-Related Adverse Effects

Adverse effects of immune checkpoint inhibitors are based on the mechanism of action and present as single or multiple organ inflammatory diseases. Patients should be advised of these risks and the various ways in which immune-related adverse effects may manifest. The most common adverse effects associated with cemiplimab include fatigue, rash, and arthralgias. However, it is important to emphasize that any organ system may be impacted from treatment.⁷ Patients are encouraged to report any new or worsening symptoms.  

“We are partners in the care of our patients. They are the experts of their bodies, and we are the experts for all matters associated with pharmacotherapy. Together, we form a partnership emphasizing open and ongoing communication,” explained Ms. Rubin. Despite this mantra, patients do not always adhere to the recommended reporting guidelines. Thus, measures should be implemented to overcome this barrier to health care including regularly scheduled follow-up phone calls or home health-care visits.

Patients are the experts of their bodies, and we are the experts for all matters associated with pharmacotherapy. Together, we form a partnership emphasizing open and ongoing communication.

One challenge faced by the multidisciplinary care team is determining whether new clinical symptoms are medication-related side effects or disease-related manifestations. “This is a common obstacle faced by the multidisciplinary team,” Ms. Rubin told JNCCN 360. If there are concerns about toxicity, then cemiplimab should be temporarily held, and the appropriate diagnostic workup should be performed to identify the cause of the newly emerged clinical symptom. Interventions are determined based on the grading of the condition, with management initiated per standard guidelines.^8–10

“There is always someone available to assist our patients with their needs. We want them to know they are not alone, and we are here to help them every step of the way,” said Ms. Rubin.

Additional Surgical Considerations?

When evaluating more clinically complex patient cases, one of the most important questions is whether a patient should receive neoadjuvant cemiplimab before surgical intervention or should proceed directly to surgery. The multidisciplinary team considers a multitude of factors, including the patient’s age, socioeconomic issues, the invasiveness of the tumor, the involvement of additional critical structures, and the risk of disease progression during neoadjuvant treatment. “Given that these cancers are common in older adults with multiple comorbidities, there are many instances where patients simply refuse surgical management,” explained Dr. Guo. “These surgeries require major reconstruction and may result in cosmetic deformities.”

The surgical approach is dependent on the extent of reconstruction required, the site of reconstruction, and the primary surgeon. More complex cases requiring reconstructive free flaps are best handled by a collaborative approach between a surgical oncologist and a reconstructive surgeon with the dual goals of reducing the duration of surgery and improving clinical outcomes. Prolonged surgeries may be associated with increased postoperative complications.¹¹

Postoperatively, patients usually recover well and should be followed regularly by the multidisciplinary team. Because the risk of new malignancy is increased in these patients, ongoing follow-up with a dermatologist is critical. Adjuvant radiation therapy remains the standard of care after surgery for advanced cutaneous squamous cell carcinoma. However, as evidenced in a recent phase II trial, many patients who had a major or complete pathologic response underwent observation with or without adjuvant immunotherapy.¹² In many cases, patients have achieved a pathologic complete response or a major pathologic response after combined neoadjuvant cemiplimab and curative surgical resection. Decision-making regarding the next best step for each patient should be patient-centered and multidisciplinary.

Clinical Trials and Knowledge Gaps

Despite the observed clinical benefits associated with neoadjuvant cemiplimab thus far, some questions remain unanswered. Determining which patients should be offered neoadjuvant cemiplimab remains a challenge. The associated treatment-related adverse events limit its utility for all patients, particularly those on extensive immunosuppression regimens. Currently, phase III clinical trials are being designed to investigate this question and identify the ideal candidates for treatment with neoadjuvant cemiplimab.

The optimal number of neoadjuvant cemiplimab doses is still an open question. Moreover, although reductions in tumor size from neoadjuvant immunotherapy have now been shown in early phase II clinical trials, it is yet unknown whether there are any long-term benefits or increased risks of recurrence or new malignancies in these patients.

The current literature has demonstrated clinical improvements with the use of neoadjuvant cemiplimab in White individuals, which represents the patient population most commonly impacted by skin cancer.¹³ However, for non-White patients, the data may be limited because of the nature of the disease. Therefore, additional investigative efforts analyzing the efficacy of neoadjuvant cemiplimab in non-White patient populations are needed.

“The biggest takeaway from current clinical trials is that immunotherapy works well. Patients now have options on how to manage their cancer, and through a collaborative and multidisciplinary approach, we can reach a decision that is best suited for each patient,” commented Dr. Guo.  

Will Neoadjuvant Cemiplimab Become a New Standard?

The observed clinical benefits associated with neoadjuvant cemiplimab suggest it may be of benefit for reducing tumor morbidity and improving clinical outcomes for this patient population. However, this therapeutic option is not without risks, as are all medical therapies, including immunotherapies. Patients deemed suitable for treatment with neoadjuvant cemiplimab should be extensively educated and closely monitored.

“Providers should be vigilant. They should learn as much as they can about cemiplimab including how to manage the associated toxicities, and should share their experiences with their colleagues,” urged Ms. Rubin.

Dr. Guo emphasized that although cemiplimab is the primary immunotherapy being investigated, for patients with locally advanced or metastatic cutaneous squamous cell cancer, it is “not the only PD-1–blocking antibody that can be used in these patients.” Other agents with similar underlying mechanisms should be as efficacious and result in similar beneficial outcomes.¹⁴ “This is important for both patients and providers to know about,” she stated.

Disclosures

Theresa Guo, MD, reported no conflicts of interest.

Krista M. Rubin, CNP, reported no conflicts of interest.

References

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13. Apalla Z, Nashan D, Weller RB, et al. Skin cancer: epidemiology, disease burden, pathophysiology, diagnosis, and therapeutic approaches. Dermatol Ther (Heidelb) 2017;7(suppl 1):5–19.
14. S. Food & Drug Administration. U.S. Department of Health and Human Services. FDA approves pembrolizumab for cutaneous squamous cell carcinoma. Available at https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-pembrolizumab-cutaneous-squamous-cell-carcinoma. Accessed March 1, 2024.