(NEW) Cemiplimab Combination Treatment for Solid Organ Transplant Recipients

Posted: Thursday, November 7, 2024

Editor’s Note: Cemiplimab-rwlc is a category 2A recommendation in the NCCN Clinical Practice Guidelines in Oncology for cutaneous squamous cell carcinoma. However, in recipients of solid organ transplants, the regimen discussed here (ie, cemiplimab + mTOR inhibitor + high-dose prednisone) is neither approved by the U.S. Food and Drug Administration for the indication nor is it an NCCN recommendation. These individuals are at much higher risk for squamous cell carcinoma than nontransplant patients, and so this regimen may be worth considering in select situations.

Risk for Squamous Cell Carcinoma in Recipients of Solid Organ Transplants

In 2022, almost 40,000 kidney transplants were performed in the Western hemisphere (North, Central, and South America), with more than 25,000 in Europe and more than 18,000 in the Western Pacific.¹ Although other organs, such as the liver, heart, and lungs, are also successfully transplanted frequently, kidney transplants constitute the majority of these procedures.

Solid organ transplant recipients are at a significantly elevated risk for developing cutaneous squamous cell carcinoma (cSCC) because of the long-term immunosuppressive therapy required to prevent graft rejection; the risk for melanoma is also increased.² Studies indicate that these individuals may exhibit a 65- to 200+-fold increased incidence of cutaneous SCC compared with the general population.^3,4

Kristin Bibee, MD, PhD, currently with the Department of Dermatology at the University of Virginia School of Medicine in Charlottesville, shared these comments: “We don’t completely understand the reasons for this highly elevated risk, although we know it is multifactorial. The primary explanation has been that immunosuppressive medication used after transplant to suppress rejection also limits the body’s immune surveillance of skin cells with DNA damage that occurs as a result of ultraviolet light. Whereas someone who is not on immunosuppressive drugs may be able to identify and remove those damaged cells, such protective mechanisms are reduced or prevented from working by immunosuppressive medications.”

Moreover, Dr. Bibee pointed out, researchers in this area believe that some of the immunosuppressant agents (especially older agents such as azathioprine) may have toxic effects on the keratinocytes, “which are the cells in the skin that transform into the squamous cell carcinoma,” she told JNCCN 360. “There’s also some evidence that these agents may prompt a particular mutation signature in the keratinocytes that may be driving cancer.”⁵ Some medications used prophylactically in the organ transplant setting, such as voriconazole to prevent or treat fungal infections, may also have a direct effect in stimulating the development of cancer, she added.

Immunotherapy for Advanced Cutaneous Squamous Cell Carcinoma

Among nontransplant populations, only about 5% of those who develop cSCC experience advanced or metastatic disease that cannot be addressed with local techniques, such as surgery or radiation therapy. In contrast, skin cancer–specific mortality for transplant patients is nine times higher than in immunocompetent patients.⁶ Moreover, researchers have reported that cSCC that develops in recipients of organ transplants behaves more aggressively than in immunocompetent individuals.⁷

Researchers have reported that cSCC that develops in recipients of organ transplants behaves more aggressively than in immunocompetent individuals.

Historical Treatment Options for cSCC in the Solid Organ Transplant Setting

Prior to the advent of immunotherapy, treatment options for recipients of solid organ transplants were limited and comprised either traditional chemotherapy with platinum-based regimens or targeted therapies with agents such as cetuximab.

Stating that chemotherapy has been ineffective in treating skin cancer, Arianna Maida, PA-C, with the Dana Farber Cancer Institute (DFCI) cutaneous oncology team, shared these comments with JNCCN 360: “Organ transplant patients were not eligible to participate in clinical trials of immunotherapies for skin cancer, so there were no data about safety, risks, or efficacy.”

In 2019, the team at DFCI initiated a pioneering trial using cemiplimab in recipients of kidney transplants with cSCC. The DFCI team selected the mTOR inhibitor sirolimus for immune suppression because of its antiproliferative activity. The mTOR inhibitor class is not generally used as a first-line immunosuppression medication for these patients because of side effects and concern for efficacy when compared with calcineurin inhibitors. Nevertheless, for this purpose, Dr. Bibee explained: “It was hypothesized that the antiproliferative effects of the mTOR inhibitor and its alternative mechanism of action for immunosuppression would be worth the potential for greater toxicities. Moreover, high doses of steroids were also used to enhance the safety of the regimen.” The investigators observed that patients did well with respect to maintaining their transplanted organs⁸ and that immunotherapy may be considered in this setting without jeopardizing the organ.

Despite these results, Dr. Bibee emphasized the need for a “delicate conversation with patients about balancing the risk for transplant rejection vs treatment for the cancer.” These trials have been conducted in patients with renal transplants because in the case of rejection that leads to loss of function of the transplanted organ, Dr. Bibee told JNCCN 360, patients can be maintained on dialysis.

“In my experience with patients who have had kidney transplants, none of them want to think about the possibility that they would have to go back to dialysis,” Dr. Bibee said. “In fact, multiple patients said they would rather die of skin cancer than go back on dialysis. So, although dialysis may represent a theoretical ‘option,’ it may not be a tenable option for many of these patients.”

Gauging the Depth of Immunosuppression

The goal of immunosuppression in the organ-transplant setting, according to Dr. Bibee, is to use the lowest dosage that will prevent organ rejection. “Unfortunately, there is no assay or marker to determine that level,” she explained, “so surrogates, such as urinary BK virus levels, are used as a relative marker for immunosuppression levels.”

Dr. Bibee continued: “Another marker that has been hypothesized to be useful in identifying rejection is circulating donor-specific DNA levels.”⁹ In the study performed on renal transplant patients with advanced cutaneous malignancies led by Johns Hopkins, donor-specific DNA levels were elevated prior to the elevation in serum creatinine. This technology may be helpful in early identification of rejection episodes, Dr. Bibee suggested, potentially allowing for earlier intervention.

Innovative Cemiplimab Regimen

When considering next steps, investigators noted that fortunately, immunotherapy could be used without endangering the transplanted organ. “What we found in the case of nivolumab,” Dr. Bibee observed, “was that we needed to add another immunotherapy agent with a different immunologic target—ipilimumab—to achieve responses in some of the patients.” Dual immunotherapy is commonly used in the treatment of cutaneous cancers, such as melanoma, in nontransplant patients.

A phase I clinical trial conducted by Hanna et al explored the combination of a single immunotherapy agent, cemiplimab, plus an mTOR inhibitor (sirolimus or everolimus), and pulsed prednisone.¹⁰ The existing immunosuppressive regimen was tapered over time to achieve transition to the mTOR inhibitor. Cemiplimab was given intravenously once every 3 weeks with prednisone at 40 mg for 4 days (starting 1 day before cemiplimab administration), followed by 20 mg on days 4 through 6 and 10 mg every day until the day before the next cemiplimab dose.

The rationale for the pulsed prednisone is that the “patient is receiving more protection around the time the immunotherapy is administered, with a taper thereafter,” explained Lillian Flanagan, PA-C, also with the DFCI cutaneous oncology team. “[However], those changes often cause all kinds of issues, such as sleep disturbances and especially diabetic fluctuations,” she said.

When asked about the transition to an mTOR inhibitor, Ms. Flanagan shared these thoughts with JNCCN 360: “We usually recommend at least 2 weeks of transitioning from the immunosuppressive regimen, most commonly mycophenolate mofetil, to either tacrolimus or sirolimus, depending on the nephrologist’s preference.” A conversation about prednisone is required, as well, she continued. Rhondine King, NP, a medical oncology colleague with the head and neck cancer team at DFCI, added: “For most patients, the side effects of tacrolimus or sirolimus are generally well tolerated, whereas the toxicities of higher-dose prednisone, which range from mood changes to elevated blood sugars, are more challenging.”

Reiterating Dr. Bibee’s point about the balance of risk vs benefit in this setting, Ms. Flanagan commented: “With this cemiplimab-containing regimen, the vast majority of patients did not have problems with their kidneys. A critical piece of the overall care is monitoring not only creatinine and kidney function, but also the level of immunosuppression. Therefore, we coordinate very closely with the nephrology and transplant teams to ensure we are all aligned.”

A critical piece of the overall care is monitoring not only creatinine and kidney function but also the level of immunosuppression.

Ongoing studies (ClinicalTrials.gov identifier NCT05896839) are exploring the modification of the mTOR inhibitor and steroid doses to improve tolerability while preserving transplanted organs, Dr. Bibee noted. “When designing and using these regimens, we need to be mindful that we have dual goals: preservation of the transplanted organ and elimination of the malignancy,” she stressed.

Caring for Patients With Solid Organ Transplants

In terms of coordinating different surgical and medical professionals as a team, at Johns Hopkins, it is not uncommon for the transplant group to bring in dermatology before transplant, even as early as when the patient is listed for transplant, Dr. Bibee explained. “We are looking for ways to reduce and mitigate the posttransplant risk of cancer. This is especially true with kidney transplant patients, who may be on the list for some time and may be on dialysis.” During that waiting period, she continued, the team can initiate patient education and encourage vigorous sun-protection behaviors, and “we can even treat some early skin disease or damage to prevent progression. There are great data around sun protection for these patients,” Dr. Bibee told JNCCN 360. “We know from work out of Australia¹¹ that sunscreen use and sun-protective behaviors are effective.”

It is not uncommon for the transplant group to bring in dermatology before transplant, even as early as when the patient is listed for transplant.

Additionally, Dr. Bibee noted that B3 vitamin supplementation (eg, nicotinamide or niacinamide) may be considered in these patients along with field therapy using various techniques⁵ to prevent early skin damage from progressing to cancer.

Risk stratification tools, including mobile apps,¹² have been developed on the basis of large data sets. These tools may be used to determine an individual’s risk according to key characteristics, such as skin pigmentation, level of immunosuppressive therapy, age, and organ transplanted.

The team at DFCI emphasized the importance of early, frequent, and continuous communication among the members of all provider teams. “If something is noted (ie, a suspicious cutaneous lesion), we try to get all the teams (eg, transplant team/nephrologist, medical oncology, dermatology) involved as early as possible,” Ms. Flanagan said. If medical therapy such as immunotherapy is being considered, she added, “we want to reduce or prevent the risk for organ rejection—and this may happen even before any treatment is initiated.”

Patient Education

Unlike some malignancies, where lesions develop internally and are not apparent to patients, cutaneous cancers can be observed by patients themselves. Although all of the provider teams are involved in monitoring patients, Dr. Bibee explained, “we do a great deal of patient education, because most people worry about dark spots and moles, which can be suspicious for melanoma. And while the risk for melanoma is also increased, the risk for squamous cell carcinoma is way higher.”

“I talk with patients about skin ulcers that don’t heal, even in areas that are not exposed to sunlight such as the groin and genitals,” Dr. Bibee continued. “We tell patients to look for new spots on the skin that may bleed on their own. The goal is to describe what squamous cell carcinoma, basal cell carcinoma, and Merkel cell skin cancer look like, so patients and caregivers might recognize them early.”

Psychosocial Aspects of Cancer After Organ Transplantation

Recipients of solid organ transplants vary widely with respect to their performance status because they span many age groups, comorbidities, and years on immunosuppression. Some are quite healthy, whereas others may be frailer, Ms. Flanagan pointed out. “Psychologically, these patients face an emotional minefield,” she said. “On the one hand, they are scared of organ rejection. On the other hand, they have an aggressive skin cancer.”

Ms. King’s work in head and neck oncology often sees her caring for a younger population, those in their late 30s and early 40s. "Psychological issues are a huge part of the overall picture and are critical to the care we provide,” she told JNCCN 360. “The need for an organ transplant is dramatic and often traumatic for all patients, and especially for younger individuals who face many years of dealing with a precarious medical condition. When an aggressive cancer is added to the mix,” Ms. King added, “it is often overwhelming. Depending on the patient’s preferences, we often involve psychological services.”

Teamwork and Communication

Fluid and frequent communication with patients and their local care teams is paramount, Ms. King stressed. “My patients are usually younger and often need to travel from outside of Massachusetts. Given this, challenges sometimes arise in terms of managing side effects. Once they leave Dana-Farber, I want to make sure they have all the resources they need for treatment, including social work,” she said. “If patients get their treatment at DFCI but then go back to their communities for weekly blood work,” Ms. Maida added, “we make sure to communicate with those facilities to make sure the labs are done, and we can review results.”

To ensure the best outcomes possible in these situations, Ms. Flanagan concluded: “We recommend getting the multidisciplinary teams together as early as possible. This is particularly important because we are not all experts about some aspects of overall care for these patients. We’ve had to learn a lot about organ transplants during our care for these patients in these situations.”

Disclosures

Kristin Bibee, MD, PhD, reported no conflicts of interest.

Arianna Maida, PA-C, reported no conflicts of interest.

Lillian Flanagan, PA-C, reported no conflicts of interest.

Rhondine King, NP, reported no conflicts of interest.

References

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