Checking in on immune checkpoint inhibitors
Immune checkpoint inhibitors offer hope for non-melanoma skin cancer patients
By Heidi Splete, Contributing Writer, July 1, 2022
Patients with advanced non-melanoma skin cancer see new hope on the horizon, thanks to recent developments in the number and effectiveness of new drugs to improve survival.
“Patients with advanced non-melanoma skin cancer are now benefitting from the successes of immunotherapy previously observed in melanoma,” wrote Connor J. Stonesifer, MD, of Columbia University, and colleagues in an evidence review published in Frontiers in Oncology in 2021.
Immune checkpoint inhibitors (ICIs) have demonstrated success in the treatment of metastatic melanoma. Although early treatment is the best opportunity to manage cSCC, many patients progress to advanced disease, and more options are becoming available.
According to the Skin Cancer Foundation, cutaneous squamous cell carcinoma (cSCC) is the second most common form of skin cancer in the United States, and five times more common than melanoma. Merkel cell carcinoma (MCC) is rare, but MCC patients are also poised to benefit from ICIs, based on recent and ongoing research.
The challenges of cSCC include a high mutational burden, according to a report in JAAD in 2020. However, immunotherapy has become central to the management of advanced tumors through the inhibition of several target proteins: cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death-1 (PD-1), and programmed cell death ligand-1 (PD-L1).
“Prior to the availability of immunotherapy, there were few therapies that could lead to durable benefit for patients with advanced cSCC or MCC,” said Paul Nghiem, MD, PhD, FAAD, of the University of Washington School of Medicine and the Fred Hutchinson Cancer Center in Seattle.
“Patients treated with immunotherapy, including cemiplimab and pembrolizumab for cSCC, and avelumab and pembrolizumab for MCC, have overall response rates that can be as high as 50-60%,” said Dr. Nghiem, who was a coauthor of the JAAD report. “These responses are often quite durable and have favorable side effect profiles compared to cytotoxic chemotherapy,” he noted.
Pembrolizumab and cemiplimab (both anti-PD-1) are FDA-approved for metastatic or locally advanced cSCC, said Dr. Nghiem. Dr. Nghiem serves as a paid consultant to Pfizer, Rain Therapeutics, Instil Bio, and EMD Serono, and received grants to his institution from EMD Serono and Bristol Myers Squibb.
Cemiplimab was approved in 2018 and showed a lasting effect and favorable safety profiles in a phase 2 study of adults with metastatic cSCC. In a 12-month follow-up study presented at the 2019 annual meeting of the American Society of Clinical Oncology, data from 59 patients showed a duration of response that exceeded 12 months in 76% of 29 patients who responded to treatment; durable disease control was 63%, and the median progression-free survival was 18.4 months. Patients were treated with cemiplimab 3 mg/kg every two weeks. No new safety signals occurred in the follow-up study and the results support the FDA approval for metastatic cSCC or local advance cSCC for patients as alternatives to surgery or radiation, the researchers said.
Pembrolizumab was granted an approval in 2021 for the treatment of cSCC not curable by surgery or radiation.
Results of a phase 2 study published in the Journal of Clinical Oncology in 2020 were promising; patients treated with pembrolizumab showed an objective response rate (ORR) of 38.5% at 15 weeks, and a median progression-free survival of 8.4 months. In the preliminary findings, approximately two-thirds of the patients experienced adverse events (67%) and 10% of these discontinued the study as a result. A total of 8% experienced severe AEs that included cholestasis and colitis.
The 2021 approval was based on a global, open-label phase 2 trial in which cSCC patients with locally advanced disease treated with pembrolizumab showed an ORR of 50% after a median of 14.9 months, and cSCC patients with recurrent/metastatic disease showed and ORR of 35.2% after a median of 27.2 months.
According to the report by Barrios at al, data on the use of nivolumab for cSCC have been limited mainly to case reports but have shown some benefit in recurrent cSCC. Adverse events reported with nivolumab use include weight loss, nausea, fatigue, hyponatremia, hip pain, and hyperglycemia, and one death from arrhythmia was attributed to nivolumab in cSCC, the reviewers said.
“It has been surprising to see the robust responses to neoadjuvant immunotherapy in high-risk (stage III-IV) cSCC and MCC patients in the preoperative setting,” Dr. Nghiem said. “In recent studies, striking pathologic responses to cemiplimab (cSCC) and nivolumab (MCC) were seen in about half of cases. Expanding access to immunotherapy in this setting could help patients avoid disfiguring surgery while preventing future cancer recurrences by treating the entire body, which is at risk in these patients,” he emphasized.
Merkel cell considerations
For MCC patients, current ICI options include avelumab, approved in 2017, and pembrolizumab, approved in 2018.
The approval of avelumab, another anti-PD-L1 agent, was supported by interim data from a phase 2 study of 39 adult patients. In that study, published in JAMA Oncology, patients received 10 mg/kg of avelumab as a first-line treatment for MCC in one-hour intravenous infusions every two weeks until confirmed disease progression, unacceptable toxic effects, or study withdrawal. Overall, the objective response rate was 62.1% at a minimum follow-up of three months, and 93% of patients showed a duration of response of at least three months. No grade 4 adverse events or treatment-related deaths were reported.
Data in support of pembrolizumab were published in the New England Journal of Medicine in 2016. In a phase 2 study, 26 MCC patients received at least one dose of pembrolizumab (2 mg/kg every three weeks). The primary endpoint was objective response rate; this occurred in 56% of patients who had at least one evaluation. The response rate was higher (62%) for patients with MCPyV-positive tumors than for those with virus-negative tumors (44%). The progression-free survival rate at six months was 67%, and 15% of the patients experienced drug-related grade 3 or 4 adverse events, including myocarditis in one patient and elevated alanine aminotransferase and aspartate aminotransferase levels, but both patients experienced reduction in these events after discontinuing pembrolizumab, and both also had ongoing tumor regressions, the researchers wrote.
Nivolumab is not currently approved for MCC, but showed potential in a non-comparative, open-label study of 25 MCC patients with virus-positive tumors. In the study, published as a meeting abstract in Cancer Research in 2017, patients were treated with 240 mg of nivolumab every two weeks until disease progression or unacceptable toxicity. The overall objective response rate was 68%, and 67% of these responses occurred at approximately eight weeks. The response rate was 71% for treatment-naïve patients and 63% in patients with 1-2 previous systemic therapies. Overall survival at three months was 92%; progression-free survival was 82%. As for safety, 20% of the patients experienced a grade 3 or 4 adverse event, and 12% of patients experienced treatment-related adverse events that led them to discontinue nivolumab. These results were preliminary, but the researchers highlighted the rapid and durable tumor regressions in both treatment-naïve and treatment-experienced patients.
Anti-PD(L)1 immunotherapies including retifanlimab, atezolizumab, and nivolumab continue to be investigated for cSCC and MCC, said Dr. Nghiem. “Early results show similar efficacy of these agents to currently FDA-approved immunotherapies in advanced cSCC and MCC,” he said. Immunotherapies (both FDA-approved and non-FDA-approved agents) are occasionally used off-label, “depending on logistical and access issues or in combination with other immunotherapies, such as the CTLA-4 inhibitor, ipilimumab,” Dr. Nghiem said. “For a small subset of patients, these agents are also used in the neoadjuvant or adjuvant setting outside of a clinical trial,” he noted. “Key differences among these agents include differences in the dosing interval; for example, every four weeks for nivolumab versus every two weeks for avelumab,” he explained.
Side effect surprises
“Seeing and hearing about some of the side effects have been surprising along the way, as more and more patients are treated with immune checkpoint inhibitors,” said Jennifer N. Choi, MD, FAAD, chief of the division of oncodermatology at Robert H. Lurie Comprehensive Cancer Center at Northwestern University. “Some of the side effects, like new-onset type 1 diabetes, were not necessarily expected until they were observed. By now, most possible side effects have been reported, so we as practitioners know what to expect,” she said. “However, in the setting of COVID and COVID vaccines, there may be interesting new side effects, such as unexpected dermatologic eruptions, that we may observe in patients on immune checkpoint inhibitors,” she noted. Dr. Choi has served as a principal investigator for Incyte and Veloce Pharmaceuticals, a speaker for Bayer, and a consultant for Biotest AG.
Don’t discount the potential for long-term side-effects, Dr. Choi added. “Keep in mind that some side effects can occur as a delayed event, occurring even after a year of being on ICI treatment or even after ICI treatment has been discontinued,” she said. “Therefore, all patients on ICI treatment should be followed up on a regular intermittent basis, even after ICI treatment has been discontinued,” she emphasized.
“A multidisciplinary approach with medical oncology is essential for every patient eligible to receive immunotherapy,” said Dr. Nghiem. “Patients should be well-informed of the potential serious side effects (for example, immune-mediated dermatitis, colitis, pneumonitis, or myocarditis) that can lead to discontinuation of therapy in about 15% of patients,” he said. “Treatment discussions also need to include comparison to other available options including surgery/radiation when appropriate as well as clinical trials,” he added.
Keeping checkpoint inhibitor adverse events in check
Approximately one-third of patients on ICIs will develop a cutaneous adverse event, according to Jennifer N. Choi, MD, FAAD, of Northwestern University.
The three reported adverse events associated with ICIs are:
Rash: 4% — 39%
Pruritus: 17% —21%
Vitiligo: 9% — 11%
Current data indicate that approximately half of patients using a combination of nivolumab and ipilimumab report rash (44%-65%) and pruritus (17%-65%), said Dr. Choi, who serves as chief of the division of oncodermatology at Northwestern.
The potential downsides to treating advanced non-melanoma skin cancers with ICIs include the immune-related adverse effects, which can affect any organ, said Dr. Choi. The most severe potential side effects include the heart (risk of myocarditis), the lungs (risk of severe pneumonitis), or the nervous system (risk of encephalitis), she said. “Such side effects can be life-threatening. However, the good news is that death from immune-related side effects is rare, occurring in less than 2% of cases,” she noted.
“The ultimate goal is always to avoid discontinuing ICI treatment if possible so patients can continue receiving the anti-tumor benefit from the ICI,” said Dr. Choi.
Dr. Choi’s tips for managing side effects:
Start with steroids. The most common first line of treatment of ICI-induced side effects is topical or systemic steroids. “We try to avoid the use of systemic steroids at high doses particularly if the patient is early on in their treatment with ICI, so if the side effect is not severe, we optimize the use of ultra-potent topical steroids and topical non-steroidal medications,” she said.
Add alternatives. “We also utilize other non-steroid modalities of treatment, such as phototherapy, acitretin, methotrexate, apremilast, dupilumab, and other biologics, to treat the various dermatologic side effects, depending on the particular type of side effect it is,” Dr. Choi explained.
Follow frequently. “Close follow-up is needed for all patients who experience adverse events during treatment,” Dr. Choi said. “They should be followed every 2-4 weeks, depending on the side effect, until the side effect is resolved,” she added. “Sometimes side effects become permanent and need long-term management, such as in development of type 1 diabetes or hypothyroidism,” Dr. Choi noted. “Sometimes side effects become chronic, and they can persist even after ICI treatment is discontinued,” she added. Chronic side effects can occur in up to 40% of patients, and these patients will need to be followed on a long-term, intermittent basis, Dr. Choi emphasized.
The next doors to open
“Addressing how to treat patients who do not respond to or are not eligible for immunotherapy remains the largest looming question in advanced stage cSCC and MCC,” said Dr. Nghiem. “Many trials are on the horizon or currently underway to discover new ways to approach these patients,” he said. Novel approaches under investigation include: toll-like receptor agonists, injectable oncolytic viruses (such as TVEC), small molecules that target different parts of the cell cycle (MDM2 inhibitors, ATR inhibitors), and transgenic and adoptive T cell therapies alone or in combination with immunotherapy, Dr. Nghiem said.
Although the current data are promising, more research is needed, not only to identify biomarkers that predict response or resistance to ICIs in non-melanoma skin cancer, but also to identify concomitant therapies that maximize the potential of ICIs, Stonesifer and colleagues concluded in their evidence review.