Cemiplimab-rwlc in Advanced Cutaneous Squamous Cell Carcinoma (2026)

For decades, the diagnosis of advanced cutaneous squamous cell carcinoma (CSCC)—locally advanced or metastatic disease no longer amenable to curative surgery or radiation—carried a poor prognosis and had limited options for systemic therapies. The introduction of cemiplimab-rwlc, an anti–PD-1 monoclonal antibody, via 2019 U.S. Food and Drug Administration approval transformed this landscape by establishing immune checkpoint inhibition as an appropriate treatment option for this challenging malignancy.¹

While initial data from the pivotal phase II EMPOWER-CSCC-1 trial demonstrated unprecedented objective response rates (ORR) and led to the drug's regulatory approval, investigators continued to evaluate the long-term durability of cemiplimab’s clinical benefit.¹ A 2025 long-term analysis of the largest prospective advanced CSCC dataset to date demonstrated impressive responses and extended survival.² These results confirm that cemiplimab confers lasting disease control, prolonged progression-free survival (PFS), and sustained overall survival (OS)—fundamentally redefining the long-term therapeutic horizons for a patient population that once faced an incurable disease.² Given this established long-term efficacy, clinical practice must now shift toward optimizing real-world administration of cemiplimab and navigating nuances associated with its administration.

Redefining Prognosis: Long-Term Efficacy and Survival

Long-term follow-up from EMPOWER-CSCC-1 continues to demonstrate cemiplimab’s robust and durable efficacy among patients with advanced CSCC. At a 42.5-month follow-up, patients in Groups 1 through 3 (n = 193), who received weight-based or flat-dose cemiplimab every 2 or 3 weeks for up to 54 weeks, achieved an ORR of 47.2%. These responses proved highly durable, yielding an estimated 12-month duration of response (DOR) of 88.3% and a median PFS of 26.0 months.² Notably, the median OS for these groups was not reached (95% confidence interval [CI] = 56.0 months to not evaluable), and the estimated 48-month survival rate for Group 2 (patients with locally advanced CSCC) was 73.5%.

Real-world evidence, however, suggests slightly different results than EMPOWER-CSCC-1 trial findings. While patients with head and neck CSCC tend to exhibit stronger responses to cemiplimab, those with genital involvement, poor performance status, or prior exposure to chemotherapy or radiation often experience inferior outcomes.³ Therefore, patient selection for either cemiplimab or chemotherapy plays a critical role in determining treatment outcomes.

Poorva Vaidya, MD, an Assistant Clinical Professor at the University of California, Irvine, who specializes in the treatment of patients with skin cancer, shared these thoughts: “When starting cemiplimab, it can sometimes take two to three cycles of treatment to see results. Sometimes, especially in the neoadjuvant setting, even if we do not see a strong clinical response, the immune system is still being primed and the tumor microenvironment is indeed responding.”

Patient Selection and Navigating Special Populations

Navigating the Elderly Demographic

The durability demonstrated in the EMPOWER-CSCC-1 trial changes the prognosis for advanced CSCC; however, achieving these optimal outcomes in real-world practice demands clinical vigilance when treating specific patient populations.

While clinicians may initially hesitate to use cemiplimab in older patients, this patient cohort demonstrated favorable responses; thus, age alone should not preclude patients from receiving immunotherapy.

 Dr. Vaidya said, “My elderly patients can tolerate [cemiplimab] far better than I thought. And yes, the toxicities are real. Even though I see far less than 45%, [given that] immune-mediated toxicities can be serious or life-threatening, I don't discount them. But I would not let just age discount offering the patient a really effective treatment.”

In EMPOWER-CSCC-1, across all study groups, the median patient age was 70 years or older, prompting investigators to emphasize the need for high clinical vigilance, as age-related comorbidities can compromise a patient's tolerance to adverse events.² Real-world evidence reflects this older demographic and highlights prognostic variables. A recent multivariable analysis of patients with CSCC across U.S. practices where the median patient age was 78 years showed that improved OS was positively correlated with younger patient age, a favorable baseline Eastern Cooperative Oncology Group performance status, and primary disease confined strictly to the head and neck. Specifically, younger cohorts (those aged < 60 years) achieved improved OS compared to those aged 80 years or older.⁴ These findings align with the clinical expectation that mortality risk increases with advancing age.⁴ Thus, age alone should not determine therapy selection but does need to be considered in monitoring and safe administration.

“I have patients in their 90s who are taking this medication and tolerating it with minimal side effects. When they do get an immune-mediated adverse event then, of course, they might have less capacity to tolerate it, but in those situations, I am always assessing for that response, to see when therapy can be discontinued,” commented Dr. Vaidya.

 Immunocompromised Patients

Immunocompromised patients, particularly solid organ transplant recipients, face a heightened risk of developing aggressive CSCC. Historically, these patients have been excluded from pivotal immune checkpoint inhibitor trials due to their risks of allograft rejection, autoimmune flares, and potentially diminished antitumor efficacy, leaving clinicians to navigate a significant gap in evidence-based management.⁵ Recent trial data, however, are helping to bridge this gap.

In a study evaluating cemiplimab where immunocompromised patients comprised 26.9% (n = 35) of the cohort, efficacy was comparable between immunocompetent and immunosuppressed patient groups. The study showed no significant differences in ORR (76.8% vs 62.9%; P=0.12) or disease control rate (DCR, 81.1% vs 68.6%; P=0.13). Specifically, transplant recipients experienced an 80% ORR and DCR, with PFS and toxicity rates remaining consistent across all groups.⁵ While these findings confirm that PD-1 inhibitors offer a safe and effective treatment strategy for immunosuppressed patients with CSCC, their use in solid organ transplant recipients requires rigorous, multidisciplinary coordination to safely mitigate the risk of organ rejection.⁵

Real-world evidence further supports this approach. The CASE study, the only U.S.-based real-world analysis of cemiplimab monotherapy in advanced CSCC to date, demonstrated an ORR of 37.4%, with an encouraging 42.9% ORR among immunocompromised patients, though OS data is not yet available.⁶ Additionally, broader real-world analyses of cemiplimab-treated patients indicated that the OS of immunocompromised patients is comparable to that of their immunocompetent counterparts, even if the specific subgroup of allogeneic and solid organ transplant recipients currently remains too small to draw definitive conclusions.⁴

“Many of us [practitioners] are becoming more comfortable using immunotherapy [such as cemiplimab] in this patient population, and we have seen good, durable clinical responses. [However], the approach can still be high-risk and we need more data on the optimal treatments for [patients with] comorbid conditions such as arthritis, ulcerative colitis, and others. The potential benefit of treatment must always be weighed against potential risk.” commented Dr. Vaidya.

Overcoming Real-World Practice Challenges

Dosing

Beyond carefully navigating complex populations, optimizing dosing of cemiplimab is equally vital for improving patient adherence and clinical workflows.

Data from Group 6 (n = 165) of EMPOWER-CSCC-1, where patients received a fixed dose of cemiplimab at 350 mg every 3 weeks for up to 108 doses, demonstrated consistent antitumor activity, achieving an approximate 44.8% ORR at a shorter follow-up of 8.7 months. The data for this cohort are still maturing, thus the median DOR and median PFS have not yet been reached.² These findings provide clinicians with high confidence that using an every-3-week schedule does not compromise antitumor activity. Recently published results from a retrospective study using the 350 mg every-3-weeks regimen showed a PFS of 14 months, which was similar to the 14.7 months reported in Group 6 of the EMPOWER-CSCC-1 study.³

In addition to clinical efficacy, fixed dosing simplifies administration, reduces the potential for dosing errors, and may improve oncology clinic workflows. Shifting to an every-3-weeks fixed dose may also improve patients' quality of life compared to more frequent or weight-based dosing schedules. Furthermore, the every-3-week regimen provides regular, consistent care and follow-up, which may be helpful for patients in identifying and managing any potential therapy-related toxicities.

Commenting on scheduling, Dr. Vaidya noted, “I always stick to the 3-week dosing. Recently we've seen trials in the adjuvant setting for high-risk disease [administering] double the dose every 6 weeks. While that might be an option, that's not something that I've implemented yet. I still see my patients every 3 weeks. I check their labs, and they have access to my nursing team to address any toxicities.”

Safety and Toxicity

Proactively anticipating and managing cemiplimab’s adverse event profile is critical to ensuring uninterrupted administration and optimizing long-term outcomes.

Dr. Vaidya shared, “At the time that I introduce cemiplimab, patients are provided with handouts about their condition, their drug therapy, what to expect at the first day of treatment and in regards to general toxicities, as well as the threshold for calling the clinic. I always say to my patients that no side effect is too small—we would rather know about the adverse event and help them triage it, rather than wait until the next clinic visit when the toxicity has [potentially] escalated to a serious degree.”

The safety data in EMPOWER-CSCC-1 reveals a reassuring lack of severe cumulative toxicities with cemiplimab. Despite a notable difference in follow-up duration between Groups 1 through 3 (42.5 months) and Group 6 (8.7 months), the rates of serious treatment-emergent grade 3 or higher events remained manageable and consistent across the trial arms (31.1% vs 34.5%). The most common grade 3 or higher adverse events were hypertension and pneumonia. This suggests that serious toxicities typically emerge early in treatment, and that prolonged exposure to cemiplimab does not lead to a continuous, compounding risk of severe adverse events for patients on long-term therapy.² Accordingly, treatment discontinuation rates due to any-grade adverse events were relatively low, at 10.4% in Groups 1 through 3 and 13.9% in Group 6.²

While the trial data noted that the incidence rate of grade 3 or higher adverse events in Group 6 exceeded 45%—a higher-than-typical incidence rate that may present management challenges in clinical practice—real-world data suggests a more favorable toxicity profile.² A recent retrospective study found that while 50.6% of patients receiving cemiplimab experienced at least one adverse event of any grade, the rate of grade 3 or higher adverse events was much lower, at 15.7%, including one case requiring hospitalization due to acute myocarditis. Discontinuation rates due to adverse events were 8.4%, which were similar to those seen in EMPOWER-CSCC-1.³

“[While the patient] demographics are similar to those of my patients, I see fewer toxicities than the reported 45%,” said Dr. Vaidya. “Toxicity management really depends on what the adverse effect is, the comorbidities, and the patient’s age. It also depends on the patient's goals of care. Of course, if it's something more serious like pneumonitis or a cardiac toxicity, we have a lower threshold to stop treatment altogether.”

Lastly, to support long-term treatment adherence and optimize patient outcomes, practitioners should establish connections with practitioners in subspecialties to improve toxicity management. This is particularly helpful to clinicians who practice at smaller, more rural settings.

“It is really important to have good relationships and connections with your subspecialty team, because [sometimes] it may take a village to manage some of the toxicities [that we see with cemiplimab]. While many of the adverse events can be managed in oncology clinics, subspecialties have developed a lot of expertise and nuanced management of these toxicities, making tapping into their expertise really important,” concluded Dr. Vaidya.

Treatment Discontinuation Thresholds

 Determining the optimal duration of immune checkpoint inhibition remains a critical consideration in the long-term management of advanced CSCC. Current prescribing guidelines for metastatic and locally advanced CSCC recommend continuing cemiplimab until disease progression, unacceptable toxicity, or up to 24 months.⁷ However, a retrospective study evaluating survival rates among 95 patients who discontinued cemiplimab for various reasons suggested that shorter durations may still yield robust outcomes. Almost one-quarter (23%) of the patients discontinued the immunotherapy due to causes other than disease progression. Notably, patients who discontinued cemiplimab early and those who completed the standard treatment course experienced similar OS: 28.3 months and 25.2 months, respectively.⁸ The lack of differences in OS, PFS, and disease-specific survival between cohorts suggests that continuing cemiplimab beyond 1 year may not provide substantial additional efficacy advantages, and could potentially put patients at risk of developing treatment-related adverse events.⁸ Ultimately, additional data defining optimal duration of therapy are needed to help refine clinical decision-making and standardize patient management strategies.

Conclusion

Although CSCC is a serious and potentially life-threatening diagnosis, recent therapeutic breakthroughs have fundamentally changed the disease’s clinical trajectory, enabling patients to achieve complete, long-lasting remissions. The final long-term analysis of the EMPOWER-CSCC-1 trial definitively establishes cemiplimab as a highly effective and durable treatment option for patients with advanced CSCC.

Disclosure

Dr. Vaidya reported a consulting or advisory role with Immunocore. 

References

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6. Rabinowits G, Homsi J, Park SJ, et al. 825P Cemiplimab-rwlc survivorship and epidemiology (CASE): a prospective study of the safety and efficacy of cemiplimab in patients with advanced cutaneous squamous cell carcinoma (CSCC) in a real-world setting. ESMO Congress 2022. Abstract 825P.

7. Libtayo (cemiplimab-rwlc) [package insert]. Tarrytown, NY: Regeneron Pharmaceuticals, Inc; 2025. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/761097s032lbl.pdf. Accessed August 14, 2026.

8.   Mallardo D, Sparano F, Vitale MG, et al. Impact of cemiplimab treatment duration on clinical outcomes in advanced cutaneous squamous cell carcinoma. Cancer Immunol Immunother. 2024;73(8):160.