Cemiplimab Data From EMPOWER-CSCC-1 and C-POST Reshape Advanced CSCC Care

CancerNetwork® convened a panel of experts for an Around the Practice® program to discuss identifying high-risk patients with advanced cutaneous squamous cell carcinoma (CSCC) and optimizing the multidisciplinary treatment journey. The panel was moderated by Gaurav Singh, MD, MPH, FACMS, assistant clinical professor in the Department of Surgery at City of Hope Cancer Center Chicago in Illinois. Singh was joined by Soo Park, MD, associate professor of medicine and dermatology in the Division of Hematology-Oncology at UC San Diego Health in California; Jonathan D. Schoenfeld, MD, MPhil, MPH, professor of radiation oncology at Harvard Medical School, director of head and neck and melanoma radiation oncology at Dana-Farber Brigham Cancer Center, and Endowed Chair in Radiation Oncology at Brigham and Women’s Hospital in Boston, Massachusetts; Vernon Sondak, MD, chair of the Department of Cutaneous Oncology at Moffitt Cancer Center in Tampa, Florida; and Jonathan Zager, MD, chief academic officer and senior member in the Department of Cutaneous Oncology and Sarcoma at Moffitt Cancer Center.

The panel explored the features that place patients at high risk of progression, the multidisciplinary journey these patients navigate, and the evidence supporting cemiplimab-rwlc (Libtayo) across the advanced and adjuvant settings, including the phase 2 EMPOWER-CSCC-1 trial (NCT02760498) and the phase 3 C-POST trial (NCT03969004).

High-Risk Features and the Multidisciplinary Path

Singh / Advanced CSCC affects approximately 40,000 patients every year, and…around 15,000 patients die every year from the disease. Are there certain features that portend a worse prognosis or an advanced risk of progression, recurrence, or metastasis?

Park / A lot of these tumors are relatively low risk and highly curable, but we do have a subset that behaves aggressively, and the challenge is identifying those tumors. I group the concerning features into categories: tumor size and depth, pathologic characteristics, anatomic location, patient factors such as immune suppression, and clinical behavior. Any tumor [larger] than 4 cm, I would consider high risk, and sometimes even a tumor of about 2 cm, especially on the head and neck in a sensitive location, like near the eyelid. Any tumor that invades the fascia, muscle, cartilage, or bone is high risk, as is a poorly differentiated tumor or one with perineural or lymphovascular invasion. Immune suppression is one of the strongest risk factors; we see that in transplant patients, whose skin cancers tend to be more biologically aggressive. I also think about whether the tumor is rapidly growing, ulcerated, bleeding, painful, or recurrent, since recurrence may reflect resistant tumor biology.

Schoenfeld / We’re seeing an increasing number of patients with high-risk features or immunosuppression who may be appropriate for multidisciplinary care, and the earlier that communication is started, the more seamless the transition. We have a high-risk multidisciplinary cutaneous oncology tumor board, and we try to present these patients even before Mohs surgery or resection so radiation and medical oncology are aware and patients can be considered for clinical trials.

Singh / Surgery is often first line for advanced cutaneous squamous cell carcinoma, but what are some features that you see in patients with recurrent or advanced or metastatic disease that help you consider systemic therapy for these patients, and how do you have that discussion and navigate that with your patients?

Sondak / There are a few red flags to watch for, including signs of major nerve involvement, unexplained pain radiating down a nerve pathway, and evaluation of the regional lymph nodes so we’re not missing nodal metastases. It’s a conversation with the patient because almost anything can be removed with a big enough operation, but we want to [consider] the morbidity, the reconstruction, and the functional implications.

Checkpoint Inhibitors: Mechanisms, Key Trials, and Real-World Data

Singh / Checkpoint inhibitors have dramatically changed the landscape of CSCC management. Could you talk about the mechanism of action of PD-1 and PD-L1 inhibitors, and why they’re effective in this disease?

Zager / High UV exposure leads to high cumulative sun damage and a higher tumor mutation burden, which is the signature for a potential response to immunotherapy where you have these malignancies that have these high tumor mutation burden counts, and then you hope that immunotherapy works well, which has been the case. We’re going to examine it later in further discussion [about] squamous cell carcinoma and the new anti–PD-1 and anti–PD-L1 immunotherapies, as opposed to standard chemotherapy, which does have a response rate in squamous cell carcinoma, but it’s shorter-lived and also associated with toxicity, especially in the [older] population that might not tolerate it very well. That’s why immunotherapy has revolutionized care for these patients with unresectable systemic metastasized squamous cell carcinoma, even borderline resectable squamous cell carcinoma. We’ll discuss it in the adjuvant therapy as well.

Singh / Several checkpoint inhibitors have now been utilized in the world of cutaneous squamous cell carcinoma. Could you walk us through how you decide among options for patients with this disease state? Could you also discuss the phase 2 EMPOWER-CSCC-1 trial, which has the largest amount of prospective data, and how it applies to your patients, particularly those with advanced disease?

Park / We have 3 drugs now that are FDA approved for this disease. They are cemiplimab, pembrolizumab [Keytruda], and cosibelimab-ipdl [Unloxcyt]. Across all these drugs, the overall message is consistent: This remains a tumor that is highly immunotherapy responsive in many patients. Cemiplimab was the first agent that established PD-1 as a standard treatment for these patients who had metastatic or locally advanced cancer that was no longer amenable to surgery or curative radiation. Pembrolizumab also demonstrated similar activity, and that was seen in the phase 2 KEYNOTE-629 trial [NCT03284424]. Those patients also had clinically meaningful and durable responses. Most recently, there’s a drug called cosibelimab, which I want to emphasize is not a PD-1 inhibitor, but is a PD-L1 inhibitor. That was approved in 2024 and received an updated label in 2025 from the FDA.¹ That’s based on data from the phase 1 CK-301-101 study [NCT03212404]. In those patients, when they had locally advanced or metastatic disease that was also not amenable to curative surgery or radiation, the response rates were about 50%. Across all these trials, the general response rates are about 35% to 50%, and this can vary depending on whether you’ve gotten prior chemotherapy and/or radiation. What I think is most impressive about all these trials is the durability of response. The largest and most mature data set for PD-1 use in cutaneous squamous cell carcinoma is from the phase 2 EMPOWER-CSCC-1 trial, and that used cemiplimab.² This was a prospective pivotal trial that enrolled patients with locally advanced and metastatic cutaneous squamous cell carcinoma, and those patients were not able to be cured by surgery or radiation. It showed that these patients had an overall response rate of about 47% in the early FDA data set, but what was even more practice changing than that is that these responses were deep, they were durable, and they were ongoing at the time of analysis. That is totally practice changing because then we have now identified that these drugs can, in a meaningful proportion of patients, achieve long-term disease control with immunotherapy alone. This matters because before immune therapy for these patients, I only had chemotherapy or EGFR-targeted therapies. Although those treatments can produce responses, they tend not to be durable, and it is more difficult to maintain them.

Singh / EMPOWER-CSCC-1 demonstrated the efficacy and durability of cemiplimab as primary treatment. Could you talk about the phase 3 C-POST trial and how it has broadened how we use immunotherapy for these patients?³

Schoenfeld / We treat a large number of patients we’d like to cure who have high-risk features, and despite up-front surgery and adjuvant radiation, a lot of them still recur, including those with nodes with extranodal extension, multiple involved lymph nodes, advanced T4 lesions, and in-transit lesions. This was a very positive study; there was a significant improvement in disease-free survival [HR, 0.32].⁴ It’s a huge benefit for our patients, and this is now a standard option for patients who are high risk and still have a high risk of relapse after surgery and radiation.

Singh / I always go back to the C-POST criteria, and I like to cite that [HR] reduction in recurrence or mortality to my patients. How do you weigh the other adjuvant data, including KEYNOTE-630 [NCT03833167]?

Schoenfeld / It’s important to have a balanced discussion with patients about the data that exist. The eligibility criteria for the C-POST and KEYNOTE studies were slightly different and [the studies were] conducted differently, so we’re guided by the data we have to recommend the best option.

Singh / With the real-world data that have been emerging, what have you noticed that’s applicable to your patients, and how do you navigate those discussions with specific patient populations that perhaps were not included in these trials?

Park / I enjoy real-world data because a lot of the patients who we see in clinic, specifically for this disease, they are often older, more frail, more medically complex than those patients who were enrolled in the clinical trials. Many of these patients have poor [ECOG] performance status. They may have organ dysfunction. They may have autoimmune disease. Some have a transplant history. They may have other immunosuppressive conditions that would have excluded them from these pivotal trials. I enjoy it when a company is committed to conducting a phase 4 registry study because that allows us to track health outcomes over time in very specific patient subsets. One example is cemiplimab. The company was committed to tracking data outcomes in patient subsets that were not included in the clinical trials, and what was reassuring to see is that the response rates were broadly similar, even outside of the clinical trial setting. We’ve all seen those retrospective studies of PD-1 where the response rates are very similar to what we also see in the clinical trials. That just tells me that this drug, this class of drugs, it works well for these patients, and even if they are older or even if they have a lot of comorbid conditions. The question now is not [whether] this drug works…. The real question is: Can this drug be used safely in this patient, and can this patient benefit from it and live long enough to see that benefit? That’s a very nuanced discussion.

Clinical Implementation, Sequencing, and Future Directions

Singh / Why is it so important for all of us across multiple disciplines and specialties to work together to give our patients the best outcomes? What can community clinicians do if they’re having trouble finding a medical oncologist or radiation oncologist? How can they reach them to make sure that their patient has equal and equitable access?

Schoenfeld / One of the important things is establishing those lines of communication as early as possible because it can be hard when there’s a time sensitivity. Patients already had surgery, and they need to start radiation in that 4- to 6-week window that we think is ideal. If you’re only then looking to schedule an appointment for that patient to establish connections, that can be challenging for patients and for providers on both sides. It comes down to what we were saying before about having these high-risk patients, whom we try to identify up front, and starting that multidisciplinary dialogue up front. Maybe this is a patient who either now or in the future could be treated with neoadjuvant immune therapy. Maybe this is a patient who needs to start radiation soon or is going to need more time for healing after surgery. All of those are issues that are best dealt with as early as possible. The more lines of communication and the better those are established, the more it becomes second nature to community oncologists and academic oncologists in terms of their collaboration across these higher-risk patients.

Singh / Currently, there are no established biomarkers that have been proven to be effective in the world of cutaneous squamous cell carcinoma. Where do you think the field is headed when it comes to these biomarkers, and how do you see these biomarkers playing a role in the especially high-risk patients?

Park / We don’t have any validated predictive biomarkers for CSCC, unlike EGFR-mutated lung cancer or HER2-positive breast cancer, so treatment decisions are largely based on clinical rather than molecular factors. PD-L1 expression has been looked at, but we see responses even with low or absent PD-L1 expression, so I don’t use it to guide treatment. Tumor mutation burden [TMB] is intriguing; CSCC has one of the highest TMB levels among solid tumors, attributed to chronic UV damage, which is probably why it’s so sensitive to immunotherapy. But CSCC arising from a chronic wound, ulcer, or burn tends to have low TMB and a less robust immunotherapy response. The immunocompromised population, including patients with chronic lymphocytic leukemia, is challenging, and I counsel them that their response may be less predictable. The conversation is even more nuanced in solid organ transplant recipients, since immunotherapy carries a real risk of graft failure. Cemiplimab has data from a small study, the phase 1/2 CONTRAC trial [NCT04339062], in which kidney transplant recipients were cross-tapered to an mTOR inhibitor with pulsed-dose prednisone; no patient lost their graft, and that’s been my experience as well, though this remains an area needing further investigation.⁴

Singh / I’ve noticed there’s no TMB testing required for cemiplimab. In the C-POST trial, a subgroup analysis found efficacy was consistent regardless of TMB, although firm conclusions can’t be drawn since the study wasn’t powered for that comparison. What are you most excited about when it comes to future directions in CSCC, and what areas of unmet need do you see?

Zager / It comes down to a couple of different buckets. One, neoadjuvant therapy. We’ve seen that in several cancers, melanoma in particular, giving neoadjuvant therapy to these patients will probably lead to longer response durations and longer recurrence-free survival, just as we’ve seen with almost every single solid tumor in neoadjuvant therapy. That doesn’t just entail giving neoadjuvant therapy to bulky primary or regionally metastatic [disease]. [It may also mean] giving 1 or 2 doses of an anti–PD-1 or anti–PD-L1 inhibitor to the higher-risk patients prior to definitive radiation or surgery, [whose tumors were] resected by the dermatologist or shaved off by the dermatologist as a biopsy.... We can expand the neoadjuvant approach, like we’ve seen in some other skin cancers as well. Secondly, adding therapies together with EGFR antibodies can also [show an] increase in responses, especially in the immunotherapy refractory population. By combining therapies, chemotherapy plus more immunotherapy, or EGFR inhibition and immunotherapy, maybe we can augment our responses in this refractory group. And lastly, what we really haven’t touched upon just yet, and I’m also excited for, is intralesional. There are some studies, the phase 1/2 IGNYTE [NCT03767348] and the phase 2 CERPASS [NCT04050436] studies, using RP1 [vusolimogene oderparepvec-wtpg], which is an intralesional agent, plus or minus immunotherapy to again augment and overcome immune checkpoint inhibition resistance in these patients, and we’ve seen some very promising results. Those are the 3 buckets: neoadjuvant therapy, the combination of systemic therapies, and immunotherapy plus intralesional therapies, which I’m excited to see.

References

1. FDA approves cosibelimab-ipdl for metastatic or locally advanced cutaneous squamous cell carcinoma. FDA. Updated December 13, 2024. Accessed August 4, 2026. https://tinyurl.com/mv2c2ybn

2. Hughes BGM, Guminski A, Bowyer S, et al. A phase 2 open-label study of cemiplimab in patients with advanced cutaneous squamous cell carcinoma (EMPOWER-CSCC-1): final long-term analysis of groups 1, 2, and 3, and primary analysis of fixed-dose treatment group 6. J Am Acad Dermatol. 2025;92(1):68-77. doi:10.1016/j.jaad.2024.06.108

3. Rischin D, Porceddu S, Day F, et al; C-POST Trial Investigators. Adjuvant cemiplimab or placebo in high-risk cutaneous squamous-cell carcinoma. N Engl J Med. 2025;393(8):774-785. doi:10.1056/NEJMoa2502449

4. Hanna GJ, Dharanesswaran H, Giobbie-Hurder A, et al. Cemiplimab for kidney transplant recipients with advanced cutaneous squamous cell carcinoma. J Clin Oncol. 2024;42(9):1021-1030. doi:10.1200/JCO.23.01498