Behind the FDA Approval: Adjuvant Cemiplimab Shifts Treatment Paradigm in High-Risk CSCC

On October 8, 2025, the US FDA approved the immunotherapy cemiplimab-rwlc (Libtayo) for adjuvant treatment of adult patients with cutaneous squamous cell carcinoma (CSCC) at high risk of recurrence following surgery and radiation.

The approval came after results from the pivotal phase 3 C-POST study (NCT03969004)¹ demonstrated cemiplimab’s potential to improve disease-free survival (DFS) and reduce the risk of recurrence or death by 68% (HR, 0.32; 95% CI, 0.20–0.51; P <.0001) compared with placebo.² While cemiplimab was approved by the FDA in 2018 and is the current standard-of-care for advanced CSCC, this new approval for adjuvant treatment extends the agent’s clinical application for use in an earlier setting, broadening treatment options for patients.

In an interview with Targeted Oncology, Vishal A. Patel, MD, FAAD, FACMS, associate professor of Dermatology and of Medicine (Hematology/Oncology) at George Washington (GW) University School of Medicine and Health Sciences and director, Cutaneous Oncology Program at GW Cancer Center, discussed the clinical significance of the C-POST trial and the benefits of having this new option available for oncologists and patients.

Targeted Oncology: Could you provide some background on the C-POST trial?

Vishal A. Patel, MD: C-POST is a pivotal phase 3, randomized, double blind, placebo-controlled trial that tested adjuvant cemiplimab vs placebo in adults with resected [CSCC] who remained at high risk for recurrence after surgery and postoperative radiation therapy.

Understanding [the study population] is key to understanding the significance of this trial. Eligibility deliberately targeted patients we worry about the most. While we utilize the term “high-risk,” [it] can mean a lot of things to [many] different providers, in [many] different settings. “High-risk” for dermatologists is more focused on disease that is at risk for local recurrence, [and] for oncologists, tumors that are at risk for either distant or locoregional metastases. The “high-risk” criteria in this trial focused on the tumors with the highest risk of recurrence, informed by previous studies––in particular, a study performed in Australia over a decade ago, a [TROG 05.01 – POST] study [NCT00193895]³ that looked at adjuvant chemotherapy added to radiation therapy after surgery in patients with high-risk [CSCC]––which did not show a benefit, but helped us understand which subgroups of patients had the poorest outcomes.

The criteria included patients with specific nodal disease, [which could be] a lymph node greater than 2 cm with extracapsular extension, or if there were greater than 3 lymph nodes, regardless of size, as well as tumors that had non-nodal high-risk features, such as tumors with in-transit metastases, or T4 tumors that are invading the bones, tumors with clinical or radiographically-significant perineural invasion [PNI]. So, not just any PNI that's microscopic, but those that were causing symptoms, numbness, facial droop, or can be identified on radiographic imaging. Lastly, [the criteria included] locally recurrent tumors that had an additional risk factor like poor differentiation or size.

All patients completed curative intent surgery and postoperative radiation therapy before [randomization], which keeps the question tightly focused on whether the systemic immune checkpoint inhibitor could add value to the optimal local therapy. That time to therapy was also a short window after radiation was completed. Patients were randomized 1:1 to cemiplimab or placebo for approximately 48 weeks, utilizing the standard 358-mg dosing of cemiplimab every 3 weeks, for 12 weeks at first, and then switching to a higher 700-mg dosing every 6 weeks for up to 36 more weeks.

The primary end point of this study was DFS, with key secondary end points including freedom from locoregional recurrence, freedom from distant recurrence, and safety. In total, 415 patients were enrolled and had a median follow-up of about 24 months at the primary analysis.

What gap was this study meant to fill in the treatment landscape?

Historically, we haven't had a systemic adjuvant therapy that's been proven to be helpful in this scenario in a randomized setting or approach, specifically reduc[ing] the risk of recurrence in this population. Earlier trials looked at the addition of chemotherapy to radiation but did not show an improvement in outcomes compared [with] patients [who] do not receive chemotherapy. We follow these patients closely [and] hope to catch recurrences early, but when recurrences occur, especially in the head and neck that are morbid, they're disfiguring [and] unresectable. Relapses carry not only a mortality risk, but also the quality of life and the impact on the patients are substantial. So, the gap is simple and stark: Prevention. Could a systemic therapy help reduce the chance that this type of residual disease be resolved before it declared itself?

Many have suggested that salvage therapy with immunotherapy is a better option than adjuvant therapy; certainly, that may make sense in certain patients [and] scenarios. However, in a number of patients, especially as we understand the natural history of [CSCC] and that patients can have a wide presentation [across ages], utilizing an adjuvant approach to prevent recurrence may not only substantially increase the quality of life, but [also reduce] the potential burden on that patient of the morbidity of their disease. So, the answer of, “did this study fill a gap?” was a resounding “yes.” Being able to at least provide an option to the oncologist to consider a robust impact of adjuvant therapy is helpful.

Now, the decision with the patient and provider comes up to if that [therapy] makes sense for that patient. [If] the patient [is] older, the risk of recurrence may not be as impactful if there are other comorbidities or the patients have limited life expectancy. On the other hand, patients may be younger and more amenable to systemic toxicities related to adjuvant therapy. The goal is to reduce the risk of recurrence when the patient becomes older; in which case, this therapy and the 68% reduction may be meaningful to that patient.

Therefore, it is important for the oncologist to consider those nuances, [which] can help improve the outcomes of those patients that may fall through the cracks and have not received off-label neoadjuvant therapy, or those patients that we worry may have a harder time receiving salvage systemic therapy later. It's a gap we needed to fill, and I'm excited that we now have this robust data as well as approval to offer that option to patients, if it makes sense.

What were the results of the study, and why are they significant?

The topline data were remarkable and robust. The primary end point, DFS, had a HR of 0.32 ... Locoregional control HR was 0.2 and distant control HR was 0.35. The effect size was relevant across all tumor subgroups, both nodal and non-nodal disease of the cohorts enrolled.

The [efficacy] results of C-POST were consequential because the outcomes were unequivocally positive. Treatment with cemiplimab led to a 68% risk reduction of DFS ... as good as it gets in the adjuvant setting. The 24-month DFS was 87.1% compared [with] 64.1% for placebo. Those are large, practice-changing numbers. Compare [with] that, for reference, the adjuvant therapies in melanoma that have been approved: both targeted and systemic immunotherapies have had HRs in the [0.4–0.6] range. This is substantially better than that. It underpins why, on October 8, the FDA approved adjuvant cemiplimab for high-risk resected CSCC after surgery and radiation.

For safety, grade 3 adverse events [AEs] occurred in about 24% of patients on cemiplimab, whereas treatment discontinuation due to an AE occurred in just under 10% of patients. The AE profile is consistent with what we know about PD-1 inhibitors––no new signals or AEs, and generally managed well with the established algorithms that we have incorporated into both salvage or metastatic intention-to-treat therapies, as well as adjuvant therapies in the melanoma setting.

What do you see as the next line of research with this agent?

Two tracks are emerging as to what's next. [The] first is optimization in CSCC [through] biomarkers and selection. Can we figure out who will benefit most? Where can we safely emit therapy? Efforts are ongoing right now to examine biomarkers such as PD-L1 testing tumor mutational burden, immune infiltrate, and circulating tumor DNA to refine that risk. However, when looking at C-POST, it's important to know that biomarker use is not necessary to recommend or to utilize the therapy. In fact, especially in [SCC], we have seen that tumors respond that are PD-L1 positive or have low expressions or even negative, as well as across different tumor mutational burdens. At this time, we're not utilizing biomarkers or selections, but [are] hopeful that we'll be able to hone in on which patients will benefit the most.

Second, timing and combinations are of interest, both in the neoadjuvant approach or perioperative both before and after surgery, or in combination with other types of destructive therapy. Radiation, for example, can synergize with PD-1, which is currently under study. Other trials are exploring sequencing or integrating cemiplimab with intralesional treatments or radiation and surgery in various sequences to improve outcomes.

We're also looking at the broader immuno-oncology [IO] landscape. Cemiplimab is [being] studied in a variety of other tumors, but it's especially interesting in nonmelanoma skin cancer. We're looking at it both in basal cell carcinoma as well as in pivotal and registrational trials related to neoadjuvant therapy for CSCC.

There's also excitement around potentially utilizing cemiplimab earlier in the disease spectrum and in lower-risk tumors which may be treated with intralesional cemiplimab to augment surgical outcomes or to avoid surgery altogether. There is a recently launched phase 3 trial [NCT06585410]⁴ evaluating intralesional cemiplimab compared with surgery from a DFS standpoint.

The bottom line is that we have now moved from a phase of recognizing and understanding that immunotherapy has a clear and critical role in the treatment of CSCC, to now figuring out and personalizing the therapeutic approach: which patients, how long, and with which combinations or partner therapies are ideal and optimal. As oncologists, it’s very critical to understand the nuance of where the therapy fits in, as well as the broader utilization and how that will impact AE management for optimal patient selection.

Could you describe how you would use cemiplimab in a real-world case?

Case 1: A patient may have lymph node disease and appear to have 1 lymph node with possibly a smaller second lymph node on radiographic imaging. They also have a large primary lesion on the temple or the cheek, which is resected either by the head and neck surgeon or in combination with the Mohs surgeon for the primary tumor. And final pathology shows not only that the primary tumor is invading deeply and wrapped around the facial nerve, but also that the lymph nodes dissection of the patient reveals there are now 3 lymph nodes that are positive, including 1 large node 2 cm in size.

Given the 2 cm size, 3 lymph node presence, and facial nerve [involvement], this patient is at a high risk for recurrence, fulfill[ing] 2 criteria within C-POST, and would certainly be recommended for postoperative radiation therapy based on current National Comprehensive Cancer Network [NCCN] guidelines, but we now have evidence that the addition of adjuvant cemiplimab therapy would be very much in line and should be potentially considered for this high-risk profile.

Case 2: To highlight the importance of the full histologic evaluation, another [potentially rarer case] could be a patient who’s treated with Mohs surgery or with a wide local resection for a tumor on the scalp, per se, without realizing that tumor did go all the way down to the bone, has begun to even invade into the bone, or that there are in-transit metastases only determined after surgical resection of the primary tumor, again showing potentially 1 or 2 high risk features that puts the patient at substantial risk for recurrence. Adjuvant therapy can potentially reduce that risk of recurrence or death by 68%.

I think there are going to be [several] scenarios where surgeons or oncologists are surprised by the end result and have to appropriately risk-stratify and apply the inclusion criteria from C-POST to see if patients would potentially qualify from benefit of this now-approved therapy.

REFERENCES:

1. Study of Adjuvant Cemiplimab Versus Placebo After Surgery and Radiation Therapy in Patients With High Risk Cutaneous Squamous Cell Carcinoma. ClinicalTrials.gov. Updated September 19, 2025. Accessed October 21, 2025. https://clinicaltrials.gov/study/NCT03969004

2. Libtayo® (cemiplimab) Phase 3 Data in the Adjuvant Treatment of Post-Surgical High-Risk Cutaneous Squamous Cell Carcinoma (CSCC) Have Potential to Be Practice-Changing. News release. Regeneron. Published May 31, 2025. Accessed October 17, 2025. https://tinyurl.com/5fp9t8vn

3. Post-operative Concurrent Chemo-radiotherapy Versus Post-operative Radiotherapy for Cancer of the Head and Neck. ClinicalTrials.gov. Updated April 6, 2018. Accessed October 21, 2025. https://clinicaltrials.gov/study/NCT00193895

4. Study of Intralesional Cemiplimab in Adult Patients With Early Stage Cutaneous Squamous Cell Carcinoma. ClinicalTrials.gov. Updated October 9, 2025. Accessed October 21, 2025. https://clinicaltrials.gov/study/NCT06585410