3 Things You Should Know About Cutaneous Squamous Cell Carcinoma

Release Date: May 6, 2026

Expiration Date: May 6, 2027

Learning Objectives

Upon successful completion of this activity, you should be better prepared to:

• Evaluate the latest efficacy and safety findings from key trials assessing immune checkpoint inhibitors as monotherapy or in combination regimens for the treatment of advanced cutaneous squamous cell carcinoma (cSCC)
• Assess the mechanistic and clinical differences between PD-1 and PD-L1 inhibitors used for the management of advanced cSCC
• Incorporate patient- and disease-specific characteristics into individualized treatment plans using immunotherapy for advanced cSCC

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Physicians’ Education Resource®, LLC, is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

Physicians’ Education Resource®, LLC, designates this enduring material for a maximum of 0.25 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Acknowledgment of Commercial Support

This activity is supported by an educational grant from Sun Pharmaceutical Industries, Inc.

Off-Label Disclosure/Disclaimer

This activity may or may not discuss investigational, unapproved, or off-label use of drugs. Learners are advised to consult prescribing information for any products discussed. The information provided in this activity is for accredited continuing education purposes only and is not meant to substitute for the independent clinical judgment of a health care professional relative to diagnostic, treatment, or management options for a specific patient’s medical condition. The opinions expressed in the content are solely those of the individual faculty members and do not reflect those of PER® or any company that provided commercial support for this activity.

How to Receive Credit

1. Read this activity in its entirety.
2. Go to https://www.gotoper.com/ime26mxfcscc-postref to access and complete the posttest.
3. Answer the evaluation questions.
4. Request credit using the drop-down menu.

You may immediately download your certificate.

Activity

Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer in the United States, accounting for about 20% of non-melanoma skin cancers (NMSCs).¹ While patients with cSCC have a higher rate of all-cause mortality compared with the general population,² estimating the incidence and cancer-specific mortality of the disease is challenging, as NMSCs are not monitored by cancer registries.¹ Here are 3 things you should know about cSCC.

1. Cutaneous SCC has a remarkably high median tumor mutational burden (TMB).

The National Comprehensive Cancer Network (NCCN) risk stratification criteria identify patients with cSCC who are at low, high, or very high (including lesions greater than 4 cm in diameter) risk for local recurrence, metastases, or death.³ Although the majority of cSCCs are successfully treated with primary surgical intervention with or without radiation therapy (RT),⁴ the risk for metastatic disease in patients with cSCC is 4% overall and 7% to 13% for solid organ transplant recipients.^5,6

Historically, systemic treatments for locally advanced (LA)/unresectable or metastatic cSCC have relied on platinum-based chemotherapy and EGFR inhibitors, but these are associated with disappointingly low (event-free) survival rates.^7-9 Checkpoint inhibitors (CPIs) are a logical treatment for cSCC given the disease’s high TMB and risk associated with immunosuppression.^5,6,10 The mutational landscape of cSCC is dominated by cytidine-to-thymidine transitions associated with repair of UVB radiation-mediated DNA damage,¹¹ and encompasses an exceedingly high median TMB compared with other solid tumors.¹⁰

While TMB is highly correlated with response to PD-1 inhibitors in solid tumors,¹⁰ the TMB between individual cases of cSCC varies widely. In a real-world cohort study of 61 patients with advanced cSCC, a higher median TMB was associated with response to CPI therapy (25.4 vs 10.6 mutations per megabase, P = .02).¹²

2. PD-1 inhibitors have been studied in the adjuvant setting with mixed results.

Investigators for the double-blind, phase 3 C-POST study (NCT03969004) randomly assigned 415 participants with high-risk LA cSCC to receive cemiplimab or placebo after surgery and postoperative RT.¹³ With a median follow-up of 24 months, cemiplimab improved disease-free survival (DFS; primary end point) vs placebo (24-month DFS, 87.1% vs 64.1%; HR, 0.32; 95% CI, 0.20 to 0.51; P < .001).¹⁴ Freedom from local-regional (9 vs 40 events; HR, 0.20; 95% CI, 0.09 to 0.40) and distant (10 vs 26 events; HR, 0.35; 95% CI, 0.17 to 0.72) recurrence was also improved with cemiplimab vs placebo. Although there was a numerical trend toward improved overall survival (OS) with cemiplimab, this association had not achieved statistical significance at the time of the reported interim analysis (Table).¹⁴ Adjuvant cemiplimab was approved by the FDA for adults with cSCC at high risk for recurrence after surgery and RT, and it is a category 1 NCCN-preferred treatment following RT for patients with cSCC and extremely high-risk nodal and non-nodal features and negative postoperative margins.^3,15

Pembrolizumab was also evaluated in the adjuvant setting in the double-blind, phase 3 KEYNOTE-630 study (NCT03833167), which enrolled 450 patients with high-risk LA cSCC following surgery and RT.¹⁶ In this study, however, the PD-1 inhibitor failed to meet the primary end point of improved recurrence-free survival (RFS), defined as time from randomization to the first event of local or regional recurrence of index lesion, distant metastasis, or death due to any cause (24-month RFS; 78.3% for pembrolizumab vs 68.6% for placebo; HR, 0.76; 95% CI, 0.53 to 1.10; P = .07243). Although no study participants died due to treatment-related adverse events, pembrolizumab demonstrated a numerically worse OS (24-mo OS, 87.3% with pembrolizumab vs 90.7% with placebo; HR, 1.47; 95% CI, 0.87 to 2.48) with a median study follow-up of 28.6 months.

3. Immune checkpoint inhibition is the standard of care for unresectable cSCC.

The FDA has approved the PD-1 inhibitors cemiplimab and pembrolizumab, and the PD-L1 inhibitor cosibelimab, for the treatment of advanced cSCC not amenable to curative surgery and/or RT, based on phase 2 studies (Figure).^17-19Participants in the EMPOWER-CSCC-1 phase 2 study (NCT02760498) with either metastatic (group 1) or LA (group 2) cSCC received 3mg/kg cemipimab every 2 weeks.²⁰ Participants in group 1 had not received a prior PD-1/PD-L1 inhibitor.²¹ Participants in group 2 were not candidates for surgery or RT.²² With a median follow-up of 18.5 months, group 1 had an objective response rate (ORR) of 50.8%, median progression-free survival (PFS) of 18.4 months, and median OS of 57.7 months.²⁰ With a median follow-up of 15.5 months, group 2 had an ORR of 44.9% and a median PFS of 18.5 months, and median OS was not reached. A third group of patients with metastatic cSCC who received a fixed dose of cemiplimab 350 mg intravenously every 3 weeks achieved an ORR of 46.4%.

One hundred fifty-nine participants with advanced cSCC received pembrolizumab in the phase 2 KEYNOTE-629 study (NCT03284424).²³ The ORR was 51.9% for patients with LA disease (median follow-up, 52.4 months) and 35.2% for patients with recurrent/metastatic (R/M) disease (median follow-up, 64.7 months). The median PFS was 14.4 months and 5.7 months in the LA and R/M cohorts, respectively. The median OS was not reached in the LA cohort, and 23.8 months in the R/M cohort.

And in a third phase 2 study (NCT03212404), participants with LA or metastatic cSCC received cosibelimab.²⁴ Unlike cemiplimab and pembrolizumab, cosibelimab is a PD-L1 inhibitor that has a functional Fc region that may bind and activate natural killer (NK) cells.²⁵ With a median follow-up of 29.3 months for the patients with metastatic cSCC and 24.1 months for the patients with LA cSCC, the ORRs were 50.0% and 54.8%, respectively.²⁴

The rate of severe immune-related adverse events (irAEs) associated with cosibelimab was 3.6%,²⁴ which was lower than the rates reported in the phase 2 studies of pembrolizumab (8.8%, grade ≥3 immune-mediated AEs and infusion reactions) and cemiplimab (10.7% to 19.2%, any grade ≥3 irAE in groups 1, 2, or 3).^26,27 By blocking PD-L1 interactions with PD-1 and CD80, but sparing PD-L2 to PD-1 binding,²⁸ anti–PD-L1 inhibition is thought to maintain some checkpoint signaling, thereby reducing autoimmunity.^29,30 Furthermore, by blocking PD-L1 interaction with CD80, PD-L1 inhibitors may enhance T-cell expansion and prevent induction of T-cell anergy.³¹

Key References

10. Yarchoan M, Hopkins A, Jaffee EM. Tumor mutational burden and response rate to PD-1 Inhibition. N Engl J Med. 2017;377(25):2500-2501. doi:10.1056/NEJMc1713444

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

24. Ruiz ES, Muñoz-Couselo E, Montaudié H, et al. Efficacy and safety of cosibelimab in advanced cutaneous squamous cell carcinoma: results from a pivotal open-label study with a median follow-up of ≥2 years. J Am Acad Dermatol. 2026;94(1):48-56. doi:10.1016/j.jaad.2025.09.009

For a full list of references go to https://www.gotoper.com/ime26mxfcscc-postref

CME POSTTEST QUESTIONS

You are referred a patient with a suspicion of a 4.2-cm skin lesion on her forearm, identified by her primary care doctor. Further workup confirms cutaneous squamous cell carcinoma with well-defined borders, well-differentiated disease, and no evidence of nodal, perineural, or vascular involvement.

What risk category would this tumor fall under?

1. Low risk
2. High risk
3. Very high risk

Which of the following reflects a theoretical advantage of PD-L1 inhibition compared with PD-1 inhibition in cancer immunotherapy?

1. Enhanced ADCC via disruption of the binding of PD-L1, but not PD-L2, to PD-1
2. Enhanced recruitment of NK cells, which are more strongly suppressed by PD-L1-related signaling
3. Reduced immune-related adverse events by sparing PD-L2:PD-1 binding
4. Reduced immune-related adverse events through preferential activation of regulatory T cells

The phase 3 KEYNOTE-630 study of adjuvant pembrolizumab vs placebo after curative-intent surgery and radiotherapy for high-risk, locally advanced CSCC, which of the following end points was significantly improved with adjuvant pembrolizumab?

1. OS, but not RFS
2. RFS, but not OS
3. RFS and OS
4. Neither RFS nor OS

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To learn more about this topic, including information on managing cutaneous squamous cell carcinoma with immune checkpoint inhibitor combinations and in solid organ transplant recipients, go to https://www.gotoper.com/ime26mxfcscc-activity.

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