Comparing Safety, Tolerability, and Clinical Fit of Advanced cSCC Immunotherapies

Cutaneous squamous cell carcinoma (cSCC) is usually treated with surgery or radiation, but when the disease advances beyond curative-intent treatment, management stops being a single specialty’s decision. At 3 recent Dermatology Times Evolving Paradigms events, Darrell S. Rigel, MD, MS; Neal Bhatia, MD; and Gaurav Singh, MD, MPH, FACMS, moderated discussions with dermatologists, Mohs surgeons, and medical oncologists on advancing multidisciplinary care in cSCC. All 3 groups reviewed a case of a 72-year-old man with locally advanced, node-positive disease and examined how systemic immunotherapy options are reshaping referral and treatment decisions. Rather than focusing on individual presentations, discussions centered on shared clinical challenges: comparing trial data across 3 approved checkpoint inhibitors, reading cross-trial comparisons with appropriate caution, managing immune-related adverse events, and bridging referral gaps between dermatology and oncology. Rigel is a dermatologist at Cooper Clinic in Dallas, Texas, clinical professor of dermatology at NYU Grossman School of Medicine in New York, and adjunct professor of dermatology at UT Southwestern Medical School; Bhatia is a dermatologist and director of clinical dermatology at Therapeutics Clinical Research in San Diego, California; and Singh is a dermatologist and Mohs micrographic surgeon at City of Hope Cancer Center Chicago in Illinois.

Catch up on part 1 here.

Safety Data and Adverse Event Management

Safety data drew as much attention as efficacy across the 3 events. Any-grade immune-related adverse events occurred in 27.6% of patients on cosibelimab, 23.3% on pembrolizumab, and 68.9% on cemiplimab, with grade 3 or higher rates of 3.6%, 8.8%, and 15.0%, respectively.6-8 Serious treatment-emergent adverse events followed a similar pattern, occurring in 32.8% of cosibelimab patients compared with 54.7% for pembrolizumab and roughly 39% to 44% for cemiplimab.^6-8

Commonly reported adverse events across all 3 agents included fatigue, anemia, diarrhea, pruritus, and arthralgia, generally at a low grade. Pneumonitis of any grade occurred in 1.0% of cosibelimab patients, 3.8% of pembrolizumab patients, and up to 7.3% of cemiplimab patients, with grade 3 or higher pneumonitis observed in 3.1% of the cemiplimab groups.

Colitis was reported in 1.3% of patients receiving pembrolizumab, all grade 3 or higher, and was not reported at grade 3 or higher with cosibelimab or cemiplimab in these cohorts.^6-8

At Rigel’s event, discussion of adverse event management revealed a graded, context-dependent approach. Attendees drew clear distinctions between toxicities they consider manageable without interrupting therapy, such as thyroid abnormalities, and those requiring prompt intervention and drug discontinuation, including colitis and pneumonitis. “If they’re having colitis, for example, that’s more serious, and that’s when I would stop the drug and start steroids,” an attendee said.

Another attendee added that even low-grade pneumonitis warrants immediate action. “We take it very seriously and initiate treatment, initiate the steroid, stop the immunotherapy, and involve the concerned consultant, a pulmonologist in that case,” the attendee said. Underlying autoimmune disease surfaced as a factor that could prevent initiating immunotherapy entirely, with attendees disagreeing modestly on the threshold.

One attendee described working closely with rheumatology to stabilize underlying conditions before proceeding, while another was more cautious. “Even if they’re under control, I would say it’s a concern, because you can activate their immune system and cause exacerbation of that disorder,” an attendee said. At Singh’s event, the panel was openly skeptical of a cross-trial slide showing a treatment-related death rate as high as 12.6% for pembrolizumab, compared with 3.1% for cosibelimab and 2.6% to 8.5% for cemiplimab.

One oncologist countered that contemporary checkpoint inhibitors all carry roughly a 1% to 2% mortality rate in broader practice. Whether PD-L1 blockade is inherently safer than PD-1 blockade remains unsettled, and participants noted that other PD-L1 agents have underperformed in other tumor types, without a direct comparison to allow a firm conclusion. As one oncologist put it, “it’s the clinical data that [matter]. The mechanism makes for a fancy drug.”

Where Cosibelimab May Fit

Cemiplimab carries the deepest clinical track record of the 3 agents and is the only one with a positive adjuvant trial to date. The phase 3 C-POST trial recently expanded the drug into the adjuvant setting, demonstrating a significant disease-free survival benefit (HR, 0.32) in patients at high risk of recurrence after surgery and radiotherapy, though overall survival did not differ.⁷ Pembrolizumab’s adjuvant counterpart, the phase 3 KEYNOTE-630 trial, was negative, failing to improve recurrence-free survival when reported at a 2025 conference.⁸

Several panelists at Singh’s event said the results have tempered their enthusiasm for reflexively reaching for pembrolizumab as an off-the-shelf first-line option. Cosibelimab, by contrast, has no neoadjuvant or adjuvant data and no head-to-head trials against either comparator. Most panelists described themselves as intrigued by its apparent tolerability but inclined to gather their own experience before adopting it broadly. Rigel closed his event by noting cosibelimab’s favorable adverse event profile as potentially meaningful for this patient population, while acknowledging its shorter follow-up. Where cosibelimab may fit, Singh’s group concluded, is as an additional first-line option rather than a displacement of established agents, particularly for clinicians who value having tolerability data on hand. Interest in cosibelimab was growing across all 3 events but remained largely untested in day-to-day practice.

Building the Multidisciplinary Team

All 3 discussions framed effective cSCC management as requiring strategic collaboration across a wide care team, including medical, radiation, and surgical oncology; dermatologic oncology; Mohs surgery; general dermatology; plastic surgery; geriatrics; head and neck surgery; ear, nose, and throat surgery; and general practice.⁹

Moderators presented a consistent set of triggers for consulting a multidisciplinary tumor board: when a clear treatment path is not defi ned, when a center lacks access to a needed specialist or novel therapy, when a patient’s likelihood of cure has dropped significantly, when more than 2 to 3 risk features are present, or when nonsurgical treatment becomes an option.⁹

Attendees generally endorsed this framework but described uneven ability to act on it. Clinicians in closed health systems described faster turnaround through regular tumor boards, while those in single-specialty private practice described more friction in reaching one.

This supplement has been produced independently by Dermatology Times and supported through an educational grant by Sun Pharmaceuticals.

Click here to download the full supplement: “Coordinating Systemic Therapy for Advanced Cutaneous Squamous Cell Carcinoma.”

Read part 1 here and stay tuned for part 3 coming later this week!

References

6. 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

7. 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

8. Hughes BGM, Munoz-Couselo E, Mortier L, et al. Pembrolizumab for locally advanced and recurrent/ metastatic cutaneous squamous cell carcinoma (KEYNOTE-629 study): an open-label, nonrandomized, multicenter, phase II trial. Ann Oncol. 2021;32:1276-1285. doi:10.1016/j.annonc.2021.07.008

9. Claveau J, Archambault J, Ernst DS, et al. Multidisciplinary management of locally advanced and metastatic cutaneous squamous cell carcinoma. Curr Oncol. 2020;27:e399-e407. doi:10.3747/co.27.6015