Clinicians Weigh Immunotherapy Selection and Referral Roles in Advanced CSCC

Nikhil Khushalani, MD, recently led a Dermatology Times Evolving Paradigms roundtable event in Tampa, Florida, guiding a discussion among dermatologists, Mohs surgeons, medical oncologists, and surgical oncologists on advancing multidisciplinary care in cutaneous squamous cell carcinoma (CSCC). Khushalani is an oncologist and vice chair of the department of cutaneous oncology at Moffitt Cancer Center in Tampa. The event focused on systemic therapy selection, referral roles between dermatology and oncology, and adverse event management, working through a single detailed patient case alongside broader group discussion.

Choosing Among Systemic Immunotherapies for Advanced CSCC

Khushalani reviewed the 3 FDA-approved systemic immunotherapies for advanced CSCC: cemiplimab (Libtayo; Regeneron), pembrolizumab (Keytruda; Merck), and cosibelimab (Unloxcyt; Sun Pharma). Cosibelimab, the newest of the 3, is a PD-L1 blocking antibody, while cemiplimab and pembrolizumab are PD-1 blocking antibodies. He walked through response rates, duration of response, and safety data across the pivotal trials for each agent, response rates in the metastatic setting fell around 45% to 50% across all 3, with complete response rates ranging from 12% to 20%.

One attendee asked why cemiplimab appeared to carry higher rates of immune-related toxicity than cosibelimab despite similar efficacy signals.

"I really don't think there's any difference from an efficacy standpoint between the two PD-1 agents," Khushalani said. He noted lower reported treatment-related toxicity with cemiplimab may relate to its PD-L1 mechanism sparing PD-L2 signaling, though he cautioned cross-trial comparisons remain difficult given differing patient populations and reporting standards.

Several attendees weighed in on real-world experience with the 3 agents, citing formulary access and familiarity as drivers of prescribing patterns more than perceived efficacy differences.

Working Through a High-Risk CSCC Case

The group discussed a case involving a 72-year-old White man with a 3-cm nodular lesion on the left central frontal scalp, no immunosuppression and no prior skin cancers. Imaging identified a 2.6-cm left parotid node concerning for metastasis, confirmed as metastatic CSCC by fine needle aspiration.

The patient underwent Mohs surgery clearing in 1 stage, left parotidectomy with 1 of 18 nodes positive without extracapsular extension, and adjuvant radiotherapy. Final pathology showed a poorly differentiated tumor, 5.7 mm in depth, with extensive perineural invasion.

Khushalani noted a risk calculator estimated roughly a 35% risk of local recurrence, a 15% risk of nodal metastases, and an 8% risk of distant metastases for this patient. The group debated whether the case met criteria from the C-POST trial for adjuvant systemic therapy.

"You don't really meet the exact criteria of C-POST, but it's worth a discussion given the fact that this is certainly considered to be high-risk disease," Khushalani said.

One attendee offered a more granular risk assessment. "If this was a recurrence, he would fall into the extremely high risk. As it is, he might be only very high risk and not quite extremely high risk," an attendee said. The discussion extended to neoadjuvant approaches for patients presenting with palpable nodal disease, with several attendees noting they would favor systemic therapy before surgery in this scenario.

Referral Patterns and Multidisciplinary Coordination

Live polling of the group found 84.6% refer out 25% or fewer of their patients with CSCC for systemic therapy, and 92.3% identified medical oncology, rather than dermatology, as primarily responsible for systemic therapy recommendations. Attendees described referral workflows shaped heavily by insurance access and regional availability of multidisciplinary centers.

"It's insurance, sadly, is one of the very first things you have to look at," an attendee said, describing the added coordination required to route high-risk patients to appropriate specialists. Other attendees described simultaneous referrals to radiation oncology and medical oncology, with weekly tumor boards used to align on treatment plans across specialties.

Recognizing and Managing Immune-Related Adverse Events

The group discussed which immune-related adverse events most concerned the medical oncologists in the room, including hepatitis, myocarditis, uveitis, and neurologic events, several of which the group agreed would preclude rechallenging a patient with the same therapy. Attendees also discussed prolonged courses of neoadjuvant or adjuvant immunotherapy leading to permanent endocrine toxicity, including a recent case of adrenal insufficiency following more than a year of treatment.

"We have to remember that no more immunotherapy is better for the patients," an attendee said, noting shorter courses can still achieve meaningful tumor response without accumulating chronic toxicity.

Dermatologists in the group described a preference for co-managing cutaneous toxicities, including flares of keratoacanthomas during treatment, rather than discontinuing systemic therapy outright. Several noted ongoing uncertainty about whether immunotherapy contributes to keratoacanthoma pathogenesis or simply makes existing lesions more visible through inflammation.

Khushalani closed the program by emphasizing how far multidisciplinary collaboration in CSCC has evolved from a once largely sequential model of care.

"Now, it's a concerted effort right up front," Khushalani concluded.

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

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