Squamous Cell Carcinoma Updates for the Dermatologist

David M. Miller, MD, PhD

2026-09-19

What changed since last year?

What changed since last year?
The 2025–2026 signal
Immunotherapy expanded after definitive local therapy and toward earlier disease—while response began to guide subsequent care.
01
Adjuvant therapy becomes real
C-POST establishes a postoperative role for cemiplimab in a narrowly defined, very-high-risk population.
02
Response begins to guide what comes next
De-Squamate, MATISSE, and FIRST move beyond documenting response toward adapting subsequent treatment.
03
Immunotherapy reaches earlier disease
CLEAR directly tests intralesional cemiplimab against primary surgery for selected early invasive CSCC.
The update is not simply “more immunotherapy.” It is an expansion across the disease continuum—and a growing effort to reduce or reshape subsequent care.
Rischin et al. N Engl J Med. 2025;393:774–785; Ladwa et al. J Clin Oncol. 2025;43:2888–2896; Breukers et al. Nat Med. 2025;31:4055–4064; Miller et al. J Immunother Cancer. 2026;14(7):e015029; Migden et al. J Clin Oncol. 2025;43(16_suppl):TPS9612. CLEAR, NCT06585410.

Section

01
After surgery and radiation
Clear margins no longer always mean treatment is finished.
C-POST changes postoperative care—but only if we preserve the boundaries of the evidence.

C-POST: a large reduction in recurrence risk

C-POST: a large reduction in recurrence risk
Disease-free survival
Adjuvant cemiplimab reduced the risk of recurrence or death by 68%.
Trial design
Who was studied and what was tested?
01
Resected high-risk CSCC
Completed surgery and postoperative radiotherapy.
→
02
Randomized phase 3
Double-blind adjuvant cemiplimab versus placebo.
→
03
Primary endpoint: DFS
Did systemic therapy reduce recurrence after definitive local therapy?
Clinical implication: C-POST asks whether the patient who looks “done with surgery” may still benefit from additional systemic treatment.
Hazard ratio
0.32
95% CI, 0.20–0.51
Trial summary
No. of events
Median DFS
Cemiplimab
24
NR
Placebo
65
49.4 mo
P<0.001
Positive randomized trial First phase 3 adjuvant success in resected high-risk CSCC.
Selected population Patients had completed surgery and postoperative radiotherapy.
Dermatologist takeaway: identify the patient who is “done with surgery” but not necessarily done with treatment.
Rischin et al., N Engl J Med. 2025;393:774–785. FDA approval, cemiplimab-rwlc adjuvant CSCC, 2025.

The label is broad. The evidence is not.

The label is broad. The evidence is not.
The approval creates clinical latitude; C-POST tells us where the evidence is strongest.
FDA label
Broad
“High risk of recurrence after surgery and radiation”
The indication does not define the exact pathologic criteria for “high risk.”
vs
C-POST evidence base
Selected
Exceptionally high-risk postoperative disease
ContextSurgery + postoperative radiation
NodalNodal — ECE + node ≥20 mm, or ≥3 involved nodes
NonnodalITM, T4 bone invasion, clinical PNI, or recurrent disease + another high-risk feature
Practical question: Does the patient merely fit the label—or do they resemble the population in whom benefit was demonstrated?
FDA prescribing information for cemiplimab.

Similar question. Different answer.

Similar question. Different answer.
Two adjuvant PD-1 trials asked a similar postoperative question—but the results diverged.
C-POST
cemiplimab
POSITIVE
C-POST disease-free survival Kaplan–Meier curve
HR 0.3295% CI, 0.20–0.51 · P<0.001
KEYNOTE-630
pembrolizumab
ENDPOINT NOT MET
KEYNOTE-630 recurrence-free survival Kaplan–Meier curve
HR 0.7695% CI, 0.53–1.10 · P=0.072
The lesson: “Adjuvant PD-1 works” is an incomplete summary. Population, risk definition, treatment schedule, and trial design matter.
Rischin et al. N Engl J Med. 2025;393:774–785; Koyfman et al. J Clin Oncol. 2025;43(16_suppl):6000. KEYNOTE-630; NCT03833167.

Section

02
From response to decision-making
The new question is not whether the tumor responds.
It is whether response can safely change surgery, radiation, drug exposure—or observation.

The question changed

The question changed
Established foundation
Can preoperative immunotherapy produce a deep response?
Yes—high pathologic response rates established proof of principle.
→
2025–2026 refinement
Can response change what happens next?
The new question is whether response can safely change surgery, radiation, drug exposure—or observation.
Three studies, one directional signal
2025
De-Squamate
Pembrolizumab · response-adapted de-escalation
Clinical complete responders could avoid planned surgery and radiotherapy.
2025
MATISSE
Nivolumab ± low-dose ipilimumab
Regimen, timing, and early PET assessment are becoming design variables.
2026
FIRST
Frontline immunotherapy with response-guided subsequent treatment
Response—not a predetermined calendar—may better organize subsequent care.
The recent advance is treatment adaptation—not the discovery of neoadjuvant therapy.
Ladwa et al., De-Squamate, J Clin Oncol. 2025; Breukers et al., MATISSE, Nat Med. 2025; Miller et al. J Immunother Cancer. 2026;14:e015029.

De-Squamate: response can omit planned local therapy

De-Squamate: response can omit planned local therapy
Pembrolizumab was used first, then PET/CT and mapping biopsies helped decide whether surgery and radiotherapy were still needed.
Response-adapted design
01 Pembrolizumab 200 mg q3w × 4 cycles
→
02 Week 12 assessment FDG-PET ± CT/MRI + mapping biopsies
→
03 Adapt local therapy omit surgery/RT if cCR; omit RT if pCR
The important move was not simply “neoadjuvant pembrolizumab.” It was using response to prospectively change curative-intent treatment.
What happened?
63%
clinicopathologic complete response 17 of 27 patients
48% cCR → planned surgery and radiotherapy omitted
15% pCR → adjuvant radiotherapy omitted
0
recurrences among cpCR patients 12-month EFS 94%
Dermatologist framing: De-Squamate makes response an actionable clinical state—not just an interesting pathologic endpoint.
Ladwa et al. J Clin Oncol. 2025;43:2888–2896. De-Squamate.

MATISSE: brief therapy, early assessment, organ-preservation signal

MATISSE: brief therapy, early assessment, organ-preservation signal
Two infusions of neoadjuvant nivolumab ± low-dose ipilimumab produced high response rates—and raised the question of whether early responders always need standard local therapy.
Randomized phase 2 design
Arm A
Nivolumab weeks 0 and 2
Arm B
Nivolumab + low-dose ipilimumab nivolumab weeks 0 and 2; ipilimumab week 0
01 Treat briefly ultra-short neoadjuvant ICB
→
02 Assess at week 4 surgery ± RT planned as SOC
→
03 Use response organ-preservation signal in selected complete responders
What MATISSE added
55% pathologic response NIVO
80% pathologic response NIVO + IPI
9/10
patients declining surgery/RT achieved durable organ preservation clinical complete remission after two ICB infusions alone
100%
2-year disease-specific survival in responders MPR or PPR; CCR cohort also reported 100% DSS/RFS/OS at 24 months
Early FDG-PET change helped identify responders and may support future response-guided de-escalation.
Dermatologist framing: MATISSE strengthens the “brief treatment → early assessment → response-guided next step” idea, but it remains a signal—not a reason to skip planned local therapy outside a trial.
Breukers et al. Nat Med. 2025. MATISSE; NCT04620200.

FIRST: response guides what comes next

FIRST: response guides what comes next
FIRST reframes “neoadjuvant immunotherapy” as a response-guided strategy: treat briefly, assess early, then decide what treatment is still necessary.
Retrospective cohort + causal framework
189 patients treated with ICI as part of initial CSCC management
2019–2025 real-world MGB cohort
01 Start upfront ICI resectable, borderline-resectable, locally advanced, or limited metastatic CSCC
→
02 Assess response clinical · radiographic · pathologic
→
03 Select next treatment continue, operate, radiate, observe, or intensify
Bayesian models and landmark analyses were used because dose, surgery, and radiation are chosen in response to early clinical benefit.
What supported the framework?
63%
objective response 119 of 189 patients
49%
received ≤2 doses 92 of 189 patients
1/50
recurrences after complete response without surgery median follow-up 25.4 months
Bayesian adjusted analysis Posterior estimates suggested additional doses may improve outcomes, but uncertainty around incremental benefit beyond early exposure remained substantial.
FIRST does not show that one or two doses are universally sufficient. It supports using observed response—not a predetermined calendar—to organize subsequent care.
Miller et al. J Immunother Cancer. 2026;14:e015029.
These materials are provided to you solely as an educational resource for your personal use. Any commercial use or distribution of these materials or any portion thereof is strictly prohibited.

FIRST: what happened after cCR without surgery?

FIRST: what happened after cCR without surgery?
Among 50 patients with clinical complete response who omitted surgery, recurrence was rare across dose groups.
cCR without surgery
Number of ICI doses
Recurrence by dose
Vital status by dose
Overall summary
Clinical complete response
50
patients
Achieved cCR and did not undergo surgery.
1 dose
Single-dose exposure
2
4.0% of cCR cohort
No recurrence
2
100% within dose lane
Recurred
0
0% within dose lane
Alive
2
100%
Disease/treatment-related death
0
0%
Other-cause death
0
0%
2 doses
Two-dose exposure
13
26.0% of cCR cohort
No recurrence
13
100% within dose lane
Recurred
0
0% within dose lane
Alive
10
76.9%
Disease/treatment-related death
0
0%
Other-cause death
3
23.1%
3 doses
Three-dose exposure
3
6.0% of cCR cohort
No recurrence
3
100% within dose lane
Recurred
0
0% within dose lane
Alive
1
33.3%
Disease/treatment-related death
1
33.3%
Other-cause death
1
33.3%
≥4 doses
Extended exposure
32
64.0% of cCR cohort
No recurrence
31
96.9% within dose lane
Recurred
1
3.1% within dose lane
Alive
26
81.2%
Disease/treatment-related death
1
3.1%
Other-cause death
5
15.6%
Entire cCR no-surgery cohort
50
patients
Recurrence
No recurrence
49
98% of cohort
Recurred
1
2% of cohort
Vital status
Alive
39
78% of cohort
Disease/treatment-related death
2
4% of cohort
Other-cause death
9
18% of cohort
Clinical message: only 1 of 50 patients recurred—and that recurrence occurred in the ≥4-dose group.
Miller et al. J Immunother Cancer. 2026;14:e015029.
These materials are provided to you solely as an educational resource for your personal use. Any commercial use or distribution of these materials or any portion thereof is strictly prohibited.

FIRST: our response-guided approach

FIRST: our response-guided approach
Identify the patient → give two doses → reassess at week 6 → let response guide what comes next.
1
✚
Identify the right patient
High-risk resectable CSCC where surgery may be morbid or treatment sequence itself matters.
→
2
2
Give two doses
Brief initial immunotherapy creates the first decision window.
→
3
6w
Reassess at week 6
Clinical, radiographic, and pathologic response define the next move.
✓
If responding
Preserve the response-guided window
Visit 1 Reassess again about 6 weeks later
→
Visit 2 Reassess again about 6 weeks later
→
Adapt care Observe, de-escalate selected treatment, or proceed only if needed
↗
If not responding after dose 2
Do not lose the local-control window
Proceed to surgery / definitive local therapy Response argues for more treatment, not less.
Our framework: brief initial treatment, early reassessment, and response-guided subsequent care.
Miller et al. J Immunother Cancer. 2026;14(7):e015029.
These materials are provided to you solely as an educational resource for your personal use. Any commercial use or distribution of these materials or any portion thereof is strictly prohibited.

Section

03
From response to decision-making
Immunotherapy moves earlier
CLEAR tests whether selected invasive CSCC can be treated before—or instead of—surgery.

How early can immunotherapy move?

How early can immunotherapy move?
CLEAR moves the question from highly morbid resectable disease to selected early invasive tumors.
Advanced / unresectable
IV checkpoint blockade
ESTABLISHED
→
High-risk resectable
Response-adapted systemic therapy
MATURING
→
Selected early invasive CSCC
Intralesional cemiplimab vs surgery
CLEAR · PHASE 3 · RECRUITING
The provocative question
Could selected invasive SCCs eventually be treated in the dermatology office without excision?
Why this room should care: Las Vegas Dermatology is listed as a recruiting site. This is not practice-changing yet—but it directly tests whether surgery must remain the default first treatment for every invasive CSCC.
CLEAR phase 3 trial, NCT06585410.

CLEAR-CSCC: testing surgery as the default

CLEAR-CSCC: testing surgery as the default
Phase 3 · intralesional cemiplimab versus primary surgery for selected early invasive CSCC
01
Who is being studied?
  • Early invasive CSCC
  • Target lesion 1.0–2.0 cm
  • Head/neck, hand, or pre-tibial surface
  • Eligible for Mohs or complete margin assessment
02
What is the comparison?
  • Randomized phase 3
  • Intralesional cemiplimab
  • versus primary surgery / standard of care
  • Open-label, parallel assignment
03
What will decide success?
  • Event-free survival
  • Investigator-assessed EFS up to 1 and 3 years
  • Composite complete response at week 13
  • Safety and surgical/biopsy defect size
The conceptual leap
CLEAR asks whether selected invasive CSCC can be treated before—or instead of—surgery, not after surgery has failed.
Dermatologist framing: this is not practice-changing yet; it is a direct test of how far treatment sequence can move.
ClinicalTrials.gov NCT06585410; Migden et al., J Clin Oncol. 2025;43(16_suppl):TPS9612.

As immunotherapy moves earlier, who owns the patient?

As immunotherapy moves earlier, who owns the patient?
CLEAR raises a practical question: when treatment starts to look like office-based cancer care, which specialty becomes the front door?
Front door
Dermatology
  • Identifies the lesion early
  • Biopsy, risk recognition, surveillance
  • May become central if treatment becomes office-based
Resection decisions
Derm surgery / Mohs
  • Defines margin strategy
  • Assesses whether surgery remains necessary
  • Critical if response changes surgical extent
Complex anatomy
Surgical oncology
  • Function-preserving decisions
  • Nodal disease, reconstruction, morbidity
  • Key partner for high-risk head & neck disease
Systemic therapy
Medical oncology
  • Drug delivery and toxicity management
  • Escalation, de-escalation, duration
  • Central while therapy remains systemic or infusion-based
The answer is probably not one specialty. It is a multidisciplinary model with a changing front door.

One-minute advanced-disease update

One-minute advanced-disease update
Advanced CSCC now has multiple checkpoint options—but the clinically hard questions are still about selection, duration, stopping, and local therapy.
PD-1
Cemiplimab
Established advanced-disease activity now extends into a defined adjuvant population.
The same drug now frames both advanced and selected postoperative disease.
PD-1
Pembrolizumab
Mature KEYNOTE-629 follow-up reinforces durable activity in advanced CSCC.
Useful confirmation of PD-1 activity, but not an adjuvant-positive story.
PD-L1
Cosibelimab
Adds an approved PD-L1 option for advanced disease.
More choice, but comparative clinical advantages remain uncertain.
Still unresolved
Who responds?
How long to treat?
When can we stop?
How should local therapy be integrated?
Dermatologist takeaway: know the available systemic options—but refer early when the key question is treatment sequence, not simply drug choice.
Rischin et al. N Engl J Med. 2025;393:774–785; Grob et al. Ann Oncol. 2024;35:829–839; Stratigos et al. J Clin Oncol. 2025;43:671–680; FDA, cosibelimab approval for advanced CSCC, 2024.

Three things to do differently on Monday

Three things to do differently on Monday
1
Find the true postoperative adjuvant candidate
C-POST is practice-changing, but it is not permission to treat every tumor called “high risk.”
2
Treat sequence as a clinical decision
For highly morbid resectable disease, preserve the opportunity for response to inform what comes next.
3
Watch the boundary move—without outrunning the evidence
CLEAR is testing immunotherapy in early disease; do not substitute an investigational strategy for proven surgery outside a trial.
The 2025–2026 story is an expansion of where immunotherapy is used—and a refinement of how response should shape subsequent care.
Rischin et al. N Engl J Med. 2025;393:774–785; FDA, cemiplimab adjuvant CSCC approval, 2025; Ladwa et al. J Clin Oncol. 2025;43:2888–2896; Breukers et al. Nat Med. 2025;31:4055–4064; Miller et al. J Immunother Cancer. 2026;14:e015029; CLEAR, NCT06585410.