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Peer-reviewedCC BYJournal for ImmunoTherapy of Cancer

Integrated tumor and circulating immune profiling in the NEO-CESQ trial of perioperative cemiplimab for resectable cutaneous squamous cell carcinoma

  • Dirk Schadendorf1
  • Diana Giannarelli2
  • Elisabeth Livingstone3
  • Corrado Caracò4
  • Miriam Paone5
  • Domenico Mallardo5
  • Paolo A Ascierto6
  • Luisa Piccin7
  • Paola Queirolo8
  • Claudia Trojaniello5
  • Mario Mandala9
  • Daniela Massi10
8 more authors
  • Franco Bassetto11
  • Paolo Bossi12
  • Elisabetta Pennacchioli13
  • Francesco Spagnolo14
  • Vittorio Rampinelli15
  • Francesco Giovacchini16
  • Paola Schiavo17
  • Giampiero Parrinello14
17 affiliations
  1. 1Klinik und Poliklinik für Dermatologie, Venerologie und Allergologie, Universitatsklinikum Essen, Essen, Germany
  2. 2Epidemiology and Biostatistics, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma, Italy
  3. 3Dermatology, University of Duisburg-Essen, Essen, Germany
  4. 4Melanoma and Skin Cancers Surgery Unit, Istituto Nazionale Tumori IRCCS Fondazione “G. Pascale”, Naples, Italy
  5. 5Melanoma, Cancer Immunotherapy and Development Therapeutics, Istituto Nazionale Tumori IRCCS Fondazione Pascale, Naples, Italy
  6. 6Dipartimento di Neuroscienze e Scienze Riproduttive ed Odontostomatologiche, Università degli Studi di Napoli “Federico II“, Naples, Italy
  7. 7Veneto Institute of Oncology IOV IRCCS, Padova, Italy
  8. 8Division of Medical Oncology for Melanoma, Sarcoma and Rare Tumors, European Institute of Oncology IRCCS, Milan, Italy
  9. 9Medicine and Surgery, University of Perugia, Perugia, Italy
  10. 10University of Florence, Florence, Italy
  11. 11Plastic Surgery Clinic, Padua University Hospital, Padua, Italy
  12. 12Humanitas University, Milan, Italy
  13. 13Melanoma and Sarcoma Surgery, European Institute of Oncology IRCCS, Milan, Italy
  14. 14IRCCS Ospedale Policlinico San Martino, Genoa, Italy
  15. 15Department of Medical and Surgical Specialties, University of Brescia, Brescia, Italy
  16. 16Maxillofacial Surgery Unit, Perugia, Italy
  17. 17Clinical Research Technology S.r.l. (CRT), Salerno, Italy
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Abstract

Background Perioperative immune checkpoint inhibition is emerging as a promising strategy for high-risk, resectable cutaneous squamous cell carcinoma (CSCC). However, biomarkers capable of predicting pathological response and recurrence remain undefined. We report clinical and translational findings from NEO-CESQ (NCT04632433), a multicenter, single-arm phase II trial evaluating neoadjuvant plus adjuvant cemiplimab in patients with stage III–IV resectable CSCC.Methods Patients received neoadjuvant cemiplimab followed by surgery and adjuvant treatment. The primary endpoint was major pathological response (MPR; <10% viable tumor) assessed in the intention-to-treat population. Survival outcomes were estimated using HRs with 95% CIs. Exploratory translational analyses included baseline tumor transcriptomics (NanoString PanCancer IO 360) and longitudinal serum cytokine profiling. Differential expression and signature enrichment analyses were performed to identify molecular correlates of response. An exploratory transcriptional classifier associated with recurrence-free survival was developed, and its performance was evaluated using the area under the curve (AUC).Results MPR was achieved in 11 of 25 patients (44%), while pathological complete response (pCR) occurred in nine patients (36%). With a median follow-up of 42 months, MPR was associated with improved event-free survival (HR 0.16, 95% CI 0.03–0.75), although recurrence events were limited. Patients achieving pCR exhibited lower circulating interleukin 6 (IL-6) levels prior to adjuvant therapy compared with non-pCR patients, but IL-6 did not significantly discriminate MPR status or survival outcomes. Tumor transcriptomic analyses revealed enrichment of interferon-γ-related signatures in responders, whereas non-responders showed higher expression of WNT5A and CD276. An exploratory 10-gene classifier (“NeoSquamos”) demonstrated an AUC of 0.838 for recurrence-free survival prediction, though based on a limited number of events.Conclusions These findings provide an integrated view of tumor and systemic immune dynamics during perioperative programmed death 1 blockade in CSCC. Candidate biomarkers, including transcriptomic signatures and circulating cytokines, may help refine risk stratification, although prospective validation in larger cohorts is required.Trial registration number NCT04632433.

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Cite

BibTeXRIS
BibTeX
@article{schadendorf2026integrated,
  title = {{Integrated tumor and circulating immune profiling in the NEO-CESQ trial of perioperative cemiplimab for resectable cutaneous squamous cell carcinoma}},
  author = {Dirk Schadendorf and Diana Giannarelli and Elisabeth Livingstone and Corrado Caracò and Miriam Paone and Domenico Mallardo and Paolo A Ascierto and Luisa Piccin and Paola Queirolo and Claudia Trojaniello and Mario Mandala and Daniela Massi and Franco Bassetto and Paolo Bossi and Elisabetta Pennacchioli and Francesco Spagnolo and Vittorio Rampinelli and Francesco Giovacchini and Paola Schiavo and Giampiero Parrinello},
  journal = {Journal for ImmunoTherapy of Cancer},
  year = {2026},
  month = nov,
  doi = {10.1136/jitc-2026-016059},
  url = {https://doi.org/10.1136/jitc-2026-016059},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Integrated tumor and circulating immune profiling in the NEO-CESQ trial of perioperative cemiplimab for resectable cutaneous squamous cell carcinoma
AU  - Dirk Schadendorf
AU  - Diana Giannarelli
AU  - Elisabeth Livingstone
AU  - Corrado Caracò
AU  - Miriam Paone
AU  - Domenico Mallardo
AU  - Paolo A Ascierto
AU  - Luisa Piccin
AU  - Paola Queirolo
AU  - Claudia Trojaniello
AU  - Mario Mandala
AU  - Daniela Massi
AU  - Franco Bassetto
AU  - Paolo Bossi
AU  - Elisabetta Pennacchioli
AU  - Francesco Spagnolo
AU  - Vittorio Rampinelli
AU  - Francesco Giovacchini
AU  - Paola Schiavo
AU  - Giampiero Parrinello
PY  - 2026
DA  - 2026/11/08
JO  - Journal for ImmunoTherapy of Cancer
DO  - 10.1136/jitc-2026-016059
UR  - https://doi.org/10.1136/jitc-2026-016059
AB  - Background Perioperative immune checkpoint inhibition is emerging as a promising strategy for high-risk, resectable cutaneous squamous cell carcinoma (CSCC). However, biomarkers capable of predicting pathological response and recurrence remain undefined. We report clinical and translational findings from NEO-CESQ (NCT04632433), a multicenter, single-arm phase II trial evaluating neoadjuvant plus adjuvant cemiplimab in patients with stage III–IV resectable CSCC.Methods Patients received neoadjuvant cemiplimab followed by surgery and adjuvant treatment. The primary endpoint was major pathological response (MPR; <10% viable tumor) assessed in the intention-to-treat population. Survival outcomes were estimated using HRs with 95% CIs. Exploratory translational analyses included baseline tumor transcriptomics (NanoString PanCancer IO 360) and longitudinal serum cytokine profiling. Differential expression and signature enrichment analyses were performed to identify molecular correlates of response. An exploratory transcriptional classifier associated with recurrence-free survival was developed, and its performance was evaluated using the area under the curve (AUC).Results MPR was achieved in 11 of 25 patients (44%), while pathological complete response (pCR) occurred in nine patients (36%). With a median follow-up of 42 months, MPR was associated with improved event-free survival (HR 0.16, 95% CI 0.03–0.75), although recurrence events were limited. Patients achieving pCR exhibited lower circulating interleukin 6 (IL-6) levels prior to adjuvant therapy compared with non-pCR patients, but IL-6 did not significantly discriminate MPR status or survival outcomes. Tumor transcriptomic analyses revealed enrichment of interferon-γ-related signatures in responders, whereas non-responders showed higher expression of WNT5A and CD276. An exploratory 10-gene classifier (“NeoSquamos”) demonstrated an AUC of 0.838 for recurrence-free survival prediction, though based on a limited number of events.Conclusions These findings provide an integrated view of tumor and systemic immune dynamics during perioperative programmed death 1 blockade in CSCC. Candidate biomarkers, including transcriptomic signatures and circulating cytokines, may help refine risk stratification, although prospective validation in larger cohorts is required.Trial registration number NCT04632433.
SN  - 2051-1426
ER  -