Phase II Trial Reports High Response Rates With Neoadjuvant Cemiplimab in Cutaneous Squamous Cell Carcinoma

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In an international, multicenter phase II clinical trial, almost two-thirds of patients with stage II to IV cutaneous squamous cell carcinoma had tumors nearly or completely eradicated by neoadjuvant treatment with cemiplimab-rwlc, an agent targeting PD-1. The results were presented at the European Society for Medical Oncology (ESMO) Congress 2022 by Neil D. Gross, MD, Professor of Head and Neck Surgery at The University of Texas MD Anderson Cancer Center, Houston.1

In the study of 79 patients, by independent central pathology review, 63.3% had either a pathologic complete response (50.6%), indicating 0% viable tumor cells remaining, or a major pathologic response (12.7%), with up to 10% viable tumor cells. This met the study’s primary endpoint, and function-preserving surgery was enabled in some cases, Dr. Gross reported.

“These results represent one of the highest response rates to neoadjuvant anti–PD-1 monotherapy in any solid cancer so far and likely are the start of a practice change for how we treat advanced resectable cutaneous squamous cell carcinoma.”

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“These results represent one of the highest response rates to neoadjuvant anti–PD-1 monotherapy in any solid cancer so far and likely are the start of a practice change for how we treat advanced resectable cutaneous squamous cell carcinoma,” Dr. Gross said. The findings were simultaneously published in The New England Journal of Medicine.2

Dr. Gross said that at his institution, in multidisciplinary conferences for such patients, the neoadjuvant use of cemiplimab has become part of the conversation. “It has such a dramatic effect on their outcomes,” he commented.

Need for Treatment

Many individuals with cutaneous squamous cell carcinoma are easily treated, but in rare instances, tumors grow and spread, requiring aggressive surgery and adjuvant radiation therapy. “I’m a head and neck surgeon. I have treated many such patients and have witnessed the cumulative destructive effects of these treatments and the impact on quality of life,” Dr. Gross said.

Cemiplimab is approved for advanced cutaneous squamous cell carcinoma not amenable to curative surgery or radiotherapy; in this setting, it has produced response rates of up to 50% and durable disease control. In the curative setting, however, there are no approved systemic therapies. “Seeing many of these patients in my clinical practice, I designed this trial to bring cemiplimab to earlier-stage disease,” he explained.


  • An international phase II trial evaluated the anti–PD-1 agent cemiplimab-rwlc in stage II–IV cutaneous squamous cell carcinoma.
  • Cemiplimab was given in the neoadjuvant setting to patients intended for curative resection.
  • Complete or major pathologic responses were observed in 63.3% of patients.
  • This treatment may spare many patients the need for disfiguring surgery and radiation therapy.

In a pilot study of 20 patients with resectable stage III or IV disease conducted at MD Anderson, 55% of patients achieved a pathologic complete response after two doses of neoadjuvant cemiplimab.3 About 3 years later, the responses appeared to be durable. The high pathologic response rate in that study prompted the current international, multicenter trial to confirm the drug’s efficacy, this time including patients with stage II disease.

About the Phase II Study

The single-arm study enrolled 79 patients in the United States, Australia, and Europe with operable stage II to IV cutaneous squamous cell carcinoma. Median patient age was 73 years, 84.8% were male, and 94% had stage III or IV tumors. Patients received up to four doses of neoadjuvant cemiplimab followed by curative-intent surgery, with optional adjuvant radiation therapy.

Of the 79 patients, 62 received all four doses and 70 underwent surgery. Of the nine patients who did not have surgery, three declined because their cancer responded to the immunotherapy, two were lost to follow-up or were noncompliant, two developed progressive disease (both had aggressive or bulky tumors are baseline), and two experienced adverse events. At a median follow-up of 9.7 months, there have been no recurrences, he reported.

Dr. Gross’ presentation focused on the neoadjuvant portion of the study. The findings beyond pathologic and radiologic assessment will be reported later.

Key Findings and Toxicity

“Radiologic imaging underestimated the pathologic response,” he noted. Although 63.3% of patients had a complete or major pathologic response on pathologic assessment, 62.0% were partial responses, and 6.3% were complete responses on imaging assessment. The imaging response assessments, therefore, were not parallel to pathologic response in most cases, with these exceptions: the five patients with complete radiologic responses also had pathologic responses (complete or major), and the five who had progressive disease also lacked a pathologic response. “Interestingly, we saw that 16 patients had stable disease by radiologic response assessment, and of them, nearly half—44%—still had a pathologic complete or major response,” said Dr. Gross.

The use of cemiplimab spared many patients a grueling course of multimodality treatment. “For example, one patient presented with an aggressive tumor involving her forehead, including the upper eyelid. She was planned for aggressive surgical resection, including orbital exenteration, extensive reconstruction, and postoperative adjuvant radiation therapy. This patient went on trial and had a partial response on imaging, which was typical for the study, and a complete pathologic response at the time of resection and was spared the orbit,” he said.

Tumor mutational burden and PD-L1 expression were only slightly associated with tumor response, Dr. Gross stated. “These findings suggest these biomarkers alone may be insufficient for segregating patients for treatment.”

Overall, 14 patients (17.7%) experienced grade ≥ 3 adverse events. The most common events of any grade were fatigue (30.4%), rash (13.9%), diarrhea (13.9%), and nausea (13.9%). One death, from exacerbation of cardiac failure, was considered related to treatment. There were no new safety signals for the anti–PD-1 immunotherapy. 


DISCLOSURE: Dr. Gross has received advisory board and consulting fees from Sanofi, PDS Biotechnology, Shattuck Labs, Dragonfly Therapeutics, and Genzyme.


1. Gross ND, Miller DM, Khushalani N, et al: Neoadjuvant cemiplimab in patients with stage II–IV (M0) cutaneous squamous cell carcinoma: Primary analysis of a phase II study. ESMO Congress 2022. Abstract 789O. Presented September 12, 2022.

2. Gross ND, Miller DM, Khushalani NI, et al: Neoadjuvant cemiplimab for stage II to IV cutaneous squamous-cell carcinoma. N Engl J Med. September 12, 2022 (early release online).

3. Ferrarotto R, Amit M, Nagarajan P, et al: Pilot phase II trial of neoadjuvant immunotherapy in locoregionally advanced, resectable cutaneous squamous cell carcinoma of the head and neck. Clin Cancer Res 27:4557-4565, 2021.

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