Neoadjuvant-Intent Immunotherapy in Advanced, Resectable Cutaneous Squamous Cell Carcinoma

Abstract

Importance: In clinical trials, preoperative immune checkpoint inhibitors (ICIs) have shown clinical activity in advanced cutaneous squamous cell carcinoma (cSCC). However, these studies excluded patients with relevant comorbidities.

Objective: To evaluate radiologic and pathologic response rates to neoadjuvant-intent programed cell death protein 1 (PD-1) ICIs in a clinical population.

Design, setting, and participants: This cohort study of patients who were treated with neoadjuvant cemiplimab or pembrolizumab for advanced cSCC from January 2018 to January 2023 was conducted at 2 academic institutions in Boston, Massachusetts. Median follow-up was 9.5 months (range, 1.2-40.5).

Exposures: Cemiplimab or pembrolizumab.

Main outcomes and measures: Primary outcomes were radiologic and pathologic response rates. Secondary outcomes were 1-year recurrence-free survival, progression-free survival, disease-specific survival, and overall survival.

Results: This cohort study included 27 patients (including 9 patients [33.3%] with a history of lymphoma). Most patients were male (18 of 27 [66.7%]), with a median age of 72 years (range, 53-87 years). Most primary tumors were located on the head/neck (21 of 27 [77.8%]). There were no unexpected delays in surgery. The median number of doses before surgery was 3.5 (range, 1.0-10.0). Five patients (18.5%) ultimately declined to undergo planned surgery due to clinical responses or stability, and 1 (3.7%) did not undergo surgery due to progressive disease. The overall pathologic response rate (pathological complete response [pCR] or major pathological response) was 47.4% (9 of 19), and the overall radiologic response rate (radiologic complete response or partial response) was 50.0% (8 of 16). The pCR rate (7 of 19 [36.8%]) was higher than the radiologic complete response rate (2 of 16 [12.5%]). The pCR rate among patients with cSCC and concomitant lymphoma was 25.0%. The 1-year recurrence-free survival rate was 90.9% (95% CI, 50.8%-98.7%), progression-free survival was 83.3% (95% CI, 27.3%-97.5%), disease-specific survival was 91.7% (95% CI, 53.9%-98.8%), and overall survival was 84.6% (95% CI, 51.2%-95.9%).

Conclusions and relevance: The results of this cohort study support the reproducibility of neoadjuvant-intent immunotherapy for cSCC in the clinical setting, including for patients with a history of lymphoma. Outside of clinical trials, it is not infrequent for patients to opt out of surgery for regressing tumors. The inclusion of higher-risk patients and preference for nonsurgical treatment are 2 factors that might explain the numerically lower pathologic response rate in this institutional experience.

Figure 1.. Consort Diagram of the Patient Selection Process at 2 Academic Institutions

Of 291 patients treated with an anti–programmed cell death 1 (PD-1) immune checkpoint inhibitor (ICI) for cutaneous squamous cell carcinoma (cSCC), 27 (9.3%) were ultimately included, 16 (59.3%) of whom were evaluable for radiologic response and 19 (70.4%) of whom were evaluable for pathologic response.

Figure 2.. Pathologic and Radiologic Responses in 27 Patients Who Received Neoadjuvant Cemiplimab or Pembrolizumab for Advanced but Resectable Cutaneous Squamous Cell Carcinoma

The blue dashed lines indicate pathology-based criteria for complete response (pCR; 100% nonviable tumor), major pathologic response (MPR; ≥90% but <100% nonviable tumor), pathologic partial response (pPR; ≥50% but ≤90% nonviable tumor), and pathologic nonresponse (pNR; <50% nonviable tumor). The black dashed lines indicate imaging-based criteria for radiologic complete response (rCR; 100% decrease in the sum of target-lesion diameters), partial response (rPR; ≥30% decrease in the sum of target-lesion diameters), stable disease (rSD; neither rPR nor rPD), or progressive disease (rPD; ≥20% increase in the sum of target-lesion diameters) per RECIST, version 1.1. ^aPatients who declined planned surgery due to clinical response or stability. ^bOne patient who had progressive disease precluding surgery. ^c0% Nonviable tumor (pNR) on pathologic evaluation.

Figure 3.. Clinical Courses for 27 Patients Who Received Neoadjuvant Cemiplimab or Pembrolizumab for Locoregionally Advanced but Resectable Cutaneous Squamous Cell Carcinoma

MPR indicates major pathologic response; pCR, pathologic complete response; pNR, pathologic nonresponse; RT, radiotherapy. ^aPatients who declined planned surgery due to clinical response or stability. ^bOne patient who had progressive disease precluding surgery. The dotted line separates patients who did not undergo surgery (below line) from patients who did undergo surgery (above line).