Libtayo (cemiplimab-rwlc)

These monoclonal antibodies target immune checkpoints, including cytotoxic T-lymphocyte-associated protein 4 (ipilimumab and tremelimumab), programmed death 1 (nivolumab, pembrolizumab, cemiplimab, and dostarlimab), programmed death ligand 1 (atezolizumab, avelumab, and durvalumab), and lymphocyte activation gene 3 (relatlimab), and effectively augment the immune response against tumor cells. Despite clinical improvements with immunomodulatory therapy, with corticosteroids the mainstay of treatment, mortality remains high, particularly in those with associated myocarditis or respiratory failure requiring intubation, where mortality occurs in up to 50%. ICI withdrawal can lead to cancer progression and death, highlighting a need for improved approaches to ICI rechallenge, performed in limited patients with variable success to date.

P2, N=77, Terminated, Regeneron Pharmaceuticals | Active, not recruiting --> Terminated; Sponsor Decision related to study drug supply

P2, N=34, Recruiting, University of Southern California | Trial completion date: Jun 2025 --> Jun 2026 | Trial primary completion date: Jun 2024 --> Jun 2025

P1, N=50, Recruiting, Regeneron Pharmaceuticals | Trial completion date: Sep 2026 --> Jul 2025 | Trial primary completion date: Sep 2026 --> Jul 2025

Cemiplimab is a safe and effective therapy, particularly in elderly patients. Well-differentiated tumors with low proliferative index, intratumoral inflammatory infiltrate, and tumor necrosis may predict better clinical response.

Following initiation of standard chemotherapy agents, carboplatin and paclitaxel, the patient developed a diffuse, itchy rash over her abdomen, back, and bilateral upper and lower extremities. Biopsy of the rash revealed a diffuse non-resectable cutaneous squamous cell skin carcinoma (cSCC) in situ. Consequently, a PD1-inhibitor was added to her neoadjuvant chemotherapy regimen, which resulted in complete response to both metastatic ovarian and diffuse cSCC in situ at time of surgery.

P1, N=36, Recruiting, Grey Wolf Therapeutics Pty Ltd | Not yet recruiting --> Recruiting

P2, N=18, Completed, Radboud University Medical Center | Recruiting --> Completed | Trial completion date: Oct 2025 --> Oct 2024 | Trial primary completion date: Jul 2024 --> Oct 2024

P3, N=1535, Recruiting, Regeneron Pharmaceuticals | Trial completion date: Aug 2032 --> Jun 2031 | Trial primary completion date: Mar 2026 --> Jun 2025

P2, N=73, Recruiting, Regeneron Pharmaceuticals | Trial completion date: Feb 2031 --> Mar 2030

P2, N=77, Active, not recruiting, Alliance for Clinical Trials in Oncology | Recruiting --> Active, not recruiting

P2, N=126, Recruiting, Duke University | Not yet recruiting --> Recruiting

Immune checkpoint inhibitors (ICIs) have shown great success, with FDA-approved drugs like PD-1 inhibitors (Nivolumab, Pembrolizumab, Cemiplimab), PD-L1 inhibitors (Atezolizumab, Durvalumab, Avelumab), and CTLA-4 inhibitors (Ipilimumab, Tremelimumab), alongside LAG-3 inhibitor Relatlimab. This review aims to fill this gap by providing an analysis of the current clinical status of ICIs, emerging biomarkers, mechanisms of resistance, strategies to enhance therapeutic efficacy, and assessment of adverse effects. This review is crucial to furthering our understanding of ICIs and optimizing their application in cancer therapy.

P2, N=152, Not yet recruiting, Intergroupe Francophone de Cancerologie Thoracique

P2, N=40, Not yet recruiting, M.D. Anderson Cancer Center

A patient with metastatic cutaneous squamous cell carcinoma developed a severe hypersensitivity reaction to pembrolizumab and subsequently to cemiplimab, despite premedication.

P2/3, N=520, Recruiting, Regeneron Pharmaceuticals | Not yet recruiting --> Recruiting

P1, N=13, Active, not recruiting, H. Lee Moffitt Cancer Center and Research Institute | Trial completion date: Sep 2025 --> Dec 2025 | Trial primary completion date: Sep 2024 --> Dec 2024

P2, N=40, Recruiting, M.D. Anderson Cancer Center | Not yet recruiting --> Recruiting

Multiplexed immunofluorescence on 93 NSCLC samples identified higher intratumoral CD8+PD1+ T cells (p = 0.02) in tumors with PD-L1 TPS greater than or equal to 90% versus 50% to 89%. Pembrolizumab and cemiplimab were found to have long-term survival benefit and favorable genomic and immunophenotypic profile in patients with advanced NSCLC with PD-L1 TPS greater than or equal to 90% compared with TPS 50% to 89%.

P1, N=10, Active, not recruiting, University of Southern California | Recruiting --> Active, not recruiting | N=16 --> 10 | Trial completion date: Aug 2025 --> Aug 2026 | Trial primary completion date: Aug 2024 --> Aug 2025

P1, N=160, Recruiting, BioNTech SE | Trial completion date: Aug 2027 --> Nov 2028 | Trial primary completion date: Jan 2026 --> Apr 2027

P2, N=120, Recruiting, Regeneron Pharmaceuticals | Not yet recruiting --> Recruiting

P=N/A, N=500, Recruiting, Regeneron Pharmaceuticals | N=300 --> 500

P2, N=112, Not yet recruiting, Weill Medical College of Cornell University

P2/3, N=378, Not yet recruiting, SWOG Cancer Research Network

P1/2, N=61, Active, not recruiting, EMD Serono Research & Development Institute, Inc. | Recruiting --> Active, not recruiting | N=180 --> 61 | Trial completion date: Sep 2026 --> Mar 2025 | Trial primary completion date: Aug 2026 --> Jun 2024

P2, N=142, Recruiting, Genelux Corporation | Not yet recruiting --> Recruiting

While acknowledging limitations inherent to a small subgroup analysis, the HR of 0.86 observed in Japanese patients suggests an emerging survival benefit despite a 4.6-month shorter median duration of follow-up versus the overall study population.

P1/2, N=31, Recruiting, M.D. Anderson Cancer Center | Suspended --> Recruiting

P2, N=113, Completed, Regeneron Pharmaceuticals | Active, not recruiting --> Completed | Trial completion date: Oct 2024 --> May 2024

P1, N=40, Recruiting, Memorial Sloan Kettering Cancer Center | N=30 --> 40

P2, N=88, Recruiting, Memorial Sloan Kettering Cancer Center

P3, N=415, Active, not recruiting, Regeneron Pharmaceuticals | Recruiting --> Active, not recruiting | Trial primary completion date: May 2026 --> Nov 2026

AI-powered spatial analysis suggests that combination therapy with Pexa-vec and cemiplimab enhances the immune response, evidenced by increased TIL densities in the tumor microenvironment.Table 1: Changes in TIL Densities from Pre- to Post-TreatmentMeasureCohortPre-Treatment (mm²)(Median, IQR)Post-Treatment (mm²)(Median, IQR)p-value isTILOverall (n = 18)87.53 (179.37-114.65)214.02 (257.50-389.74)0.0040 Arm A (n = 9)41.30 (257.13-81.61)190.17 (830.30-389.34)0.0078 Arm B (n = 9)165.43 (180.52-147.69)390.17 (340.11-387.14)0.1641iTILOverall (n = 18)88.89 (129.08-116.99)161.11 (376.62-321.79)0.0237 Arm A (n = 9)56.42 (125.56-101.70)157.44 (421.03-469.55)0.0273 Arm B (n = 9)96.27 (57.33-132.29)154.92 (194.87-184.03)0.3716sTILOverall (n = 18)100.91 (291.38-193.61)219.37 (370.85-466.27)0.0599 Arm A (n = 9)35.59 (257.13-67.38)140.55 (286.46-157.15)0.0391 Arm B (n = 9)303.37 (171.24-319.84)353.58 (189.15-735.39)0.4961

The rapidly expanding class of therapies targeting immune checkpoints for the treatment of various cancers now includes 8 clinically approved agents: a lymphocyte-activation gene 3 (LAG-3) inhibitor (relatlimab), a cytotoxic T lymphocyte associated protein 4 (CTLA-4) inhibitor (ipilimumab), three programmed cell death protein 1 (PD-1) inhibitors (nivolumab, pembrolizumab and cemiplimab), and three programmed cell death ligand-1 (PD-L1) inhibitors (atezolizumab, durvalumab, and avelumab). Previously, we reviewed the mechanisms of immune-related adverse events (irAEs), strategies for management of irAEs, and highlighted similarities as well as differences amongst clinical guidelines from the National Comprehensive Cancer Network (NCCN), American Society of Clinical Oncology (ASCO), Society for Immunotherapy of Cancer (SITC), and European Society for Medical Oncology (ESMO). Herein, we provide an update that includes discussion of changes to these clinical guidelines since our last review, the new LAG-3 targeted agents, emerging patterns of irAEs, and new directions for improved monitoring and treatment of irAEs that could incorporate interdisciplinary pharmacist-led teams, artificial intelligence, and pharmacogenomics.

P3, N=369, Not yet recruiting, Regeneron Pharmaceuticals

P1/2, N=31, Suspended, M.D. Anderson Cancer Center | Initiation date: Nov 2024 --> Aug 2024 | Not yet recruiting --> Suspended

However, targeted therapies such as sonidegib and vismodegib - sonic hedgehog pathway inhibitors - have emerged that have been approved for treating BCC, as have anti-PD1 immunotherapies, such as cemiplimab, with their success likely based on the high tumor mutational burden seen in some of these tumors. Epidermal growth factor receptor (EGFR) inhibitors also serve a role in treating this condition as well. Molecular studies on metastatic/advanced BCC and other rare malignancies may inform treatment therapeutic decisions.

Cemiplimab confirmed efficacy and safety data in real-life cSCC patients. Overexpression of CCL-20 and CXCL-8 could represent biomarkers of lack of response to immunotherapy.

P2, N=27, Not yet recruiting, Melanoma and Skin Cancer Trials Limited | Trial completion date: Nov 2027 --> Dec 2028 | Initiation date: Aug 2024 --> Dec 2024

P1, N=22, Active, not recruiting, H. Lee Moffitt Cancer Center and Research Institute | Recruiting --> Active, not recruiting | N=32 --> 22