Cemiplimab Plus Imiquimod and Laser Therapy As Neoadjuvant Treatment In Cutaneous Basal Cell Carcinoma

Overview

Basal cutaneous cell carcinoma (BCC) is the most common skin cancer. Early-stage disease is managed with surgery or radiation that cure more than 95% of patients. Surgical excision is the treatment of choice and by far the most convenient and effective means of achieving cure of any invasive BCC, Surgery is rarely contra-indicated even in old, debilitated patients, but in locally advanced tumors surgery has the potential of having functional and cosmetic consequences, due to a big tumor size or difficult locations and it is not uncommon tumors that are borderline for the indication of curative surgery. Patients with high-risk disease who have large primary lesions are usually not amenable to a definitive cure with local intervention and may experience significant morbidity, disfigurement, or functional deficits. In some patients, the tumors recur and progress locally being radiotherapy and Hedgehog inhibition therapy available options. Recently, cemiplimab was the first immunotherapy approved by the FDA and EMEA for locally advanced BCC after Hedgehog pathway inhibition The imiquimod (1-(2-methylpropyl)-1-H-imidazole \[4,5-c\] quinolone-amine) is a synthetic compound capable of activating the cells of the immune system, helping to control viruses, tumors, and intracellular parasites The combination of imiquimod plus anti PD-1 antibody could be synergistic. The main hypoteis is that combining cemiplimab, an immune checkpoint inhibitor targeting PD-1, and local treatment with the Toll-like receptor 7 (TLR7) agonist imiquimod may increase immune response against tumor and result in an increase in the rate of definitive cure y in patients with basal cell carcinoma (BCC) who have a high risk of recurrence after surgery alone or a high risk of morbidity, disfigurement, or functional deficits: to increase the rate of definitive cure. The CEMIQUID study main aims to evaluate: 1. The safety and toxicity of the combination of intravenous cemiplimab plus topical imiquimod (plus fractional laser therapy) as neoadjuvant treatment in patients with high risk and potentially resectable BCC. 2. The antitumoral activity in terms of 3-years rate of relapse-free survival (RFS) according to RECIST 1.1 of intravenous cemiplimab as single therapy or in combination with topical imiquimod plus fractional laser therapy as neoadjuvant treatment in patients with high risk and potentially resectable BCC. Patients with high risk, potentially resectable basal cell carcinoma (BCC), enrolled in the Phase Ib part of the study will receive treatment with intravenous (iv) cemiplimab plus topical imiquimod plus fractional laser therapy as neoadjuvant treatment. Patients enrolled in the Phase II part will be randomized to receive neoadjuvant cemiplimab as a single agent or the Phase Ib combination with imiquimod and fractional laser therapy

1. RATIONALE Combining cemiplimab, an immune checkpoint inhibitor targeting PD-1, and local treatment with the Toll-like receptor 7 (TLR7) agonist imiquimod may increase immune response against tumor and result in an increase in the rate of definitive cure y in patients with basal cell carcinoma (BCC) who have a high risk of recurrence after surgery alone or a high risk of morbidity, disfigurement, or functional deficits: to increase the rate of definitive cure. 2. OBJECTIVE Combining cemiplimab, an immune checkpoint inhibitor targeting PD-1, and local treatment with the Toll-like receptor 7 (TLR7) agonist imiquimod may increase immune response against tumor and result in an increase in the rate of definitive cure y in patients with basal cell carcinoma (BCC) who have a high risk of recurrence after surgery alone or a high risk of morbidity, disfigurement, or functional deficits: to increase the rate of definitive cure. Primary objective: * The primary objective for the Phase Ib part of the trial is to evaluate the safety and toxicity of the combination of intravenous cemiplimab plus topical imiquimod (plus fractional laser therapy) as neoadjuvant treatment in patients with high risk and potentially resectable BCC. * The primary objective for the Phase II of the trial it to evaluate the antitumoral activity in terms of 3-years rate of relapse-free survival (RFS) according to RECIST 1.1 of intravenous cemiplimab as single therapy or in combination with topical imiquimod (plus fractional laser therapy) as neoadjuvant treatment in patients with high risk and potentially resectable BCC. Secondary objectives: * To evaluate pathological complete response rate (pCR) according to Immune-Related Pathologic Response Criteria' (irPRC) criteria. * To evaluate the activity in terms of response rate (RECIST 1.1), duration of response, clinical benefit, RFS/PFS and OS. * To evaluate the rate of resectability (downstaging) of BCC after 4 cycles of treatment. * To evaluate safety of the intended treatment regimen based on the frequency and severity of adverse events and Treatment-related adverse events (TRAEs) assessed by NCI CTCAE v5.0. * Translational research 3. PRIMARY TRIAL ENDPOINTS * Phase Ib: incidence of adverse events (AE) and treatment-related AEs (TRAEs) assessed by NCI CTCAE v5.0 * Phase II: RFS rate at 3 years, defined as the proportion of patients free of locoregional progression or recurrence, distant metastasis (RECIST v 1.1). 4. SECONDARY TRIAL ENDPOINTS * Pathologic complete response (pCR) * Objective response rate (ORR) * Clinical benefit rate (CBR) * Duration of clinical benefit (DBC) * Relapse-free survival (RFS) * Overall survival (OS) * Adverse events (AE) and treatment-related AEs (TRAEs) * Molecular alterations in biological samples 5. TRIAL DESIGN CEMIQUID is a multi-center, open-label, phase Ib/II, two-cohort study. The study is divided into two phases: Phase Ib: 6 patients will be included and the main objective will be to evaluate the safety and toxicity of the combination of intravenous cemiplimab plus topical imiquimod (plus fractional laser therapy) as neoadjuvant treatment in patients with high risk and potentially resectable BCC. Phase II: If the treatment is deemed feasible on Phase Ib, 12 additional patients will be included to evaluate the antitumoral activity. On treatment clinic visits will occur every 3 weeks ±3 days. Computed tomography (CT), digital photography and lymph node ultrasonography (if applicable) will be used at baseline, prior to the third dose of neoadjuvant cemiplimab and prior to surgery to assess tumor response. Long term follow up of tumor evolution after surgical intervention will adhere to local standard clinical practice. The trial includes the assessment of safety (AEs, comorbidities) throughout the study period at every visit, and an exploratory study to evaluate the prognostic value and correlation between clinical features or molecular alterations. 6. TRIAL POPULATION Patients with high risk, potentially resectable basal cell carcinoma (BCC). High risk is defined as any of the following: 1. at least 1 large lesion still resectable, but with increased risk for cosmetic disfigurement or functional defects by assessment of the enrolling physician. 2. Having basosquamous, infiltrative, sclerosing/morpheaform, micronodular, and BCC with carcinosarcomatous differentiation features. 3. Patients with large (≥ 3 cm in diameter in areas of intermedium risk of recurrence such as forehead, cheek, chin, neck, scalp or ≥ 5 cm for lesions in trunk/extremities) recurrent BCC. 4. Multicentric tumors that would require a cosmetic disfigurement or functional defects. 7. STUDY TREATMENT All patients enrolled in the Phase Ib part of the study will receive treatment with intravenous (iv) cemiplimab 350 mg every 3 weeks plus topical imiquimod 5% cream self-applied once daily 5 days per week, and ablative fractional CO2 laser 10.600nm (±10nm) at 1- or 3-week intervals, for a total of 4 neoadjuvant cycles (12 weeks). The study treatment may be discontinued prematurely in case of unacceptable toxic effects, or disease progression. Patients enrolled in the Phase II part will be randomized to receive neoadjuvant cemiplimab 350 mg every 3 weeks as a single agent or the Phase Ib combination with imiquimod and CO2 laser. 8. ETHICAL CONSIDERATION Cemiplimab is approved and might be considered the standard of care for patients with metastatic or locally advanced BCC who are not candidates for curative surgery. Imiquimod is a topical standard treatment for patients with BCC. Patients with high risk BCC require surgeries that may involve comorbidities or disfigurement. Combining both treatments may have a synergistic activity and induce tumor size reduction easing its resection. The neoadjuvant timings proposed will not substantially delay the surgical intervention. The use of 4 doses of cemiplimab in the neoadjuvant setting has been previously tested in 79 patients with CSCC and resulted in a feasible and safe therapy. The study is designed as Ib because doses recommended for cemiplimab and imiquimod are well justified by previous experience in clinical trials and use under marketed conditions. Given the different mechanisms of action and the type of administration, it is not expected to have overlapping toxicities that may require dose modifications of the initial recommended doses. Therefore, dose escalation is not required and the trial includes the dosing of one or more cohorts of patients at the recommended dose. The potential risks of cemiplimab and imiquimod are well known based on clinical trials and marketing experience. Most frequent AEs are immune-related and could be properly managed with adequate care. The protocol already includes safety measures to minimize the risks. Therefore, the potential benefits of cemiplimab and imiquimod as combined neoadjuvant treatmnt in patients with BCC outweigh the risks. The study will be conducted in accordance with the principles of the Helsinki Declaration Adopted by the 18th World Medical Assembly, Helsinki, Finland, June 1964 updated to its latest version Helsinki, Finland, October 2024. With the Good Clinical Practice (GCP) standards issued by the Working Party on Medicinal Product Efficacy of the European Economic Community (1990) (CPMP / ICH / 135/95).