Since the FDA approval of cemiplimab in 2018, systemic therapies for the treatment of advanced or metastatic CSCC have gained prominence.
Cutaneous squamous cell carcinoma (CSCC) is the second most common keratinocyte carcinoma. It has historically comprised 20% of skin cancers, but data suggest that its incidence may be increasing as the population ages.1-3 Most commonly, CSCC presents as a scaly, erythematous area or as a lifted plaque, but it can have ulcerative, papulonodular, or exophytic features in its invasive form.4 The low- or high-risk status associated with a CSCC lesion is determined by staging the disease.1 Additional risk factors include tumor location, size, a history of immunosuppression, lymph node involvement, and being the site of previous radiotherapy (RT).3 CSCCs that are considered high risk for metastasizing or becoming advanced are often larger than 2 cm in diameter or exhibit deep invasiveness (ie, > 2 mm thick or invading the deep reticular dermis or subcutaneous fat), including invasion of angiolymphatic or perineural tissue.3,4
Surgical procedures, such as Mohs micrographic surgery, are the favored surgical option for high-risk disease, while RT is also a potential option due to patient preference, cosmesis, or function preservation.3 With complete resection of regional disease, adjuvant therapy is not suggested unless it is within the scope of a clinical trial; however, for patients with complete resection of extracapsular extension (ECE) or other high-risk regional disease, RT should be considered with or without systemic therapy. With partial disease resection or inoperable disease, RT can be combined with chemotherapy (ie, cisplatin, cisplatin with 5-fluorouracil, or carboplatin) or with an epidermal growth factor receptor (EGFR) inhibitor (ie, cetuximab).
For certain patients in whom surgical or RT options are not feasible, targeted systemic therapies, such as the programmed cell death protein 1 (PD-1) inhibitor, cemiplimab— approved in 2018—offer a nonsurgical treatment alternative.3,5,6 As of 2020, cemiplimab represents the standard-of-care first-line therapy for patients with advanced, unresectable CSCC that is not amenable to surgery or definitive RT. Pembrolizumab is also a recommended treatment for regionally recurrent or distant metastatic CSCC.3
Since the FDA approval of cemiplimab in 2018, systemic therapies for the treatment of advanced or metastatic CSCC have gained prominence. At the 2020 American Society of Clinical Oncology (ASCO) Virtual Scientific Program (VSP), new data were presented that highlight potential new utilization avenues for systemic therapies, such as cemiplimab and other potential targeted systemic agents. This article reviews recently presented and/or published data related to emerging possibilities for the systemic treatment of advanced or metastatic CSCC.
New Possibilities for the Utilization of Cemiplimab
EMPOWER Follow-Up Studies
The approval of cemiplimab was based on results from the EMPOWER-CSCC-1 trials.7,8 In the phase 1 cohort of EMPOWER-CSCC-1, enrolled patients had locally advanced or metastatic CSCC determined to be nonresectable (by a history of disease recurrence after 2 or more surgeries, anticipated surgical complications, or potential deformity). The phase 2 cohort expanded the patient parameters to include patients with regional or distantly metastasized disease (or both) in addition to patients with locally advanced disease. Patients were administered cemiplimab 3 mg/kg intravenously (IV) every 2 weeks for up to 48 weeks in phase 1 and for up to 96 weeks in phase 2 until disease progression or intolerable toxicity.7 The reported response rate was 50% in the expansion cohort (n = 26), with a response rate of 47% in the metastatic disease cohort (n = 59). Among those who responded in the metastatic disease group, 57% had a duration of response (DOR) of 6 months or longer, with 82% showing continued response (and continuing treatment) at the point of data cutoff.7 Adverse events (AEs) occurred in 15% or more of the metastatic disease group, with a 7% rate of treatment discontinuance due to serious adverse events (SAEs).7
Three-year follow-up data from EMPOWER-CSCC-1 were presented at this year’s ASCO VSP. With a median follow-up of 15.7 months, findings showed a 46.1% overall response rate (ORR) and a complete response (CR) of 16.1% of patients, 89 of whom reached CR within a median of 11.2 months. DOR and overall survival (OS) were unreached at the reporting time.9
In addition to the 3-year follow-up data, a recently published analysis from phase 2 of the EMPOWER study evaluated fixed cemiplimab-rwlc dosing and included a long-term analysis of weight-based cemiplimab-rwlc dosing.10 In this open-label, nonrandomized, multicenter, international study, the weight-based group (referred to as Group 1, n = 59) were administered cemiplimab-rwlc at 3 mg/kg IV every 2 weeks for up to 96 weeks, whereas Group 3 (n = 56) received cemiplimab-rwlc at a fixed dose of 350 mg IV every 3 weeks for up to 54 weeks (with the option to continue to 96 weeks). The primary end point for either group in this study was overall response rate (ORR), with secondary end points including DOR, progression-free survival (PFS), quality of life (QOL), CR, OS, and safety. The median age of patients in both groups was 71 years; eligible patients had histological exam-confirmed diagnoses of invasive CSCC, along with an ECOG performance status score of 0 or 1, acceptable organ function, and a tumor lesion(s) measurable according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1).10 Patients were excluded if they had a history of immunosuppression due to an autoimmune disease within the past 5 years, PD-1/PD-L1 inhibitor treatment, solid organ transplantation, or other (eg, hematologic) cancers. For Group 1, the median follow-up was 16.5 months, with a median of 31.0 cemiplimab-rwlc doses received; for Group 3, it was 8.1 months with a median of 11.5 doses.10
The ORR per independent central review (ICR) for the Group 1 update was 49.2% (95% CI, 35.9%-62.5%) and the primary analysis ORR per ICR for Group 3 was 41.1% (95% CI, 28.1%-55.0%). The combined ORR for the 2 groups was 45.2% (95% CI, 35.9%-54.8%). While a median DOR had not been reached in either group at the time of data cutoff, for those responding in Group 1, the Kaplan-Meier estimated DOR per ICR was 88.9% at 12 months (95% CI, 69.3%- 96.3%) and it was 95.0% at 8 months for Group 3 (95% CI, 69.5%-99.3%). Median PFS and OS were also unreached for both groups. The median time to response per ICR for Group 1 was 1.9 months, 2.1 months for Group 3, and 2.1 months for the combined groups. Investigators observed decreases in lesion diameters in the patients deemed “most evaluable” per ICR; in both groups, the majority of these decreases in size were detected at the point of the first response assessment.10
Regarding safety, a treatment-emergent AE of any grade was experienced by 98.3% of patients in both groups, with 100% of Group 1 and 96.4% of Group 3 experiencing an any-grade AE. AEs caused 10.2% of the Group 1 patients and 5.4% of the Group 3 patients to discontinue treatment. The AEs most commonly reported for both groups were fatigue (27.0%), diarrhea (23.5%), and nausea (20.9%). For the combined groups, AEs of grade 3 or higher were reported at a rate of 45.2% and treatment-related AEs (TRAEs) were reported in 71.3% of the patients. One reported death (in Group 3) was not considered treatment-related.10
The Impact of Cemiplimab on Quality of Life
Other study findings related to the use of cemiplimab in advanced or metastatic CSCC evaluated its benefits beyond clinical trial parameters and settings. For instance, one of the presented studies was a post-hoc analysis of the phase 2 EMPOWER-CSCC-1 trial to evaluate patientreported health-related QOL (HRQOL). This analysis used the European Organization for the Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30) to evaluate patient HRQOL from baseline to cycle 5 (C5) of treatment.11 Trial patients (N = 193) had invasive disease, 1 or more lesions, and an ECOG performance status of 0 or 1 and were treated with cemiplimab-rwlc 3 mg/kg IV every 2 weeks or with 350 mg IV every 3 weeks. Results demonstrated a clinically meaningful pain score improvement from baseline to C5, with improvement or stable trends detected in the other questionnaire domains. Additionally, the majority of the patients showed stability or clinical improvement across crucial questionnaire areas. Similar symptom patterns were reported across each patient, including nausea/vomiting, diarrhea, constipation, loss of appetite, and dyspnea.11
Cemiplimab as First-Line Therapy
Findings were also presented from a retrospective study evaluating cemiplimab-rwlc as a first-line therapy in locally advanced CSCC, in which investigators sought to ascertain the need for local intervention. The study included patients from a single institution who had undergone more than 1 excision and/or repair or who had nodal or regional disease. The response of patients with radiologically measurable disease was assessed according to RECIST criteria, but in the absence of measurable disease, the treating physician evaluated patient response. The selected patients had received 2 or more cemiplimab-rwlc doses within a 2-year time frame. Results indicated that 61% (n = 36) of the patients were able to avoid surgical or RT local intervention. The treatment also demonstrated an ORR of 69%. The median treatment duration was 6 months, with a median of 6 doses administered. AEs were reported for 31% of the patients, the most common of which was dermatitis. At the time of the presentation, 31% of the patients were continuing on cemiplimab-rwlc, and a phase 2 study of cemiplimab-rwlc in the neoadjuvant setting is planned.12
Adjuvant Cemiplimab in High- Risk CSCC
Investigators of a currently-recruiting study shared the design for a double-blind, multicenter, phase 3 trial of cemiplimab-rwlc in the adjuvant setting for high-risk CSCC patients following surgery and RT.13 Eligible patients will have at least 1 feature of high-risk disease criteria, which include node involvement and ECE, in-transit metastasis, perineural invasion, T4 lesion, and recurrent disease with an additional risk factor.13 Part 1 of the study will randomize patients (N = 412) from 100 sites, 1:1, to placebo or cemiplimab-rwlc at 350 mg IV every 3 weeks for up to 48 weeks. In part 2, which will be unblinded, patients from either group who experience disease recurrence after 3 or more months post-treatment may elect (open label) cemiplimab-rwlc treatment for up to 96 weeks.13 The study’s primary end point will be disease-free survival; secondary end points will include OS and freedom from locoregional and distant relapse.
Other Emerging Approaches to Advanced CSCC
In addition to various cemiplimab-related findings presented at the 2020 ASCO VSP, the program also showcased new data from rising novel therapeutics. One of these presentations involved the immune checkpoint inhibitor (ICI), nivolumab, which was investigated as a first-line therapy in locally advanced or metastatic CSCC in an open-label phase 2 study.14 In the study, patients (N = 24) with locally advanced, locoregional, and nodal or metastatic CSCC were administered nivolumab 3 mg/kg IV every 2 weeks until intolerable toxicity, disease progression, or 12 months of treatment were completed.14 The study’s primary end point was the best objective response rate (bORR) using RECIST criteria at 24 weeks; the secondary end points were safety/ tolerability, PFS, and OS.14 At the time of data cutoff, 62.5% of the patients were continuing treatment, with 3 patients having completed 12 months of treatment (with subsequent surveillance) and 6 patients having either died or progressed while on treatment. The bORR was 54.5%, with 77.0% of 22 evaluable patients having disease control. The DOR, OS, and PFS had not been reached at the time of the presentation, and 21.0% of the patients experienced a grade 3 or greater TRAE, with 1 patient discontinuing the treatment due to intolerable toxicity.14
Another targeted agent, the toll-like receptor 9 (TLR9) agonist, cavrotolimod (AST-008), is currently under investigation, with previously reported data suggesting its activation of immune cells and cytokine response.15,16 The ongoing, open-label, multicenter, phase 1b/2 doseexpansion trial design will compare treatments in cohorts of patients with advanced or metastatic Merkel cell carcinoma (MCC) or CSCC. The phase 2 study will compare cavrotolimod plus flat-dose pembrolizumab with cavrotolimod plus cemiplimab-rwlc in patients whose disease progressed on ICI monotherapy. The primary end point is the efficacy of cavrotolimod with either pembrolizumab or cemiplimab-rwlc, and secondary end points include safety and pharmacokinetic and pharmacodynamic evaluation.16
Beyond the 2020 ASCO VSP, published results in advanced CSCC demonstrate potential for other novel immunotherapies. Because CSCCs highly express EGFR, EGFR inhibitors have gained attention for their potential in CSCC treatment.6 One such agent, cetuximab, has been investigated as a monotherapy in the treatment of advanced CSCC.17 A retrospective study of cetuximab included patients (N = 58) with advanced disease and varied treatment histories; 36.2% were treatment-naïve, more than 90.0% were chemotherapy-naïve, and 5.2% had only undergone RT.17 The patients’ median age was 83.2 years, and the most common CSCC primary tumor locations were head and neck (60.3%), extremity (27.6%), and trunk (12.1%). There was a history of immunosuppression among 32.8% of the patients (more than 6 months of steroid use in 7 patients; organ transplant in 2; other solid malignancy in 1; heart, lung, or kidney failure in 7; and chronic lymphocytic leukemia or myeloid leukemia in 2). The primary end point was disease control rate (DCR) as defined by RECIST at 6 weeks, with secondary end points including 12-week DCR, 6- and 12-week objective response rate, PFS, OS, and safety.17
Of the 58 patients, 55 reached the primary end point calculation at week 6, and 50 reached the secondary, 12-week end point; the median follow-up was 11.7 months. The 6-week DCR was 87.0% (95% CI, 75.5%-94.7%) and the 12-week DCR was 70.0% (95% CI, 55.4%-82.1%). A CR was achieved by 5.5% of the patients, with 47.2% achieving a partial response (PR); in 34.6%, disease remained stable, and 12.7% had disease progression. At 6 weeks, ORR was 52.7% and at 12 weeks, 42.0%. Toxicity was experienced by 88.0% of the patients (most AEs reflecting those previously reported with cetuximab), with cutaneous AEs (ie, folliculitis) reported most frequently. SAEs affected 16.0% of the patients. One patient discontinued treatment due to a hypersensitivity response, and no deaths were reported in association with the treatment.17
Cetuximab has also been studied in combination with RT, albeit on a significantly smaller scale, for the treatment of locally advanced CSCC.18 In a single-center, 2-year study of patients with locally advanced, nonresectable CSCC, 8 patients were treated with cetuximab 400 mg/m2 as a loading dose prior to RT and then received weekly cetuximab at 250 mg/m2 through the end of the course of RT. RT was dosed at 6600 cGy/30 fr (n = 2), 6300 cGy/30fr (n = 2), and 5500 cGy/22 fr (n = 4). Included patients had a median age of 81 years and an ECOG performance status between 0 and 2; patients were excluded if they had received RT previously in the planned RT field. Metastatic disease was ruled out prior to treatment via computed tomography (CT) and positron emission tomography (PET) scans. The primary end point was PET-defined CR. Kaplan-Meier estimated OS, PFS, and disease-specific survival were also measured. Six patients experienced CR, and 2 patients had PR. At the time of reporting, and with a median follow-up of 25 months, a CR persisted in 5 patients, with 1 patient having PR after recurrence; that patient is now being given palliative systemic treatment. The majority of the AEs were grade 1 to 2, with 7 grade 3 AEs reported relating to cutaneous reactions or fatigue. The 2-year PFS rate was 83.3%, the cause-specific survival was 87.5%, and OS was 87.5%. Two non–treatment-related deaths occurred during the follow-up period. The first death was in a patient who had disease progression at 4 months and died following ineffective, short-term palliative chemotherapy, and the other death was attributable to complications in a patient who had maintained a CR 31 months post-treatment.18
Another EGFR inhibitor, panitumumab, with a demonstrated EGFR binding specificity, has been investigated as a therapy for patients with advanced CSCC.19,20 In a 2019 retrospective single-center study of patients with nonresectable CSCC (and with histological exam-confirmed CSCC), panitumumab monotherapy was compared with panitumumab combined with RT. The primary end point was best ORR per RECIST criteria; secondary end points included PFS, OS, and 6-week and 6-month DCR and ORR. Patients (N = 25) had a median age of 86 years, and 68% had a World Health Organization performance status of 2 or more. Locally advanced tumors were reported in 64% of the patients, regional lymph node extension in 32%, and distant lung metastasis in 1 patient. Patients were included with or without prior treatment: 9 patients had undergone surgical excision (with subsequent relapse in 7 of those patients), 1 patient had platinum-based chemotherapy, and 16 had tumors assessed as indicating systemic therapy.19
Panitumumab was administered 6 mg/kg IV every 2 weeks for a median of 8 doses and a median 96 days of exposure. Radiation therapy was administered concurrently to 15 of the patients (at < 40 Gy for 10 patients and > 40 Gy for 5 patients, with 1 patient receiving a dose of 70 Gy). The RT was continued 3 months after panitumumab treatment cessation for 2 patients, who had residual tumors. The best ORR was 52%, with a 16% CR rate, and 9 patients showed a PR. All patients experienced CR, and 5 of the 9 patients with PR were given both interventions. At the 6-week and 6-month time points, ORRs were, respectively, 12% and 28%. The median PFS was 6.9 months, and median OS was 10.5 months. In their discussion, the authors noted that the dose of RT was low. They also suggested that the combination of panitumumab and RT synergistically affected response.19
Other EGFR inhibitors, such as gefitinib, erlotinib, and lapatinib, have been studied in different CSCC settings over the past several years with mixed results. Findings have generally shown that the EGFR inhibitors were less effective than chemotherapy in terms of response rates, although AEs associated with EGFR were more tolerable than those of platinum-based chemotherapy.6,20
The trials highlighted in this article suggest a promising future for emerging therapies for advanced and metastatic CSCC in the first-line and adjuvant treatment settings. In addition to recent results of cemiplimab-rwlc use in CSCC continuing to generate and encourage longer-term data at the 2020 ASCO VSP, data for nivolumab use and the trial design for cavrotolimod, the emerging therapeutic, signal the potential for additions to future standards in advanced and metastatic CSCC management. With these and other new data emerging, the expansion of immunotherapy use into adjuvant and neoadjuvant settings could provide physicians with the ability to individualize treatment selection for patients and thereby improve patient outcomes.