By Monique Biryiana
Sponsored by Regeneron and Sanofi.
Dr Schadendorf provides an overview of the evolving treatment paradigm for advanced cutaneous squamous cell carcinoma (CSCC) and discusses the data supporting use of the immunotherapy cemiplimab▼ (Libtayo®), a PD-1 checkpoint inhibitor. Of note, advanced CSCC is a comprehensive term that encompasses both metastatic CSCC and locally advanced CSCC.
In the UK and the EU, cemiplimab is the only approved systemic therapy for adult patients with metastatic or locally advanced CSCC who are not candidates for curative surgery or curative radiation.
Accompanying this article is a photo gallery of patient experiences following cemiplimab treatment. These patients were treated with cemiplimab as part of a Phase 2 clinical trial, and patient responses to treatment may vary.1,2
This article was written by the author, however, Sanofi and Regeneron had editorial control over the content.
Q: How often do you see advanced cutaneous squamous cell carcinoma (CSCC) in your practice?
In a dermatological practice, CSCC is seen on a daily basis. Most CSCC cases are easy to detect and treat, and treatment is usually surgery and/or radiation therapy.3 However, advanced CSCC is rarer, and we see this in our centres perhaps twice or three times a week.
Q: In your experience, do your patients understand that CSCC can progress to an advanced stage?
Patients may not initially understand that CSCC can become locally advanced or metastasize. However, they usually become aware if and when the disease progresses to advanced stages. As physicians, it’s important that we educate our patients on the factors that put them at greater risk for developing advanced CSCC.
One of these factors is the location of the CSCC tumour, such as the face, hands, and feet, along with the size and thickness of the lesion.4 In addition, these patients may have comorbidities which make them more susceptible to developing advanced CSCC or a history of unsuccessful primary treatments – usually surgery, often in combination with radiation.3,5,6
Relapses of CSCC are common in the head and neck, as tumours in this region are more difficult to operate and perform radiation therapy on.3
Q: How do you define locally advanced disease?
There is no strict definition for locally advanced disease. However, there is a clinical understanding that would characterise this stage as CSCC without metastasis, which has grown deeply in the local area and/or has invaded underlying structures such as subcutaneous fat, nerves, cartilage, bone, and vessels. Regardless, this stage is characterised by the destruction of local tissue.7
Q: Why is it important to correctly diagnose locally advanced disease?
Locally advanced disease is difficult to treat and cure. Approximately 80% of locally advanced CSCCs are localised in the head and neck area, so larger operations or surgical procedures may lead to mutilation, disfigurement, and possibly disablement, depending on the exact location of the carcinoma and the therapeutic approach chosen.3,4,8
One should also keep in mind that patients with CSCC are often aged 65 and above. Therefore, these patients may have limited capacity to endure any difficult or extensive surgical procedures or radiation treatment.4,5
In my opinion, this is why there is such a high medical need for treatment methods in situations where surgery or radiation will not be curative.
Q: How do you determine if a patient is at high risk for developing advanced CSCC?
There is no universal agreement, nor algorithm, to define a high-risk patient. But I think most of the experts will agree that high-risk CSCC is defined by a certain thickness measured in millimetres, where the tumour has grown deeper into the skin and is histologically less differentiated. Perineural or vessel invasion is a characteristic of locally advanced disease that may put the patient at higher risk for metastasis. The presence or absence of these types of invasions should be included in the patient’s histological report.3,6,7
In addition, other clinical factors that are associated with high-risk disease include specific tumour locations – such as the ears – or at other anatomic locations where older scars are present: for example, after prior radiation therapy, chronic inflammation, wound or accident-associated scars. Chronic alterations and inflammation over time also contribute to the development of high-risk CSCC.3,6 These are some of the main features characterising high-risk CSCC.
Q: At what point should a dermatologist or Mohs surgeon involve an oncologist?
I think patients should be referred to a medical oncologist as soon as features of locally advanced disease are identified, and surgery or radiation are not treatment options, as there are other types of treatment available. This includes systemic therapy.4 At this point, we should be discussing the patient’s comorbidities, tumour characteristics, wishes, and treatment goals in a multi-disciplinary manner, within a multi-disciplinary tumour board. It is of critical importance that the patient receives the right treatment and treatment sequence.4
Q: Is there anything unique about the multi-disciplinary team (MDT) for advanced CSCC? How does it differ from other types of cancers?
The MDT is critical for patients because you’re bringing together expertise from different surgical disciplines. This might include ear, nose and throat (ENT) specialists; dermatologists; surgical oncologists; radiation oncologists; plastic surgeons; and medical oncologists.3 The collaboration of these different disciplines is important in determining the right strategy for each individual patient. It is not only the characteristics of the lesion (i.e., whether it is high-risk for advanced disease, locally advanced, or metastatic), but also the comorbidities of the patient that are essential to consider.3,8 For instance, many elderly patients have various comorbidities of the heart or their metabolism that need to be taken into account to make the best treatment decision for them.
Q: Outside the academic setting, participating in MDTs can be challenging. Can you comment on how dermatologists should handle this?
MDTs outside of an academic setting are obviously more of a challenge. There is no question about that. For example, the ENT surgeon may feel unable to make a full judgement of the patient outside of the academic setting. In this example, I would suggest that the ENT surgeon refer this patient to a specialist centre, where there is an MDT so that the patient can benefit from the expertise available across the different specialities.3 Otherwise, important features may be missed, which may result in a delayed diagnosis or treatment, including mutilating or disfiguring procedures, as well as life-threatening complications.
Q: Can you explain the role of immunotherapy in the treatment of advanced CSCC?
We have mentioned that early-stage CSCC is easy to treat, and this is the vast majority of cases seen in routine practice.3 At this point, we should focus on removing the lesion and following these patients with the aim of identifying subsequent CSCCs and any other skin cancer.9 However, about 5% of these patients will develop advanced CSCC and require additional care.10,11
Over the years, we have learnt that the skin is vulnerable to damage elicited by the sun.3,8 Exposure to sun induces a lot of DNA damage in the cell nucleus and at the end of the malignant transformation.8 This is the reason why skin-derived tumours very often exhibit a high tumour mutational load, which is equivalent to a high number of DNA breaks.3,11
While the mutational load for melanoma is extremely high, for CSCC, the mutational load is even higher.3,11 It has been demonstrated that tumour mutational burden is associated with response to checkpoint blockade by immunotherapy, and this formed the rationale for investigating the immunotherapy cemiplimab (a PD-1 checkpoint inhibitor) in patients with advanced CSCC.11
Specifically, cancers with a high tumour mutational burden often express the ligand to the T-cell receptor PD-1 (programmed cell death-1). When this ligand interacts with PD-1, it can suppress the immune response to CSCC.12 Cemiplimab is designed to block this suppression by binding to PD-1, thereby helping to restore the antitumour T-cell response. Cemiplimab received regulatory approval as a first-line treatment for adult patients with metastatic or locally advanced CSCC who are not candidates for curative surgery or curative radiation.1,3,11
Q: At what point should physicians consider using cemiplimab, especially in cases of locally advanced disease?
As the only treatment approved in the treatment of advanced CSCC, I believe cemiplimab should be the first-line standard of care for patients with metastatic CSCC or locally advanced CSCC who are not candidates for curative surgery or radiation.1 Historically, the average life expectancy has been approximately one year for a patient with advanced stage CSCC.13-15
Cemiplimab is also appropriate for elderly patients with advanced CSCC, as long as there are no contraindications. In cemiplimab clinical trials, there were no overall differences in safety or effectiveness between elderly and younger patients.1 This is notable because, before cemiplimab received marketing approval, about 30 to 40% of these elderly patients would not have been eligible for any type of systemic treatment, as they were not fit to receive a platinum-based systemic treatment.13,16
Q: Does PD-L1 (programmed death-ligand 1) expression need to be considered when treating advanced CSCC with an immunotherapy?
Oncologists who have experience with checkpoint inhibitors know that in certain diseases, the level of PD-L1 expression is a useful tool for guiding treatment. However, this is not the case for cemiplimab in advanced CSCC. The data collected from the CSCC clinical trials indicate that there is not a correlation between the level of PD-L1 expression and clinical response, and cemiplimab was shown to induce clinical responses across a variety of PD-L1 expression levels.1
Q: Can you elaborate on the data that led to the EMA’s recent approval of cemiplimab?
The recent approval of cemiplimab was based on a pivotal, open-label, multi-centre, non-randomised Phase 2 study called EMPOWER-CSCC-1*. It was further supported by two advanced CSCC expansion cohorts from a multi-centre, open-label, non-randomised Phase 1 trial. Both trials involved patients with locally advanced CSCC who were not candidates for surgery or radiation and metastatic CSCC (i.e. nodal or distant metastasis).1
In EMPOWER-CSCC-1, 193 patients with a median age of 72 years, were treated in three different groups.1 Group 1 included 59 patients with metastatic CSCC treated with 3 mg/kg of cemiplimab every two weeks, Group 2 included 78 patients with locally advanced CSCC treated with 3 mg/kg every two weeks, and Group 3 included 56 patients with metastatic CSCC treated with a fixed dose of 350 mg every three weeks.1
The data reviewed by the EMA indicated that all three treatment groups demonstrated substantial and durable responses following cemiplimab treatment.1 The objective response rate (ORR) for Group 1 was 49.2% (95% CI: 35.9%-62.5%) with a median duration of follow-up of 16.5 months for all patients in this group. The ORR for Group 2 was 43.6% (95% CI: 32.4%-55.3%), with a median duration of follow-up of 9.3 months for all patients in this group, and the ORR for Group 3 was 39.3% (95% CI: 26.5%-53.2%) with a median duration of follow-up of 8.1 months for all patients in this group.1 Additionally, the percentage of patients in Group 1, Group, 2, and Group 3 who had a duration of response (DOR) ≥6 months was 93.1%, 67.6%, and 63.6%, respectively.1
Finally, the pharmacokinetic analyses showed that cemiplimab exposures in patients was consistent across all groups.1
Q: What was the safety profile of cemiplimab in clinical trials?
In the data submitted to the EMA, the safety of cemiplimab was evaluated in 591 patients with advanced solid malignancies, including 219 advanced CSCC patients from both EMPOWER-CSCC-1 and the two expansion cohorts from the Phase 1 trial.1
Immune-related adverse reactions occurred in 20.1% of patients treated with cemiplimab in clinical trials, which included Grade 5 (0.7%), Grade 4 (1.2%) and Grade 3 (6.1%) events.1
Immune-related adverse reactions led to permanent discontinuation of cemiplimab in 4.4% of patients. The most common immune-related adverse reactions were hypothyroidism (7.1%), pneumonitis (3.7%), immune-related skin adverse reactions (2.0%), hyperthyroidism (1.9%) and hepatitis (1.9%) (see “Description of selected adverse reactions” below, and special warnings and precautions for use in section 4.4 and recommended treatment modifications in section 4.2 in the SmPC).1
Adverse reactions were serious in 8.6% of patients and led to permanent discontinuation of cemiplimab in 5.8% of patients.1 Serious adverse reactions included cellulitis, sepsis, pneumonia, pneumonitis and urinary tract infection.1
Q: What is the approved dose of cemiplimab in the EU?
350 mg every three weeks administered as an intravenous infusion over 30 minutes. Treatment may be continued until disease progression or unacceptable toxicity.1, 17
*Patients with any of the following were excluded from EMPOWER-CSCC-1: autoimmune disease that required systemic therapy with immunosuppressant agents within 5 years; history of solid organ transplant; history of pneumonitis within the last 5 years; prior treatment with anti-PD-1/PD-L1 or other immune checkpoint inhibitor therapy; active infection requiring therapy, including known infection with human immunodeficiency virus, or active infection with hepatitis B or hepatitis C virus; chronic lymphocytic leukaemia (CLL); brain metastases or Eastern Cooperative Oncology Group (ECOG) performance score ≥ 2.
1. Libtayo Product Information [Internet]. Ema.europa.eu. 2019 [cited 23 October 2019]. Available from: https://www.ema.europa.eu/en/documents/product-information/libtayo-epar-product-information_en.pdf
2. Data on File. Regeneron Pharmaceuticals Inc.
3. Schmults CD, et al. High-Risk Cutaneous Squamous Cell Carcinoma A Practical Guide for Patient Management. Springer. ISBN 978-3-662-47081-7 (eBook). DOI 10.1007/978-3-662-47081-7.
4. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Squamous Cell Skin Cancer V.1.2020. National Comprehensive Cancer Network, Inc. 2019.
5. Garcovich, et al. Skin Cancer Epidemics in the Elderly as An Emerging Issue in Geriatric Oncology. Aging Dis. 2017 Oct;8(5):643–661.
6. Jennings L, Schmults CD. Management of high-risk cutaneous squamous cell carcinoma. J Clin Aesthet Dermatol. 2010;3(4):39-48.
7. Califano JA, Lydiatt WM, Nehal KS, et al. Cutaneous squamous cell carcinoma of the head and neck. In: Amin MB, Edge SB, Greene FL, et al, eds. AJCC Cancer Staging Manual. 8th ed. Springer; 2017:171-181.
8. Lucas R, et al. Solar Ultraviolet Radiation. Global burden of disease from solar ultraviolet radiation. Environmental Burden of Disease Series, No. 13. World Health Organization 2006.
9. Burton KA, Ashack KA, Khachemoune A. Cutaneous squamous cell carcinoma: a review of high-risk and metastatic disease [published online June 29, 2016]. Am J Clin Dermatol. 2016;17(5):491-508. doi:10.1007/s40257-016-0207-3.
10. Mansouri B, Housewright C. The treatment of actinic keratoses—the rule rather than the exception. J Am Acad Dermatol 2017; 153(11):1200. doi:10.1001/jamadermatol.2017.3395.
11. Migden M, Rischin D, Schmults C, Guminski A, Hauschild A, Lewis K et al. PD-1 Blockade with Cemiplimab in Advanced Cutaneous Squamous-Cell Carcinoma. New England Journal of Medicine. 2018;379(4):341-351.
12. Alsaab HO, Sau S, Alzhrani R, et al. PD-1 and PD-L1 Checkpoint Signaling Inhibition for Cancer Immunotherapy: Mechanism, Combinations, and Clinical Outcome. Front Pharmacol. 2017;8:561. Published 2017 Aug 23. doi:10.3389/fphar.2017.00561
13. Jarkowski, A. (2014). Systemic Therapy in Advanced Cutaneous Squamous Cell Carcinoma (CSCC). American Journal of Clinical Oncology, 00(00), 1-4.
14. Foote, M.C. (2014). Phase II study of single-agent panitumumab in patients with incurable cutaneous squamous cell carcinoma. Annals of Oncology, 25, 2047–2052.
15. Maubec, E. (2001). Phase II Study of Cetuximab As First-Line Single-Drug Therapy in Patients With Unresectable Squamous Cell Carcinoma of the Skin. Journal of Clinical Oncology, 29 (25), 3419-3426.
16. Szturz P, Vermorken JB. Treatment of Elderly Patients with Squamous Cell Carcinoma of the Head and Neck. Front Oncol. 2016;6:199. Published 2016 Aug 31. doi:10.3389/fonc.2016.00199.
17. Libtayo Product Information [Internet]. UK PI. 2019 [cited 18 December 2019].
Prescribing Information: LIBTAYO (cemiplimab) 350mg concentrate for solution for infusion
Please refer to Summary of Product Characteristics (SPC) prior to use.
Presentation: Each vial contains 350mg of cemiplimab in 7ml of solution.
Indication: LIBTAYO as monotherapy is indicated for the treatment of adult patients with metastatic or locally advanced cutaneous squamous cell carcinoma who are not candidates for curative surgery or curative radiation.
Dosage and Administration: Treatment must be initiated and supervised by physicians experienced in the treatment of cancer. LIBTAYO must be administered by intravenous infusion over 30 minutes through an intravenous line containing a sterile, non-pyrogenic, low- protein binding, in-line or add-on filter (0.2 micron to 5 micron pore size). Other medicinal products should not be co-administered through the same infusion line. Recommended dose: The recommended dose of LIBTAYO is 350 mg, every 3 weeks. Treatment may be continued until disease progression or unacceptable toxicity. Dose modifications: No dose reductions are recommended. Dosing delay or discontinuation may be required based on individual safety and tolerability. Recommended modifications to manage adverse reactions are provided in Table 1 of the SPC.
Special Populations: Paediatric (<18 years): Safety and efficacy has not been established. Elderly: No dose adjustment is recommended. Renal impairment: No dose adjustment is recommended, however there are limited data for LIBTAYO in patients with severe renal impairment (CLCr<30ml/min). Hepatic impairment: No dose adjustment is recommended for patients with mild hepatic impairment. LIBTAYO has not been studied in patients with moderate or severe hepatic impairment.
Contraindications: Hypersensitivity to the active substance or to any of the excipients.
Precautions and Warnings: Traceability: To improve traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded. Immune-related adverse reactions (IRARs): IRARs may involve any organ system. Most IRARs initially manifest during treatment however, they can occur after discontinuation of cemiplimab. IRARs should be managed with cemiplimab treatment modifications, hormone replacement therapy (if clinically indicated), and corticosteroids. For suspected IRARs, patients should be evaluated to confirm an IRAR and to exclude other possible causes. Depending upon the severity of the adverse reaction, cemiplimab should be withheld or permanently discontinued. Immune-related pneumonitis: defined as requiring use of corticosteroids with no clear alternate aetiology, including fatal cases, has been observed. Patients should be monitored for signs and symptoms of pneumonitis and if suspected pneumonitis should be evaluated with radiographic imaging as indicated based on clinical evaluation and managed with cemiplimab treatment modifications and corticosteroids. Immune-related diarrhoea or colitis: defined as requiring use of corticosteroids with no clear alternate aetiology, has been observed. Patients should be monitored for signs and symptoms of diarrhoea or colitis and managed with cemiplimab treatment modifications, anti-diarrhoeal agents, and corticosteroids. Immune-related hepatitis: defined as requiring use of corticosteroids with no clear alternate aetiology, including fatal cases, have been observed. Patients should be monitored for abnormal liver tests prior to and periodically during treatment as indicated based on clinical evaluation and managed with cemiplimab treatment modifications and corticosteroids. Immune-related endocrinopathies: defined as treatment-emergent endocrinopathies with no clear alternate aetiology, have been observed. Thyroid disorders (Hypothyroidism/Hyperthyroidism): Thyroid disorders can occur at any time during the treatment. Patients should be monitored for changes in thyroid function at the start of treatment and periodically during the treatment as indicated based on clinical evaluation. Patients should be managed with hormone replacement therapy (if indicated) and cemiplimab treatment modifications. Hyperthyroidism should be managed according to standard medical practice. Hypophysitis: Immune-related hypophysitis has been observed. Patients should be monitored for signs and symptoms of hypophysitis and managed with cemiplimab treatment modifications and corticosteroids. Adrenal insufficiency: Patients should be monitored for signs and symptoms of adrenal insufficiency during and after treatment and managed with cemiplimab treatment modifications and corticosteroids. Type 1 Diabetes mellitus: Immune-related type 1 diabetes mellitus, including diabetic ketoacidosis, has been observed. Patients should be monitored for hyperglycaemia and signs and symptoms of diabetes as indicated based on clinical evaluation and managed with oral anti-hyperglycaemics or insulin and cemiplimab treatment modifications. Cemiplimab should be withheld and anti- hyperglycaemics or insulin should be administered in patients with severe or life-threatening (Grade ≥ 3) hyperglycaemia. Cemiplimab should be resumed when metabolic control is achieved. Immune-related skin adverse reactions: defined as requiring use of systemic corticosteroids with no clear alternate aetiology, including severe cutaneous adverse reactions (SCARs), such as Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) (some cases with fatal outcome), and other skin reactions such as rash, erythema multiforme, pemphigoid, have been reported in association with cemiplimab treatment. Patients should be monitored for evidence of suspected severe skin reactions and exclude other causes. Patients should be managed with cemiplimab treatment modifications and corticosteroids. Cases of SJS, fatal TEN and stomatitis occurred following 1 dose of cemiplimab in patients with prior exposure to idelalisib, who were participating in a clinical trial evaluating cemiplimab in Non- Hodgkins Lymphoma (NHL), and who had recent exposure to sulfa containing antibiotics. Patients should be managed with cemiplimab treatment modifications and corticosteroids as described above. Immune-related nephritis: defined as requiring use of corticosteroids with no clear alternate aetiology, has been observed in patients receiving cemiplimab. Patients should be managed with cemiplimab treatment modifications and corticosteroids. Other IRARs: Other fatal and life-threatening IRARs have been observed in patients receiving cemiplimab including paraneoplastic encephalomyelitis and meningitis. Patients should be monitored for signs and symptoms of IRARs and managed with cemiplimab treatment modifications and corticosteroids. Infusion-related reactions: Cemiplimab can cause severe or life-threatening infusion-related reactions. Patients should be monitored for signs and symptoms of infusion-related reactions and managed with cemiplimab treatment modifications and corticosteroids. Cemiplimab should be interrupted or the rate of infusion slowed for mild or moderate infusion-related reactions. The infusion should be stopped and cemiplimab should be permanently discontinued for severe (Grade 3) or life- threatening (Grade 4) infusion-related reactions. Patients excluded from clinical studies: Patients that had active infections or that were immunocompromised were not included in the main study. Fertility, Pregnancy and Lactation: No clinical data available on the possible effects of cemiplimab on fertility. No effects observed in fertility study on cynomolgus monkeys. Women of childbearing potential should use effective contraception during treatment with cemiplimab and for at least 4 months after the last dose of cemiplimab. Cemiplimab, as an IG4, has the potential to be transmitted across the placenta from the mother to the developing foetus. Cemiplimab is not recommended during pregnancy and in women of childbearing potential not using effective contraception unless the clinical benefit outweighs the potential risk. It is unknown whether cemiplimab is secreted in human milk. If a lactating woman chooses to be treated with cemiplimab, she should be instructed not to breastfeed while being treated with cemiplimab and for at least 4 months after the last dose. Interactions: No pharmacokinetic drug-drug interaction studies have been conducted with cemiplimab. The use of systemic corticosteroids or immunosuppressants before starting cemiplimab, except for physiological doses of systemic corticosteroid (≤10 mg/day prednisone or equivalent), should be avoided because of their potential interference with the pharmacodynamic activity and efficacy of cemiplimab. However, systemic corticosteroids or other immunosuppressants can be used after starting cemiplimab to treat IRARs.
Adverse Reactions: Very common: Diarrhoea, Fatigue, Pruritus and Rash. Common: Alanine aminotransferase increased, Arthralgia, Arthritis, Aspartate aminotransferase increased, Blood alkaline phosphatase increased, Blood creatinine increased, Hepatitis, Hyperthyroidism, Hypothyroidism, Infusion related reaction, Musculoskeletal pain, Pneumonitis, Stomatitis. Uncommon: Adrenal insufficiency, Central nervous system inflammation, Chronic inflammatory demyelinating polyradiculoneuropathy, Encephalitis, Guillain- Barre syndrome, Hypophysitis, Immune thrombocytopenic purpura, Keratitis, Meningitis, Muscular weakness, Myasthenia gravis, Myocarditis, Nephritis, Neuropathy peripheral, Paraneoplastic encephalomyelitis, Pericarditis, Sjogren’s syndrome, Thyroiditis, Type 1 diabetes mellitus, Vasculitis. UK List price: £4650 per vial. Legal Category: POM. Marketing Authorisation Number: EU/1/19/1376/001. Marketing Authorisation Holder: Regeneron Ireland U.C., Europa House, Harcourt Centre, Harcourt Street, Dublin 2, Ireland. For more information please contact: Sanofi, 410 Thames Valley Park Drive, Reading, Berkshire, RG6 1PT, UK. firstname.lastname@example.org Tel: 0845 372 7101. Date of preparation: July 2019.
This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions.
March 2020 SAGLB.LIB.19.11.1713
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