Identifying Patients With Advanced Cutaneous Squamous Cell Carcinoma (CSCC) Eligible for Systemic Therapy

Featuring Eric Whitman, MD, and Ezra Cohen, MD, FRCPSC, FASCO

Dr Ezra Cohen: Hello. I'm Dr Ezra Cohen, and I'm a medical oncologist at University of California San Diego.

Dr Eric Whitman: And I'm Dr Eric Whitman, and I'm a surgical oncologist at the Atlantic Melanoma Center in Morristown, New Jersey. In this video, Dr Cohen and I will discuss how to identify patients with metastatic cutaneous squamous cell carcinoma or CSCC, or with locally advanced CSCC who are not candidates for curative surgery or curative radiation and should be considered for systemic therapy and consultation with a medical oncologist. There are certain situations where surgery might not be appropriate in patients with locally advanced CSCC. One example is patients with invasive disease. This includes patients with a locally invasive tumor extending into underlying tissue, cartilage, bone, or nerve. Also, patients with nodal involvement due to direct invasion from overlying skin, or those with perineural involvement due to direct extension that is apparent on imaging, might not be appropriate candidates for surgery.

Additionally, those with in-transit metastases of the skin without evidence of nodal, parotid, or distant disease may not be appropriate candidates for surgery. The location of disease can also dictate whether a patient is a candidate for surgery. Patients with periorbital lesions threatening the eye or patients with lesions with direct extension into the sinuses might not be candidates for surgery. Substantial morbidity or deformity could be anticipated as a result of surgery. For example, nasal or auricular lesions requiring rhinectomy or auriculectomy. Thus, the expected deformity or morbidity should be considered when assessing whether a patient is a candidate for surgery. Recurrence also factors into whether a patient is a candidate for surgery. Further surgery may not be appropriate for patients with recurrence of CSCC at the same site after two or more surgical procedures. Additionally, those with a deep recurrence underlying the site of a previous resected cutaneous lesion with no nodal or metastatic involvement would not be candidates for surgery. Finally, patients who refuse surgery or have other conditions deemed to be contraindicating for surgery should not receive surgery.

Dr Ezra Cohen: In addition to situations where a patient with locally advanced CSCC might not be a candidate for curative surgery, there are certain situations where curative radiation might not be appropriate. The location of disease is an important factor when considering radiation. Tumors in anatomically challenging locations for which radiation therapy would be associated with an unacceptable toxicity, those in poorly vascularized or easily traumatized areas, or those with advanced lesions invading bones, joints, or tendons might not be appropriate for radiation. The patient's treatment history can also influence the decision to use radiation. Patients for whom further radiation therapy would exceed the threshold of acceptable cumulative dose or who have lesions that have been previously irradiated might not be appropriate candidates. Additionally, patients who refuse radiation therapy who have tumors which are deemed unlikely to respond to radiation therapy based on clinical judgment or who have other conditions that are deemed to contraindicate radiation therapy might not be appropriate candidates.

For certain high-risk patients, guidelines recommend a more aggressive treatment approach and more frequent follow-up as well as a multidisciplinary team assessment and consideration of multiple treatment modalities. In the management of patients with complicated high-risk tumors, regional recurrence, or distant metastasis, the NCCN Clinical Practice Guidelines in Oncology for Squamous Cell Skin Cancer recommend consultation with a multidisciplinary tumor board. The multidisciplinary team might include dermatologists, medical oncologists, pathologists, radiation oncologists and Mohs surgeon, as well as other surgeons and other specialties on a case-to-case basis. The NCCN Guidelines do not specify a specific list of disciplines that must be included in a multidisciplinary tumor board.

Dr Eric Whitman: LIBTAYO is the first FDA approved therapy indicated for the treatment of patients with metastatic CSCC or locally advanced CSCC who are not candidates for curative surgery or curative radiation. LIBTAYO is a PD-1 inhibitor that helps restore the antitumor T-cell response. It is approved as a first- or later-line therapy for appropriate patients with advanced CSCC.

Dr Ezra Cohen: Warnings and precautions for LIBTAYO include immune-mediated reactions, which may be severe or fatal, can occur in any organ system or tissue, and include immune-mediated pneumonitis, colitis, hepatitis, endocrinopathies, dermatologic adverse reactions, nephritis and renal dysfunction, and solid organ transplant rejection. Warnings and precautions also include infusion-related reactions, complications of allogeneic hemopoietic stem cell transplantation, and embryo fetal toxicity. Monitor for symptoms and signs of immune-mediated adverse reactions.

Dr Eric Whitman: Please see additional important safety information throughout this video and accompanying full prescribing information.

Dr Ezra Cohen: Here you can see images of a 70-year-old male with cranial and auricular lesions who was diagnosed with locally advanced CSCC and was not a candidate for curative surgery or curative radiation. The patient was enrolled in the LIBTAYO cemiplimab-rwlc clinical trial program. This patient had undergone a series of surgical interventions and radiotherapy for 4 years, which included resection of the right parotid gland, definitive radiotherapy to the right preauricular area, and incisional biopsy of the skin. The patient experienced recurrence and complained of ongoing pain at the right preauricular area. At the time of screening, the patient presented with cranial and auricular lesions. The tumor stage was T3, N0, M0. The patient had 4 lesions with the largest being 93 millimeters in diameter. Per the investigator, the patient was not considered a candidate for curative surgery or curative radiation because there was significant local invasion that precluded complete resection, and a multidisciplinary team deemed that radiotherapy was contraindicated.

In clinically challenging cases of locally advanced CSCC such as this one, it is important to identify patients who are not candidates for curative surgery or curative radiation when assessing treatment options. According to the NCCN Clinical Practice Guidelines in Oncology, or NCCN Guidelines, cemiplimab-rwlc or LIBTAYO is a category 2A preferred recommended systemic therapy option for appropriate patients with locally advanced or regional CSCC when curative surgery and curative radiation therapy are not feasible, or distant metastatic or regionally recurrent CSCC when curative surgery and curative radiation therapy are not feasible. Please see important safety information throughout the video and full prescribing information via adjacent link or at libtayohcp.com.

Narrator: Important safety information.

Warnings and precautions.

Severe and fatal immune-mediated adverse reactions: Immune-mediated adverse reactions which may be severe or fatal can occur in any organ system or tissue at any time after starting treatment. While immune-mediated adverse reactions usually occur during treatment, they can also occur after discontinuation. Immune-mediated adverse reactions affecting more than one body system can occur simultaneously. Early identification and management are essential to ensuring safe use of PD-1/PD-L1-blocking antibodies. The definition of immune-mediated adverse reactions included the required use of systemic corticosteroids or other immunosuppressants and the absence of a clear alternate etiology. Monitor closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate liver enzymes, creatinine and thyroid function at baseline and periodically during treatment. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies including infection, institute medical management promptly including specialty consultation as appropriate. No dose reduction for LIBTAYO is recommended. In general, withhold LIBTAYO for severe Grade 3 immune-mediated adverse reactions. Permanently discontinue LIBTAYO for life-threatening Grade 4 immune-mediated adverse reactions, recurrent severe Grade 3 immune-mediated adverse reactions that require systemic immunosuppressive treatment or an inability to reduce corticosteroid dose to 10 milligrams or less of prednisone equivalent per day within 12 weeks of initiating steroids. Withhold or permanently discontinue LIBTAYO depending on severity. In general, if LIBTAYO requires interruption or discontinuation, administer systemic corticosteroid therapy, one to two milligrams per kilogram per day prednisone or equivalent, until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroids. The incidence and severity of immune-mediated adverse reactions were similar when LIBTAYO was administered as a single agent or in combination with chemotherapy.

Immune-mediated pneumonitis: LIBTAYO can cause immune-mediated pneumonitis. In patients treated with other PD-1/PD-L1-blocking antibodies, the incidence of pneumonitis is higher in patients who have received prior thoracic radiation. Immune-mediated pneumonitis occurred in 2.6% (33 of 1,281) of patients receiving LIBTAYO including Grade 4 (0.3%), Grade 3 (0.6%), and Grade 2 (1.6%). Pneumonitis led to permanent discontinuation in 1.3% of patients and withholding of LIBTAYO in 1.4% of patients. Systemic corticosteroids were required in all patients with pneumonitis. Pneumonitis resolved in 61% of the 33 patients. Of the 18 patients in whom LIBTAYO was withheld, 10 reinitiated after symptom improvement. Of these, 4 out of 10 (40%) had recurrence of pneumonitis. Withhold LIBTAYO for Grade 2 and permanently discontinue for Grade 3 or 4. Resume in patients with complete or partial resolution, Grade 0 to 1, after corticosteroid taper. Permanently discontinue if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone to less than 10 milligrams per day or equivalent within 12 weeks of initiating steroids.

Immune-mediated colitis: LIBTAYO can cause immune-mediated colitis. The primary component of immune-mediated colitis was diarrhea. Cytomegalovirus, CMV infection reactivation, has been reported in patients with corticosteroid refractory immune-mediated colitis treated with PD-1/PD-L1-blocking antibodies. In cases of corticosteroid refractory immune-mediated colitis, consider repeating infectious workup to exclude alternative etiologies. Immune-mediated colitis occurred in 2% (25 of 1,281) of patients receiving LIBTAYO including Grade 3 (0.8%) and Grade 2 (0.9%). Colitis led to permanent discontinuation in 0.4% of patients and withholding of LIBTAYO in 1.2% of patients. Systemic corticosteroids were required in all patients with colitis. Colitis resolved in 56% of the 25 patients. Of the 16 patients in whom LIBTAYO was withheld, 6 reinitiated LIBTAYO after symptom improvement. Of these, 4 out of 6 (67%) had recurrence. Withhold LIBTAYO for Grade 2 or 3 and permanently discontinue for Grade 4. Resume in patients with complete or partial resolution, Grade 0 to 1, after corticosteroid taper. Permanently discontinue if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone to less than 10 milligrams per day or equivalent within 12 weeks of initiating steroids.

Immune-mediated hepatitis: LIBTAYO can cause immune-mediated hepatitis. Immune-mediated hepatitis occurred in 2.4% (31 of 1,281) of patients receiving LIBTAYO including fatal (less than 0.1%), Grade 4 (0.3%), Grade 3 (1.6%), and Grade 2 (0.2%). Hepatitis led to permanent discontinuation of LIBTAYO in 1.4% of patients and withholding of LIBTAYO in 0.7% of patients. Systemic corticosteroids were required in all patients with hepatitis. Additional immunosuppression with mycophenolate was required in 13% (4 of 31) of these patients. Hepatitis resolved in 39% of the 31 patients. Of the 9 patients in whom LIBTAYO was withheld, five reinitiated LIBTAYO after symptom improvement. Of these, 1 out of 5 (20%) had recurrence. For hepatitis with no tumor involvement of the liver, withhold LIBTAYO if AST or ALT increases to more than 3 and up to 8 times the upper limit of normal (ULN) or if total bilirubin increases to more than 1.5 and up to 3 times the ULN. Permanently discontinue LIBTAYO if AST or ALT increases to more than 8 times the ULN or total bilirubin increases to more than 3 times the ULN. For hepatitis with tumor involvement of the liver, withhold LIBTAYO if baseline AST or ALT is more than 1 and up to 3 times ULN and increases to more than 5 and up to 10 times ULM. Also, withhold LIBTAYO if baseline AST or ALT is more than 3 and up to 5 times ULN and increases to more than 8 and up to 10 times ULN. Permanently discontinue LIBTAYO if AST or ALT increases to more than 10 times ULN or if total bilirubin increases to more than 3 times ULN. If AST and ALT are less than or equal to ULN at baseline, withhold or permanently discontinue LIBTAYO based on recommendations for hepatitis with no liver involvement. Resume in patients with complete or partial resolution, Grade 0 to 1, after corticosteroid taper. Permanently discontinue if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone to less than 10 milligrams per day or equivalent within 12 weeks of initiating steroids.

Immune-mediated endocrinopathies: For Grade 3 or 4 endocrinopathies, withhold until clinically stable or permanently discontinue depending on severity.

Adrenal insufficiency: LIBTAYO can cause primary or secondary adrenal insufficiency. For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement, as clinically indicated. Withhold LIBTAYO depending on severity. Adrenal insufficiency occurred in 0.5% (6 of 1,281) of patients receiving LIBTAYO including Grade 3 (0.5%). Adrenal insufficiency led to permanent discontinuation of LIBTAYO in 1 (less than 0.1%) patient. LIBTAYO was withheld in 1 (less than 0.1%) patient due to adrenal insufficiency and not reinitiated. Systemic corticosteroids were required in 83% (5 out of 6) patients with adrenal insufficiency. Of these, the majority remained on systemic corticosteroids. Adrenal insufficiency had resolved in 17% of the 6 patients.

Hypophysitis: LIBTAYO can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism. Initiate hormone replacement as clinically indicated. Withhold or permanently discontinued depending on severity. Hypophysitis occurred in 0.5% (7 of 1,281) of patients receiving LIBTAYO including Grade 3 (0.2%) and Grade 2 (0.3%) adverse reactions. Hypophysitis led to permanent discontinuation of LIBTAYO in 1 (less than 0.1%) patient and withholding of LIBTAYO in 2 (0.2%) patients. Systemic corticosteroids were required in 86% (6 of 7) of patients with hypophysitis. Hypophysitis resolved in 14% of the 7 patients. Of the 2 patients in whom LIBTAYO was withheld for hypophysitis, none of the patients reinitiated.

Thyroid disorders: LIBTAYO can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement or medical management of hyperthyroidism as clinically indicated. Withhold or permanently discontinue LIBTAYO depending on severity.

Thyroiditis: Thyroiditis occurred in 0.6% (8 of 1,281) of patients receiving LIBTAYO including Grade 2 (0.3%) adverse reactions. No patient discontinued LIBTAYO due to thyroiditis. Thyroiditis led to withholding of LIBTAYO in 1 (less than 0.1%) patient. Systemic corticosteroids were not required in any patient with thyroiditis. Thyroiditis resolved in 13% of the 8 patients. Blood thyroid stimulating hormone increased and blood thyroid stimulating hormone decreased have also been reported.

Hyperthyroidism: Hyperthyroidism occurred in 3% (39 of 1,281) of patients receiving LIBTAYO including Grade 3 (less than 0.1%) and Grade 2 (0.9%). No patient discontinued treatment and LIBTAYO was withheld in 7 (0.5%) of patients due to hyperthyroidism. Systemic corticosteroids were required in 8% (3 of 39) of patients. Hyperthyroidism resolved in 56% of 39 patients. Of the seven patients in whom LIBTAYO was withheld for hyperthyroidism, 2 patients reinitiated LIBTAYO after symptom improvement. Of these, none had recurrence of hyperthyroidism.

Hypothyroidism: Hypothyroidism occurred in 7% (87 of 1,281) of patients receiving LIBTAYO including Grade 3 (less than 0.1%) and Grade 2 (6%). Hypothyroidism led to permanent discontinuation of LIBTAYO in 3 (0.2%) patients. Hypothyroidism led to withholding of LIBTAYO in 9 (0.7%) patients. Systemic corticosteroids were required in 1.1% (1 of 87) of patients with hypothyroidism. Hypothyroidism resolved in 6% of the 87 patients. Majority of the patients with hypothyroidism required long-term thyroid hormone replacement. Of the 9 patients in whom LIBTAYO was withheld for hypothyroidism, 1 reinitiated LIBTAYO after symptom improvement and did not have recurrence of hypothyroidism.

Type 1 diabetes mellitus, which can present with diabetic ketoacidosis: Monitor for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold LIBTAYO depending on severity. Type 1 diabetes mellitus occurred in less than 0.1% (1 of 1,281) of patients Grade 4. No patient discontinued treatment due to Type 1 diabetes mellitus. Type 1 diabetes mellitus led to withholding of LIBTAYO in 0.1% of patients. Treatment was reinitiated after symptom improvement. Patient received long-term insulin therapy.

Immune-mediated nephritis with renal dysfunction: LIBTAYO can cause immune-mediated nephritis. Immune-mediated nephritis occurred in 0.7% (9 of 1,281) of patients receiving LIBTAYO including fatal (less than 0.1%), Grade 3 (less than 0.1%), and Grade 2 (0.5%). Nephritis led to permanent discontinuation in 0.2% of patients and withholding of LIBTAYO in 0.4% of patients. Systemic corticosteroids were required in all patients with nephritis. Nephritis resolved in 78% of the 9 patients. Of the 5 patients in whom LIBTAYO was withheld, 4 reinitiated LIBTAYO after symptom improvement. Of these, 1 out of 4 (25%) had recurrence. Withhold LIBTAYO for Grade 2 or 3 increased blood creatinine and permanently discontinue for Grade 4 increased blood creatinine. Resume in patients with complete or partial resolution, Grade 0 to 1, after corticosteroid taper. Permanently discontinue if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone to less than 10 milligrams per day or equivalent within 12 weeks of initiating steroids.

Immune-mediated dermatologic adverse reactions: LIBTAYO can cause immune-mediated rash or dermatitis. Exfoliative dermatitis including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug rash with eosinophilia and systemic symptoms (DRESS) has occurred with PD-1/PD-L1-blocking antibodies. Immune-mediated dermatologic adverse reactions occurred in 1.9% (24 of 1,281) of patients receiving LIBTAYO including Grade 3 (0.9%) and Grade 2 (0.8%). Immune-mediated dermatologic adverse reactions led to permanent discontinuation in 0.2% of patients and withholding of LIBTAYO in 1.3% of patients. Systemic corticosteroids were required in all patients with immune-mediated dermatologic adverse reactions. Immune-mediated dermatologic adverse reactions resolved in 71% of the 24 patients. Of the 17 patients in whom LIBTAYO was withheld for dermatologic adverse reaction, 13 reinitiated LIBTAYO after symptom improvement. Of these, 5 out of 13 (38%) had recurrence of the dermatologic adverse reaction. Topical emollients and/or topical corticosteroids may be adequate to treat mild-to-moderate non-exfoliative rashes. Withhold LIBTAYO for suspected SJS, TEN, or DRESS. Permanently discontinue LIBTAYO for confirmed SJS, TEN, or DRESS. Resume in patients with complete or partial resolution, Grade 0 to 1, after corticosteroid taper. Permanently discontinue if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone to less than 10 milligrams per day or equivalent within 12 weeks of initiating steroids.

Other immune-mediated adverse reactions

The following clinically significant immune-mediated adverse reactions occurred at an incidence of less than 1% in 1,281 patients who received LIBTAYO or were reported with the use of other PD-1/PD-L1-blocking antibodies. Severe or fatal cases have been reported for some of these adverse reactions.

Cardiac/vascular: Myocarditis, pericarditis, and vasculitis. Permanently discontinue for grades 2, 3, or 4 myocarditis.

Nervous system: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome, myasthenia gravis including exacerbation, Guillain-Barré syndrome, nerve paresis, and autoimmune neuropathy. Withhold for Grade 2 neurological toxicities and permanently discontinue for grades 3 or 4 neurological toxicities. Resume in patients with complete or partial resolution, Grade 0 to 1, after corticosteroid taper. Permanently discontinue if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone to less than 10 milligrams per day or equivalent within 12 weeks of initiating steroids.

Ocular: Uveitis, iritis, and other ocular inflammatory toxicities. Some cases can be associated with retinal detachment. Various grades of visual impairment to include blindness can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss.

Gastrointestinal: Pancreatitis to include increases in serum amylase and lipase levels, gastritis, duodenitis, stomatitis.

Musculoskeletal and connective tissue: Myositis, polymyositis, dermatomyositis, rhabdomyolysis, and associated sequelae including renal failure, arthritis, polymyalgia rheumatica.

Endocrine. hypoparathyroidism.

Other (hematologic/immune): Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenia, solid organ transplant rejection.

Infusion-related reactions.

Severe or life-threatening infusion related reactions occurred in 0.2% of patients receiving LIBTAYO as a single agent. Monitor patients for signs and symptoms of infusion-related reactions. Common symptoms of infusion-related reaction include nausea, pyrexia, and vomiting. Interrupt or slow the rate of infusion or permanently discontinue LIBTAYO based on severity of reaction.

Complications of allogeneic HSCT.

Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with a PD-1/PD-L1-blocking antibody. Transplant-related complications include hyperacute graft versus host disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease (VOD), after reduced intensity conditioning and steroid requiring febrile syndrome without an identified infectious cause. These complications may occur despite intervening therapy between PD-1/PD-L1 blockade and allogeneic HSCT. Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with a PD-1/PD-L1-blocking antibody prior to or after an allogeneic HSCT.

Embryo-Fetal toxicity.

LIBTAYO can cause fetal harm when administered to a pregnant woman due to an increased risk of immune-mediated rejection of the developing fetus resulting in fetal death. Advise women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with LIBTAYO and for at least 4 months after the last dose.

Adverse reactions.

LIBTAYO as a single agent. The most common adverse reactions greater than or equal to 15% are fatigue, musculoskeletal pain, rash, diarrhea, and anemia.

LIBTAYO in combination with platinum-based chemotherapy. The most common adverse reactions greater than or equal to 15% are alopecia, musculoskeletal pain, nausea, fatigue, peripheral neuropathy, and decreased appetite.

Use in specific populations.

Lactation. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment and for at least 4 months after the last dose of LIBTAYO. Females and males of reproductive potential, verify pregnancy status and females of reproductive potential prior to initiating LIBTAYO.

Please see full prescribing information.