The Role of Immunotherapy as a Treatment Option in Advanced CSCC

A closer look at data for the PD-1 inhibitor LIBTAYO^® (cemiplimab-rwlc) from the largest prospective clinical dataset in advanced CSCC. LIBTAYO is indicated for the treatment of patients with mCSCC or laCSCC who are not candidates for curative surgery or curative radiation.^1-11

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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 mg 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 (1 to 2 mg/kg/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.

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 3.2% (26/810) of patients receiving LIBTAYO, including Grade 4 (0.5%), Grade 3 (0.5%), and Grade 2 (2.1%). Pneumonitis led to permanent discontinuation in 1.4% of patients and withholding of LIBTAYO in 2.1% of patients. Systemic corticosteroids were required in all patients with pneumonitis. Pneumonitis resolved in 58% of the 26 patients. Of the 17 patients in whom LIBTAYO was withheld, 9 reinitiated after symptom improvement; of these, 3/9 (33%) 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 mg 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 2.2% (18/810) of patients receiving LIBTAYO, including Grade 3 (0.9%) and Grade 2 (1.1%). Colitis led to permanent discontinuation in 0.4% of patients and withholding of LIBTAYO in 1.5% of patients. Systemic corticosteroids were required in all patients with colitis. Colitis resolved in 39% of the 18 patients. Of the 12 patients in whom LIBTAYO was withheld, 4 reinitiated LIBTAYO after symptom improvement; of these, 3/4 (75%) 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 mg 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% (16/810) of patients receiving LIBTAYO, including fatal (0.1%), Grade 4 (0.1%), Grade 3 (1.4%), and Grade 2 (0.2%). Hepatitis led to permanent discontinuation of LIBTAYO in 1.2% of patients and withholding of LIBTAYO in 0.5% of patients. Systemic corticosteroids were required in all patients with hepatitis. Additional immunosuppression with mycophenolate was required in 19% (3/16) of these patients. Hepatitis resolved in 50% of the 16 patients. Of the 5 patients in whom LIBTAYO was withheld, 3 reinitiated LIBTAYO after symptom improvement; of these, none 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 ULN. 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 mg 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 0.4% (3/810) of patients receiving LIBTAYO, including Grade 3 (0.4%). Adrenal insufficiency led to permanent discontinuation of LIBTAYO in 1 (0.1%) patient. LIBTAYO was not withheld in any patient due to adrenal insufficiency. Systemic corticosteroids were required in all patients with adrenal insufficiency; of these, 67% (2/3) remained on systemic corticosteroids. Adrenal insufficiency had not resolved in any patient at the time of data cutoff

• 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 discontinue depending on severity. Hypophysitis occurred in 0.4% (3/810) of patients receiving LIBTAYO, including Grade 3 (0.2%) and Grade 2 (0.1%) adverse reactions. Hypophysitis led to permanent discontinuation of LIBTAYO in 1 (0.1%) patient and withholding of LIBTAYO in 1 (0.1%) patient. Systemic corticosteroids were required in 67% (2/3) of patients with hypophysitis. Hypophysitis had not resolved in any patient at the time of data cutoff

• 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% (5/810) of patients receiving LIBTAYO, including Grade 2 (0.2%) adverse reactions. No patient discontinued LIBTAYO due to thyroiditis. Thyroiditis led to withholding of LIBTAYO in 1 patient. Systemic corticosteroids were not required in any patient with thyroiditis. Thyroiditis had not resolved in any patient at the time of data cutoff. Blood thyroid stimulating hormone increased and blood thyroid-stimulating hormone decreased have also been reported

• Hyperthyroidism: Hyperthyroidism occurred in 3.2% (26/810) of patients receiving LIBTAYO, including Grade 2 (0.9%). No patient discontinued treatment and LIBTAYO was withheld in 0.5% of patients due to hyperthyroidism. Systemic corticosteroids were required in 3.8% (1/26) of patients. Hyperthyroidism resolved in 50% of 26 patients. Of the 4 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% (60/810) of patients receiving LIBTAYO, including Grade 2 (6%). Hypothyroidism led to permanent discontinuation of LIBTAYO in 1 (0.1%) patient. Hypothyroidism led to withholding of LIBTAYO in 1.1% of patients. Systemic corticosteroids were not required in any patient with hypothyroidism. Hypothyroidism resolved in 8.3% of the 60 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; 1 required ongoing hormone replacement therapy

• 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 0.1% (1/810) of patients, including Grade 4 (0.1%). No patient discontinued treatment due to type 1 diabetes mellitus. Type 1 diabetes mellitus led to withholding of LIBTAYO in 0.1% of patients

Immune-mediated nephritis with renal dysfunction: LIBTAYO can cause immune-mediated nephritis. Immune-mediated nephritis occurred in 0.6% (5/810) of patients receiving LIBTAYO, including fatal (0.1%), Grade 3 (0.1%), and Grade 2 (0.4%). Nephritis led to permanent discontinuation in 0.1% of patients and withholding of LIBTAYO in 0.4% of patients. Systemic corticosteroids were required in all patients with nephritis. Nephritis resolved in 80% of the 5 patients. Of the 3 patients in whom LIBTAYO was withheld, 2 reinitiated LIBTAYO after symptom improvement; of these, none 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 mg 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 1.6% (13/810) of patients receiving LIBTAYO, including Grade 3 (0.9%) and Grade 2 (0.6%). Immune-mediated dermatologic adverse reactions led to permanent discontinuation in 0.1% of patients and withholding of LIBTAYO in 1.4% of patients. Systemic corticosteroids were required in all patients with immune-mediated dermatologic adverse reactions. Immune-mediated dermatologic adverse reactions resolved in 69% of the 13 patients. Of the 11 patients in whom LIBTAYO

Validated in the Largest Prospective Clinical Trial Program for Advanced CSCC2-11

In September 2018, LIBTAYO was approved by the U.S. FDA as the first systemic treatment for adults with mCSCC or laCSCC who are not candidates for curative surgery or curative radiation.^2,12

The FDA approval was based on data from an open-label, non-randomized, multicohort Phase 2 trial called EMPOWER-CSCC 1 (Study 1540) and was further supported by two advanced CSCC cohorts from an open-label, non-randomized, multicohort Phase 1 trial (Study 1423).² In total, the studies enrolled 219 patients with mCSCC (nodal or distant) or laCSCC who were not candidates for curative surgery or curative radiation. Both studies excluded patients with autoimmune disease who required systemic therapy with immunosuppressant agents within 5 years; history of solid organ transplant; prior treatment with anti–PD-1/PD-L1–blocking antibodies or other immune checkpoint inhibitor therapy; infection with human immunodeficiency virus, hepatitis B, or hepatitis C; or ECOG performance score ≥2.²

Study 1540: EMPOWER-CSCC 1 (n=193)²

• Patients received LIBTAYO 3 mg/kg intravenously every 2 weeks for up to 96 weeks or LIBTAYO 350 mg every 3 weeks for up to 54 weeks. Treatment continued until progression of disease, unacceptable toxicity, or completion of planned treatment.²
• The primary endpoint was confirmed ORR by ICR, and secondary endpoints included DOR, CR rate, safety and tolerability.^2,13

• The recommended dosage of LIBTAYO is 350 mg administered as an intravenous infusion over 30 minutes every 3 weeks until disease progression or unacceptable toxicity.²

Demonstrated efficacy in patients with advanced CSCC who received LIBTAYO in Study 1540^2,14,15,†

Response rates in patients with mCSCC or laCSCC who were not candidates for curative surgery or curative radiation²

†Data cutoff was September/October 2018.^15‡ The numerator includes the number of patients whose observed DOR reached at least the specified times of 6 or 12 months. Patients who did not have the opportunity to reach the specified time point were included in the denominator only.² Plus sign (+) denotes ongoing at last assessment.²

• In the mCSCC, laCSCC, and combined advanced CSCC groups, median durations of follow-up were 16.5 months, 9.3 months, and 11.1 months, respectively. In the mCSCC LIBTAYO 350 mg Q3W group, median duration of follow-up was 8.0 months²

• Median TTR was 1.9 months (range, 1.7-9.1 months) in the combined advanced CSCC groups and 2.1 months (range, 2.0-8.3 months) in the mCSCC LIBTAYO 350 mg Q3W group^2,14

Study 1423: CSCC Cohorts (n=26)²

• Patients received LIBTAYO 3 mg/kg intravenously every 2 weeks for up to 48 weeks. Treatment continued until progression of disease, unacceptable toxicity, or completion of planned treatment.²

• The primary endpoint was to characterize the safety and tolerability of LIBTAYO, and the secondary endpoints included antitumor activity.^2,13

• The recommended dosage of LIBTAYO is 350 mg administered as an intravenous infusion over 30 minutes every 3 weeks until disease progression or unacceptable toxicity.

Safety profile in patients with advanced CSCC in clinical studies²

Adverse reactions in ≥10% of patients with mCSCC or laCSCC who were not candidates for curative surgery or curative radiation and who received LIBTAYO in Study 1423 and Study 1540²

Toxicity was graded per National Cancer Institute Common Terminology Criteria for Adverse Events (NCICTCAE) v4.03.² *Fatigue is a composite term that includes fatigue and asthenia.² †Rash is a composite term that includes rash, rash maculopapular, erythema, dermatitis, dermatitis bullous, rash generalized, pemphigoid, rash erythematous, rash macular, rash pruritic, drug eruption, psoriasis, and skin reaction.² ‡Pruritus is a composite term that includes pruritus and pruritus allergic.² §Diarrhea is a composite term that includes diarrhea and colitis.² IIMusculoskeletal pain is a composite term that includes back pain, pain in extremity, myalgia, musculoskeletal pain, and neck pain.² ¶Cough is a composite term that includes cough and upper airway cough syndrome.²

• The most common Grade 3-4 adverse reactions (≥2%) were cellulitis, anemia, hypertension, pneumonia, musculoskeletal pain, fatigue, pneumonitis, sepsis, skin infection, and hypercalcemia²

• LIBTAYO was permanently discontinued due to adverse reactions in 8% of patients²

• Adverse reactions resulting in permanent discontinuation were pneumonitis, cough, pneumonia, encephalitis, aseptic meningitis, hepatitis, arthralgia, muscular weakness, neck pain, soft tissue necrosis, complex regional pain syndrome, lethargy, psoriasis, rash maculopapular, proctitis, and confusional state²

• Serious adverse reactions occurred in 35% of patients2 • Serious adverse reactions that occurred in at least 2% of patients were pneumonitis, cellulitis, sepsis, and pneumonia2

Efficacy endpoints in patients with advanced CSCC in Study 1423²

• 50% ORR (13 out of 26 patients [95% CI, 30%-70%]); all responses were PRs²

• Median time to response was 1.9 months (range: 1.7-7.3 months)²

• 85% of responders (11 out of 13) reached a DOR ≥6 months²

• In this trial, DOR range was 1.0 to 20.3 months.¹⁵

*Data cutoff date was June 30, 2018.¹⁵ Median duration of follow-up was 13.3 months.²

was withheld for dermatologic adverse reactions, 7 reinitiated LIBTAYO after symptom improvement; of these, 43% (3/7) 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 mg 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 <1% in 810 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 mg 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, 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 thrombocytopenic purpura, solid organ transplant rejection

Infusion-related reactions

Severe infusion-related reactions (Grade 3) occurred in 0.1% of patients receiving LIBTAYO as a single agent. Monitor patients for signs and symptoms of infusion-related reactions. The most common symptoms of infusion-related reaction were nausea, pyrexia, rash, and dyspnea. Interrupt or slow the rate of infusion for Grade 1 or 2, and permanently discontinue for Grade 3 or 4.

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

In the pooled safety analysis of 810 patients, the most common adverse reactions (≥15%) with LIBTAYO were musculoskeletal pain, fatigue, rash, and diarrhea

In the pooled safety analysis of 810 patients, the most common Grade 3-4 laboratory abnormalities (≥2%) with LIBTAYO were lymphopenia, hyponatremia, hypophosphatemia, increased aspartate aminotransferase, anemia, and hyperkalemia

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 in females of reproductive potential prior to initiating LIBTAYO

NCCN Clinical Practice Guidelines in Oncology

Following the approval, the NCCN updated its guidelines for the treatment of advanced CSCC to recommend LIBTAYO as a Category 2A, preferred systemic therapy option when curative surgery and curative radiation therapy are not feasible for patients with laCSCC, regional CSCC or regionally recurrent or distant mCSCC.¹⁶,¶ ¶

Category 2A recommendation is based upon lower-level evidence; there is uniform NCCN^® consensus that the intervention is appropriate. All recommendations are Category 2A unless otherwise specified.¹⁶ NCCN is a registered trademark of the National Comprehensive Cancer Network^® (NCCN^®).¹⁶

Long-term Data from Study 1540^15,17,†

The following data represent a 3-year follow-up for Group 1, and 2-year follow-up for Group 2 and Group 3.† Follow-ups for each group are based on time from primary analysis for Study 1540¹⁷

† For these long-term data, the predetermined data cutoff date was October 11, 2020.^{17 ‡} Based on number of patients with confirmed CR or PR.¹⁷ § Percentages are based on number of patients with confirmed CR or PR. The numerator includes the number of patients whose observed duration of response reached at least the specified time. Patients who did not have the opportunity to reach the specified timepoint were included in the denominator only. Because responses for some patients are ongoing, the percentages at the specified timepoints may increase as data mature.¹⁵ Adapted with permission from Rischin et al, 2021.¹⁷

Tumor response assessment in patients by ICR across analyses in Study 1540^1,2,13,14,17

Response rates in patients with mCSCC or laCSCC who were not candidates for curative surgery or curative radiation² Response rates are based on analysis by independent central review of Study 1540 at time of data cutoff.

Long-term safety data for Study 1540¹⁷

Adverse reactions in ≥10% of patients with mCSCC or laCSCC who were not candidates for curative surgery or curative radiation and who received LIBTAYO in Study 1540¹⁷

Grade ≥3 adverse reactions occurred in 95 patients (49.2%). The most common Grade ≥3 adverse reactions were hypertension (n=9, 4.7%), anemia, cellulitis, and pneumonia (all n=8, 4.1%).¹⁷