Checkpoint Inhibitors Present Unique Adverse Events, Require Careful Management Strategies in Breast Cancer

Most, but not all, immunotherapy-related adverse events (irAE) occur throughout the first 12 weeks of treatment, and can affect any organ, according to La-Urshala Brock, FNP-BC, CNM, RNF, a clinical instructor specializing in breast and gynecologic cancers at the Nell Hodgson Woodruff School of Nursing with Emory University.¹

Brock recently presented during the 39th Annual Miami Breast Cancer Conference® about immunotherapy-related adverse event management, in a lecture titled, “Immunotherapy Adverse Effects,” which focused specifically on toxicities associated with pembrolizumab (Keytruda).

In July 2021, the PD-L1 inhibitor pembrolizumab was approved by the FDA to treat patients with triple-negative breast cancer (TNBC) in the neoadjuvant meeting in conjunction with chemotherapy, to be continued as an adjuvant monotherapy after surgery.²

The approval for pembrolizumab was supported by findings from the randomized, multicenter, double-blind, placebo-controlled KEYNOTE-522 trial (NCT03036488).³ Results demonstrated a 37% reduction in the risk of disease progression that precluded definitive surgery, a local/distant recurrence, a second primary cancer, or death from any cause (HR, 0.63; 95% CI, 0.48-0.82; P = .00031).The recommended dose for intravenous pembrolizumab is 200 mg every 3 weeks.²

Notably, this approval also marked the first immunotherapy to treat patients with high-risk early-stage TNBC. However, the introduction of the agent also opens the door for more toxicity management education for nurses who care for patient with breast cancer.

“Immunotherapies present with a novel spectrum of AEs that differ in important ways from those associated with chemotherapy and targeted agents,” said Brock. “When you're using immunotherapy, truly any organ can be affected. The median onset is 4 to 5 weeks [after beginning treatment], but adverse events can happen as early as when you start the treatment.”

Atezolizumab (Tecentriq), a PD-L1 inhibitor, was granted accelerated approval for TNBC to be given every 3 weeks with weekly nab-paclitaxel (Abraxane) in 2019, but this agent was withdrawn from market, since it was not shown to improve survival in patients with locally unresectable metastatic, PD-L1–positive disease.⁴

In her discussion, Brock highlighted a wide range of toxicities that are associated with immune checkpoint inhibitiors (ICI)—particularly for patients with TNBC receiving pembrolizumab. Toxicities of interest include dermatitis, endocrine effects, adrenal insufficiencies, lung effects, colitis, hepatotoxicity, and ocular side effects, in addition to a couple rarer immune-related AEs (irAEs).

Dermatitis

ICIs may induce low-grade rashes in many patients. This can include reticular erythema, papules, and plaques. In more rare cases, Stevens-Johnson syndrome or toxic epidermal necrolysis, palmar–planta dysesthesia may also occur.

Effective management of skin-related toxicities involve frequent photo documentation of the toxicity and follow-up photos to track potential changes, as well as consulting a dermatologist to obtain a biopsy. For low-grade toxicities, symptomatic treatment with antihistamines typically prove to be effective. However, for high-grade toxicities, treatment with topical or oral steroids may be appropriate. In addition, if symptoms progress to grade 3, treatment should be withheld, and if symptoms worsen to grade 4, treatment should be discontinued.^5,6,7,8

“We hold at this point,” said Brock. “You could think about using rituximab [Rituxan] for treatment. You want to continue steroids until the blisters have resolved completely and then [once] the blisters have resolved, you want to slowly taper the steroids.”

Endocrine Toxicities

Endocrine toxicities occur in approximately 10% of patients receiving pembrolizumab. Nurses should watch for vision changes, weight gain or weight loss, dizziness, constant chilliness or feeling cold, constipation, and hair loss. Other signs of endocrine toxicities include increased headaches or changes in headache patterns, increased heartbeat, increased urination, increased tiredness, increased thirst or appetite, changes in mood, and increased sweating.⁸

Patients suspected to be experiencing these toxicities should have their thyroid-stimulating hormone (TSH) and free thyroxine (FT4) checked every 4 to 6 weeks with complete blood count (CBC) and comprehensive metabolic panel (CMP).

Adrenal Insufficiency

Adrenal insufficiency, or Addison’s disease, means that the adrenal glands produce insufficient amounts of the hormone cortisol, Brock explained. Signs and symptoms include extreme fatigue, darkening skin or hyperpigmentation, low blood pressure or fainting, abdominal pain, muscle or joint pain, salt craving, weight loss, depression or behavioral changes, and nausea, vomiting, or diarrhea.

For primary adrenal insufficiency, the workup should include assessing morning cortisone and adrenocorticotropic hormone (ACTH) levels, as well as CMP to assess sodium, glucose, potassium, and carbon dioxide.

If a patient has elevated TSH levels but normal or low FT4, then hypothyroidism is the cause. So long as the toxicity remains a grade 1 (TSH < 10 ml U/L or asymptomatic), they may continue receiving the checkpoint inhibitor with continued TSH and FT4 monitoring.

For hypophysitis, or inflammation of pituitary gland, the workup should include assessing morning cortisone as well as ACTH, TSH, FT4, testosterone in men, follicle-stimulating hormone (FSH), luteinizing hormone (LH), estrogen in premenopausal women, and an MRI of the brain with or without contrast with pituitary cuts.

If the hypothyroidism progresses to a grade 2 (TSH > 10 mIU/L or symptomatic), the ICI should be withheld, an endocrinologist should be consulted, and a thyroid hormone supplementation should be implemented. The patients will continue to require TSH and FT4 checks every 6 weeks, but if the severity reduces to a grade 1 event, they may continue treatment.

In the event of grade 3/4 hypothyroidism, the ICI should be withheld until symptoms resolve to baseline with thyroid supplementation.

If a patient has low TSH and high, normal, or elevated FT4 levels, then this person is experiencing hyperthyroidism. As long as the toxicity remains at grade 1, they may continue receiving the ICI with continued TSH and FT4 checks every 2 to 3 weeks.

If the hyperthyroidism progresses to a grade 2, the ICI should be withheld until symptoms return to baseline and an endocrinologist should be consulted. A beta blocker might also be considered.

For grade 3/4 hyperthyroidism, the ICI will need to be withheld until symptoms resolve to baseline with thyroid supplementation. In addition, at this grade, hospitalization may be required if thyroid storm occurs. Prednisone should be considered at a dosage of 1 to 2 mg/kg daily and then put on a tapering schedule.

“With hyperthyroidism, what I want to mention here is that if someone is experiencing symptoms, we can use a beta blocker, but we also still want to be consulting endocrinology,” Brock highlighted. “One of the risk factors here when we get to grade 4 is the risk for thyroid storm. That is why it is important to have endocrinology involved.”

In less than 1% of patients, ICI-mediated endocrinopathy type 1 diabetes mellitus may occur with rapid onset anytime following therapy initiation.

Management for this toxicity involves monitoring serum glucose at baseline and prior to each cycle of ICI. An endocrinologist should be consulted, and generally, lifelong insulin therapy will be required. Once blood sugar is well controlled, the ICI therapy can be restarted.

Lung Toxicity

Pneumonitis equates to inflammation of the lung parenchyma. This irAE occurs between 0% to 10% of patients, but the odds increase when patients receive combination therapy as opposed to monotherapy, as well as if there has been previous thoracic radiation.^9-11 The onset time for lung toxicity can range from 2 to 24 months, however, the median onset time is 3 months.

Cough, fever, dyspnea, and chest pain should be evaluated when monitoring for lung toxicity. Patients who experience these symptoms will need a chest x-ray and CT scan. The threshold for obtaining a CT scan of the chest and a pulmonary consultation should be low, noting that CT findings typically lag patient symptoms.

Management includes routine pulse oximetry checks in addition to potential CT scans, as well as administration of high-dose steroids, starting at 1 to 2 mg/kg daily, and tapering across 45 to 60 days. If symptoms return, the steroids may require retapering.

If within 72 to 96 hours of steroid initiation there is no symptom relief, patients should receive infliximab-axxq (Avsola) at 5 mg/kg. In most cases, the addition of immunosuppressants will help to resolve the issue.Infectious workup should include a nasal swab for potential viral pathogens, including COVID-19.

Notably, lung toxicity has been associated with immune checkpoint inhibitors but is an uncommon AE; less than 5% of patients experience this irAE, and less than 1% report high-grade lung toxicity while receiving this type of immunotherapy. In comparison, lung toxicity tends to present more in patients receiving ipilimumab (Yervoy) plus nivolumab (Opdivo), explained Brock.

Colitis

Colitis occurs in approximately 8% to 27% of patients receiving ICIs. Onset of GI toxicities typically appear about 5 to 10 weeks after treatment begins but can occur months after treatment with the ICI has stopped.

Initial workup for colitis should include CBC, CMP labs to assess TSH, c-reactive protein (CRP), HIV, hepatitis A and B; whereas interferon gamma release assay should be used to look for tuberculosis (TB). In addition, stool cultures to identify C. diff, CMB, ova, and parasites are recommended; lactoferrin should identify inflammation of digestive tracts and calprotectin can determine immune bowel disease (≤80 ug/g) vs inflammation (levels on 80 ≥ 1, 60 ug/g); and a CT scan.

At grade 1 severity, the ICI can either continue or be temporarily withheld. Providers should discuss dietary changes with their patients and review hydration strategies, and antdiarrheal administration may also be effective.

If the inflammation progresses to grade 2 level, the ICI should be withheld until symptoms return to grade 1 or less. A GI specialist should be consulted for an EGD/colonoscopy and prednisone should be administered at a dosage of 1 mg/kg daily. In addition, stools should be checked for inflammatory markers, such as lactoferrin and calprotectin. Once the symptom returns to grade 1, the steroids should be tapered across 4 to 6 weeks.

Grade 3 inflammation requires a hold on the ICI. Hospitalization may be required if there is electrolyte imbalance and dehydration. Providers should rule out CMV via colonoscopy and consult a GI specialist. Corticosteroids given at a dosage of 1 to 2 mg/kg day or infliximab at a dosage of 5 to 10 mg/kg daily should be administered.

“With colitis, there could be another rebound,” said Brock. “Someone could resolve back to a ready to a grade 1; if that occurs then, of course, we restart the steroids or increase the steroids and start again—slowly tapering once the symptoms improve.”

If the severity level reaches a grade 4, it is now life-threatening, and treatment should be discontinued permanently.

Hepatotoxicity/Immune-Mediated Hepatitis

Hepatotoxicity or immune-mediated hepatitis occurs in approximately 2% to 10% of patients receiving pembrolizumab and onset usually occurs between 6 to 12 weeks after treatment initiation. Symptoms include drowsiness, jaundice, right-sided abdominal pain, severe nausea or vomiting, increased bleeding, or bruising, decreased appetite, and abnormal liver blood tests (aspartate aminotransferase [AST], alanine transaminase [ALT], and bilirubin).

For grade 1 inflammation (AST or ASLT > upper limit of normal [ULN] to 3.0 and/or total bilirubin 1.0 ULN > 1.5 ULN), ICI treatment may continue but liver function should be monitored 1 to 2 times weekly. For grade 2 inflammation (ASR or ALT > 3.0 ULN to < 5.0 and/or total bilirubin 1.0 ULN to 3.0 ULN with symptoms), the ICI should be held until severity resolves to a grade 1.

In addition, the liver should be monitored every 3 days if the patient is symptomatic. If the symptom reaches statistical significance, after 3 to 5 days they can receive corticosteroids at a dosage of 0.5 to 1.0 mg/kg daily. This will require tapering over 1 month. Lastly, any hepatoxic medication should be halted.

For grade 3 inflammation (ASR or ALT 5 x 20 x ULN and/or total bilirubin >3-10 x ULN with symptoms such as biopsy-fibrosis or cirrhosis), the ICI should be discontinued permanently, and the patient should be monitored every 1 to 2 days. Corticosteroids should be administered at a dosage of 1 to 2 mg/kg/day, and the patient should be referred to a hepatologist.

If the symptom progresses to grade 4 (ASR or ALT >20 x ULN and/or total bilirubin > 10 x ULN, with symptoms such as ascites or encephalopathy), they will need to be hospitalized with daily lab monitoring and consultation from a hepatitis. They should receive methylprednisone at a dosage of 2 mg/kg daily.

Ocular Symptoms

Ocular symptoms typically occur in less than 1% of patient receiving PD-1/PD-L1 inhibitors alone or in combination. Symptoms include eyelid swelling, blurred vision, double vision, or color vision changes, photophobia, painful eye movement, scotomas, proptosis or bulging eyes, and visual field changes.

If a patient appears to be experiencing an ocular toxicity, they should be referred to an ophthalmologist and receive a slit-lamp exam.

Treatment management for uveitis or inflammation of the middle of the eye, and iritis, or inflammation of the iris, are similar. For grade 1 inflammation, ICI treatment should continue but a referral to an ophthalmologist should be made. For grade 2 inflammation (anterior uveisis), the ICI should be held until ophthalmology evaluation and topical or systematic corticosteroids can be administered. These can continue once the issue resolves or returns to grade 1 and the patient resumes ICI treatment.

If symptoms progress to grade 3 (posterior uveitis), the ICI should be discontinued permanently, and systematic and topical corticosteroids should be administered. Lastly, if symptoms become grade 4, not only should the ICI be discontinued permanently, but the patient may need emergency care.

Rare irAEs

In addition, rare irAEs that may present in patients receiving ICIs include myocarditis and pericarditis; nephritis; pancreatitis; musculoskeletal toxicities such as arthritis, arthralgia, myalgia, and myositis; and neurologic toxicities such as peripheral neuropathy, myasthenia gravis, and Guillain-Barré Syndrome.

General Principles of ICI Toxicity Management

In conclusion, for grade 1 toxicities (mild or asymptomatic toxicities), the patient can continue receiving the ICI without steroids or intervention. Patients with grade 1 toxicities may benefit from antihistamines.

For grade 2 toxicities (moderate toxicities), a specialist should be consulted, and steroids should be considered. The ICI should be withheld until the symptom returns to grade 1; if the grade 2 symptoms persist for more than 12 weeks, the ICI should be discontinued.

If symptoms progress to grade 3, the ICI should be held (or, in the case of pneumonitis, discontinued), and prednisone should be administered. A specialist should be consulted, and hospitalization may become necessary. If these symptoms remain consistent, the ICI should be discontinued.

Grade 4 toxicities are life-threatening. Unless the symptom is endocrine-related, grade 4 toxicities signify that the ICI should be immediately discontinued. The patient will need hospitalization, and to continue receiving prednisone. If the steroid does not yield symptom improvement, infliximab should also be considered.

Other important considerations include using a proton pump inhibitor or H2 blocker for gastritis, sulfamethoxazole/trimethoprim/fluconazole for opportunistic infections, and calcium and vitamin D for osteoporosis, Brock noted.

Furthermore, counseling patients and caregivers should involve setting evidence-based expectations for benefits. Patients may have heard of the drug and have misconceptions based on popular stories in the news. It should be clear that benefits taking longer to emerge with immunotherapy compared with treatments like chemotherapy and targeted therapy. Therefore, patients with significant tumor burden or rapidly progressing disease often cannot afford to elect these types of therapies.

For nurses caring for patients beginning immunotherapy, it is essential to emphasize the importance of monitoring and promptly reporting symptoms.

“Emphasize [the importance] of monitoring and promptly reporting symptoms,” Brock urged. “[Teach them to] contact the oncology care team if [they are] experiencing any new signs or symptoms [and to] report any visits to the emergency department and other healthcare providers.”

In addition, patients should also always always carry an immunotherapy wallet. Lastly, patients need adequate irAE management education.

“Discontinuing ICIs because of AEs does not worsen survival,”¹² she noted. “Treating irAEs with steroids does not worsen response or survival.”^13,14 

References

1. Brock LA. Immunotherapy adverse effects. Presented at: 39th Annual Miami Breast Cancer Conference®; March 3-6, 2022; Miami Beach, FL.
2. This Keytruda combination is the first immunotherapy regimen approved for high-risk early-stage triple-negative breast cancer (TNBC). News release. Merck. July 27, 2021. Accessed March 15, 2022. https://bit.ly/3id6Rou
3. Schmid P, Cortes J, Dent R, et al. Event-free survival with pembrolizumab in early triple-negative breast cancer. N Engl J Med. 2022;386(6):556-567. doi:10.1056/NEJMoa2112651
4. Roche provides update on Tecentriq US indication for PD-L1-positive, metastatic triple-negative breast cancer. News release. Roche. August 27, 2021. Accessed August 27, 2021. https://bit.ly/3ypzC6K
5. Weber JS, Postow M, Lao CD, Schadendorf D. Management of adverse events following treatment with anti-programmed death-1 agents. Oncologist. 2016;21(10):1230-1240. doi:10.1634/theoncologist.2016-0055.
6. Haanen JBAG, Carbonnel F, Robert C, et al. Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up [published correction appears in Ann Oncol. 2018;29(suppl 4):iv264-iv266]. Ann Oncol. 2017;28(suppl_4):iv119-iv142. doi:10.1093/annonc/mdx225
7. Sanlorenzo M, Vujic I, Daud A, et al. Pembrolizumab cutaneous adverse events and their association with disease progression. JAMA Dermatol. 2015;151(11):1206-1212. doi:10.1001/jamadermatol.2015.1916
8. Freeman-Keller M, Kim Y, Cronin H, Richards A, Gibney G, Weber JS. Nivolumab in resected and unresectable metastatic melanoma: characteristics of immune-related adverse events and association with outcomes. Clin Cancer Res. 2016;22(4):886-894. doi:10.1158/1078-0432.CCR-15-1136
9. NCCN guidelines for management of immunotherapy-related toxicities. NCCN. Accessed March 18, 2022. https://bit.ly/34TwdEN
10. Haanen JBAG, Carbonnel F, Robert C, et al. Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up [published correction appears in Ann Oncol. 2018 Oct 1;29(Suppl 4):iv264-iv266]. Ann Oncol. 2017;28(suppl_4):iv119-iv142. doi:10.1093/annonc/mdx225
11. Chen X, Zhang Z, Hou X, et al. Immune-related pneumonitis associated with immune checkpoint inhibitors in lung cancer: a network meta-analysis. J Immunother Cancer. 2020;8(2):e001170. doi:10.1136/jitc-2020-001170
12. Harbeck, N. Immunotherapy in TNBC: rationale and current clinical standards. Clinic Care Options Oncology. Accessed March 18, 2022. https://bit.ly/3MYh1rf
13. Brahmer JR, Laccheti C, Schneider BJ, et al. National Comprehensive Cancer Network. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy. American Society of Clinical Oncology Clinical Practice Guidelines. J Clin Oncol. 2018;36(17):1714-1768. doi:10.1200/JCO.2017.77.6385
14. Emens, LA, Adams S, Cimino-Matthews A, et al. Society for Immunotherapy of Cancer (SITC) clinical practice guidelines on immunotherapy for the treatment of breast cancver. J Immunother Cancer. 2021; 9(8):e002597. doi:10.1136/jitc-2021-002597