CME
Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™
ABIM MOC: maximum of 1.00 Medical Knowledge MOC point
Released: September 18, 2023
Expiration: September 17, 2024
Overview of Immune-Related Adverse Events
Immunotherapy has revolutionized the treatment of many different malignancies, and immune checkpoint inhibitors (ICIs) are now integral to the management of patients with advanced endometrial cancer. By blocking checkpoint proteins (eg, CTLA-4, PD-1) or their ligands (PD-L1), these agents disrupt immunosuppressive signaling by cancer cells, thereby enabling T-cells to recognize and attack the tumor.1 Current NCCN guidelines recommend PD-1/PD-L1 inhibitors as monotherapy, in combination with chemotherapy, or in combination with a VEGF-targeted agent in various settings for advanced endometrial cancer.2
The global immune activation induced by ICIs can cause a range of irAEs—essentially autoimmune conditions that can affect any tissue in the body and vary in severity.3,4 That said, irAEs most commonly affect the skin, gastrointestinal system, liver, and endocrine system. The clinical images shown here demonstrate some of the physical and radiologic manifestations of these toxicities.
These irAEs can be quite different in both presentation and management from the toxicities caused by cytotoxic chemotherapy. In this focused module, I will discuss identifying and managing irAEs in patients with endometrial cancer receiving ICIs as monotherapy, in combination with chemotherapy, and in combination with the VEGF-targeted agent lenvatinib.
Safety of Single-Agent Immunotherapies in Endometrial Cancer
Single agent immunotherapy is associated with adverse events that are mostly low grade and quite manageable. The 2 most common agents used in endometrial cancer are the PD-1 inhibitors pembrolizumab and dostarlimab. The top rows of this table show the low incidence of grade ≥3 treatment-related adverse events reported in the KEYNOTE-158 and GARNET trials of pembrolizumab and dostarlimab, respectively, in patients with endometrial cancer that is mismatch repair deficient (dMMR) or microsatellite instability‒high (MSI-H).5,6 The bottom rows show the very low incidence of irAEs reported in these trials.
Safety of Immunotherapies in Combination With Chemotherapy
Next, we will look at the safety profile of immunotherapies when combined with chemotherapy. An important development in 2023 was the adoption of ICIs in combination with carboplatin/paclitaxel into standard of care for primary advanced or recurrent endometrial cancer.7 This development was motivated by positive results from the phase III ENGOT-EN6/GOG-3031/RUBY trial, which is assessing dostarlimab in combination with carboplatin/paclitaxel, and the phase III NRG GY018 trial, which is assessing pembrolizumab in combination with carboplatin/paclitaxel.8,9 We will focus on dostarlimab plus carboplatin/paclitaxel because more comprehensive safety data are available from RUBY.
In brief, RUBY randomized patients to receive dostarlimab or placebo plus chemotherapy, followed by single-agent dostarlimab or placebo maintenance.9 Although both arms experienced high rates of treatment-emergent adverse events (TEAEs), the addition of immunotherapy to standard chemotherapy did not result in a notably more toxic profile. As shown here, grade ≥3 TEAEs were observed in 59.8% of patients on the placebo plus chemotherapy arm. There was a relatively small increase in this rate to 70.5% with the addition of immunotherapy. Overall, the combination of immunotherapy plus standard chemotherapy is well tolerated.
irAEs With Immunotherapy Plus Chemotherapy
As would be expected, RUBY reported more irAEs in patients who had dostarlimab vs placebo added to chemotherapy.9 Treatment-related irAEs were reported in 38.2% vs 15.4% of patients, respectively. Of those, 16.6% vs 6.1% were grade ≥3. The specific irAEs were generally consistent with those reported for ICI monotherapy, with patients most commonly experiencing hypothyroidism, rash, arthralgias, and ALT increases. Again, we see that the endocrine system, skin, and liver are most likely to be affected by irAEs.
Quality of Life With Immunotherapy Plus Chemotherapy
How do these toxicities and the antitumor activity of dostarlimab plus chemotherapy affect quality of life? At ASCO 2023, Mirza and colleagues10 presented data on health-related quality of life (HRQoL) and patient reported outcomes from the RUBY trial. Compared with baseline, patients who received the combination regimen maintained their HRQoL and exhibited no differences vs those who received placebo plus chemotherapy.
In the cohort with dMMR disease—the patients who had the greatest progression-free survival and overall survival benefit with dostarlimab plus chemotherapy9—there were significant differences in patient-reported outcomes.10 Specifically, these patients experienced significant improvements in back and pelvis pain at the end of the combination treatment period vs the placebo arm.
This improvement in back and pelvis pain likely reflects how well the immunotherapy is controlling and counteracting pelvic disease, which is very common and can be quite extensive in endometrial cancer. Another option for controlling the pain and symptoms of pelvic disease is palliative radiation, which is generally well tolerated but comes with the risk of diarrhea and other complications.
Taken together, these safety and quality of life data suggest that adding immunotherapy to chemotherapy causes a small increase in toxicity but comes with improvements in overall HRQoL compared with the deterioration seen with chemotherapy alone.
Workup for More Common irAEs
Moving on, we will now discuss the identification and workup of 4 of the more common irAEs: colitis, hepatitis, nephritis, and pneumonitis.
Colitis
The evaluation and workup of diarrhea/colitis are particularly challenging in the setting of endometrial cancer. Many patients have a history of whole-pelvic radiation, which can cause acute and chronic diarrhea. It is important to do a very thorough evaluation with a referral to our GI colleagues and a colonoscopy to help determine whether the diarrhea/colitis may be radiation induced vs immune mediated. A colonoscopy can identify differences in vascular patterns that reflect the etiology; for example, radiation can cause decreased vasculature, telangiectasias, and even structural changes to the colon, such as strictures.11
Timing can sometimes help determine the cause of the diarrhea. When related to radiation, patients typically develop acute diarrhea after 2 weeks of treatment.12 However, patients also can experience onset of diarrhea months to even years after completing their radiation therapy.11 This makes it more challenging to determine the cause because the median onset for immune-related diarrhea is approximately 7-8 weeks with PD-1 inhibitors.13
It is important to bear in mind that diarrhea can have many causes beyond radiation or immunotherapy. Thus, the NCCN recommends that patients receiving ICI-based therapy who present with diarrhea should undergo laboratory evaluation with stool studies to rule out infectious etiologies.2 Patients with grade ≥2 diarrhea/colitis—essentially, ≥4 bowel movements per day above baseline—should be considered for GI consultation. Those with these higher-grade events and suspicion for complications also should be considered for imaging for diagnostic purposes.
Hepatitis
As with colitis, the workup for hepatitis relies on imaging and laboratory assessments to rule out other potential etiologies.2 In particular, it is important to rule out viral causes and alcohol use and to perform a thorough review for any medications (eg, acetaminophen) that could be causing or contributing to the hepatitis. Timing also can help here, with the median onset for immune-related hepatitis being approximately 7-8 weeks after initiating PD-1 inhibitors.13 Again, consider a GI or Hepatology consultation for patients with grade ≥3 hepatitis, defined as ALT/AST increases >5-20x ULN.2
Nephritis
It is also important to rule out potential causes of nephritis, which could include IV contrast agents, urinary tract infections, or certain medications.2 A patient’s fluid status also can contribute to the development of nephritis. Immune-related renal complications typically develop later than other irAEs, with a median onset of approximately 15-16 weeks with PD-1 inhibitors.13
Pneumonitis
It can be challenging to identify the etiology of pneumonitis. Are the symptoms related to the ICI, COVID-19, pneumonia, or another cause? The evaluation for pneumonitis includes imaging (ie, chest CT with contrast if not contraindicated) and an infectious workup.2 Timing can help here, with immune-related pneumonitis having a median onset of 9-10 weeks with PD-1 inhibitors.13
Patients with grade ≥2 pneumonitis—defined as the presence of new or worsening symptoms such as shortness of breath, dry cough, or chest pain—should be considered for referral to Pulmonary with bronchoscopy and consideration of a lung biopsy, if feasible or indicated.2 A cardiac consultation also should be considered for those experiencing higher-grade pneumonitis.
Workup for Rarer and/or More Lethal irAEs
As I mentioned earlier, irAEs can affect any tissue in the body and can range in severity from mild to life-threatening. Shown here are 4 of the rarer and/or more lethal irAEs: hypophysitis, myasthenia gravis, myocarditis, and myositis. These events illustrate the importance of having a high index of suspicion for irAEs, along with the need to counsel patients to report any symptom, no matter how trivial.
Hypophysitis
Symptoms of hypophysitis include pronounced fatigue, changes in blood pressure, and nausea.2 Patients experiencing symptoms that might be related to hypophysitis should be considered for a brain MRI.2 Of importance, if the patient has polyurea or polydipsia with elevated serum sodium, consider workup for diabetes insipidus.
Myasthenia Gravis
Be sure to consult with Neurology when your patients present with muscle weakness or other symptoms of myasthenia gravis.2 The workup might include brain and/or spine MRI to rule out central nervous system disease.
Myocarditis
An early Cardiology consult and evaluation is also important for patients with symptoms of myocarditis such as chest pain, shortness of breath, fatigue, arrhythmia, or fainting.2 The workup is extensive and thorough because, although this is a very rare irAE, it is highly lethal.
Myositis
Patients with symptoms of myositis (ie, skeletal muscle weakness) also should be evaluated for myasthenia gravis and myocarditis.2 The workup includes blood tests and muscle strength testing of both proximal and distal muscles.
General Principles for Managing irAEs
Anticipation, preparation, and knowledge are key to mitigating irAEs.14 It is imperative to educate patients and caregivers about these toxicities and to have them contact you immediately about any new symptoms.
We recommend checking for irAEs at each cycle for the first 3 months of treatment.2 This includes clinical and laboratory assessments. Because endocrinopathies are quite common with immunotherapy, thyroid tests should be done every cycle for the first 3 months and then every 2-3 cycles thereafter.
Treatment of most irAEs relies on symptomatic management, steroids to suppress the immune processes, and withholding or permanent discontinuation of immunotherapy as needed.2,14 An exception here is for endocrinopathies; once hormone supplementation is established, the patient typically can continue immunotherapy without need for steroids.
In general, management of irAEs is guided by CTCAE version 5.0 grading of severity.
In collaboration with the NCCN, Clinical Care Options has developed a free interactive algorithm tool to help HCPs quickly access case-specific recommendations from NCCN Guidelines® on irAE management for their unique patient scenarios.
Managing Immune-Related Diarrhea/Colitis in Patients With Advanced Endometrial Cancer
As noted earlier, diarrhea/colitis is particularly challenging in the setting of endometrial cancer, given how common it is for patients to have received whole-pelvic radiation. Determining the etiology of the diarrhea is very important to proceeding with management. For example, we can treat radiation-induced diarrhea with steroid enemas but usually would not use systemic steroids.15 By contrast, systemic steroids are the mainstay for treatment of immune mediated diarrhea—meaning systemic steroids would be likely to resolve immune-mediated diarrhea but not radiation-induced diarrhea. To further complicate matters, if there is an infectious cause for the diarrhea, then steroids could potentially make it worse.16
If our workup indicates that the diarrhea/colitis is indeed immune related, management depends on the grading. Grading is based on the increase in the number of bowel movements per day above baseline and the presence or absence of colitis symptoms.2
Grade 1 and 2 immune-related diarrhea/colitis are treated more with symptom management, such as over-the-counter antidiarrheals, hydration, and diet modifications.2 For grade 1, the NCCN recommends considering withholding immunotherapy; for grade 2, holding immunotherapy is recommended. Patients with grade 2 diarrhea/colitis should receive systemic steroids, starting with oral steroids. If nonresponsive, immunosuppression should be escalated to IV steroids with consideration of adding other immunosuppressive agents (eg, infliximab or vedolizumab). If the low-grade diarrhea/colitis is persistent, the patient should undergo outpatient workup.
For grade 3 and 4 immune-related diarrhea/colitis, in my practice I would admit the patient to the hospital and expedite their workup and evaluation. The NCCN recommends admission and IV methylprednisolone, with strong consideration of adding additional immunosuppression (eg, infliximab or vedolizumab) if there has been no improvement within 24-48 hours. The NCCN also recommends permanent discontinuation of immunotherapy for grade 4 events. For grade 3, immunotherapy absolutely should be held; if the toxicity resolves, rechallenge with a PD-1 agent can be considered.
Assessment
Multidisciplinary Tools for Optimizing Team Communication and Patient Education
Communication, patient education, and prevention are essential to optimizing outcomes during and after treatment with ICI-based therapy. I will review some of the tools available to help the multidisciplinary team optimize their care for patients receiving immunotherapy.17
Patient Checklist
Education on irAEs is essential for patients who are initiating ICI-based therapy, are currently in treatment, or have stopped treatment. A patient checklist can help communicate to patients and caregivers which signs and symptoms they should be particularly alert for and when to contact the oncology team.
Nursing Checklist
Given that irAEs are different from what your clinical staff may be prepared for based on their experience with cytotoxic chemotherapy, it is helpful to develop a checklist for the nursing team. This can help provide consistent structure when nurses are performing patient assessments during triage calls or infusion intake.
Lab Tracker and Electronic Health Records
Centralized recordkeeping is important to keep all HCPs up to date on irAE monitoring and management. Electronic health records are a good resource to use for tracking irAE management, when immunotherapy is being held, and for the details of any immunosuppressive therapy.
Immunotherapy Wallet Card
Even with an established electronic health record system, it is essential that the care team provide patients with an immunotherapy wallet card. This is a portable hardcopy card developed by the Oncology Nursing Society that provides information on patients’ anticancer treatment and how to contact their oncology care team. Patients and caregivers should be instructed to share the wallet card with any HCP they see (eg, urgent care, primary care).
CTCAE Version 5.0
Finally, it is important to understand how to grade toxicities. HCPs should use CTCAE version 5.0 for classifying the severity of anticancer therapy–related toxicities—an essential step in determining optimal management per NCCN guidelines and effectively communicating with other HCPs about the toxicity.
Safety of Immunotherapy in Combination With VEGF-Targeted Therapy
We will now move on to discussing management of adverse events associated with combination immunotherapy and VEGF targeted therapy. The FDA has approved lenvatinib, a multikinase inhibitor that targets VEGF, in combination with pembrolizumab for treatment of patients with advanced endometrial carcinoma that is not MSI-H or dMMR, who had disease progression after systemic therapy in any setting, and who are not candidates for curative surgery or radiation.18
This combination initially received an accelerated approval in 2019, followed by regular approval in 2021 based on positive results from the phase III Study 309/KEYNOTE-775 trial.19 KEYNOTE-775 enrolled patients with advanced or recurrent endometrial cancer of any histology except carcinosarcoma and sarcoma who had received 1-2 lines of platinum-based chemotherapy.20
Study 309/KEYNOTE-775: Adverse Events
Shown here are the TEAEs reported from Study 309/KEYNOTE-775.20,21 The most common TEAEs with lenvatinib/pembrolizumab are hypertension, hypothyroidism, and diarrhea. Hypertension is a class effect of VEGF inhibitors, as is proteinuria, another common toxicity. We will pay particular attention to the management of these key TEAEs.
General Management of Adverse Events With Lenvatinib/Pembrolizumab
Most adverse events that emerge with lenvatinib/pembrolizumab are managed with supportive care plus withholding 1 or both agents.18,20,22-25 HCPs should have a low threshold for holding and dose reducing lenvatinib. As a tyrosine kinase inhibitor, this agent has a much shorter half-life than pembrolizumab—approximately 28 hours vs 22 days, respectively.18,25 For most of the key TEAEs listed on this slide (eg, fatigue, diarrhea), if a toxicity resolves within several days of holding lenvatinib, then you know the causative agent was lenvatinib. If the toxicity persists or worsens, you need to consider alternative etiologies, holding pembrolizumab, and initiating steroids.
The starting dose for lenvatinib is 20 mg based on clinical trials. However, in clinical practice, most patients who have poor performance status and/or multiple comorbidities will not be able to tolerate this high dose and should instead start at 14 mg or even 10 mg. It is incredibly important to collaborate with nurses and pharmacists to support adherence
Managing Adverse Events With Lenvatinib/Pembrolizumab: Hypertension
Hypertension is an on-target toxicity—the consequence of inhibiting VEGF signaling.26 Hypertension is one of the most common adverse events related to lenvatinib/pembrolizumab and can be both debilitating and difficult to manage. As we saw earlier, 65.0% of patients who received lenvatinib/pembrolizumab on KEYNOTE-755 developed hypertension, with 39.2% experiencing events that were grade ≥3.20,21 Some HCPs even would recommend a prophylactic antihypertensive prescription for medications such as hydralazine for patients to initiate at home. It is certainly important to optimize blood pressure control before initiating treatment with lenvatinib/pembrolizumab.18,20,22
The next step in successful management of hypertension is close monitoring. We recommend that patients monitor their blood pressures at home and notify the office if their blood pressure increases above normal range. The clinic also should check blood pressure regularly during treatment.
Lenvatinib should be held for grade 3 hypertension that occurs despite optimal hypertensive therapy and should be permanently discontinued for grade 4 hypertension. Lenvatinib also should be permanently discontinued for any arterial thrombotic event.
Managing Adverse Events With Lenvatinib/Pembrolizumab: Hypothyroidism
Hypothyroidism is part of the safety profile for both lenvatinib and pembrolizumab when given as single agents.24 It is important to regularly monitor thyroid tests to detect this endocrine toxicity as soon as it emerges.
When the severity of the hypothyroidism reaches grade 2, you should initiate thyroid replacement hormones. Pembrolizumab generally can be continued, with holding necessary only until the patient is stable on replacement hormones. Lenvatinib dose modifications rarely are needed for hypothyroidism.
Managing Adverse Events With Lenvatinib/Pembrolizumab: Proteinuria
Proteinuria is another on-target toxicity of VEGF inhibitors but also can be indicative of immune-related nephritis.2,27 Thus, it is important to assess regularly for proteinuria using a urine dipstick.24 If the urine dipstick shows ≥2+ or an increase in proteinuria severity, you should perform a 24 hour urine collection to grade the proteinuria. Depending on the results, lenvatinib should be held, dose reduced, or even permanently discontinued.
Case: Patient With Immune-Related Encephalopathy
To conclude this discussion, I want to end with a case from my practice illustrating the importance of patient education, HCP communication, and having a high index of suspicion for novel symptoms, as well as the efficacy of prompt management of irAEs.
The patient was a 45-year-old woman with metastatic endometrial cancer who was receiving single agent pembrolizumab. She presented to the ER with altered mental status. Neurology was consulted, and she underwent a head CT and MRI, which was negative for a stroke. She had a lumbar puncture that was notable for an elevated lymphocyte count, and autoimmune encephalitis was suspected.
The patient began receiving steroids, and her altered mental status resolved. Pembrolizumab was subsequently discontinued, and she has had no permanent toxicities from this event, fortunately.
Encephalopathy is an extremely rare irAE. As we have just discussed, most irAEs are low grade and manageable, with patients able to resume or even continue immunotherapy. That said, this unusual case emphasizes the importance of educating patients and caregivers on watching for new signs and symptoms and when to seek urgent care. The immunotherapy wallet card that I described earlier also can help when communicating with other HCPs about which anticancer therapies the patient is receiving, particularly if the patient is presenting to a clinic outside of the record system used by the oncology care team. Finally, by promptly initiating steroids and discontinuing immunotherapy, the patient was able to recover.
Key Takeaways
ICIs—whether as single agents or in combination with chemotherapy or lenvatinib—are now essential to the standard of care in frontline and later-line management of advanced endometrial cancer. As immunotherapies become more widely used in endometrial cancer, managing the associated irAEs is critical to optimizing patient outcomes.
The key to optimal irAE management is patient and caregiver education. This education must cover potential irAEs and reinforce the importance of notifying HCPs at the onset of any symptoms. When an irAE does occur, the workup and management depend on critical thinking and a differential diagnosis to find the etiology of the toxicity, particularly when ICIs are given as part of a combination regimen. Successful management relies on supportive care, ICI holds, immunosuppressive therapy, and specialist consultations as needed. It really does take a team, and that team includes everyone from the physicians, nurses, and pharmacists to the patients and their caregivers.
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