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RCC Outcomes Optimization

CE / CME

Optimizing Outcomes for Patients With RCC

Pharmacists: 1.00 contact hour (0.1 CEUs)

Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™

Released: April 07, 2023

Expiration: April 06, 2024

CME/CE Information

Activity

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1
Course Completed

A New Spectrum of Adverse Events With IO-Based Therapy

Unfortunately, all of our medicines have associated AEs. Because most frontline treatment options include an IO‑based backbone, my clinical team and I spend a lot of time educating patients prior to their first treatment about what AEs to be aware of with immunotherapy. Essentially, these can be an inflammation anywhere in the body, similar to an autoimmune process. The most common AEs are rash, fatigue, and joint aches. More severe (and fortunately, less common) irAEs include colitis, pneumonitis, and encephalitis. Educating patients on these toxicities is of utmost importance because early intervention can lead to improved outcomes.37-40

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Time of Onset and Toxicity Grade of Immune-Related Adverse Events in Patients Receiving PD-1/PD-L1 Antibodies

Immunotherapy AEs can occur at any time. Each specific irAE does have a window where it is more likely to occur, but in general I tell patients that some of the most frequent toxicities can occur in the first 12 weeks of treatment, particularly if IO/IO combination treatment is used.41

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Rates of AEs in IO-Based Combination Therapy for RCC

Looking at all the frontline IO combination trials, grade 3/4 AEs certainly occurred across the board, but incidence varied among the trials and agents used. All of the IO/TKI combinations had grade 3/4 hypertension, with the highest (27.6%) occurring in the CLEAR study of pembrolizumab/lenvatinib, but no grade 3/4 hypertension was noted in the CheckMate 214 study of ipilimumab/nivolumab. All of the trials had some level of liver function test elevation that was grade 3/4. Higher levels of hypophysitis occurred with combination PD‑1/CTLA-4 therapy.20,22,42,43

When thinking about frontline treatment selection, the AE profile is very important to take into consideration.

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General Guidelines for Management of irAEs

Several guidelines are available for the management of irAEs. ASCO, the National Comprehensive Cancer Network (NCCN), and the Society for Immunotherapy of Cancer have published guidelines to assist with grading and treatment of irAEs.44-46 The management of irAEs is immune suppression, typically with high‑dose steroids in the form of prednisone or methylprednisolone.

Typically, for a grade 1 toxicity, supportive care is provided. It does not necessarily require holding therapy.

If a patient has a grade 2 toxicity or moderate symptoms, it is recommended to hold the immune checkpoint inhibitor and consider initiation of steroids (prednisone 0.5-1 mg/kg/day). 

Grade 3 toxicity is medically significant but not life-threatening. The immune checkpoint inhibitor should be held and steroids initiated (prednisone 1-2 mg/kg/day). The patient may require admission for additional workup and monitoring, as well as consults with other specialties (eg, gastroenterology, dermatology).

Some patients unfortunately are refractory to high-dose steroids for the management of irAEs. For those cases, secondary immune‑specific agents are added, for example, using mycophenolate in the setting of liver function test abnormalities that are resistant to steroids. For diarrhea, infliximab or vedolizumab can be considered. 

The NCCN publishes regularly updated consensus guidelines for the management of irAEs. Together with NCCN, CCO has developed an Interactive Decision Support Tool to help healthcare professionals manage irAEs in patients receiving immune checkpoint inhibitor‒based therapy using specific patient characteristics. Enter specific patient characteristics, such as organ system and toxicity grade, and receive irAE management recommendations tailored to that patient. An update to this tool will be coming to the CCO website soon. 

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Expert Consensus on Managing AEs Associated With IO/VEGF TKI Combination Therapy

One of the challenging issues with IO/TKI combinations is determining which agent is causing the toxicity. With diarrhea specifically, I consider which TKI the patient is receiving and its half-life. Being familiar with the half-life of the different TKIs is helpful when watching improvement in symptoms by holding the agent. If the patient has grade 3/4 diarrhea, I hold both the TKI and the immune checkpoint inhibitor and assess if inpatient admission is warranted for workup with a colonoscopy and steroid initiation. On the other hand, if the diarrhea is lower grade, perhaps grade 2, I hold the TKI and see if the diarrhea improves.47,48 If I see improvement after holding the TKI, alterations to the dosing or schedule of the TKI can increase tolerability when restarted.

Clinical symptoms also can help determine the underlying cause. If a patient reports significant pain, blood, or mucus in the stool, these symptoms are more typical with an irAE.

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A 71-year-old man with hypertension, diabetes, and recurrent metastatic clear cell RCC status post right radical nephrectomy is started on axitinib/pembrolizumab. During his first cycle of therapy, he develops grade 2 diarrhea. What would be the most appropriate treatment for this patient?

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