CE / CME
Pharmacists: 1.00 contact hour (0.1 CEUs)
Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™
Released: May 25, 2023
Expiration: May 24, 2024
Rationale for Combining ICIs and Anti-VEGF Agents
Eric Jonasch, MD:
We will now move on to discussing AE management in patients receiving ICI/anti-VEGF combination therapy. But first, why treat patients with this combination?
In brief, the rationale for combining ICIs and anti-VEGF agents is, first, that anti-VEGF agents are capable of downregulating some of the immunosuppressive effects of VEGF on immune cells.14 Second, blood vessels in tumors can be tortuous, abnormal, and not very good at delivering immune cells into the microenvironment. This means that normalizing the vasculature can help immune cells get where they need to go.
In individuals with advanced RCC, these ICI/anti-VEGF combinations clearly outperform TKI monotherapy, as we will discuss momentarily. Whether these are synergistic or additive effects has not been clearly determined, but their combination has become a mainstay of therapy for our patients.
FDA Approvals of ICI/Anti-VEGF Combination Therapies as of May 2023
Eric Jonasch, MD:
Multiple ICI/anti-VEGF combinations have received FDA approval since 2019 for advanced hepatocellular carcinoma (HCC), endometrial carcinoma, and RCC. Atezolizumab/bevacizumab is approved for HCC, and the approvals for RCC include avelumab/axitinib, nivolumab/cabozantinib, pembrolizumab/axitinib, and pembrolizumab/lenvatinib.15-20
Pembrolizumab/lenvatinib also is approved for endometrial carcinoma that is mismatch repair proficient (pMMR)/not microsatellite instability–high.
Efficacy of Approved ICI/Anti-VEGF Combination Therapies in Registrational Trials
Eric Jonasch, MD:
Clinical trials have demonstrated that the combination of ICI and anti-VEGF agents significantly decreases the risk of death, providing clinically significant OS benefits vs sunitinib for patients with RCC vs sorafenib for HCC and vs chemotherapy for endometrial carcinoma.21-27 These therapies now are recommended for first-line treatment of RCC, first-line treatment of HCC, and treatment of pMMR endometrial carcinoma.28-30
Rates of Select TRAEs With ICI or Axitinib Monotherapy and ICI/Axitinib Combination Therapy in Advanced RCC
Eric Jonasch, MD:
This table summarizes some of the treatment-related AEs associated with ICI/axitinib combination therapy: diarrhea, alanine aminotransferase (ALT)/aspartate aminotransferase (AST) increases, and fatigue.31 Later, we also will discuss cardiovascular AEs associated with this combination.
We can see here that the individual trials reported lower rates of diarrhea and fatigue with ICI monotherapy than with axitinib as monotherapy or in combination with ICI for advanced RCC.31-36 Although the ICI monotherapy studies here did not report ALT/AST increases, we saw earlier that ALT/AST elevations were reported to occur at any grade in 1% to 4% of patients with diverse malignancies who received anti–PD-1 ICIs, with approximately 1% experiencing grade ≥3 events.8 Those rates are lower than what we see reported here for ICI/axitinib combination therapies in advanced RCC.
When to Use Established Guidelines for Managing Common TRAEs With ICI/Axitinib Combination Therapy
Eric Jonasch, MD:
We now will review current guidance on managing toxicities with ICI/anti-VEGF combination regimens. This is important because some combinations have very specific toxicities. For example, pembrolizumab/lenvatinib has distinct toxicities that I will highlight. By contrast, there are fewer distinct toxicities with nivolumab/cabozantinib and pembrolizumab/axitinib.
We have guidelines for managing ICI monotherapy toxicities from the National Comprehensive Cancer Network, the American Society of Clinical Oncology (ASCO), the European Association of Urology, the European Society for Medical Oncology, and the Society for Immunotherapy of Cancer.12,13,37-39 We also have expert-based consensus recommendations on managing specific overlapping toxicities related to pembrolizumab/axitinib from a review paper authored by Dr Viktor Grünwald, myself, and other colleagues.31 Managing these overlapping toxicities—which can be related to the ICI, axitinib, or both—will be the focus of the next part of our discussion.
Managing AEs With ICI/Axitinib: Diarrhea
Eric Jonasch, MD:
The first of these overlapping toxicities is diarrhea. For grade 1 diarrhea, providing supportive care (eg, loperamide), monitoring, and continuing both agents is recommended.31
For grade 2 diarrhea, you can hold axitinib, which has a relatively short half-life of approximately 4 hours, and watch for diarrhea resolution. If the diarrhea resolves within several days, then you know that the causative agent was axitinib. If you do not quickly see improvement after holding axitinib, you definitely need to hold the ICI and start corticosteroids.
If the grade 2 diarrhea improves within several days of holding axitinib, you then can consider resuming axitinib either at its same schedule and dose or switching from the twice-daily schedule to an intermittent schedule with 24- to 48-hour breaks and/or reducing the dose.
With grade 3/4 diarrhea, you should hold both agents, reach out to your GI specialists as we discussed earlier, and likely start steroids. If you do not see an initial response to therapy, perform a colonoscopy to rule out infectious causes and escalate treatment.
Managing AEs With ICI/Axitinib: Hepatitis
Eric Jonasch, MD:
Turning to hepatitis next, for grade 1 hepatitis you can monitor the patient and continue both agents.31 If the patient has an ALT of 53 U/L and an AST of 62 U/L, for example, you do not have to change therapy. But if the patient develops grade 2 hepatitis, a very reasonable initial step is to hold axitinib and continue the ICI while monitoring the patient. If that does not improve the hepatitis, hold the ICI and initiate steroids.
For high-grade hepatitis, you have to look more closely at what is happening with the patient. If only their transaminases are affected, you can probably get away with initiating steroids, and you can decide which drug to hold. But you are definitely starting steroids for grade 3/4 hepatitis. Then, if the severity further increases, move on to using mycophenolate—recall that you should avoid infliximab for hepatitis. If there is any-grade bilirubin elevation, rule out other causes with a full workup and stop both drugs while also involving your hepatology colleagues.
Managing AEs With ICI/Axitinib: Escalation of Immunosuppression for Immune-Related Hepatitis
Eric Jonasch, MD:
We have additional algorithms on when to escalate immunosuppression with IV steroids and mycophenolate for immune-related hepatitis.31 As mentioned previously, we want to involve the experts in this situation.
Managing AEs With ICI/Axitinib: Fatigue
Eric Jonasch, MD:
Fatigue is a very interesting AE and one of the more challenging and multifactorial toxicities associated with these combination therapies. Many anticancer agents cause relatively low-grade fatigue, and fatigue usually is not something that warrants therapy interruption.31 If fatigue worsens to grade 2, we start to ask whether it is caused by the ICI agent, axitinib, or both. You can first hold axitinib or dose adjust to see whether that helps with the fatigue.
The differential diagnosis for fatigue includes endocrine issues, so you have to look at thyroid-stimulating hormone, cortisol, and testosterone. If the fatigue is severe and associated with decreased blood pressure, it could be because of hypophysitis or adrenal insufficiency.
Managing AEs With ICI/Axitinib: Cardiovascular AEs
Eric Jonasch, MD:
Cardiovascular AEs are complicated because TKIs by themselves can cause problems with cardiac function.31 Long-term studies with sunitinib and pazopanib have shown that a decrease in ejection fraction can occur with TKIs alone. TKI-related hypertension must be fully managed, as it can obviously cause problems for the patient. If you notice decreased cardiac function and suspect myocarditis, get an early referral to a specialist and look at the patient’s ECG, send out labs for troponins, and look at brain natriuretic peptide to determine whether there is heart failure. If you suspect heart failure, immediate and early intervention is absolutely necessary.
Rates of Key TRAEs With Pembrolizumab/Lenvatinib in Endometrial Carcinoma and RCC
Eric Jonasch, MD:
Next, we will discuss the management of AEs associated with the combination of pembrolizumab and lenvatinib in endometrial carcinoma and RCC. Lenvatinib-related hypertension is an important AE that we really need to pay attention to and aggressively manage with this combination.22,23,40-42 This multikinase inhibitor targets VEGF, as do axitinib and cabozantinib, and hypertension is a class effect of VEGF inhibitors. As you can see in this table, hypertension occurred in more than one half of patients who received pembrolizumab/lenvatinib, with grade ≥3 events noted in 36% of patients with endometrial carcinoma and 25% of patients with RCC.
Another common toxicity with both pembrolizumab and lenvatinib is hypothyroidism, so laboratory tests for thyroid hormone levels are standard for all patients receiving these agents.
Proteinuria is also common with this combination and is another class effect of VEGF inhibition. As shown here, any-grade proteinuria was reported in 25% of patients with endometrial carcinoma and 28% with RCC, of which 4% and 7% were grade ≥3 events, respectively. We definitely see a higher degree of proteinuria with lenvatinib combinations vs those involving axitinib or cabozantinib, so that is important to remember and watch out for with this regimen.
General Management of AEs With Pembrolizumab/Lenvatinib
Eric Jonasch, MD:
The general management of AEs associated with pembrolizumab/lenvatinib is similar to the approach we discussed with ICI/axitinib.17,19,22,23,40-42 Again, for low-grade AEs, you should hold the TKI and reduce its dose if you think the AE is being caused by the TKI or modify the treatment with pembrolizumab if appropriate.
Managing AEs With Pembrolizumab/Lenvatinib: Hypertension
Eric Jonasch, MD:
Hypertension is an on-target toxicity reflecting the successful inhibition of the VEGF signaling pathway.43 If you see hypertension with the combination of pembrolizumab and lenvatinib, you need to start antihypertensive medications, and if the patient is already receiving them, modify the dose or add additional medications.17,19,22,23,40-42 This is very important because hypertension can be quite significant, and if you cannot control it, you need to interrupt the lenvatinib treatment and resume at a lower dose.
Of interest, there is a relationship between TKI-related hypertension and improved outcomes. In the phase III SELECT trial, which compared lenvatinib monotherapy with placebo in patients with thyroid cancer, developing hypertension while receiving lenvatinib was associated with better outcomes.44 There was an OS benefit in the patients who developed hypertension, with OS not reached vs 21.7 months in those who did not develop hypertension while receiving lenvatinib (HR: 0.43; 95% CI: 0.27-0.69). This is another example of an on-target toxicity serving as a marker for improved outcomes, although that does not mean that we should ignore hypertension. We still need to optimally manage this toxicity but feel reassured that it might mean a better response for our patient.
Managing AEs With Pembrolizumab/Lenvatinib: Hypothyroidism
Eric Jonasch, MD:
Hypothyroidism from lenvatinib and pembrolizumab is not much different from the hypothyroidism caused by other combinations of ICIs with anti-VEGF agents.17,19,22,23,40-42 These thyroid AEs usually start as an inflammatory response and hyperthyroidism, which burns out and shifts to hypothyroidism. You need to be ready for that shift and initiate thyroid replacement hormone therapy when appropriate. It is relatively rare to need to adjust or discontinue either agent.
Managing AEs With Pembrolizumab/Lenvatinib: Proteinuria
Eric Jonasch, MD:
As I mentioned earlier, you need to monitor for proteinuria with pembrolizumab and lenvatinib.17,19,22,23,40-42 Some patients may suddenly develop lower-extremity swelling, with a dipstick showing substantial proteinuria. The main treatment, unfortunately, is through dose withholding, dose reductions, and, in some cases, permanent discontinuation of lenvatinib. Proteinuria is not an easy toxicity to fix beyond reducing kidney exposure to this agent.
Select AEs With Nivolumab/Cabozantinib
Eric Jonasch, MD:
Shifting now to AEs associated with nivolumab/cabozantinib, this regimen’s safety profile is not particularly different from those we discussed with other combinations of ICIs with anti-VEGF agents.45 As with all of these combination therapies, it is important to determine whether the ICI and/or the TKI is causing the AE. With this combination, you usually hold cabozantinib first because its shorter half-life (approximately 99 hours) means that if this agent is responsible, the toxicity will usually begin to improve within a few days. By contrast, nivolumab has a half-life of approximately 25 days.
That being said, I do want to address management of ALT/AST elevations with nivolumab/cabozantinib.
Managing AEs With Nivolumab/Cabozantinib: ALT/AST Elevations
Eric Jonasch, MD:
In most cases, patients experience a relatively low level of transaminitis. Transaminitis can be related to either agent in this combination.45 You usually would hold cabozantinib first, and if the transaminitis resolves, cabozantinib can then be restarted at a reduced dose. If the transaminitis persists, or there are other indications it is more likely to be related to nivolumab, you would hold the nivolumab and either resume therapy if the transaminitis resolves or consider discontinuing for severe transaminitis with elevated bilirubin.
Patient Case: 57-Year-Old Man With ALT/AST Elevations on Nivolumab/Cabozantinib
Eric Jonasch, MD:
Let’s discuss a case scenario involving ALT/AST elevations with nivolumab/cabozantinib.
A 57-year-old man with no prior comorbidities develops gross hematuria and is found to have a 9-cm left renal mass and multifocal metastatic disease in the lungs, mediastinum, and bone. A biopsy is consistent with clear cell RCC, and the patient is started on nivolumab 480 mg IV every 4 weeks plus cabozantinib 40 mg by mouth daily per the CheckMate 9ER trial.
He feels well, but when labs are done at the time of his second infusion, you see that he has an ALT of 348 U/L, AST of 843 U/L, and—at the moment—normal total bilirubin. This is grade 3 transaminitis.
What should you do? Do you continue both agents and add prednisone? Do you discontinue cabozantinib and monitor the transaminitis to see if it improves? Do you discontinue both agents and start a moderately high dose of prednisone at 1 mg/kg? Or do you discontinue both agents and start infliximab?
Case Continued: Steroid-Refractory Hepatitis
Eric Jonasch, MD:
The patient stops both agents and starts prednisone. His ALT/AST levels are rechecked after a few days but have not declined, and now the total bilirubin is starting to rise slightly beyond the upper limit of normal. This is a worrisome sign. When you see transaminases and bilirubin going up, you start worrying about worsening hepatic damage.
The patient is admitted and started on IV methylprednisolone—basically an escalation of the steroids—but after a few days, you see his ALT/AST and bilirubin worsen slightly. Hepatology is consulted, a viral panel is performed, and the antihepatic antibodies are pending. A liver biopsy demonstrates an inflammatory pattern consistent with immune-related toxicity.
You definitely should escalate immunosuppression at this point. Should you further increase the dose of steroids, start infliximab, start vedolizumab, or start mycophenolate?
Case Continued: Escalating Immunosuppression for Steroid-Refractory Hepatitis
Eric Jonasch, MD:
If you further increase the dose of steroids, you are not really going to help this patient. He already has had a steroid trial, and his hepatitis is not responding, so that would not be appropriate. As mentioned before, infliximab may be hepatotoxic and is not recommended for immune-related hepatitis. Vedolizumab is recommended for steroid-refractory colitis but would not be appropriate for steroid-refractory hepatitis. So, escalating immunosuppression by adding mycophenolate would be the optimal approach.
Multidisciplinary Strategies for Supportive Care and Prophylaxis With Anti-VEGF TKIs
Eric Jonasch, MD:
All members of the multidisciplinary care team can have a role in preventing and mitigating AEs associated with ICI/anti-VEGF combinations.45 For diarrhea, prophylaxis includes patients keeping a stool diary to share with HCPs and altering their diet to one less likely to upset their digestion. Antidiarrheal agents can be offered as supportive care, as can hydration and moisture-barrier ointment.
Prophylaxis for fatigue includes establishing the patient’s fatigue history, encouraging healthy diet and fluid intake, and activity. Supportive care for fatigue includes referrals to a nutritionist and physical therapist, as well as psychosocial interventions.
Stomatitis is an AE associated with cabozantinib. Regular dental examinations are recommended for patients, as is careful oral hygiene with frequent brushing and use of mouthwash. Supportive care includes sodium bicarbonate–containing oral rinses, swishing ice chips, and gum or candy to stimulate saliva production.
Avoiding hot water, friction, and pressure on the hands and feet may help patients avoid palmar–plantar erythrodysesthesia. If it develops, creams containing urea, salicylic acid, or ammonium lactate may be helpful. There are also topical numbing agents to help relieve symptoms, and oral analgesics can be considered if topical therapy is ineffective.
Evaluate blood pressure before starting treatment to check for preexisting hypertension. During treatment, patients should frequently monitor their blood pressure. Supportive care for hypertension includes antihypertensive agents and the avoidance of CYP3A4 inhibitors.
Educating Patients and Caregivers About AEs Related to ICI/Anti-VEGF Combination Therapies
Eric Jonasch, MD:
When treating individuals with an ICI/anti-VEGF combination, education, prophylaxis, and supportive care are critical to continuing—and therefore benefiting from—therapy. It takes a team, and that team includes everyone from the physician, nurse, and pharmacist to the patient and their caregivers. All team members are responsible for ensuring that patients can manage their AEs and know when to reach out to the care team.
For AEs such as low-grade diarrhea, hand‒foot syndrome, or rash, our oncology nurses educate patients on how to proactively stop the targeted therapy themselves. If the patient develops a minor but bothersome AE on Saturday and do not want to contact the on-call physician, they feel empowered to stop their TKI and see whether that helps them over the weekend. We make a point to empower patients to make their own decisions, and the oncology nurses teach patients what is and is not okay as part of the process. This underscores how oncology nurses are critically important in making sure patients know how to do this safely and know when it is time to reach out.
We create some fairly manageable parameters regarding specific symptoms, such as the frequency of diarrhea. For instance, if the number of bowel movements increases from 2 per day to 4 per day and the patient develops mild cramping, they can try to manage it themselves, but if they start having 10 watery bowel movements per day, we teach them that they have to call and come in for treatment. Patients are told that if they are worried, they should not hesitate to contact the treating team, because it is critical to ensure early intervention. This comes down to communication between the family, the patient, and the treating team, and I believe that is probably one of the most important things that can be done.
Our triage line for patient AEs is managed by nurses during weekdays. On the weekends, the physicians answer those calls. Patients often are reluctant to report symptoms because they do not want to be a bother or are worried their drug will be stopped. We advise patients that the dose does not necessarily matter. What matters is that they can actually continue treatment, and the most important determinant of success is to continue therapy for a prolonged period. But if they end up hurting themselves with high doses of therapy that their bodies cannot tolerate, they will not be able to continue treatment. I try to help patients see treatment as a marathon rather than a sprint.
Another important role of the oncology nurse is to make sure patients remember what drugs they are receiving. They educate patients and caregivers to tell HCPs outside of the oncology care team about all their prescriptions and provide my institution’s on-call number so we can immediately get involved in care during emergencies. One way to make sure patients remember all this information is to provide them with ONS cards they can keep in their wallets. That way, if the patient ends up getting admitted 300 miles away, we can still be involved in their care.
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