Adverse Effects Impact Treatment Selection for VEGF-Targeted Oral TKIs in Metastatic RCC

Kidney and renal pelvic cancers are among the top 10 most common cancers in the United States, with an estimated 79,000 new diagnoses in 2022.¹ Of these cancers, renal cell carcinoma (RCC) represents the most common form, accounting for approximately 85% of kidney tumors.² RCC is further divided into different histological subtypes, with the clear cell histology (ccRCC) accounting for 70% of cases and the majority of kidney cancer deaths. Treatment options for localized disease include partial or radical nephrectomy, ablative techniques, or active surveillance. Despite these treatment options, one-third of patients with treated localized disease will develop metastatic disease recurrence.³ In addition, one-third of patients diagnosed with RCC initially present with metastatic disease and require systemic therapies as first-line treatment.⁴

Over the past 2 decades, there have been significant advances in the treatment of metastatic ccRCC. The advent of tyrosine kinase inhibitors (TKIs) that target VEGF receptors, immune checkpoint inhibitors (ICIs), and mechanistic target of rapamycin (mTOR) inhibitors has drastically improved survival outcomes. ICI and VEGF-targeted TKI combinations have become the standard of care for first-line treatment of metastatic ccRCC, whereas the mTOR inhibitors are reserved for recurrent disease.⁵

VEGF TKIs

Tyrosine kinases are a family of enzymes that play key roles in several signaling pathways that affect processes such as cell growth and differentiation, angiogenesis, and metabolism.⁶ Because of their oncogenic potential, tyrosine kinases have emerged as major targets for directed therapy in different malignancies. For RCC, the main therapeutic target for the TKI is the VEGF receptor family. Inhibiting VEGF receptors will ultimately block angiogenesis and tumor growth. Axitinib (Inlyta; Pfizer Inc), cabozantinib (Cabometyx; Exelixis, Inc), and lenvatinib (Lenvima; Eisai Co, Ltd) are the 3 VEGFtargeted TKIs used in combination with ICIs for frontline treatment of metastatic ccRCC. A comparative review of these VEGF-targeted TKIs is provided below in Table 1.^7-9

Table 1: clear cell renal cell carcinoma (ccRCC); creatinine clearance (CrCl); cytochrome P450 (CYP); Exelixis Access Services (EASE); immune checkpoint inhibitor (ICI); not applicable (N/A)

Historically, sunitinib (Sutent; Pfizer Inc) was among the first VEGF-targeted TKIs approved for first-line treatment of advanced ccRCC.⁶ In clinical trials examining other first-line treatment options for metastatic ccRCC, sunitinib is typically the control agent. For first-line treatment of advanced ccRCC, the combination of axitinib and pembrolizumab (Keytruda; Merck) was approved first in April 2019 based on the results of the KEYNOTE-426 trial (NCT02853331).¹⁰ The combination of cabozantinib and nivolumab (Opdivo; Bristol Myers Squibb) was approved next in January 2021 based on the results of the CheckMate 9ER trial (NCT03141177).¹¹ Lastly, the lenvatinib and pembrolizumab combination was approved in August 2021 based on the results of the CLEAR trial (NCT02811861).¹² These phase 3 clinical trials all showed a progression-free survival benefit in favor of the ICI/TKI combination treatment group compared with the sunitinib group. Further, all 3 ICI/TKI combinations have since been established as frontline therapies in the advanced ccRCC setting, with all 3 being equally appropriate, category 1 recommendations per National Comprehensive Cancer Network (NCCN) guidelines.5 To date, there are no head-to-head trials comparing these ICI/TKI combinations. Provider preference, insurance coverage, adverse effect (AE) profile, and patient considerations all play a role in regimen selection.

Adverse Effects of VEGF TKIs

VEGF-targeted TKIs have been associated with several class and individual AEs that may result in dose interruptions or modifications. Table 2^7-9 below compares the incidences of notable AEs for these VEGF-targeted TKIs.^7-9 Class AEs include hypertension, proteinuria, gastrointestinal (GI) toxicities, hand-foot syndrome (HFS), thromboembolic events, hepatotoxicity, and wound healing complications, seen in varying rates between the 3 agents discussed.^7-9

Table 2: tyrosine kinase inhibitor (TKI)

In addition, there are individual AEs to consider when choosing a specific VEGF-targeted TKI.^7-9 Cabozantinib and lenvatinib both carry a warning for osteonecrosis of the jaw and should be held prior to invasive dental procedures for at least 3 weeks or 1 week, respectively, whereas axitinib does not have specific recommendations around dental procedures. Dysphonia is more commonly associated with axitinib or lenvatinib, with incidences of approximately 30%, although patients receiving cabozantinib may experience dysphonia as well but with lower rates. These agents can also have varying effects on hair, with cabozantinib potentially lightening hair color and lenvatinib potentially causing hair thinning or hair loss. Other lenvatinib-specific AEs include QTc prolongation, peripheral edema, and arthralgia. Of note, these VEGF-targeted TKIs are used in combination with ICIs in the treatment of metastatic ccRCC, which may have overlapping AEs; the timing, severity, and mechanism of the AEs need to be considered to determine the causative agent of the AE and appropriate management for patients.

Role of Pharmacists in the Management of AEs

Pharmacists can play a major role in the management of AEs related to VEGF-targeted TKI therapy. The following sections highlight some of the common AEs where a pharmacist can play a role in determining next steps for the patient in the management of these toxicities.

Hypertension

Hypertension is one of the most common AEs associated with VEGF-targeted TKIs. The incidence ranges from 39% to 73%, with the highest incidence associated with lenvatinib.^7-9 Further, hypertension due to the inhibition of VEGF receptors can manifest quite rapidly, with a rise in blood pressure (BP) occurring within hours to days of therapy initiation.¹³ Mechanisms of VEGF-targeted TKI-induced hypertension can include VEGF signaling pathway inhibition and decreased levels of nitric oxide, which result in vasoconstriction and hypertension.¹⁴ Endothelin-1, a potent vasoconstrictor, has also been hypothesized to play a role in VEGF-targeted TKI-induced hypertension, but it remains unclear how VEGF inhibition increases levels of endothelin.¹⁴ If left untreated, hypertension is a risk factor for developing more severe cardiovascular complications, including heart failure and stroke.¹⁵

Early recognition of hypertension is essential for prevention of long-term cardiovascular complications. The European Society of Cardiology (ESC) guidelines on cardio-oncology recommend home BP monitoring daily during the first cycle of VEGF-targeted TKI therapy, after dose increases, and every 2 to 3 weeks afterward.¹⁵ For lenvatinib, the manufacturer lists additional BP-monitoring guidance: BP should be monitored after 1 week of lenvatinib initiation, then every 2 weeks for the first 2 months, followed by monthly monitoring thereafter.⁹

The threshold to initiate antihypertensive therapy is personalized, based on each patient’s prognosis and goals of care. In general, ESC guidelines recommend targeting a BP of less than 140 mm Hg systolic and less than 90 mm Hg diastolic for patients undergoing cancer therapy.¹⁵ If antihypertensive therapy is well tolerated, a goal BP of less than 130 mm Hg systolic and less than 80 mm Hg may also be considered. However, because the long-term complications of hypertension take years to develop, it may be reasonable to defer antihypertensives in patients with metastatic cancer who have a prognosis of less than 3 years to minimize polypharmacy and AEs.¹⁵

When initiating antihypertensive therapy, ESC guidelines recommend the first-line use of an angiotensin-converting enzyme inhibitor I (ACE-I), such as lisinopril (Zestril; AstraZeneca), or an angiotensin II receptor blocker (ARB), such as losartan (Cozaar; Merck), to reduce the risk of cancer therapy–related cardiac dysfunction.15 ACE-Is and ARBs may also be helpful for patients with proteinuria, which is a common renal AE of anti-VEGF therapies that is frequently associated with hypertension. For patients whose BP remains at 160 mm Hg systolic or greater and at 100 mm Hg diastolic or greater while on ACE-I or ARB therapy, a dihydropyridine calcium channel blocker (CCB), such as amlodipine (Norvasc; Pfizer Inc), is recommended next to provide additional BP control.¹⁵ Dihydropyridine CCBs are effective agents that cause vascular smooth muscle relaxation, resulting in decreased systemic vascular resistance and lower arterial blood pressure. Although dihydropyridine CCBs can be considered as a management option, nondihydropyridine CCBs are moderate cytochrome P450 3A4 inhibitors and are not recommended with VEGF-targeted TKIs due to their drug-drug interactions.¹⁵

VEGF-targeted TKIs are typically continued while patients are on antihypertensive therapy, but the TKI may be held in the case of severe hypertension, with a BP of 180 mm Hg systolic or greater or 110 mm Hg diastolic or greater.¹⁵ Once BP is controlled, the VEGF-targeted TKI may be restarted at a reduced dose. For patients with resistant hypertension, other antihypertensives, including β-blockers, spironolactone, thiazide diuretics, nitrates, and hydralazine, may be considered based on patient-specific factors.¹⁵ Patients with underlying heart failure or renal dysfunction may benefit from β-blockers. Spironolactone may be helpful for patients with fluid retention, provided that the patient is monitored for renal function and electrolytes. Ultimately, differences in pharmacokinetic profiles between the VEGF-targeted TKIs, patient-specific factors, and comorbidities should be taken into consideration when selecting a therapy.

HFS

HFS, also known as palmar-plantar erythrodysesthesia, is a common cutaneous AE of VEGF-targeted TKI therapy, with an incidence ranging from 27% to 42% as reported in the package inserts.^7-9 HFS is characterized by erythema, swelling, blistering, and pain on the palms of the hands, soles of the feet, or other areas exposed to friction. HFS typically occurs within the first 6 weeks of VEGF-targeted TKI initiation and can significantly affect quality of life, impair mobility, and prevent patients from carrying out activities of daily living.¹⁶

The key to management of HFS is the prevention of this AE. Patients should be counseled to apply topical moisturizers 3 times daily, beginning the same day that VEGF-targeted TKI therapy is initiated.¹⁶ Scented creams and lotions, which may contain alcohol, should be avoided to prevent further drying of the skin. Prior to VEGF-targeted TKI initiation, patients should be counseled on nonpharmacologic preventive measures, including avoiding hot water on the hands and feet, such as when washing dishes or bathing.¹⁷ Direct sunlight should be avoided as much as possible, and tight-fitting gloves or socks should be avoided to prevent further irritation. Physical activities that increase friction and pressure on the hands and feet should also be limited.¹⁷

For patients who develop HFS despite preventive strategies, treatment is largely based on symptom management. Keratolytic moisturizers containing salicylic acid, urea, or ammonium lactate can be applied twice daily to hyperkeratosis lesions.¹⁶ Topical lidocaine can be applied for mild to moderate pain.18 For severe or refractory cases, high-potency topical corticosteroids may be applied daily.¹⁷ Oral analgesics, including nonsteroidal anti-inflammatory drugs and opioids, are not broadly recommended but may be considered for cases where HFS interferes with activities of daily living.¹⁸ In addition, for severe cases, VEGF-targeted TKI therapy should be withheld until symptoms improve, at which time the VEGF-targeted TKI can be resumed at a reduced dose.¹⁶

GI Toxicity

Nausea, vomiting, and diarrhea are common GI-related AEs of VEGF-targeted TKIs. These AEs negatively impact a patient’s quality of life and can be challenging to manage, potentially leading to weight loss, dehydration, and electrolyte disturbances.

Cabozantinib and lenvatinib at doses greater than 12 mg daily are associated with a moderate to high emetic risk per NCCN.¹⁹ A 5-hydroxytryptamine-3 receptor antagonist, such as ondansetron (Zofran; Novartis), is recommended and may initially be dosed as needed daily.19 If the patient experiences nausea or vomiting, then the antiemetic should be scheduled daily. In contrast, axitinib is associated with a minimal to low emetic risk, and antiemetics can be administered on an as-needed basis only.19 For cases of breakthrough nausea or vomiting, around-the-clock dosing and consideration for the addition of an agent from a different drug class is recommended, such as the dopamine antagonist prochlorperazine (Compazine; PBM Pharmaceuticals).19 Considerations for selecting an antiemetic for breakthrough cases include the patient’s age, comorbidities, and pharmacokinetic and pharmacodynamic drug interactions.

In addition to nausea and vomiting, diarrhea is another AE that can occur during ccRCC therapy.Because diarrhea can be a nonspecific AE, potentially caused by various factors, it is important to isolate the causative agent based on the severity and onset for appropriate management. Typically, VEGF-targeted TKI-induced diarrhea presents during the first week of initiation and is generally mild and self-limiting.²⁰ In contrast, diarrhea that develops approximately 6 to 8 weeks after initiation of therapy for metastatic ccRCC may be due to immune-mediated colitis from the ICI component used as part of the ICI/TKI combination.²¹ Of note, for VEGF-targeted TKI-induced diarrhea, the severity is graded based on Common Terminology Criteria for Adverse Events version 4.0 for axitinib and lenvatinib and version 5.0 for cabozantinib in the package insert.^7-9,22 The management of diarrhea is dependent on both the grade of diarrhea and the VEGF-targeted TKI involved.

For symptom management, loperamide (Imodium; Johnson & Johnson) is typically used first at a dose of 4 mg for the initial dose, followed by 2 mg after each loose stool, with a maximum dose of 16 mg daily.²³ Patients should be counseled to contact their provider if their diarrhea does not improve within 48 hours of loperamide use or if they have more than 4 stools daily above their baseline.^7-9,23 In these cases, other agents such as diphenoxylate/atropine (Lomotil; Pfizer Inc) can be considered. Diphenoxylate/atropine is commonly dosed at diphenoxylate 5 mg/atropine sulfate 0.05 mg 4 times daily, with a maximum dose of diphenoxylate 20 mg/atropine 0.2 mg daily.²⁴

Patients with diarrhea should also be counseled to stay adequately hydrated. Oral rehydration solutions such as electrolyte-based drinks are helpful options for replenishing electrolytes.²⁰ Avoiding fatty, fried, or spicy foods may also help prevent further GI upset. For diarrhea that is unmanageable with supportive care and nonpharmacologic therapies, there are specific recommendations on holding or permanently discontinuing the VEGF-targeted therapies as shown in Table 3.^7-9

Table 3

Wound Healing Considerations

Axitinib, cabozantinib, and lenvatinib inhibit the VEGF signaling pathway, which is important for angiogenesis. As a result, patients are at higher risk for bleeding and impaired wound healing, necessitating that these medications be held perioperatively, with specific recommendations as previously shown in Table 1.^7-9

In general, VEGF-targeted TKIs should be held for at least 2 weeks after major surgery, until adequate wound healing occurs. However, there is no standard definition for what constitutes a major surgery in the setting of VEGF-related wound healing complications. Some criteria to distinguish major surgeries can include an invasive procedure where a body cavity is entered, high intraoperative blood loss, or need for intensive postoperative care.²⁵ In contrast, elective surgeries may be planned and are not for life-threatening conditions.²⁶ Surgeons should be consulted to determine the extent of the procedure, which will help guide when to hold and resume the VEGF-targeted TKI.

Overall, patients should be counseled to alert the health care team if they have any invasive dental or surgical appointments or procedures planned. In contrast to axitinib, both cabozantinib and lenvatinib should be held prior to invasive dental procedures due to the risk of development of osteonecrosis of the jaw.^7-9 For other surgical procedures, the patient and health care team should discuss the risks vs benefits of holding VEGFtargeted TKI therapy and plan when therapy should be withheld and resumed. During these discussions, patient-specific factors, such as age, and concomitant use of medications that increase bleeding risk, such as oral antithrombotics, should be taken into consideration.

Conclusion

Axitinib-pembrolizumab, cabozantinib-nivolumab, and lenvatinib-pembrolizumab are recommended ICI/TKI combinations for first-line therapy in metastatic ccRCC. The VEGF-targeted TKIs are each associated with numerous AEs that may require supportive care or treatment modifications and may have a major impact on a patient’s quality of life.

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About the Authors

Cindy Nguyen, PharmD, is a PGY2 oncology pharmacy resident at the University of Washington Medical Center and Fred Hutchinson Cancer Center in Seattle, Washington.

Dane Fritzsche, PharmD, BCOP, is a clinical oncology pharmacist at the University of Washington Medical Center and Fred Hutchinson Cancer Center in Seattle, Washington.

Jina Yun, PharmD, is a clinical oncology pharmacist at the University of Washington Medical Center and Fred Hutchinson Cancer Center in Seattle, Washington.