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The Immune Checkpoint Inhibitor Landscape:
Patient Management in Renal Cell Carcinoma (Part 2)

INTRODUCTION

Renal cell carcinoma originates in the renal cortex. It is the major cause of malignant tumors in the kidney and the 8th most commonly diagnosed malignancy in the United States (U.S.). It is curable when local disease is removed by surgery,1,2 but, unfortunately, approximately 1 in 6 patients are initially diagnosed with metastatic disease—a stage with a 5-year survival rate of only 12%.2,3 Activating the immune system with immune checkpoint inhibitors (ICIs) and inhibiting vascular endothelial growth factor (VEGF) signaling with tyrosine kinase inhibitors (TKIs), or a combination of these therapies, has become standard treatment for renal cell carcinoma.4

Prior to VEGF and ICI therapies, median survival for patients with metastatic renal cell carcinoma (mRCC) was only 10 months.5 Data from a prospective randomized trial with dual ICIs reported an 18-month survival rate of 75%.6 More recently, 2 randomized trials testing a VEGF-receptor TKI added to immunotherapy reported progression-free survival (PFS) of 14 and 15 months.7,8 (Details about the efficacy of these regimens can be found in Part I of this series.) However, the significant gains in prognosis come with toxicity, which should be anticipated, monitored, and appropriately managed to optimize outcomes. 

TREATMENT-RELATED TOXICITY

Common toxicities associated with VEGF inhibitors and ICIs that require monitoring are listed in Table 1.9-16 It must be noted that axitinib is specific for VEGF receptor tyrosine kinases9; cabozantinib also inhibits RET, MET, KIT, TRKB, FLT-3, AXL, ROS1, TYRO3, MER, and TIE-2 in addition to VEGF receptors 1, 2, and 310; and sunitinib inhibits multiple tyrosine kinases, in addition to VEGF receptors, including PDGFRB, KIT, FLT3, CSF-1R, and RET.11

The normal function of VEGF is to assist the body in stimulating new blood vessel growth. Consequently, common concerns with all agents in this class include problems with wound healing.4 In patients with mRCC, this presents a potential timing issue with drug initiation and surgery to remove the affected kidney: VEGF inhibitors need to be held during the wound-healing process after nephrectomy.9-12 Similarly, if a VEGF inhibitor is started before surgery, it should be held until it is cleared from the body (which requires an evaluation of the drug’s half-life) prior to surgery when the clinical situation allows. Axitinib was the agent chosen to combine with the immunotherapy agents because it seems to have less overlapping toxicity with the ICI agents, particularly toxicities related to the liver and lungs.7

Table 1. Boxed Warnings, Common Toxicities, and Monitoring for Renal Cell Carcinoma Drugs
Boxed warning Most common adverse events Monitoring
VEGF inhibitors

Axitinib9

None

Diarrhea, hypertension, fatigue, decreased appetite, nausea, dysphoria, hand-foot syndrome, weight loss, vomiting, asthenia, and constipation

Monitor for hypertension and manage with standard therapy. Monitor for symptoms of thromboembolism and bleeding. Monitor for signs of GI perforation or fistula periodically. Monitor thyroid function periodically. Monitor urine protein and liver enzymes periodically.

Cabozantinib10

GI perforation and fistulas; hemorrhage

Diarrhea, stomatitis, hand-foot syndrome, weight loss, decreased appetite, nausea, fatigue, oral pain, hair color changes, dysgeusia, hypertension, abdominal pain,
constipation, increase in liver function tests, increase in alkaline phosphatase, lymphopenia, neutropenia, thrombocytopenia, hypophosphatemia, and hypocalcemia

Monitor for signs of GI perforation or fistula periodically. Monitor for hypertension and manage with standard therapy. Monitor for symptoms of thromboembolism and bleeding. Monitor urine protein. Perform an oral exam and advise patients to maintain good oral hygiene to prevent osteonecrosis of the jaw.

Pazopanib12

Hepatotoxicity

Diarrhea, hypertension, hair color changes (depigmentation), nausea, anorexia, and vomiting

Monitor liver tests at weeks 3, 5, 7, and 9, then at month 3 and the end of month 4. Monitor EKG at baseline and periodically. Monitor for signs and symptoms of congestive heart failure (consider LVEF monitoring in high-risk patients). Monitor for symptoms of thromboembolism and bleeding. Monitor for signs of GI perforation or fistula periodically. Monitor thyroid function periodically. Monitor for hypertension and manage with standard therapy. Monitor urine protein periodically. Monitor for signs of infection.

Sunitinib11

Hepatotoxicity

Fatigue/asthenia, diarrhea, mucositis/stomatitis, nausea, decreased appetite/anorexia, vomiting, abdominal pain, hand-foot syndrome, hypertension, bleeding, dysgeusia/altered taste, dyspepsia, and thrombocytopenia

Monitor liver tests at baseline and with each cycle. Monitor EKG at baseline and periodically for those at risk. Monitor for signs and symptoms of congestive heart failure (consider LVEF monitoring in high-risk patients). Monitor for symptoms of thrombotic microangiopathy and bleeding. Monitor for signs of GI perforation or fistula periodically. Monitor thyroid function periodically. Monitor for hypertension and manage with standard therapy. Monitor urine protein periodically. Monitor glucose regularly for hypoglycemia. Consider an oral exam and preventive dentistry to prevent osteonecrosis of the jaw (particularly with bisphosphonates).
Immune checkpoint inhibitors

Avelumab (PD-L1i)13

None

Fatigue, infusion-related reaction, musculoskeletal pain, nausea, decreased appetite, and urinary tract infection

Monitor for signs and symptoms of pneumonitis. Monitor liver tests at baseline and periodically for hepatitis. Monitor for signs of diarrhea. Monitor for signs of adrenal insufficiency. Monitor for changes in thyroid function. Monitor glucose for diabetes and serum creatinine for nephritis.

Ipilimumab (CTLA-4i)14

Immune-mediated adverse events

Fatigue, rash, diarrhea, nausea, pyrexia, musculoskeletal pain, pruritus, abdominal pain, vomiting, cough, arthralgia, decreased appetite, and dyspnea (in combination with nivolumab)

Monitor for signs of enterocolitis (e.g., diarrhea, abdominal pain). Monitor liver function tests before each dose. Monitor for signs and symptoms of rash and pruritus. Monitor for signs of neuropathy. Monitor for hypophysitis and adrenal insufficiency, including thyroid function. Monitor for symptoms of pneumonitis. 

Nivolumab (PD1i)15

None

Fatigue, rash, diarrhea, nausea, pyrexia, musculoskeletal pain, pruritus, abdominal pain, vomiting, cough, arthralgia, decreased appetite, dyspnea, and upper respiratory infection (in combination with ipilimumab)

Monitor for symptoms of pneumonitis. Monitor for signs of colitis (e.g., diarrhea). Monitor liver function tests at baseline and periodically. Monitor for hypophysitis and adrenal insufficiency, including thyroid function. Monitor serum creatinine for nephritis. Monitor for signs and symptoms of rash. Monitor for signs of encephalitis.

Pembrolizumab (PD1i)16

None

Fatigue, musculoskeletal pain, decreased appetite, pruritus, diarrhea, nausea, rash, pyrexia, cough, dyspnea, constipation, pain, and abdominal pain

Monitor for symptoms of pneumonitis. Monitor for signs of colitis (e.g., diarrhea). Monitor liver function tests at baseline and periodically. Monitor for hypophysitis, including hypopituitarism and adrenal insufficiency. Monitor for changes in thyroid function. Monitor blood glucose for diabetes. Monitor serum creatinine for nephritis. Monitor for signs and symptoms of rash.
CTLA-4i, cytotoxic T-lymphocyte-associated protein 4 inhibitor; EKG, electrocardiogram; GI, gastrointestinal; LVEF, left ventricular ejection fraction; PD1i, programmed cell death protein 1 inhibitor; PD-L1i, programmed death-ligand 1 inhibitor; VEGF, vascular endothelial growth factor.

Although the pharmacologic mechanism of all ICIs is to reactivate exhausted T-cells, the toxicities of ICIs differ based on where they work. Ipilimumab, a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor, has a different toxicity profile than nivolumab and pembrolizumab, which are programmed cell death protein 1 (PD1) inhibitors, and avelumab, which is a programmed death-ligand 1 (PD-L1) inhibitor.17

The onset of toxicity from ICI therapy is similar between classes but drastically different than chemotherapy. The median time to ICI toxicity onset is approximately 3 months, with a range of 2 to 24 months.17 The toxicity is generally not related to the time of infusion. There is a closer association between dose and timing of toxicity due to cytotoxic chemotherapy. Patients can have toxicity 2-3 weeks after the last dose of immunotherapy and when seen outside of the oncology team for this toxicity there is a risk that the immunotherapy is not even considered. Counseling patients about the atypical timing to toxicity onset is crucial. In fact, a patient “Immunotherapy Wallet Card” with their drugs is usually provided to patients and recommended. Functionally it serves as a communication tool to prompt patients on immunotherapy to communicate this with other healthcare providers (e.g., emergency department staff).17 

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