Poor-Risk Advanced RCC: TKI Therapy & Outlook

Earle Burgess, MD:In using TKIs [tyrosine kinase inhibitors] it’s important to understand and anticipate the toxicity profile. The oncology community has been using VEGF receptor TKIs now for over a decade in kidney cancer. I think there’s a significant level of comfort with the agents, but it’s important to keep in mind the toxicity patterns. Typically in the class we’ll see gastrointestinal toxicities, with nausea, diarrhea, dysgeusia, anorexia, quite common. Cardiovascular complications occur, most notably hypertension.

There’s a smaller rate, but measurable incidents of more significant arterial and venous thromboembolic events. The more common toxicity that we encounter is the development or worsening of hypertension. Fatigue is common; less commonly hand-foot symptoms and other endocrine disorders can occur.

When treating patients with TKIs it’s important to educate them before starting about the potential toxicities. The key is for patients to understand the high incidence of gastrointestinal toxicities so that they’ll alert you before the symptoms become significant or too severe, so that an early intervention can be made in an effort to maintain dose intensity. Specifically educating patients about the possibility of nausea and diarrhea. Early intervention with supportive medication such as the antiemetics or antidiarrheals are important to maintain dose intensity.

It’s also important to understand that dose modifications were common on the studies and are common in routine clinical practice. The need for a drug holiday or dose reduction is common in most

patients. This was seen on the VEGF TKI trials, and is common anecdotally in practice as well.

Understanding that in the trials that led to the approval of these agents that dose modifications were common, it’s important to utilize this if patients are experiencing significant toxicities that can’t be managed with supportive medications in order to maintain the duration of therapy.

Clearly over the last few years we’ve had multiple new options become available for patients with advanced kidney cancer. There’s a lot of enthusiasm for the new agents that have become available both in the frontline and later line settings. Clearly there still is a large unmet need because these patients are not being cured. We are all very excited about the possibility of durable responses that are occurring with the use of immune checkpoint inhibitors, and we are eagerly looking forward to ongoing development of additional immune-based strategies, both in an effort to improve the likelihood of response and the duration of response, and also in an effort to lower the likelihood of immune-related adverse events.

We are optimistic and hopeful that with continued development of immune checkpoint-based regimens that we’ll see improved efficacy and better tolerability in the years ahead. We’re also looking forward to the development of novel classes, novel agents, first-in-class drugs that have the opportunity of further improving patient outcomes above and beyond the classes that we’re currently using.

Transcript edited for clarity.

Case: A 68-Year-Old Man With Poor-Risk RCC

A 68-year-old man presented with a 6-week history of painless intermittent hematuria, fatigue and a 7-lb weight loss.

H & P:

• History of medically controlled hypertension and hypercholesterolemia
• 30 pack/year smoking history, social alcohol use  
• Thin, ill-appearing; able to meet activities of daily living but unable to work due to fatigue. He spends more than half the day active on his feet

Labs:

• CBC: Hb 11.4 g/dL, corrected Calcium,11.2 mg/dL, WBC, PLT, LFT all WNL
• BP: 134/92
• Lipid panel: WNL
• U/A: gross hematuria

Imaging:

• CT scan of the chest/abdomen/pelvis showed a left-sided 8.7 (I believe he said 8cm) cm renal mass, para-aortic lymph nodes, and pulmonary metastases

Diagnosis:

• Underwent radical left nephrectomy; found to have Fuhrman grade 4 clear cell carcinoma without sarcomatoid features
• IMDC risk-score: poor

Treatment:

• Initiated treatment with ipilimumab 1mg/kg IV + nivolumab 3mg/kg IV q3w for 4 doses; achieved partial response; received maintenance nivolumab for 6 doses (q4w) followed by disease progression
• Patient was switched to cabozantinib 60mg PO qDay