Second-Line Treatment Options for Advanced RCC

Robert Alter, MD: When it comes to second-line therapy, I think we have to attempt to define progression. Progression may not only be disease growth. It can also be intolerability of therapy. In some situations, the financial toxicities may be a reason why patients move to second-line therapy. Or the accessibility patients may have in the winter months, patients may not be as accessible as they are in warmer climates, and therefore their ability to receive second-line therapy may be determined on patient values and not just clinical data.

It’s very hard when you give first-line therapy to predict how long the therapy will be beneficial. Obviously, toxicities are difficult to predict, which is why we have to really consider risk stratification. Risk stratification leads to our thoughts about long-term survival.

Patients who have no risk factors, who are favorable risk or good risk, have a median survival of 43 months. Patients who are deemed intermediate risk, who have 1 to 2 risk factors, have a median overall survival of 22 months. For patients who are classified as poor risk, with 3 or more factors, their survival is under 8 months. So when we think about how to take care of patients in the first-line setting, we should always be thinking about how we anticipate they’ll be tolerating and receiving a second-line therapy. And again, the sequence of therapies allows us to believe that we can approach our patients in a more optimistic, valued approach, compared to just believing that we have 1 attempt to take care of the disease.

Factors when it comes to second-line therapies, we need to think about functional performance status, laboratory studies, financial toxicities, accessibility. And I do like to assess how patients tolerated and benefitted from first-line therapy. Utilizing first-line tyrosine kinase inhibitor [TKI] therapy, if patients do benefit from VEGF inhibition and have a durable response with good tolerability, one can consider incorporating that into a second-line therapy. So if one receives Cabometyx [cabozantinib] as a first-line therapy and has a response rate and a progression-free survival of more than 1 year with good tolerability, one can consider utilizing the combination of a TKI and immunotherapy as second-line therapy, recognizing you’d still utilize the value of VEGF inhibition.

Location of metastases is very important as well. I think if a patient has evolved to have disease at a rapid growth rate and a decreasing functional performance status, whether it goes to a visceral organ or it becomes painful metastases, we have to be a little bit more aggressive when utilizing 1 therapy. Some people do believe that tyrosine kinase inhibition can offer a quicker response compared to immunotherapy. One can definitely consider incorporating a single agent or a combination tyrosine kinase inhibitor therapy regimen based upon what the patient received as first-line therapy.

If the patient did receive a combination of immunotherapy as first-line therapy, one can consider Cabometyx as their first TKI therapy based upon the CABOSUN clinical trial. Again, utilizing Cabometyx as a first-line TKI opens the door for patients to receive second-line TKI therapy—that being lenvatinib, which has been very well studied as second-line therapy and has demonstrated efficacy as well.

Transcript edited for clarity.

Case: A 58-Year-Old Man With Advanced Renal Cell Carcinoma

• August 2018: A 58-year-old man complained of fatigue and anorexia; after appropriate workup the patient was diagnosed with clear cell renal cell carcinoma
  • He underwent left total nephrectomy
• March 2019: He developed metastatic disease to the lungs bilaterally (30 x 35 mm), mediastinum and soft tissue metastatic deposits
  • MSKCC risk status: intermediate
  • ECOG 1
  • He was started on pembrolizumab 200 mg IV every 21 days + axitinib 5 mg PO q2Days
• September 2019: He developed progressive disease (45 x 50 mm); pulmonary lymph nodes increased in size and new mediastinal and hilar lymphadenopathy was noted
  • He was started on lenvatinib 18 mg PO qDay + everolimus 5 mg PO qDay
• October 2019: Due to grade 1 diarrhea, reduced dose of lenvatinib to 14 mg PO qDay + everolimus 5 mg PO qDay
• December 2019: Lesions reduced to 20 x 20 mm from September 2019; achieved partial response
• January 2020: He remained on therapy with lenvatinib + everolimus