Approaches to Second-Line Therapy in mRCC

Thomas Hutson, DO, PharmD:The patient we are discussing today had what I would consider average, or a little bit less than average response to sunitinib. In this particular patient, we need to consider then second-line therapy. One question is, should we apply the results from our first-line experience in this patient into selecting a second-line agent? It’s very tempting to do that, and I will tell you I’m guilty somewhat in practice of doing that. However, data would tell us—these are data from large retrospective series, the international consortium dataset, over 3000 patients; as well as data published from Italy and the United States—that the way one responds to frontline therapy, as well as the side effects they have with frontline therapy, do not equate to the benefit they get in the second-line setting.

Although we are tempted to say, “Hey, we have a patient that didn’t respond well to frontline VEGF inhibition, we shouldn’t choose frontline VEGF inhibition as a second-line therapy.” The retrospective data would say that that’s false, that each line of therapy should be approached individually without influence on the past lines of therapy. So, how would I apply that to data in this patient? Well that would tell me that I would not exclude a VEGF inhibitor as a second- or third-line agent just because the patient had average or less than average response to frontline therapy.

Luckily, we have agents that have multiple ways of attack. So, the agents that we would commonly think about using in the second-line setting in the United States not only are VEGF inhibitors, they actually target other things that we think are important in angiogenic escape and progression. So, for instance, with lenvatinib and everolimus, lenvatinib is a VEGF inhibitor that also targets FGF. And we believe FGF is a very important angiogenic escape pathway. And, therefore, although a patient may not have benefit to frontline VEGF inhibition, or have progression to VEGF inhibition, that hitting it with a lenvatinib type of agent may provide a significant benefit. In addition, lenvatinib is combined with an mTOR inhibitor, which is another prong of attack, if you will.

An alternative strategy would be to employ an agent such as cabozantinib as a second-line agent. And that also inhibits c-MET and AXL, which are 2 other factors that we believe are important in angiogenic escape and progression.

Finally, the third agent that is commonly considered as a second-line treatment in metastatic RCC in the United States would be the use of an immunotherapy agent such as nivolumab, and clearly that agent has a completely different mechanism of action. In summary, the way one responds to frontline VEGF inhibition, and/or the side effects that one experiences with frontline VEGF inhibition, should not dictate the choice of agent in the second-line setting.

Transcript edited for clarity.

A 70-Year-Old African-American Woman with Metastatic RCC

December 2017

• A 70-year-old African-American woman presented to her PCP with loss of appetite, fatigue, abdominal pains, and blood in her stool
• CT of the chest, abdomen, & pelvis: distal esophageal thickening and appearance of a solid mass on the inferior pole of the right kidney (3.4 × 2.6 cm); well-defined hypodense nodules in the right lobe of the thyroid (2.1 × 2.8 cm) and bilateral adrenal glands
• Biopsy of renal mass revealed neoplastic cells with clear cytoplasm arranged in nests and mitotic figures suggesting clear cell carcinoma
• FNA from the thyroid nodule revealed neoplastic clear cells on cytology
• IHC; PAX8+, CAIX+, TTF-1(-)
• Diagnosis; right-sided renal cell carcinoma with clear cell histology; thyroid and bilateral adrenal metastasis (T4N0M1)
• She underwent right radical nephrectomy, right adrenalectomy, and radiofrequency ablation of left adrenal metastasis
• She was subsequently started on sunitinib and achieved a partial response within 3 months

June 2018

• Seven months later, the patient reports having increased fatigue
• MRI shows progression in both adrenal lesions
• Therapy was changed to lenvatinib plus everolimus