Frontline Therapy Options for mRCC

Robert J. Motzer, MD:The treatment paradigm changed away from cytokine therapy to sunitinib in 2006, based on the study that compared sunitinib to interferon alpha. Since then, there have been other drugs that have been developed as first-line therapy, but for the most part, sunitinib has always been considered the reference standard for efficacy and for first-line treatment for renal cell cancer. So, sunitinib and pazopanib have been the two most commonly used TKIs in first-line therapy.

More recently, there has been a change, in that there have been studies that compared cabozantinib to sunitinib in intermediate/poor-risk patients in the first-line setting, suggesting that cabozantinib is superior to sunitinib. And there was a large phase III trial that compared ipilimumab plus nivolumab to sunitinib in first-line therapy, and this showed a survival benefit for the intermediate and poor-risk group. These are 2 new treatments that are now available to oncologists, and in certain respects we feel will replace sunitinib over time.

Between 35% and 40% of patients that are treated with sunitinib in first-line therapy will achieve an objective response. Generally, the objective responses are partial, as in this patient. The median progression-free survival to sunitinib, and most serious has been between 9 and 11 months. So this patient’s time on therapy, and time to progression were the average of what we anticipate to see with most patients with metastatic renal cancer.

There is little data that we know of that translates to why tumors become resistant to sunitinib and some of the other VEGF TKIs. There have been some proposed mechanisms of angiogenic escape. One is through the MET pathway, and another is through FGF overexpression. Some of the newer VEGF TKIs, they target—in addition to VEGF receptors—some of those pathways that are felt to be important for resistance. For example, the cabozantinib also targets the MET pathway, whereas lenvatinib, from lenvatinib plus everolimus, is not only a good inhibitor for VEGF receptor and platelet drive growth factor receptor as well, but also targets the FGF family of receptors.

Transcript edited for clarity.

A Japanese-American Male With Recurrent RCC

November 2015

• At the age of 49, a Japanese-American man presented to the ER with abdominal pains
• CT of the abdomen and pelvis revealed diverticulitis with an incidental left renal mass (4.2 cm × 8.6 cm × 2.8 cm)
• SH: Marathon runner; nonsmoker; social drinker
• He underwent sigmoid colon resection; left radical nephrectomy
• Pathology; sigmoid colon pathology revealed diverticulitis; renal pathology revealed RCC, clear cell type
• Diagnosis: RCC stage PT2a
• KPS: 90
• Fuhrman Grade: 3/4

September 2017

• Follow-up CT showed residual soft tissue in the left nephrectomy bed, pulmonary lung metastasis, and an expansile lucent osseous lesion in the right pubic ramus
• Biopsy of one of the osseous lesions confirmed mRCC
• He began systemic therapy with sunitinib for 20 weeks and achieved stable disease and some shrinkage of the bone lesion
• KPS: 90
• MSKCC risk score: Intermediate

July 2018

• The patient now complains of left pelvic pain
• Imaging shows marked progression in retroperitoneal mass; new lung metastasis
• Laboratory values:
  • CBC: WBC - 7; Hgb - 12.6; Platelet - 190; ANC — 5.2;
  • CMP; Creatinine - 1.82 mg/dL; LFTs - WNL; Calcium - 9.2 mg/dL; LDH — WNL
• MSKCC risk score: Intermediate
• KPS: 80
• The patient was treated with palliative radiation therapy to bone metastasis
• He was then started on treatment with lenvatinib/everolimus