Evolution of Targeted Therapy in mRCC

Robert J. Motzer, MD:The unmet needs for systemic therapy in kidney cancer in a TKI era are that a few patients achieve complete response, or complete disappearance of their cancer. The toxicities—all of these drugs have toxicities—although they’re managed, they are chronic toxicities that can bother patients for essentially all the time that they’re on their treatment.

One of the most troublesome side effects for all these therapies is diarrhea. So, patients with chronic diarrhea, it can impact their quality of daily living in a major sense. The same with skin toxicities that we see with these drugs, and the lack of complete response. We’ve also made tremendous progress in managing kidney cancer over the lifetime of the patient by, in certain respects, changing it to a chronic disease that’s managed by these different medications. But still, most patients with metastatic renal cancer will ultimately die from this cancer, so the cure of patients remains an unmet need.

Advanced renal cell cancer was historically considered to be one of the most difficult cancers to treat and associated with a poor prognosis. In the days or the era before the targeted therapies with TKIs, the median survival for patients with advanced renal cell cancer following diagnosis was between 8 and 12 months. There was dramatic progress that was made based on the understanding of the importance of the von Hippel-Lindau (VHL) gene and regulating angiogenesis for renal cancer, and the fact that most clear cell carcinomas of the kidney have mutatedVHLgenes. That really served as the basis for the study for sunitinib and the other VEGF TKIs in this disease that have changed the paradigm for how we treat kidney cancer, as well as the prognosis.

There were a number of these VEGF TKIs that can be considered as first generation. They were studied in the 2000 to 2010 era, and they include sunitinib, pazopanib, and axitinib, as well as sorafenib. They were all approved for different indications and were widely used for the treatment of kidney cancer.

More recently there have been newer agents that differ from these drugs, with respect to targeting profile or mechanism of action. I would say within the last 5 years these have been studied and brought in almost as a new generation for treatment for kidney cancers, as emerging treatments. These include nivolumab, which is a checkpoint inhibitor; cabozantinib, which is a VEGF TKI that targets not only VEGF receptor but MET, and also lenvatinib, which is a new, very potent tyrosine kinase inhibitor that targets VEGF receptor, platelet derived growth factor receptor, as well as the FGF family.

These drugs have been studied and brought into use in our clinic within the last 3 to 4 years. More recent even beyond that, these drugs are being combined with checkpoint inhibitors now. Lenvatinib and axitinib combined with checkpoint inhibitors with very promising results in single-arm phase II studies; now all in phase III trials. Just recently they reported, and will likely change our first-line treatment plan away from sunitinib to ipilimumab/nivolumab (Yervoy/Opdivo).

What I see moving forward that is particularly promising are the combinations of the VEGF targeted therapies and the checkpoint inhibitor therapies. In most of the single-arm studies with axitinib and pembrolizumab, or with lenvatinib and pembrolizumab, the single-arm studies have shown response rates of almost 70%, which is more than double that which we’ve seen with sunitinib. So, there are a number of large randomized phase III trials that are evaluating these various combinations compared to sunitinib, and I’m very hopeful that they will show a positive effect and result in another great gain in the benefit of kidney cancer patients to our systemic therapies.

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