Second-Line Treatment: TKI Combination Therapy

Chung-Han Lee, MD: In this patient, the selection of lenvatinib plus everolimus was selected as second-line therapy after progression on a single-agent checkpoint inhibitor. In this patient, they had an outstanding response to TKI [tyrosine kinase inhibitor] therapy, suggesting that there’s a strong VEGF component to their disease. And in these types of patients, we may consider whether they are so antiangiogenic responsive that we would want to use a regimen that would contain some sort of anti-VEGF activity.

The combination of lenvatinib plus everolimus targets 2 different pathways: the antiangiogenic pathways with lenvatinib with targeting VEGFR 1 through 3 and FGFR 1 through 4, in combination with everolimus, which is an mTOR inhibitor. This is probably one of the first combinations that we used in kidney cancer that was quite tolerable, especially hitting 2 different pathways.

This was originally FDA approved based off a randomized phase 2 study comparing the combination of lenvatinib plus everolimus versus lenvatinib alone versus everolimus as monotherapy. They demonstrated improved progression-free survival and overall survival. In this patient who had a very strong and prolonged response to VEGF-targeted therapy, it does make sense to use something that continues to address the VEGF signaling pathway, and lenvatinib plus everolimus would be a very reasonable combination in this sort of setting.

When you think about toxicities related to combination therapy, generally speaking, you’ll end up getting toxicities that are related to both medications: toxicities related to VEGF-targeted therapy and toxicities related to the mTOR-targeted therapy. Different from what we often see with the everolimus toxicity is, everolimus, the FDA-approved dose as monotherapy being 10 mg, in this combination is given at 5 mg. The potential toxicities related to everolimus include stomatitis, peripheral edema, and a small risk related to pneumonitis. Things that we often do want to watch out for are increases in the blood glucose levels and also the lipid profile. Those are things that certainly do need to be managed. In this patient, she had underlying diabetes, although it was very mild and controlled without medications. Those are things that we want to watch out for during that everolimus type combination.

The tolerability of lenvatinib is quite similar to other VEGF-targeted therapies, with toxicities that are very much related to that class of medications: potential issues with bleeding, potential issues with wound healing, rises in blood pressure, and some diarrhea that may be related to it. Most of these toxicities are dose-dependent, and there’s a lot of room to go down on the medications. The way I usually describe it to patients is I ask them, “Could you imagine living like this for the next year?” Not because a year is how long we know the medication will work, but it gives you a sense of how tolerable is this? Sometimes patients do have this tendency to want to try to power through, but we actually, with dose reduction of lenvatinib, often see that it can be effective even at relatively low doses. It really is more dependent on the patient and their tumor. I think there is that caution we provide to patients about trying not to suffer unnecessarily.

In recent years, we’ve seen a lot of progress made in the treatment of metastatic kidney cancers with the approval of multiple agents and different treatment modalities, including the incorporation of various immunotherapies for the management of disease. Even though we’ve made significant progress, RCC [renal cell carcinoma] remains a disease that is often not curable by systemic therapy. At least as of 2020, VEGF-targeted therapy remains the backbone of metastatic kidney cancer treatment. There are multiple directions that we need to go on this. One is the development of biomarkers for better risk stratification of patients, incorporation of genomics to better understand what is the optimal treatment for patients, and also the opening of various treatment modalities, targeting different pathways to further improve the outcomes of patients and getting us closer to curing the patients that we care for.

I think that right now we definitely live in a very exciting time in the treatment of RCC. We’re seeing rapid change within the field, we’re seeing new regimens come out targeting different pathways, and we’re seeing the guidelines change on a month-by-month basis. And this is all to the benefit of all the patients that we care for and treat. I hope that we continue to see this type of progress in the field.

Transcript edited for clarity.

Case Overview:

Initial presentation

• A 69-year-old woman presents with a 2-month history of fatigue, lower back pain and unintentional weight loss
• PMH: DM medically controlled
• PE: flank and lower back discomfort on palpation

Clinical workup

• Chest/abdominal/pelvic CT showed a right-sided 7.9 cm renal mass; paraaortic lymph node involvement
• Percutaneous biopsy confirmed clear cell renal cell carcinoma

Treatment and follow-up

• The patient underwent right total nephrectomy; surgery was well-tolerated
  • Follow-up at 3, 9, 12 months were unremarkable
• At 24 months the patient developed disease with multifocal disease in her lungs; Stage IV
• Labs within normal limits
• ECOG 0; good risk disease by IMDC and MSKCC risk
• She started treatment on pazopanib; well-tolerated, achieved PR
• 2 year later the patient suffered progression of disease; with increasing lung nodules, largest (30 mm)
• Lenvatinib 18 mg PO QD + everolimus 5 mg PO QD was initiated
  • Imaging at week 8 showed a 33% reduction from baseline of the largest lung lesion (20 mm);
  • At week 24 of treatment showed 40% reduction from baseline of largest lung lesion (18 mm); decrease in size of other pulmonary lesions noted
  • At 6 months she continued to have stable disease
  • At 12 months of treatment CT showed 2 new liver nodules