Second-Line Therapy Decision Factors

Chung-Han Lee, MD: There are triggers we would usually have in terms of frontline therapies and changing the frontline therapies. We continue these medications on an ongoing basis so long as the patients are deriving clinical benefit, defined by a lack of progression, no new lesions, no growth of the existing lesions, or very slow growth of new lesions, and also a question of tolerability. We want to have that all to be true, whereas if we notice that the disease was growing in some sort of way or patients were having difficulty from a tolerability standpoint, then that certainly would trigger us to think about switching treatments.

Right now in terms of what we would do as second-line treatment, a lot is based on what treatments they’ve had in the past and how they did on the treatments. In this patient in particular, they were started on a single-agent TKI [tyrosine kinase inhibitor] because they had favorable-risk disease, and from a time standpoint, combining immunotherapy [I-O] was not necessarily an option. However, they had an outstanding response to a single-agent TKI. Typically speaking, a long-term responder to a single-agent TKI is about 18 months, and the patient certainly exceeded that, and went on for more than double what the median progression-free survival was on a single-agent TKI, suggesting that there’s probably a strong VEGF component to their disease. We take that into consideration in whether or not to stick with additional VEGF-targeted therapy or think about switching to some sort of I-O-containing regimen.

In thinking about second-line therapy, the options for this patient after having been on a single-agent TKI include a single-agent checkpoint inhibitor, such as nivolumab, could consider cabozantinib as monotherapy, could consider lenvatinib plus everolimus as a combination therapy targeting both the mTOR and VEGF signaling pathways, or even other second-line TKI therapies.

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