Tolerability Helps Decide Third-Line Treatment in Advanced RCC


During a Case-Based Roundtable® Chandler H. Park, MD, led a discussion on the considerations physicians have when deciding on their treatment approach in the third line for patients with advanced renal cell carcinoma in the first article of a 2-part series.


A 66-year-old male with a history of metastatic renal cell carcinoma (RCC), status post‒left nephrectomy and adrenalectomy and clear cell RCC metastases in adrenal, recurred after 4 years. The patient was first observed based on low-volume and indolent behavior of disease, but after 18 months the total tumor burden increased. Therapy was initiated with pembrolizumab (Keytruda) plus axitinib (Inlyta), but 8 months after initiation the patient reported new symptoms. New imaging confirmed the growth of a paratracheal lymph node from 20 x 15 mm to 25 x 28 mm with new mediastinal and hilar nodal involvement, retroperitoneal nodes, and lytic osseous lesions. Cabozantinib (Cabometyx) was then initiated, but 9 months later further disease progression was documented.


  • What are the goals of therapy going into the third line for RCC? ​
  • What factors influence your third-line regimen selection?

RYAN CARR, MD: As far as [treating] patients who have had several lines of therapy, with a lot of the third-line regimens you can pick and choose [what to use], but we don't know exactly which one is better. I try to favor regimens that are easier to tolerate, so we can maintain the quality of life for these patients while hopefully extending their life.

DAVID CHISM, MD: [My approach] is to prepare for a patient's tolerability [to the chosen therapy] and consider the availability of the medicine itself, because for newer treatments it might be a little harder to get them. I then familiarize myself [with the toxicity profile so I know which one I can] deal with better vs the others. I agree that we're trying, at this point, to make sure that patients are having some meaningful quality of life, and [address] what is important to them.

SUNIL BABU, MD: The physician perspective is sometimes [just focused on enhancing the patient's] quality of life, but the patient is still looking for a cure, and that is where the contradiction comes from, especially [when treating] younger patients. There are a lot of younger patients with RCC, so it's a challenging space [to treat these patients in]. In my practice, I tend to put them on phase 1 trials with new immunotherapy agents and [novel therapy approaches] outside of what is approved if slots are available [in these trials].

CHANDLER H. PARK, MD: Does anybody think about [the patient's] prior therapy when you start getting into the third line, like how the patient tolerated a tyrosine kinase inhibitor [TKI]? Or how fast they went through immunotherapy? Do you all think about that besides considering the tolerability of the patients?

Chandler Park, MD

Chandler H. Park, MD​

President, Kentucky Society of Oncology

Advisory Dean

University of Louisville School of Medicine

Norton Cancer Institute University of Louisville

Louisville, KY

VICTOR GIAN, MD: I would say so. I think a lot of TKIs have overlapping toxicities and considering the duration of response to prior TKI therapy, or prior immunotherapy, is very important…. [There are] differences between some of the TKIs, but in my clinical experience, if they didn't do great with one [TKI], they're probably not going to do great with another. Although, that's all we have if [the patient] already failed immunotherapy. I always try to get them on a clinical trial if they're healthy enough and want to do it.

PARK: For some of my patients, if they get that tough treatment upfront, they don't tend to trust that medication, so then you wonder if they're really taking the medication. If they are [taking it], are they consistently on the medication? I also have some patients on the other side of the spectrum where they're scared, and they'll continue the treatment even if they have grade 3 [adverse events (AEs)]. So it's very tough to stabilize some of these toxicities.

Any other thoughts on some of the AEs that people have noticed with the other TKIs, and how to get that patient buy in and trust [when using these therapies]?

LOWELL ANTHONY, MD: There's a lot of individualization of dosing; you're not necessarily starting out at the package insert dose because we know, [for example], cabozantinib is toxic at 60 mg daily.1 You have to start off at a lower dose, and sometimes that's difficult to do when you're trying to cure the patient. I've found that when we rotate these TKIs, sometimes with that second TKI they'll have a better response than they did with the first one. I know that's probably atypical, but if you get the dose right [that response can be achieved]. I think that's what you have to focus on [if you want to improve] their quality of life. [The right dose] isn't necessarily the dose that’s written in the package insert as the initial dose...and part of precision medicine is about getting the right dose [for that particular patient].

Krens SD, van Boxtel W, Uijen MJM, et al. Exposure-toxicity relationship of cabozantinib in patients with renal cell cancer and salivary gland cancer. Int J Cancer. 2022;150(2):308-316. doi:10.1002/ijc.33797

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