Sequencing Choices from First- to Third-Line Regimens in ccRCC


During a Targeted Oncology™ Case-Based Roundtable™ event, Arnab Basu, MD, MPH, asked participants about what sequence of therapies they would use in the first, second, and third lines for a patient with metastatic clear cell renal cell carcinoma. This is the first of 2 articles based on this event.

Arnab Basu, MD, MPH (Moderator)

Assistant Professor

UAB Medicine

Birmingham, AB

Arnab Basu, MD, MPH (Moderator)

Assistant Professor

UAB Medicine

Birmingham, AB


A 71-year-old man with a history of metastatic renal cell carcinoma (mRCC) had left nephrectomy and adrenalectomy. Four years later, he experienced disease recurrence with lung nodules and biopsy results consistent with clear cell RCC. It was subsequently recognized that nodules had been present on scans over 2 prior years. He was observed based on low volume and indolence of disease and patient preference.

Eighteen months later, there was continued indolent growth on scans, increased total tumor burden, a new paratracheal lymph node (20 × 15 mm), and multiple growing pulmonary nodules. A decision was made to initiate systemic therapy with pembrolizumab (Keytruda) plus axitinib (Inlyta). He had stable disease on follow-up. Moderate diarrhea (well controlled with antidiarrheal medication) and mild fatigue were reported. After cycle 6, he developed fatigue, mild shortness of breath, and mild cough without chest pain. Pulse oximetry was 93% at rest. He had no fever, no recent sick contact, and he was up-to-date on his influenza vaccine. Infectious workup result was negative. A chest CT at approximately week 18 confirmed grade 3 pneumonitis, and pembrolizumab was held. Oral steroids were administered. Ultimately, pembrolizumab was discontinued, but the patient continued axitinib.

Fourteen months after initiation of systemic therapy, the patient reported increasing back pain, mild nausea, weight loss, and new onset of persistent rib pain. Imaging confirmed disease progression: growth of paratracheal lymph node (from 20 × 15 mm to 25 × 28 mm), new mediastinal and hilar nodal involvement, new retroperitoneal nodes, and new lytic osseous lesions. His ECOG performance status was 1.

Cabozantinib (Cabometyx) was initiated. Nine months later, disease progression was documented. The patient would like to continue active therapy.

“What are you most likely to recommend for this patient as third-line therapy outside of a clinical trial?”

Ipilimumab + nivolumab
Lenvatinib + everolimus
Single-agent tyrosine kinase inhibitor (eg, sunitinib, pazopanib)


  • Discuss your preferred subsequent-line sequencing strategy might vary after the first-line combination regimens – TKI (tyrosine kinase inhibitor)/IO (immunotherapy) vs IO/IO.​

ARNAB BASU, MD, MPH: A lot is going on in RCC. We [currently] talk about the IO/IO combination therapies, single-agent therapies, and TKI plus IO combinations. Looking at these options, I would like to get the participants thoughts on how you would approach these patients. I think it'll be valuable for everyone. Does anyone want to volunteer [to discuss] IO/IO, followed by VEGF-TKI or combination? What would you do in the third line for the patient?

KAMALESH BALA, MD: I would prefer to start with an IO/VEGF-TKI combination in the first line. Dual immunotherapy is something to consider, but it may be a little too toxic for some patients, so for an average patient, I would probably start with an IO/VEGF-TKI combination in the first line. Then the second-line option would probably be another VEGF-TKI agent. Then, tivozanib [Fotivda] for the third line.

BASU: Can I ask you what kind of IO/VEGF-TKI you usually like to do as frontline [therapy]?

BALA: Lenvatinib [Lenvima]/pembrolizumab is the combination that I have used and is reasonably tolerated—at least you can keep patients on it, or I have been able to keep patients on treatment.

BASU: That’s great because it's a [potent] combination. What kind of toxicities have you noticed with lenvatinib/pembrolizumab?

BALA: I think I primarily [see] fatigue; the other adverse events [AEs] are generally manageable, and fatigue is the one thing that, over time, seems to affect patients a lot. But generally, they're able to stay on treatment.

BASU: That's great. Thank you for sharing your thoughts. For second line, does anybody want to talk about IO/IO, and in which patients you choose IO/IO for frontline therapy? Why do you do it if you do?

MICHELLE LOCH, MD: I like to start with IO/IO for if they have intermediate or poor risk. That will give me the option to use the [TKIs later]...and the other thing with IO/IO is I like the 4 cycles [of ipilimumab (Yervoy)], followed by monotherapy with nivolumab [Opdivo]. That will improve the quality of life, [since] you're not taking the daily oral medication that can sometimes cause a lot of AEs.

BASU: Yes, that's one of the common reasons, and it is great for the patient. The toxicity profile gets so much better. And [the nivolumab infusion is only] once a month for a few minutes, so it makes a lot of sense. When patients progress on single-agent nivolumab, for example, what are you doing in clinic? How are you thinking about those patients?

LOCH: So as the second option, I would use something like cabozantinib as a single agent.

BASU: OK, single-agent cabozantinib, great. On progression on cabozantinib, what have you been thinking about it, and what have you been using as a third line after progression on cabozantinib.

LOCH: After cabozantinib, one of the options would be lenvatinib/everolimus [Afinitor], so adding the mTOR inhibitor as a different mechanism of action. Usually the third line is as far as they go, [since] their performance status is not that good. Usually, it's not as [well] tolerated as the first 2 lines, but still it's an option.

BASU: What kind of everolimus dosing have you used in these third-line patients?

LOCH: I use the standard [dosing] but I have some patients who end up taking everolimus every other day because of the AEs.

BASU: So you have used a lot of dose adjustments to the lenvatinib/everolimus. Great.

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