Second-Line Considerations After Immune Toxicity From Prior RCC Therapy


During a Targeted Oncology case-based roundtable event, Saby George, MD, discussed which second-line therapy would be appropriate for a patient who discontinued frontline immunotherapy/tyrosine kinase inhibitor therapy due to immune-related toxicity.

Saby George, MD

Professor of Oncology and Medicine

Director of Network Clinical Trials

Department of Medicine

Roswell Park Comprehensive Cancer Center

Buffalo, NY

Saby George, MD

Professor of Oncology and Medicine

Director of Network Clinical Trials

Department of Medicine

Roswell Park Comprehensive Cancer Center

Buffalo, NY


A 54-year-old man with a history of metastatic renal cell carcinoma (mRCC) had left nephrectomy and adrenalectomy. Four years later, he had recurrence with lung nodules with biopsy 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 indolency of disease and patient preference​.

Eighteen months later, there was continued indolent growth on scans, increased total tumor burden, a new paratracheal lymph node (2.0 × 1.5 cm), 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 was reported​. After cycle 6, he developed fatigue, mild shortness of breath, and mild cough without chest pain. Pulse oximetry was 88% at rest. He had no fever, no recent sick contact, and his flu vaccine up-to-date.​Infectious workup 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, while the patient continued on 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 (was 20 × 15 mm; now 25 × 28 mm), new mediastinal and hilar nodal involvement, new retroperitoneal nodes, and new lytic lesions​. His ECOG performance score was 1. ​

Which second-line therapy are you most likely to recommend for this patient?

Single-agent VEGF-TKI (eg, axitinib, cabozantinib)
VEGF TKI combination (ie, lenvatinib + everolimus)
Immune checkpoint inhibitor regimen (eg, nivolumab ± ipilimumab)


  • What additional workup would you order at this point? ​
  • What factors affect your decision-making for second-line therapy?​

SABY GEORGE, MD: What additional workup would you order at this point for this patient? Do we need any workup?

ASHISH A. KHOT, MD: I think I would consider doing an MRI with the brain as well, especially with the bony metastatic disease in the spine. That would be helpful before starting him on some form of second-line treatment, either cabozantinib [Cabometyx]—especially given his bony metastatic disease where we know that cabozantinib works very well—or everolimus (Afinitor) are good options.

GEORGE: That’s a great thought. Bony metastasis, and particularly spine lesions, are often associated with brain metastases, so that’s not an unreasonable consideration even in the absence of symptoms.

JOSHUA STRAUSS, MD: Yes, I agree. I think those are both good options. Some physicians would think about next-generation sequencing [NGS]. I don’t know if that would help at this point.

GEORGE: For NGS, 1 question would be whether to use the old tissue from the lung biopsy or the nephrectomy sample, or get a new biopsy.

STRAUSS: If I find it would help make a decision, I would probably get a fresh biopsy. I’m just not sure it would help in the choices at this point. You can use lenvatinib [Lenvima] plus everolimus or you can use cabozantinib regardless.1

GEORGE: Absolutely, that’s correct. That’s a great point. In the absence of a biomarker, [what factors] help you decide—response and tolerance to the prior therapy, aggressiveness of the disease, disease burden, toxicities from the previous, for TKI [tyrosine kinase inhibitor] versus immunotherapy, mechanism of action [MOA]?

MARC J. BRAUNSTEIN, MD, PhD: I think that if they received prior immune checkpoint inhibitor, even if you combine it with a TKI, that the response would be less. I would choose cabozantinib as a second line, [not] another immunotherapy in the second line in this case.

GEORGE: That makes perfect sense because the patient had a major immune-mediated adverse event [AE] that required systemic steroid and long course taper. Does anybody consider the MOA?

CHARLESSE PONDT HUANNOU, MD: Given that he was on axitinib when he progressed, you would want to vary the MOA a little bit, see if he can get better disease control with a new MOA, so adding an mTOR [inhibitor] or something like that might change the disease progression.

GEORGE: That makes sense. Do you think there are differences between TKIs? Are all the TKIs the same?

KHOT: There definitely are differences; cabozantinib has multiple targets, especially in the MET [pathway], where resistance can happen. MET and AXL [mutations] are things that you want to make sure you target because with axitinib you’re only targeting the VEGF [pathway]. FGFR, targeted by lenvatinib, is known to show resistance in that pathway when patients are on prior VEGF inhibitors. So I think both choices are good.

I think age and performance status are important. With the doublet combination, you definitely want patients to have good performance status. In terms of tolerability of single-agent cabozantinib, I think we know that it works well, and it’s very well tolerated. Patient outcomes for quality of life are also reported with cabozantinib in many studies.

GEORGE: Who would look at the National Comprehensive Cancer Network guidelines for selecting treatments here?

STRAUSS: I usually peer at them if I haven’t seen a second-line patient in a while just to make sure I didn’t miss something, to confirm it. It is important to make sure that you don’t miss a major change.

GEORGE: Absolutely. It keeps on changing and there are going to some changes in the near future based on the recent data.

RAMAN SOOD, MD: [Concerning the option to use an] immune checkpoint inhibitor…it wasn’t a long time ago that he had the exposure. He didn’t have progressive disease on the first-line immunotherapy, so given the other [options] are just changing a little bit of the MOA, not a whole lot, and immunotherapy gives a totally different MOA, is it unreasonable to cautiously consider [immunotherapy]?

GEORGE: The only problem is the grade 3 pneumonitis in this patient…his [pulse oximetry] was 88%. He required oxygen supplementation at that time along with a high-dose steroid. The question is, could that recur with reintroduction of nivolumab [Opdivo] or pembrolizumab? It could happen, not necessarily right away. This is [caused by] immune activation by the immune checkpoint inhibitor. The frequency of AEs have been [greater] in patients who already had an immune-mediated AE. I would definitely consider using it, but I would reserve it for later lines because when they have recurrent immune-mediated AE, there have been multiple reports that they have more than one immune-mediated AE—pneumonitis, nephritis, colitis, a lot of them come together, and renal insufficiency. It’s not unreasonable to choose something else and maybe revisit when you run out of options.

DAVID BRAUN, MD, PHD:I would agree with Dr George. I think it’s a reasonable thing to consider, and I think these clinical trials now are actively looking at this. So trials like CONTACT-03 [NCT04338269] are looking at immunotherapy, post-immunotherapy, and cabozantinib plus atezolizumab [Tecentriq] versus cabozantinib after you [had] prior immunotherapy. There is 1 with tivozanib [Fotivda] as well, TiNivo-2 [NCT04987203], that is looking at this very question: can you get a response after progression on prior immunotherapy.


1. NCCN. Clinical Practice Guidelines in Oncology. Kidney cancer, version 3.2023. Accessed December 8, 2022.

Related Videos
Related Content