In the first article of a 2-part series, Sumanta K. Pal, MD, leads a discussion on considerations for the treatment of patients with relapsed/refractory renal cell carcinoma in the third-line setting.
A 71-year-old male with a history of metastatic renal cell carcinoma (mRCC) was post‒left nephrectomy and adrenalectomy with clear cell RCC (ccRCC) and metastases in the adrenal gland. Four years later he experienced disease recurrence and lung nodules with biopsy were consistent with ccRCC. It was later recognized that the nodules had been present on scans over 2 prior years. The patient was observed based on low-volume and indolent behavior of disease and patient preference. However, 18 months later there was continued indolent growth observed on scans, increased total tumor burden, new paratracheal lymph nodes (2.0 × 1.5 cm), and multiple growing pulmonary nodules.
A decision was made to initiate systemic therapy with pembrolizumab (Keytruda) plus axitinib (Inlyta). Stable disease was seen on follow up with moderate diarrhea (well controlled with antidiarrheal medication) and mild fatigue reported. After treatment cycle 6, he developed fatigue, mild shortness of breath, and mild cough, without chest pain. Pulse oxygen was 93% at rest. No fever, no recent sick contact, and flu vaccine were up to date while infectious workup was negative. A CT scan of the chest at week 18 confirmed grade 3 pneumonitis, so pembrolizumab was held and once-daily steroids were administered. Pembrolizumab was then discontinued, and 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 with growth of the paratracheal lymph node (was 20 × 15 mm; now 25 × 28 mm), new mediastinal and hilar nodal involvement, new retroperitoneal nodes and new lytic osseous lesions. His ECOG performance score was 1. Cabozantinib (Cabometyx) was given at 60 mg every day, but 9 months later disease progression was documented. The patient would like to continue active therapy.
SUMANTA K. PAL, MD: There has been a tidal wave of change in treatment of patients with RCC…. One of the new options that has emerged for patients with refractory disease is tivozanib [Fotivda], which has led to some changes in current treatment algorithms. Moreover, the National Comprehensive Cancer Network [NCCN] guidelines have recently [updated their guidelines to] divide patients into those that are immunotherapy naïve or who have received prior immunotherapy.1
This is for all patients who are receiving subsequent treatment…. So, if you have a patient that has [received] no prior immunotherapy, as in the second- and third-line settings, there is no preferred option. There is no level 1 evidence [for a treatment] after somebody has [received], for instance, sunitinib [Sutent] in the upfront setting that we would consider to be most favorable, but we do think that if a patient hasn’t gotten prior immunotherapy [there some treatments that] deserve a shot. Going with cabozantinib and nivolumab [Opdivo] as a second-line treatment, or going with lenvatinib [Lenvima] and pembrolizumab, for instance, would be reasonable.
Now, those scenarios are few and far between right now because most of our patients are getting some degree of frontline immunotherapy irrespective of the strategy. If your patient has had prior immunotherapy, that puts them in the second bucket, and in that setting, axitinib, cabozantinib, lenvatinib and everolimus [Afinitor], and tivozanib are all salient options there.
One thing to bear in mind is that the risk status [of patients with RCC] does change. We often don’t recognize that VEGF inhibition prompts some immunologic changes in patients with RCC. [Previous data] have suggested—and this is a variable effect— that drugs like sunitinib can cause a decrease in myeloid-derived suppressor cells.2 However, each one of these therapies that we consider in the second-line setting has a number of different pharmacodynamic properties in terms of how hard they hit VEGF production.3
Tivozanib has pretty substantial specificity for VEGF receptors 1, 2, and 3. The profile is somewhat similar to axitinib which differentiates itself with a shorter half-life, and as you work your way down the list of tivozanib, lenvatinib, cabozantinib, sunitinib, and sorafenib, there is a lot less specificity….
What is probably more important in this setting is how you think through these options clinically. As you get into third-line treatment…what becomes a priority at that point? Are you thinking more about symptom palliation? Are you still thinking about trying to achieve a response?
DAVID KAHN, MD: Well, I only have had 1 patient recently on tivozanib. Still, I think it is [about] bouncing between considering efficacy and toxicity [for each patient at that point].
PAL: Yes. That makes sense. [Any other thoughts on] what to do for patients that are in that third-line setting in your practice?
MIGUEL GONZALEZ VELEZ, MD: It is kind of a combination of all of that. You certainly include a little bit more [emphasis on the patient’s] quality of life and what…is their goal. Usually, first- and second-line [treatment will lead to a] response among the patients. Then, towards the third line, it is more of a discussion with the patient regarding their quality of life and how to balance [efficacy alongside quality-of-life].
PAL: I completely agree. I think that the pendulum shifts a little bit [in the third-line setting], whereas in the first-line setting, you are thinking more about how to generate that most rapid tumor [response] and how you can potentially extend the patient’s response in the front line. Then, by the time you get to the third-line setting…that number of quality-of-life considerations come into the forefront. So, your sentiments do echo mine.
1. NCCN Clinical Practice Guidelines in Oncology. Kidney cancer, version 1.2024. Accessed August 14, 2023. https://tinyurl.com/h2y8hfef
2. Mantia CM, McDermott DF. Vascular endothelial growth factor and programmed death-1 pathway inhibitors in renal cell carcinoma. Cancer. 2019;125(23):4148-4157. doi:10.1002/cncr.32361
3. Fogli S, Porta C, Del Re M, et al. Optimizing treatment of renal cell carcinoma with VEGFR-TKIs: a comparison of clinical pharmacology and drug-drug interactions of anti-angiogenic drugs. Cancer Treat Rev. 2020:101966. doi:10.1016/j.ctrv.2020.101966