Second-line therapy for renal cell carcinoma (RCC) offers multiple options after progression on frontline immunotherapy plus tyrosine kinase inhibition (TKI). A virtual Case-Based Roundtable event discussing a patient with clear cell RCC was moderated by Sumanta K. Pal, MD, chair of the Kidney and Bladder Cancer Disease Team, codirector of the Kidney Cancer Program, and professor in the Department of Medical Oncology & Therapeutics Research at City of Hope Comprehensive Cancer Center. Pal reviewed the NCCN guidelines for second-line treatments, while emphasizing the distinction between selective and non-selective TKIs. He also noted the challenges of small trial sizes and the lack of data in post-checkpoint inhibitor settings for some therapies.
CASE SUMMARY
- A 61-year-old man who is married, is the father of 2 grown children, has 5 grandchildren who live nearby, and has an active lifestyle (walks daily, golfs regularly)
- History of low-volume, indolent metastatic clear cell renal cell carcinoma (RCC) status post left nephrectomy and adrenalectomy
- Observation only based on low-volume, indolent disease and patient preference
One and a half years post nephrectomy CT scan:
- New paratracheal lymph node (2.0×1.5 cm) and more than 10 pulmonary nodules on CT
- Lung biopsy results confirming metastatic clear cell RCC
- Laboratory results: within normal limits
- ECOG performance status: 1
- The patient received first-line cabozantinib (Cabometyx) plus nivolumab (Opdivo).
Follow-up:
- Decrease or stabilization in metastatic lesions was noted on follow-up imaging.
- He tolerated therapy well, with 1 interruption due to hypothyroidism on routine laboratory results (treated with levothyroxine).
- 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 progressive disease: 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 osseous lesions
- ECOG performance status: 2
Targeted Oncology: What are the NCCN-recommended treatments for a patient such as this with recurrent clear cell RCC?
Sumanta K. Pal, MD: The NCCN guidelines are challenging in some respects. I think they don’t really offer a very distinct, prescriptive mode of treatment. But a pragmatic change in the NCCN guidelines is that before, they would list out first-, second-, and third-line therapy. Now they offer some acknowledgement of the current state, which is that patients get immunotherapy [IO] in the frontline setting, and then beyond that, they’re left with a hodgepodge of options. If a patient has received prior IO, the regimens they could receive includes axitinib [Inlyta], belzutifan [Welireg], cabozantinib, lenvatinib [Lenvima]/everolimus, and tivozanib [Fotivda].1
There are other options that are noted to be “Useful in certain circumstances;” things like single-agent everolimus, pazopanib [Votrient], sunitinib [Sutent], bevacizumab [Avastin], etc, but these come with a bit of a weaker recommendation.
Belzutifan requires use of prior checkpoint inhibitor as well as VEGF TKI. Tivozanib requires use of 2 or more prior systemic therapies. This is an interesting point, because I still think that that 2 or more prior systemic therapies might also include cabozantinib and nivolumab, despite the fact that they’re given in combination. I haven’t had any trouble using tivozanib in that second-line setting based on this label. It doesn’t necessarily imply that the patient needs to be on 2 distinct lines of therapy prior.
How do you view the potency and selectivity of the TKIs in this setting?
There’s so much overlap in mechanism amongst these agents, but I think broadly speaking, we can put these therapies into 2 buckets. I usually think of selective vs non-selective inhibitors.2 In the category of selective inhibitors, there are very high potency and very selective agents like tivozanib and axitinib. Tivozanib is reasonably selective; it’s just not as potent. On the other hand, we have other non-selective inhibitors that are quite active. We have the drugs of yesteryear, like sorafenib, which is relatively low potency and non-selective. And then there are agents such as cabozantinib and lenvatinib, which have much higher potency, but are non-selective. They’re hitting [other] targets—in the context of cabozantinib, VEGF and MET, and with lenvatinib, VEGF and FGFR.
Can you discuss some of the relevant data of second-line RCC options for this patient?
I think lenvatinib and everolimus is a reasonable option, but I do think it’s very important to reflect on the fact that it was approved on the basis of a very small 150-patient trial, just 50 patients per arm in this study. That leads to some challenges. How much can we really rely on these data in the context of what is functionally a randomized phase 2 study? Even though the survival estimates are really encouraging, it is derived from a small sample. This study was also done prior to the advent of checkpoint inhibitors. No patients in this study had received prior checkpoint inhibitor.3
The same is true for axitinib. If you look at the data for axitinib, we have modest data from the AXIS trial [NCT00678392] previously, but no data in the post checkpoint inhibitor setting. I think that’s important, because we do need to have a good understanding of how these TKIs work in a more clinically relevant setting. All of our patients these days are getting checkpoint inhibitors up front.4
DISCLOSURES: Pal previously reported travel, accommodations, or expenses with CRISPR therapeutics, Ipsen, and Exelixis.
References:
1. NCCN. Clinical Practice Guidelines in Oncology. Kidney cancer; version 3.2025. Accessed July 14, 2025. https://www.nccn.org/professionals/physician_gls/pdf/kidney.pdf
2. 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;84:101966. doi:10.1016/j.ctrv.2020.101966
3. Motzer RJ, Hutson TE, Glen H, et al. Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial. Lancet Oncol. 2015;16(15):1473-1482. doi:10.1016/S1470-2045(15)00290-9
4. Rini BI, Escudier B, Tomczak P, et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet. 2011;378(9807):1931-1939. doi:10.1016/S0140-6736(11)61613-9